American Diabetes Association 76th Scientific Sessions

June 10-14, 2016; New Orleans, LA; Full Report – Obesity and Prediabetes Care – Draft

Executive Highlights

This document contains our coverage of obesity and prediabetes care at ADA 2016. Immediately below, we enclose our themes on the category, followed by detailed discussion and commentary. Talk titles highlighted in yellow were among our favorites from ADA 2016; those highlighted in blue are new full report additions from our daily coverage.

Themes

  • There was no major new obesity data this year and we saw very little representation from branded obesity pharmacotherapies this year. Aside from Novo Nordisk’s relatively minimalist booth on Saxenda (liraglutide 3.0 mg), no other obesity companies were represented on the exhibit hall floor. In addition, there was only one obesity-focused corporate symposium (supported by Novo Nordisk) on the agenda. The level of engagement from obesity drug companies has been on a sharp decline over recent ADA meetings, as 2014 featured large, bustling booths from Belviq (lorcaserin) and Qsymia (phentermine/topiramate extended-release) and 2015 had Saxenda, but only a small pop-up booth for Belviq. We are not surprised by this drop-off in marketing, given the recent challenges in the obesity drug market, although we remain hopeful that Novo Nordisk’s wealth of expertise and resources will push for greater awareness and education around obesity to gradually boost the market.
  • Notably, we saw a significant amount of promising new data on type 2 diabetes drugs in obesity management. Combination therapies, SGLT-2 inhibitors, and GLP-1 agonists were the stars of this show, headlined by phase 2 results of combination therapy with AZ’s Farxiga (dapagliflozin) and Bydureon (exenatide once weekly), which demonstrated significant ~4 kg weight loss vs. placebo in patients with obesity but not diabetes. In addition, co-administration of J&J’s Invokana (canagliflozin) and phentermine showed significantly greater weight loss vs. placebo in adults with overweight and obesity. On the GLP-1 agonist front, we saw positive results on reductions in energy intake and appetite with once-weekly GLP-1 agonist semaglutide in obesity as well as significant weight benefits from the FREEDOM-2 study of Intarcia’s ITCA 650 (implantable exenatide mini-pump) compared to Merck’s Januvia (sitagliptin) in people with type 2 diabetes. While data from currently available obesity drugs and new targets remained on the quieter side at this meeting, we were glad to see many diabetes drugs turn to this area and given the complexity of obesity, we are also pleased to see more focus on combination therapies. With the diabetes drug space having comparatively greater resources, a larger evidence pool, and established efficacy and safety, we hope to see greater movement from this market into obesity, as the disease remains a significant unmet need.
  • On the basic science front, the brain and microbiome seemed to be the main focuses within obesity research. The agenda featured several intriguing oral presentations on deep transcranial magnetic stimulation, AgRP neuronal activation, and a leptin-responsive brainstem circuit within weight management. As we’ve seen recently, GLP-1 agonists have been heavily studied in this area, as highlighted by an oral presentation examining the regulation of energy balance and glucose homeostasis via the ventromedial hypothalamic GLP-1 receptor. See our recent coverage from the European Obesity Summit for greater discussion on how the brain plays a significant role within energy balance and weight management. Additionally, we heard a decent number of presentations on how the microbiome ties into obesity, with discussions on the interaction between “diabesity” genes and the gut as well as a full symposium on how the microbiome is involved in metabolic risk from pregnancy through the life cycle. While these presentations highlight promising movement, we are increasingly aware of the complexity of both obesity and the corresponding therapies. Of the brain and microbiome, we see the brain and its neural circuitry as a more near-term target area for obesity, although we ultimately hope to see multi-targeted therapies combining these many different approaches.
    • In addition, the role of adipose tissue and its link to obesity and type 2 diabetes risk was in the spotlight at this year’s prestigious Banting lecture, delivered by Dr. Barbara Kahn (Harvard Medical School, Boston, MA). This area of research has certainly been growing rapidly within recent years, as Dr. Kahn noted our evolving understanding of adipocyte tissue as a storage depot to its role in secreting molecules and as a metabolic factory that regulates substrate availability to other tissues. Dr. Kahn illustrated the complexity and potential of studying adipose tissue, as she touched on how the molecules, lipid levels, and biochemical changes in adipose tissue can guide our search for novel drug targets for obesity and type 2 diabetes. We especially enjoyed hearing how these approaches can be used to identify our most at-risk patients and help personalize prevention and treatment efforts. For more on our growing understanding of adipose tissue, also check out the prestigious Minkowski award lecture delivered by Dr. Matthias Bluher (University of Leipzig, Germany) at this past EASD.
Table of Contents 
             

Detailed Discussion and Commentary

Posters

Coadministration of Canagliflozin (CANA) and Phentermine (PHEN) for Weight Management in Overweight and Obese Adults

PA Hollander, HE Bays, J Rosenstock, ME Frustaci, A Fung, and N Erondu

In a late-breaking poster, phase 2 results of the co-administration of J&J’s Invokana (canagliflozin) and phentermine showed significantly greater weight loss vs. placebo in adults with overweight and obesity. This study was a four-arm, 26-week study and evaluated the efficacy and safety of Invokana + phentermine, phentermine alone, Invokana alone, and placebo in 334 adults with BMIs of 30-50 kg/m2 and without type 2 diabetes or with hypertension and/or dyslipidemia and BMIs of 27-50 kg/m2. The findings demonstrated that at 26 weeks, from a mean baseline BMI of ~37 kg/m2, the Invokana + phentermine group achieved significantly greater weight loss (7.5%) compared to the other groups (4.1%, 1.9%, and 0.6% for Invokana, phentermine, and placebo, respectively). In addition, the combination therapy group had a significantly higher proportion of participants achieving ≥5% weight loss compared to placebo (67% vs. 18%). Only 18% and 42% of the Invokana and phentermine groups’ participants achieved weight loss of at least 5%. On other secondary endpoints, the combination therapy group also had a significant reduction in systolic blood pressure, with a placebo-subtracted reduction of 4.2 mmHg. Regarding safety and tolerability, no new signals emerged from these data; however, the combination therapy, phentermine, and Invokana groups all experienced increases in heart rate of 3.5 bpm, 4.1 bpm, and 0.7 bpm, respectively – an observation whose potential consequences on cardiovascular events have not yet been determined and will likely warrant further investigation. Ultimately, these findings are powerful in support of using phentermine with SGLT-2 inhibitors in chronic weight management, and we are interested to see whether Janssen will move forward with phase 3 trials, and ultimately pursue an obesity indication. Combination therapies have certainly gained significant attention within obesity management (in addition to diabetes), and we have specifically heard greater enthusiasm for the potential of GLP-1 agonists and SGLT-2 inhibitors in weight management. With so much evidence already accumulated on these various diabetes drugs, we look to see how industry, healthcare providers, and the FDA envision the movement of these products into obesity, given the troubled commercial environment for obesity compounds to date and given the extreme high need for therapy to help patients.

Liraglutide Protects Diet Induced Obesity Through Induction of Brown Adipogensis in Mice (1966-P)

J Zhou, P Chandramani-Shivalingappa, and L Li

This poster presented data showing that liraglutide (Novo Nordisk’s Victoza/Saxenda) reduced weight gain and obesity-related inflammation and upregulated genes related to brown fat tissue synthesis in mice. The experiment was conducted on four groups of C57black/6 mice that were fed either a normal (control) or a high fat sucrose diet (HFHSD) and were injected with either liraglutide or saline for five weeks. The mice were then massed and liver, fat and skeletal muscle tissue samples were taken for protein and RNA extraction. The results showed that liraglutide reduced weight gain and inflammation in mice fed a HFHSD to levels comparable to those of the mice receiving saline injections and eating a normal diet. Liraglutide also decreased paragonadal fat mass in HFHSD mice while inducing the expression of UCP-1 (a protein in brown adipose tissue that increases thermogenesis and metabolic rate) and three other related genes: PPAR-alpha, Cidea, CEBP-alpha and CEBP-beta. Liraglutide did not have any effect on fatty acid oxidation or synthesis. This study provides additional mechanistic explanations for the positive clinical results seen with liraglutide in obesity – in particular, we have not heard as much discussion about the connection to brown fat as we have about neural mechanisms of weight regulation.

Semaglutide Reduces Appetite and Energy Intake, Improves Control of Eating, and Provides Weight Loss in Subjects with Obesity

John Blundell, PhD (University of Leeds, UK)

Dr. John Blundell presented positive results on reductions in energy intake and appetite with once-weekly GLP-1 agonist semaglutide in people with obesity. This double-blind, crossover study examined the mechanisms of weight loss of semaglutide (dose-escalated to 1.0 mg) vs. placebo in 30 participants with obesity and without type 2 diabetes (baseline BMI of 34 kg/m2). At 12 weeks, the results found a reduction in body weight, with decreases in energy intake, appetite, and food intake along with overall improved control of eating. Specifically, findings demonstrated that ad libitum energy intake was lower with semaglutide vs. placebo at lunch (5 hours after standardized breakfast), evening meal, and snacks with relative reductions of 35%, 18%, and 22%, respectively. In addition, the semaglutide group achieved weight loss of 5 kg (with greater loss of fat mass compared to lean mass) vs. a small increase of 0.97 kg with placebo. Fasting overall appetite scores also indicated reduced appetite with semaglutide vs. placebo (p=0.0023), while nausea ratings were similar – suggesting that this effect was independent of side effects. Additionally, results from the overall appetite-suppression score and control of eating questionnaire indicated less cravings and greater control of eating. Notably, participants had greater reductions in energy intake of food groups of high fat and traditionally more “appealing” foods, which reflected the results from the Leeds food preference task. Dr. Blundell noted that the semaglutide group experienced a reduction in resting metabolic rate, but the difference was not statistically significant. These findings further confirm to us the impressive versatility of semaglutide, as the product has been suggested to be studied in several indications beyond type 2 diabetes, including NASH, obesity, and a range of macrovascular and microvascular complications – see more on this from our Novo Nordisk 1Q16 report. We have certainly seen significant enthusiasm for the GLP-1 agonist class within obesity – as already pioneered by Novo Nordisk’s Saxenda (liraglutide 3.0 mg) – and the eating behavior-specific findings from this study direct us back to potential mechanisms within the brain and its reward circuitry, which is marking itself as a fast growing area of research for obesity.

Questions and Answers

Q: Do you think the changes in resting metabolic rate are accounted for by the degree of weight loss?

A: Yes, when weight is lost rapidly, the body adjusts. It can drive appetite and make energy expenditure more efficient.

Subcutaneous Exendin (9-39) Effectively Treats Postbariatric Hyperinsulinemic Hypoglycemia

Colleen Craig, MD (Stanford University, Stanford, CA)

Dr. Colleen Craig presented positive results of a single ascending dose study of GLP-1 antagonist exendin (9-39) (Ex9) in people with Postbariatric Hyperinsulinemic Hypoglycemia (PBHH) (n=8). As background, PBHH is a rare but debilitating disease that approximately 0.2%-6.9% of patients experience years after bariatric surgery, characterized by severe hypoglycemia. This is hypothesized to occur due to the amplified secretion of GLP-1, which causes dysregulation of insulin and has a severe glucose lowering effect. In this small study, the pharmacokinetics, pharmacodynamics, and local tolerability of exendin, given via subcutaneous injection, was examined; timing and volume of Ex9 injections were constant but dose (10 mg-30 mg) and concentration varied. The findings demonstrated that prevention of hypoglycemia and reduction in hypoglycemic symptoms was achieved at all dose levels; specifically, these reductions were due to the improvement of the late glycemic response without altering the early glycemic responses. In addition, the candidate was well tolerated, with no huge side effect or safety signals. In conclusion, Dr. Craig thus asserted that these results illuminate a promising targeted therapy for patients suffering from PBHH. As rates of obesity increase and bariatric surgery becomes more widely used, therapies targeting the intervention’s complications will likely become increasingly important.

Dapagliflozin + Exenatide QW Reduced Body Weight and Improved Glucose Tolerance in Nondiabetic Obese Adults: A Randomized, Placebo-Controlled, Phase 2 Study

Jan Eriksson, MD, PhD (Uppsala University, Uppsala, Sweden)

Results from a phase 2 proof of concept study (n=50) of combination therapy with AZ’s Farxiga (dapagliflozin) and Bydureon (exenatide once weekly) demonstrated significant ~4 kg weight loss and glycemic improvements vs. placebo in patients with obesity but not diabetes. Participants in the double-blind, single-center study were randomized to receive either active treatment or double placebo for 24 weeks, followed by a 28-week open-label extension study; data from the extension study will be presented at EASD in September. After 24 weeks, the combination led to significant placebo-adjusted weight loss of 4.1 kg (baseline weight = 103-106 kg [227-234 lbs]; baseline BMI = 35-36; p=0.0007) or 4.2% (p=0.0005). As in most obesity drug trials, there was a wide range of responses, but far more patients achieved ≥5% weight loss with the active treatment than with placebo (36% vs. 4%). MRI analysis of body composition showed that almost all of the weight loss was due to loss of adipose tissue, with no significant change in lean tissue. The combination also produced a modest but significant 0.2% placebo-adjusted A1c reduction (baseline = 5.6%, p=0.0004), a significant drop in the proportion of patients with impaired fasting glucose and impaired glucose tolerance, and a significant placebo-adjusted blood pressure reduction of 6.4 mm Hg (p=0.026). Adverse events were fairly balanced, with slightly more GI side effects in the active treatment group.

  • These results are encouraging, though as noted during Q&A, the real test will be how the combination stacks up against each of its components alone. AZ is currently conducting a phase 3 study (n=660) of that comparison in patients with type 2 diabetes that is expected to complete in December 2017 (primary completion May 2016). As presenter Dr. Jan Eriksson noted, GLP-1 agonist/SGLT-2 inhibitor combinations are very appealing for obesity due to their complementary mechanisms of weight loss (calorie loss with the SGLT-2 inhibitor and reduced appetite/caloric intake with the GLP-1 agonist). The same could also be said for glycemic control, as the reduction in glucagon production with GLP-1 agonists could help mitigate the increased glucagon production that blunts some of the efficacy of SGLT-2 inhibitors. We expect AZ to focus primarily on type 2 diabetes with this combination but find the potential in obesity very interesting as well, particularly for a GLP-1 agonist with more potent weight effects like Novo Nordisk’s Saxenda (liraglutide 3.0 mg) or semaglutide.

Questions and Answers

Q: Could you clarify the timing of the last dose vs. the glucose measures?

A: A glucose tolerance test was performed at baseline and at 24 weeks. The dose was taken half an hour before the glucose tolerance test was started.

Q: Although I acknowledge this was a proof of concept trial, why didn’t it include monotherapy + placebo arms? You’re really asking whether there’s a synergistic or additive effect and this study didn’t answer that.

A: It’s a proof of concept for the combination and we showed robust weight loss vs. placebo, but I agree, we want a study against monotherapies as well. That would have increased the study size so we couldn’t have done it at a single center.

Oral Presentations: Weight Loss Intervention Methodology

Gastric Bypass vs. Medical/Lifestyle Care for Type 2 Diabetes in South Asians with BMI 25-40 kg/m2: The COSMID Randomized Trial

Shashank Shah (Laparo-Obeso Centre, Pune, India)

Mr. Shashank Shah presented the full results of the COSMID (Comparison of Surgery vs. Medicines for Indian Diabetes) randomized trial, which demonstrated that the benefits of Roux-en-Y gastric bypass (RYGB) for type 2 diabetes in low-BMI Indian patients appear similar to those reported in other studies of primarily higher-BMI Caucasian patients. As background, this trial is the first-ever RCT of surgical vs. non-surgical care for type 2 diabetes in South Asian patients and has the largest number of patients with a BMI <35 kg/m2 and the lowest BMI threshold studied in such an RCT. The study randomized 80 patients (baseline BMI of ~31 kg/m2; diabetes duration ~8 years; A1c of ~9.4%) with uncontrolled type 2 diabetes and BMI of 25-40 kg/m2 to either RYGB or medical/lifestyle intervention (MLI). Over two years, maximum weight loss was 26% in the RYGB arm vs. 4% in the MLI arm. At two years, compared to the MLI group, more of the surgery group achieved type 2 diabetes remission (60% vs. 2.5%), glycemic control (81% vs. 30%), and type 2 diabetes improvement (100% vs. 73%). The surgery and MLI groups achieved A1c reductions of 2.9% and 0.7%, respectively; the surgery group also used half as many diabetes medications as the MLI group. In other measures, fasting insulin was 5.2 times lower in the RYGB group and systolic and diastolic blood pressure dropped more significantly in the RYGB group. These findings uniquely contribute to the surgery literature, bringing to light how lower BMI patients of different ethnicities also greatly benefit from surgery, further supporting the expanded use of the procedure – see our first look at these results from EOS for more.

Questions and Answers

Q: You pointed out that you screened a lot of people who have type 2 diabetes and obesity. Could you speculate how you’d be able to spread this procedure out to a larger proportion of people? So many people failed screening – why?

A: There were many people below BMIs of 35. Many were also antibody negative. And not many were willing to do the follow-up. That’s the reason we typically end up excluding 10%-15%.

Q: Thinking about the availability and cost of surgery, what is realistic to expect of this?

A: This is first evidence that gastric bypass does work. In this small cohort of patients, we could not do a cost analysis. We do need to do a cost analysis. There are lots of variables.

Short-Term Effectiveness of Low Dose Liraglutide in Combination with Metformin vs. High Dose Liraglutide Alone in Treatment of Obesity

Andrej Janež, MD, PhD (University Medical Center Ljubljana, Slovenia)

Dr. Andrej Janež presented results of an open-label study, demonstrating that low dose liraglutide in combination with metformin and high dose liraglutide alone both led to significant weight reductions in women with obesity and polycystic ovarian syndrome (PCOS). In this study, 30 women (baseline BMI of 38 kg/m2) were randomized to either combination therapy of metformin (1000 mg BID) + liraglutide 1.2 mg or liraglutide 3.0 mg alone for 12 weeks. According to the results, at 12 weeks, the combination therapy and liraglutide alone groups achieved weight loss of 3.6 ± 2.5 kg (p=0.002) and 6.3 ± 3.7 kg (p=0.001), respectively; the BMI decreased 1.3 kg/m2 and 2.2 kg/m2, respectively. Notably, these between treatment differences of weight changes were not statistically significant, although the liraglutide only arm had significantly greater reductions in waist circumference (-4.2 cm vs. -2.2 cm). Regarding adverse events, side effects were reported by 8 vs. 6 participants in the liraglutide only and combination groups, respectively. Specifically, there was more nausea in the liraglutide only arm compared to the combination arm (6 vs. 4 out of 15). Additionally, the combination therapy further improved the androgen profile (+2.6 vs. -1.2 nmol/l of androstenedione). Thus, Dr. Janež concluded that while these two different treatment approaches both bring about significant weight reduction, the combination therapy was able to further improve androgen profile and tolerability. While this study was studied in obesity and PCOS and is relatively small, its findings do raise interesting questions with regards to the cost-effectiveness of Novo Nordisk’s Saxenda (liraglutide 3.0 mg) as the product is significantly more expensive than its lower-dose counterpart, Victoza (liraglutide 1.8 mg).

Questions and Answers

Q: Did you measure insulin levels or surrogate markers of insulin?

A: We looked at mostly primary anthropometric measures. This is just a pilot.

Q: Are you following the cohort for a longer period of time?

A: Yes.

Q: Any improvements in menstrual periods?

A: In the very short term, we started to see improvements with that. But we did some other studies with lira previously. When you reduce weight loss substantially, all of these outcomes improve significantly.

The Effect of 1-Year’s Endoscopic Proximal Intestinal Exclusion Using Endobarrier on 10-Year Cardiovascular Risk in Type 2 Diabetes

Robert Ryder, MD (City Hospital, Birmingham, UK)

Dr. Robert Ryder presented one-year results of EndoBarrier (extended to 10-year cardiovascular risk), finding that EndoBarrier therapy with and without liraglutide can significantly reduce 10-year cardiovascular risk in patients with diabetes and obesity failing GLP-1 agonist therapy. In this study, adults with suboptimally controlled type 2 diabetes and obesity (despite being on liraglutide 1.2 mg daily) were randomized to additional EndoBarrier therapy (n=24), EndoBarrier without liraglutide (n=24), and a control group with only an escalated dose of liraglutide (1.8 mg daily) (n=22). Q-risk score was used to calculate cardiovascular risk; this measure is a composite score that uses recognized risk factors (i.e. age, sex, diabetes status and duration, etc.). At one year, the Q-risk score fell by ~3.4%, ~2.2%, and ~1.1% in the combination therapy, EndoBarrier only, and liraglutide only groups, respectively. This translated to the estimation that one year of EndoBarrier + liraglutide treatment in 100 patients could prevent 22 events of coronary heart disease or stroke (save 18 lives) over the next ten years, ultimately suggesting that adding EndoBarrier in patients on suboptimal GLP-1 therapy can be a promising alternative within the treatment algorithm. While relatively short-term, this study highlights the potential of using multi-modal approaches in high-risk patients with obesity.

Improvements in Impact of Weight on Quality of Life-Lite (IWQoL-Lite) with Liraglutide 3.0 mg (LIRA) vs. Placebo (PBO) for Weight Management: 3-Year Data

Ronnette Kolotkin, PhD (Obesity and Quality of Life Consulting, Durham, NC)

Dr. Ronnette Kolotkin presented new data from the SCALE Obesity and Prediabetes three-year extension trial, showing that treatment with Novo Nordisk’s Saxenda (liraglutide 3.0 mg) improves quality of life compared to placebo. At 160 weeks, the Saxenda intervention group achieved greater scores on the Impact of Weight on Quality of Life-Lite (IWQoL-Lite) assessment vs. placebo (10.96 vs. 8.11; p<0.0001) – separation between the arms emerged early (at roughly six months) and were maintained over time. All domains of the IWQoL-Lite were also significantly improved in the Saxenda arm vs. placebo – physical function (13.19 vs. 9.59;), self-esteem (14.78 vs. 11.82), sexual life (9.29 vs. 6.16), public distress (5.99 vs. 4.34), work (5.87 vs. 4.42) – which translated into a greater proportion of patients experiencing improvements that were within the range typically considered clinically meaningful (7.7-12 point change). Overall, the results are not particularly surprising considering the consistent quality of life benefits we’ve seen from SCALE data over time. That said, we would point that there continues to be a powerful placebo effect in all these follow-up studies, making it challenging to parse out how much of the benefit can be attributed to Saxenda vs. weight loss in general (since both groups lost weight).

Questions and Answers

Q: There was a powerful placebo effect in this study? What drove the quality of life benefits in that group?

A: It is important to say that although people on the drug lost more weight than those on placebo, there was some weight loss in the latter group. We’ve seen this in other obesity trials with other pharmacological agents where this is this so-called powerful placebo effect. Part of it is being enrolled in a trial and receiving lifestyle counseling.

Oral Presentations: Race/Ethnic Differences Matter

The American Heart Association Ideal Cardiovascular Health and Incident Type 2 Diabetes Mellitus among African Americans: The Jackson Heart Study

Alain Bertoni, MD, MPH (Wake Forest School of Medicine, Winston-Salem, NC)

Dr. Alain Bertoni presented a study that examined the association between the American Heart Association’s ideal cardiovascular health (CVH) measures and incident type 2 diabetes among African-Americans in the Jackson Heart Study. In 2010, the AHA created the ideal CVH matrix to evaluate cardiovascular health in adults and included measures of blood pressure, physical activity, total cholesterol, healthy diet, weight, smoking status, and FPG. Given the shared risk factors between diabetes and cardiovascular disease, ideal CVH may apply to diabetes prevention and The Strong Heart Family Study previously demonstrated an association between ideal CVH and lower incident diabetes rate among Native Americans with a mean age of 38. This study used data from the Jackson Heart Study, a NHLBI-funded community-based prospective cohort study of African Americans aged 21-34. The analysis included 2,668 participants with complete baseline data on 6 of the 7 CVH metrics (blood pressure, physical activity, total cholesterol, healthy diet, weight, and smoking status) with mean age of 54.9 years (65.4% women) and 492 cases of incident diabetes occurred over 7.6 years of the study. A shocking 76% of participants in the study had only 1 or 2 ideal CVH metrics and no participant had a score of 6. After adjustment for demographic factors and CRP (high sensitivity reactive protein), each additional ideal CVH metric was associated with a 17% decreased risk of diabetes – this is huge that improvement in a single risk factor (such as smoking cessation) could cut diabetes risk by almost a fifth. This association did not persist after adjustment for the HOMA-IR measure of insulin sensitivity. Dr. Bertoni concluded that the AHA ideal CVH model could be applicable to diabetes prevention in African-American populations. These results add to the growing body of evidence for the close association between cardiovascular and diabetes risk factors and supports the logic of comprehensive interventions to modify risk of both cardiovascular disease and diabetes.

Oral Presentations: What’s New in Pediatric Type 2 Diabetes?

Birth Weight and Cardiometabolic Risk in Children: The National Health and Nutrition Examination Survey (NHANES), 1999-2014

Dianjianyi Sun, PhD (Tulane University, New Orleans, LA)

Dr. Dianjianyi Sun used data from the National Health and Nutrition Examination Survey (NHANES) to evaluate the influence of birth weight on type 2 diabetes and cardiovascular disease later in life. Dr. Sun categorized NHANES birth weight data into five weight groups and performed a retrospective analysis to measure cardiometabolic risk. According to Dr. Sun’s findings, a higher birth weight led to a significantly greater chance of obesity, as well as a significantly lower risk of high systolic blood pressure (SBP), high fasting blood glucose (FBG), and high A1c. In addition, Dr. Sun found that the associations between low birth weight and an increased risk of high blood pressure and glycemia in childhood were stronger in boys than in girls. Dr. Sun noted that these results did not produce significant differences between racial groups, but is an area for further research and clinical application. According to Dr. Sun, these results suggest that the adverse effects of abnormal prenatal growth on certain cardiometabolic outcomes begins in childhood and adolescence, which reveals the importance of cardiometabolic health screening in children.

The Shape of the Glucose Response Curve During Oral Glucose Tolerance Test (OGTT) and Biomarkers of Type 2 Diabetes Risk in Obese Youth

Joon Young Kim, PhD (University of Pittsburgh, PA)

Dr. Joon Young Kim presented an analysis of biomarkers of type 2 diabetes in 106 youth with obesity but without diabetes (average age= 15) with either monophasic (Mph) or biphasic (Bph) OGTT glucose response curves. Results showed that the Mph group had lower in vivo insulin sensitivity and worse beta cell function compared to the Bph group, putting them at higher risk of developing type 2 diabetes. The biomarkers analyzed were hepatic and peripheral insulin sensitivity, insulin secretion, beta cell function relative to insulin sensitivity, body composition (including BMI), abdominal adipose tissue, and AUC. The two groups had similar insulin and glucose concentrations (both fasting and 2-hour OGTT), BMIs, body compositions, and amounts of abdominal adipose tissue. However, the Mph group had lower insulin sensitivity (both hepatic and peripheral), no compensatory first and second phase insulin secretion, and reduced beta cell function compared to the Bph group. This data suggests that the shape of the glucose response curve could itself be a useful marker to identify patients at the highest risk of developing type 2 diabetes and target interventions to that group.

Oral Presentations: The Prediction and Prevention of Diabetes

Excess Body Mass Index: A Modifiable Risk Factor for Type 1 Diabetes Development?

Christine Ferrara, MD, PhD (University of California, San Francisco, CA)

Dr. Christine Ferrara presented her findings on the association between excess body max index (BMI) and progression of type 1 diabetes using an aggregate measure of longitudinal BMI within subject design. “Excess” BMI was calculated as the difference between measured BMI and the CDC sex/age adjusted 85th BMI percentile, weighted specifically for the interval of time passed between each visit. Nationally, as the incidence of T1D rises, BMI trends show parallel increases, which supports the “Accelerator Hypothesis” that suggests obesity-driven insulin resistance accelerates the progression of T1D. According to Dr. Ferrara’s findings, cumulative excess BMI increases the risk of T1D – the estimated five year T1D risk for patients with excess BMI was 34% in comparison to 22% in normal weight patients. The effect of cumulative excess BMI on T1D risk was modified by age. Overweight subjects between the ages of 8-13 years old showed an even greater risk of T1D – the estimated five year T1D risk for patients within this age group was 39%. These results suggest that peripubertal subjects ages 8-13 are particularly vulnerable to the effect of excess weight on the risk of developing T1D.

Questions and Answers

Q: I have two suggestions for mechanisms: infections (obese people tend to get more infections) and diet. Have you looked at either of these?

A: We have not looked at infections, but I think there is something to that. In terms of diets, we had some nutritional information on some of the subjects, but it was not complete enough to include in the analysis.

Q: How did you come up with the cutoffs for the ages?

A: A lot of debate. I chose them based on clinically relevant ages. If I saw someone who was eight years old and in puberty, I would work them up as “in puberty” and consider the age factor less. Puberty is an important component to the hormonal and biological implications of puberty. Now, we are looking at age as a continuous variable, rather than using a stratified analysis.

Q: It might be worth using sex hormone analysis to measure puberty.

A: We are working on that, but that is a very good suggestion to have specific markers for “in puberty.”

Q: Have you looked at family history or the incidence of double diabetes?

A: We have not looked at family history, but double diabetes is very interesting and is definitely something we can look into in the future.

Oral Presentations: Cellular Responses to Exercise in Insulin-Targeted Tissues

Next Generation Sequencing MEthylation Profiling in Lean and Obese with a Single Bout of Exercise

Samantha Day, BS (Arizona State University, Tempe, AZ)

In a well-organized and thoughtful presentation, Ms. Samantha Day reviewed her study that investigated whether DNA methylation patterns in skeletal muscle change following a single exercise session. The study recruited seven lean individuals and seven individuals with obesity matched for all characteristics except BMI, body fat percentage, and insulin sensitivity; of note, the two groups were matched for exercise fitness.  The participants exercised on a stationary bike (four sets of: eight minutes at 70% max VO2, two minutes at 90% max VO2, and two minutes of rest). Biopsies of the vastus lateralis were taken before exercise, as well as at 30 minutes and 24 hours after exercise. Sequencing analysis yielded over two million methylation sites, which were narrowed to only sites within promoter regions and untranslated regions. The investigators found 10 sites that were altered across the lean participants – one site where methylation increased significantly at 30 minutes and returned to baseline at 24 hours, four sites with elevated methylation at both 30 minutes and 24 hours, and five sites that had decreased methylation at 30 minutes and 24 hours. Two sites were found to be altered in the participants with obesity.

Oral Presentations: Modulators of Adipose Tissue Inflammation

SGLT2 Inhibition by Empagliflozin Attenuates Obesity-induced Insulin Resistance and Inflammation by Enhancing Fat Utilization and Macrophage Alternative Activation

Tsuguhito Ota, MD, PhD (Kanazawa University, Japan)

Dr. Tsuguhito Ota presented the results of his animal study that investigated the effects of empagliflozin on insulin resistance in obese mice given either a high-fat diet (HFD) alone or containing either 0.01% or 0.03% empagliflozin. Empagliflozin suppressed HFD-induced weight gain (16% with the 0.03% dose). The drug also increased energy expenditure – more specifically, Dr. Ota noted that the induction of UCP1 expression observed with the drug suggested that it promotes browning of white adipose tissue. In skeletal muscle, empagliflozin increased fat utilization, accompanied by elevated AMPKα and ACC phosphorylation, and increased expression of genes involved in fatty acid oxidation. Empagliflozin was also shown to improve HFD-induced glucose intolerance, hyperinsulinemia, and hepatic steatosis; furthermore, it increased insulin signaling in the mouse liver and white adipose tissue. These tissues also had reduced accumulation of both macrophages and T cells with empagliflozin, along with a change in the macrophage composition from mainly M1 (CD11c+CD206-) cells to predominantly M2 (CD11c-CD206+) cells. As we hear more obesity data on type 2 diabetes drugs, these findings point to the potential of the SGLT-2 inhibitor class in these broader indications.

Questions and Answers

Q: Some of the effects that you saw in terms of fatty acid oxidation and browning are potentially mediated by FGF21. Could that be playing a role?

A: We measured FGF21 in plasma, but it was not changed significantly, so I don’t think so.

Oral Presentations: Nutrition Research on Diet, Supplements, and Eating Patterns in Diabetes and Prediabetes

Carnosine: Novel Therapy for Prediabetes

Barbora de Courten, MD, PhD (Monash University, Melbourne, Australia)

Dr. Barbora de Courten presented results from a pilot clinical trial demonstrating that carnosine is safe and well-tolerated and may be a viable therapy for prevention of diabetes and cardiovascular disease. Carnosine, or beta-alanine L-histidine, is an endogenous peptide present in human brain tissue and cardiac and skeletal muscle. Present in red meat and fish, it is currently available as a dietary supplement; exercise physiologists recommend it to increase athletic performance and endurance. In this randomized controlled trial, people at risk for diabetes were administered either carnosine (2g daily) or placebo for 12 weeks. The study population (n=26) averaged 43 years of age with a BMI of 31.4 kg/m2. Results showed that carnosine supplementation prevented increases in insulin resistance and insulin secretion. Insulin resistance, as measured by HOMA-IR, increased in the placebo group by approximately 1 mmol/l*mU/l but remained unchanged in the carnosine group (p=0.049). Similarly, insulin secretion, as measured by HOMA-b modeling of beta cell function, increased by nearly 50% in the placebo group but was unchanged in the carnosine group (p=0.03).  Carnosine also decreased systolic blood pressure by 6 mmHg, although this was not statistically significant. The mechanism of carnosine’s putative antidiabetic and cardioprotective action on humans is unknown. Mechanisms implicated from in-vitro and animal studies show that carnosine has anti-inflammatory, anti-oxidative, anti-ischemic, chelating, and glycation reducing action. Diabetes is of course an area where there is great need for primary prevention, and Dr. de Courten expressed optimism about carnosine’s promise in a larger clinical trial to begin this summer.

Questions and Answers

Q: Will future clinical trials involve people at risk for diabetes, or people with an actual diagnosis of prediabetes?

A: In the future studies we will recruit  people at risk of type 2 diabetes (obese and pre-diabetic) as well as people with diabetes..

Q: Can you remind me how long you ran this study?

A: It was 12 weeks long.

Q: Do you have any information on the half-life of carnosine in the body?

A: The half-life in the plasma is fairly short, only 2-3 hours because carnosine is hydrolyzed by carnosinase 1. Increase in carnosine in plasma after supplementation results in increased in muscle carnosine content from where carnosine can be released as well. Turnover of carnosine in the skeletal muscle is 3-6 months.

Q: Will a 2 g dose of carnosine be adequate for individuals with a high BMI?

A: The dosage hasn’t been worked out, but studies in the literature show a biological effect for doses between 0.5 and 3.5 g. We will have more information about the dosage necessary in our next trial.

Q: Do you think the mechanism of carnosine is a GLP-1 type of mechanism or something more internal?

A: To my knowledge, there is no evidence about carnosine having effect on  GLP-1, but we know from animal and in vitro studies that carnosine has chelating properties and anti-inflammatory and anti-oxidative effects. We also know from the in-vitro cancer literature that carnosine has effects on MMP, JNK, mTOR/AKT, ERK, and SMAD3/ALK5 pathways. We will be able to look into this in the future because we will be collecting muscle and fat samples from the subjects in the next study.

Q: Do you have A1c data?

A: No, we don’t. The pilot was in people without diabetes. Large changes in HBA1c would not be expected in this population.

Dietary Influences on Insulin Sensitivity: A Randomized, Crossover Study

Kim Yoona, PhD (University of Australia, Adelaide, Australia)

Dr. Kim Yoona presented results from a study comparing the insulin sensitivity of participants (n= 50) who consumed either a diet of meat and processed foods (HMD) or a diet of whole grains, nuts, dairy and legumes (HWD), showing that, while insulin levels were higher in the HMD cohort, insulin sensitivity remained unchanged after four weeks. In the randomized crossover study, the HMD group ate 200-300 grams of processed meat and 4-6 servings of refined grains, while the HWD group ate 4 servings of dairy products, 3-4 servings of whole grains, 60-90 grams of nuts, and 70-200 grams chicken/seafood or 150-225 grams legumes. The average age of the 15 men and 35 women was 35.2 years, the average BMI was 27.2, and none of the participants had diabetes. After four weeks, an insulin sensitivity index was calculated by monitoring the last 30 minutes of a continuous low dose insulin (25mU/kg•h) and glucose (4mg/kg•min) infusion test (LDIGIT), and insulin secretion was calculated by measuring the C-peptide curve during the first 30 minutes of the LDIGIT. While insulin levels were higher for those on the HMD (119.2 pmol vs 88 pmol on the HWD), no statistically significant differences were measured for all other metrics: fasting glucose, fasting insulin, fasting C-peptide, homeostasis model assessment, LDIGIT glucose, ISI, and AUC for C-peptide. Therefore, while the insulin levels were higher with the HMD diet after four weeks, glucose sensitivity remained unchanged, as did average body mass. Neither gender, BMI, nor glucose status appeared to have an effect on the results. In our view, further testing over a longer study period is necessary to confirm the impact of the HMD and HWD diets on insulin sensitivity.

Symposium: FTO Brought Up-to-Date – The FTO Gene Locus in Obesity

The Role of the FTO Obesity Risk Locus in Browning of Human Fat

Melina Claussnitzer, PhD (Harvard Medical School, Boston, MA)

Dr. Melina Claussnitzer walked attendees through her research team’s analysis of the FTO obesity risk locus in relation to the browning of adipose tissue, pointing to her NEJM publication of this work in 2015. She noted the challenges and promises of genome-wide analysis studies, highlighting the promise of new target genes and therapeutics but the difficulties of non-coding regions and an incredible number of variants. The review of her research remained relatively basic science-focused, as Dr. Claussnitzer discussed the identification of FTO’s target genes of IRX3 and IRX5 and how this regulatory network involved regulators of adipocyte browning, with the causal nucleotide rs1421085 conserved in the adipose tissue-rich region. Upon establishing cellular phenotypic consequences, she illustrated that the analysis of co-regulators suggested an involvement in the shift from energy dissipation to lipid storage, as IRX3 and IRX5 expression was shown to impact energy utilization and thermogenesis. In addition, Dr. Claussnitzer demonstrated that single nucleotide editing of IRX3 and IRX5 can affect thermogenesis in various adipocyte cells. In closing, Dr. Claussnitzer suggested that cell phenotyping data points to functions in the brain, an area that her team is now attempting to better understand. Ultimately, research on genetic determinants of obesity remains relatively young, with most work beginning to reveal the immense complexity of these systems.

Q: Have you tried meal effects?

A: Not yet, but it’s a great idea.

Q: You pointed to some potential early effects on adipocyte type. Do you have a view of where FTO may act in terms of developmental timelines?

A: I haven’t included those in the data. But we have data from CRISPR that show that the genetic effects are visible in the timeframe of day 0 to day 3 regarding the differentiation of primary human cells. That’s on a genetic level but we see through several expression studies of IRX3/5 that biological function of IRX3/5 tend to be kept in later stages of differentiation, which leaves us wondering if the allele is acting throughout the whole differentiation process basically or through an imprint on biological function or is it just for a few days?

Symposium: The “Imitation Game” for Biology – Can We Break the Codes of Inter-Organ Cross Talk and Win the War Against Diabetes?

Intervening with Inter-Organ Cross Talk – The Next Frontier in Therapeutics?

Randy Seeley, PhD (University of Michigan, Ann Arbor, MI)

Dr. Randy Seeley discussed the implications of the Vertical Sleeve Gastrectomy (VSG) bariatric surgery procedure as a platform for understanding inter-organ communication,  highlighting the liver as a major player in this chain of communication. In studies of animal models, VSG improved glucose regulation and produced significant weight loss (-50% body fat in just 34 days) without a change in lifestyle by reducing food intake and decreasing preference for high-fat diets (HFD). According to Dr. Seeley, these data suggest that VSG impacts signaling in the brain, a striking example of  inter-organ communication. Next, Dr. Seeley discussed bile acids as the molecular target for VSG, which are necessary to break down lipids effectively and are greatly simplified as a consequence of the VSG procedure. His studies focused on the changes in FRX signaling as a key mediator for post-surgical weight loss and lower cumulative HFD intake. Dr. Seeley stated that the microbiome changes after VSG are a marker of bacteria community changes, resulting in a reduction of liver reuptake of  bile acids.

Symposium: Microbiota, Inflammation, and Diabetic Cardiovascular Disease

Interaction Between Diabesity Genes and the Gut Microbiome

C. Ronald Kahn, MD (Joslin Diabetes Center, Boston, MA)

Dr. C. Ronald Kahn discussed the extraordinarily complex interplay between genetics, diet, the microbiome, and the environment that contribute to obesity and insulin resistance, echoing comments he made at the 2014 Research Symposium on Diabetes and the Microbiome. He recounted how his lab has demonstrated a differential response to a high-fat diet between two genetically distinct mouse lines: the B6 mouse (obesity prone) and the 129 mouse (obesity resistant). In addition, Dr. Kahn’s lab found that responses to diet are not only dependent on genetics, but also on external environment. Indeed, when two groups of 129 mice were raised in different environments, they displayed significant gut microbiome variation that altered their propensity for obesity: one was obesity resistant while the other was obesity prone. Dr. Kahn’s lab also found that many of the differences in the mice’s fecal microbiome were eliminated when the two lines were bred for three generations in the same environment, but each strain still retained a unique microbiome. After three generations, the two 129 strains had very similar and low levels of weight gain. Dr. Kahn also discussed research showing that antibiotic treatment improved glucose levels in mice with obesity and insulin resistance; he suggested that antibiotics exert this effect through altering bile acid metabolism, which in turn acts through inflammatory mediators to change insulin signaling. Taken collectively, these results highlight the incredible environment-dependent variability of the gut microbiome and its broad impact on metabolic outcomes.

Symposium: More than a Gut Instinct – Potential of the Microbiome from Pregnancy through the Life Cycle

Overview of the Human Microbiome and Mechanisms for Mediating Metabolic Risk

Michael Rosenbaum, MD (West End Pediatrics, New York, NY)

Dr. Michael Rosenbaum expressed skepticism on the ability of the microbiome to inspire novel therapies in the near future. While research in rodent models has shown that altering the microbiome affects body weight, Dr. Rosenbaum cautioned against extrapolating these results to humans. We need a different dictionary to interpret what the microbiome means for humans – we see an increase in firmicutes microbiota and a decrease in bacteroides as people gain weight, but these particular changes are not observed in mice, and patients with obesity show markedly less diversity in their microbiome, which isn’t necessarily true in mice. In addition to the lack of conclusive data on the human microbiome and obesity, Dr. Rosenbaum pointed out that our inherent physiological responses almost always oppose weight loss. “If a particular ‘lean’ microbiome helps keep weight off in the long term, it’ll be the one exception to this rule,” he explained, “which is one of the reasons I’m skeptical.”

Questions and Answers

Q: Could microbes be causing browning?

A: That’s a very interesting suggestion that’s been circulating. I’m not convinced that brown adipose tissue is a major energy sink in humans. Energy intake and output are coupled, so if you change one aspect of energy expenditure, other pathways are just waiting to intervene. Maintaining body fat stores is so vital to our survival as a species that this physiological response is immediate and powerful.

Q: I’ve heard that some patients who get a fecal transplant experience weight changes, where people who weren’t fat before are getting fat due to the stool of the donor.

A: To my knowledge, these are anecdotal reports.

Q: Does glutarate play any role in weight fluctuations?

A: Yes, glutarate in the gut can affect a number of hormones related to appetite, including PYY and GLP-1. This is a fertile area of research.

Bioactive Components of Breast Milk and Evolution of the Infant Microbiome

Lars Bode, PhD (UCSD, San Diego, CA)

Dr. Lars Bode, the world expert on human milk and lactation, made the case that human breast milk oligosaccharides (HMOs) – of which there are 150 varieties – influence the infant microbiome in a manner that may have long-term consequences for development, particularly in the context of obesity and gastrointestinal function. Studies from Dr. Bode’s lab suggest that HMOs play a role in mediating host-microbe interactions, protecting against the attachment of harmful microbes (like E. coli and streptococcus) and helping beneficial gut microbes (like B. infantis) thrive. The interplay between HMOs and the infant microbiome bears special relevance for metabolic health later in life; babies nursed by mothers who lack the gene for FUT2 – an enzyme that catalyzes the synthesis of HMOs – tend to have a higher risk for Chron’s disease, pancreatitis, and type 1 diabetes.

Questions and Answers

Q: Do you think that infant’s co-ingestion of the mother’s skin flora may potentiate the individual effects you’re describing?

A: Well it goes beyond skin flora. Milk itself is not sterile, there is bacteria sitting in the milk duct. So there is a specific milk microbiome, and there are interactions between it and the oligosaccharides in the mother’s mammary gland before it even reaches the infant. I imagine this has effects on infants as well.

Q: Can there possibly be a direct effect of these oligosaccharides on metabolism?

A: It’s possible. Oligosaccharides from breast milk make it intact into the infant’s systemic system. Does it have a direct effect on metabolism, I don’t know. But it is a very interesting question.

Q: I’m a nutritionist and certified diabetes educator, and I used to counsel patients through WIC. What should I tell mothers who are thinking about breastfeeding?

A: Some of this research sounds academic and not very applied. But identifying bioactive molecules in milk can be very empowering for mothers. Formula doesn’t nearly have the entire portfolio of what mom’s mammary gland synthesizes, and we can’t put this into a box.

Q: A lot of the women that come in to my clinic may not have optimal nutrition. Many do not have a good diet, and many are obese. Should they be breastfeeding to give their babies the best chance?

A: Yes, breastfeeding is still the best choice.

Q: Is there any role for the father?

A: Well, we think about mother and what oligosaccharides she produces, but of course the father partially determines the genetics of the child and how their body will interact with these milk oligosaccharides.

The Microbiome Phenotype in Obesity and Type 2 Diabetes Mellitus and Potential Therapeutics

Annick Hartstra, PhD candidate (University of Amsterdam, the Netherlands)

Ms. Annick Hartstra posed the question “could gut bugs be the new drugs?” Microbiome composition differs between lean and obese individuals, and Ms. Hartstra found that transferring intestinal microbiota from lean into obese subjects with type 2 diabetes via fecal microbial transplantation (FMT) increased patients’ peripheral insulin sensitivity with efficacy equal to that of oral diabetic medications. Although the mechanism underlying this striking finding is not yet known, early evidence suggests that the gut microbiota of lean individuals produce more butyrate, a compound that has been shown in rodent studies to influence appetite regulation and cellular energy expenditure. 

Questions and Answers

Q: Can you talk about different types of prebiotics? Does it matter whether they are chains of glucose or fructose or amylose?

A: To be honest I don’t know. My focus is on butyrate.

Q: Is it oral butyrate? Isn’t there very little oral butyrate that gets delivered to the colon?

A: We based the dose on studies done before this, which have shown that it does end up in the colon. We are using 4 g/day.

Q: When you take the stool samples from people, are they kept in aerobic conditions? Because most of the gut microbiota are anaerobic.

A: We have a protocol for feces transplantation which has been used from the beginning. The sample must be fresh and used within 6 hours time. All we do is pour NaCl on the sample before filtering it. The way we do it is a universal method, but it may have room for being improved!

Q: For how long does insulin sensitivity improve?

A: After 6 weeks there is an increase in the insulin sensitivity, but it is gone after 18 weeks.

Symposium: Addressing Obesity and Metabolic Disturbances in a Meaningful Way – Are We There Yet?

Understanding the Mechanisms Underlying Appetite and Obesity

Hans-Rudolf Berthoud, PhD (Louisiana State University, Baton Rouge, LA)

Dr. Hans-Rudolf Bertoud’s talk on the mechanisms of obesity discussed what he believes is the bi-directional influence of bottom-up (homeostatic) and top-down (hedonics) systems. He noted that the key player in homeostatic regulation is the hypothalamus, and Dr. Berthoud provided several examples from mouse and human research demonstrating how molecular stimuli in the hypothalamus can impact one’s eating experience or satiety. We were particularly struck by his example of how dopamine – typically an appetite stimulant – is reduced via duodenojejunal bypass and facilitates weight loss. Turning to hedonic processing, Dr. Berthoud explained this “top-down” system as the way in which our expectations influence our experiences. For example, he cited studies in which participants rated “expensive” wines tasting better than less expensive wins, even when cost-blinded participants rated the wines similarly. Connecting this top-down experience to obesity, Dr. Berthoud remarked that positive vs. negative memories of eating can influence eating patterns, suggesting that if we can break hedonistic associations with food, then we may be able to help patients achieve weight loss.

Questions and Answers

Q: Do patients eat less if you show them pictures that may reduce food intake?

A: Yes, cognitive inhibition works this way. For example, at a diabetes conference, we are very aware of our environment and of the impact of food choices on diabetes – so we may choose to eat healthier options.

Drug Interventions

Arya Sharma, MD (University of Alberta, Edmonton, Canada)

Dr. Arya Sharma provided an overview of obesity as a chronic disease, its needs for risk stratification, and the various anti-obesity pharmacotherapies. He opened by stressing that obesities are heterogeneous complex disorders of multiple etiologies characterized by excess body fat, using the metaphor that weight loss is like “pulling an elastic band” to explain the biological challenges of losing and maintaining weight. Reviewing the various treatment options, he pointed to the treatment gap, commenting that while surgery can work, it’s not a scalable option. Moving to discussions on risk stratification, Dr. Sharma illustrated that BMI is not the most ideal measure, as it doesn’t correlate well with response treatment; he then discussed his well-known Edmonton Obesity Staging System, showing how its various stages were significantly more accurate in predicting mortality compared to BMI classifications. Regarding the pharmacological treatment options in obesity, Dr. Sharma emphasized that obesity is “not a simple system” (involving thermogenesis, lipolysis, the gut microbiota, bile acids, and more), highlighting that today’s current pharmacotherapies do not reflect this sophisticated system. After reviewing the data and mechanisms behind the four currently available obesity drugs, he stressed that we are waiting for “a whole bunch of new drugs that are specifically designed for the treatment of obesity based a more modern, sophisticated system of biology.” At this year’s meeting, we have been glad to see greater research into the neural and gut drivers of obesity, and we hope that greater understanding of these mechanisms as well as of surgery and our current drugs can push us forward on the path to novel effective drug targets.

Questions and Answers

Q: We have been combining drugs in diabetes. Has there been any experience using Belviq plus Contrave plus Qsymia together?

A: I’m sure people out there do that. I don’t have experience doing that. But you do hear stories of people combining these drugs.

Special Lectures and Addresses

Banting Medal for Scientific Achievement – Adipose Tissue, Inter-Organ Communication, and the Path to T2D

Barbara B. Kahn, MD (Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, MA)

Dr. Barbara Kahn delivered this year’s Banting Lecture on our growing understanding of how white adipose tissue regulates whole body metabolism via effects on insulin sensitivity, insulin secretion, food intake, energy expenditure, and body weight. She summarized many years of research, focusing on the role of the adipocyte as an endocrine gland (i.e., its effects through secretion of retinol binding protein 4, or RBP4), how adipocytes regulate energy balance through molecules that act on AMP-activated protein kinase, and the role of adipocytes in de novo lipogenesis. She noted that when glucose transport is upregulated in adipocytes, glucose is channeled to increase fatty acid synthesis (which is associated with increased insulin sensitivity). Lipidomic analysis has revealed that some of the lipids being synthesized belong to a novel lipid class that is composed of both a fatty acid group and hydroxyl fatty acid group (FAHFAs) linked by an ester bond. A single oral dose of these novel lipids in mice reduces blood glucose by potentiating glucose-stimulated insulin secretion in pancreatic islets and inducing GLP-1 secretion from gut enteroendocrine cells. In addition, these lipids enhance insulin sensitivity. She concluded, therefore, that these biosynthetic pathways could provide targets to restore or increase novel lipid levels in insulin-resistance patients and potentially improve their insulin sensitivity. In recent, unpublished studies from her group, these novel lipids were also found to reduce type 1 diabetes incidence and improve survival in non-obese diabetic mice, while her other studies have documented their ability to improve beta cell viability and increase beta cell proliferation under cytokine stress (again, highlighting their future therapeutic potential).

  • Dr. Kahn ended her presentation with a touching series of thanks and optimism for the future“As a scientist, I thank you for your discoveries that have moved the field forward. As a physician, I thank you for your compassionate care of our patients. As a person who has had type 1 diabetes for 48 years, I hope you share my hope for the future, driven by the power of scientific discovery.” We certainly do.

Hunger-Promoting Hypothalamic Neurons Control Systemic Metabolism and Drive Complex Behaviors and Longevity

Tamas Horvath, PhD (Yale University, New Haven, CT)

In his fast-paced presentation, the esteemed Dr. Tamas Horvath reviewed a series of animal studies that elucidated the role of hypothalamic NPY-AgRP neurons in hunger and behavior. Numbering only in the thousands, these neurons play a critical role in the body’s response to caloric restriction and the resulting changes in energy expenditure, as studies show that they are necessary for feeding. AgRP neurons regulate both food-related and food-unrelated motivated behaviors, likely by acting on midbrain dopaminergic circuits early in development. Dr. Horvath also presented data showing that in adult mice, activation of AgRP neurons led to changes in mental alertness (e.g., increased interest in novelty, less anxiety, greater drive for compulsive behaviors), suggesting that these neurons may play a role in diseases such as anorexia and schizophrenia.

  • Dr. Horvath opened with a broad viewpoint: seven of the 10 leading causes of death in the US are associated with diabetes, which itself is the 7th leading cause. His lab focuses on the time component of these chronic, often late-occurring conditions. Dr. Horvath postulated that the sustained, increased workload on various tissues – more specifically, increased cellular metabolism – may underlie the development of these diseases. Caloric restriction may decrease the impact of time on these tissues; thus, research into hunger and food intake may reveal future approaches to therapy.
  • Hypothalamic NPY-AgRP neurons are one of many populations of neurons responsible for regulating energy homeostasis, and are critical for endocrine adaptions associated with hunger and calorie restrictions. These cells release agouti-related protein (AgRP), neuropeptide Y (NPY), and GABA, which modulate energy expenditure. Calorie restriction leads to increased ghrelin signaling, which promotes hunger and activates AgRP cells. In contrast, the satiety hormone leptin inhibits AgRP neurons. Dr. Horvath highlighted that the neural connections between AgRP and other cells (e.g, POMC and MC4R neurons) are highly plastic and respond to the metabolic state. For more on how the hypothalamus and these neuron populations are involved in obesity, please see our interview with University of Washington’s Dr. Michael Schwartz.
  • Dr. Horvath explained that hunger drives a complex set behaviors that promote food intake, such as wakefulness, short and long term memory (to remember and locate the food source), reward circuits, decision making, locomotion (to physically pursue food), and chewing and swallowing. Hypothalamic neurons have been shown to influence these functions in healthy patients, and may play a role in the disruption of these behaviors found in diseases such as Parkinson’s and depression.
  • Dr. Horvath also presented data showing that AgRP neurons are necessary for these feeding behaviors. In addition, alterations in AgRP neuronal activity affects both hunger-motivated and non-hunger motivated behaviors. For example, AgRP inhibition in mice leads to less interest in food and more interest in novel objects and drug seeking. AgRP cells appear to impact behavior by acting on the midbrain dopamine circuits, and the finding that such neurons extend to the midbrain only in the prenatal period suggests that AgRP neurons regulate the midbrain early in development – an indication that earlier interventions may be more effective.
  • According to Dr. Horvath, acute activation of AgRP neurons in adult mice led to increased interest in novelty (open field test), increased effort to overcome anxiety (zero maze test), and increased drive to engage in compulsive behavior in the absence of food (marble burying test). To Dr. Horvath, these results indicate that AgRP neurons have an impact on mental alertness, and may play a role in diseases caused to dysregulation of these systems, such as schizophrenia and anorexia.

Symposium: ADA Pathway to Stop Diabetes Symposium

The Sense of Smell Impacts Metabolic Health and Obesity

Celine Emmanuelle Riera, PhD (University of California, Berkeley, CA)

Dr. Celine Emmanuelle Riera presented her findings on the role of the olfactory system in mediating food intake, energy expenditure, and body weight. According to her results, a loss of the sense of smell reduces diet palatability, which leads to a decrease in food intake and an increase in weight loss. Dr. Riera explained that olfactory inputs contribute largely to food selection through increasing the value of food via higher sensory cues and rewards, which drive feeding behaviors. Her study aimed to examine whether these inputs can affect systemic physiology by answering the question: does the reduction of smell acuity mediate a satiety response and modulate energy balance? Based on her findings, olfactory ablation protects against diet-induced obesity by removing the olfactory sensory cues that influence diet palatability and subsequent reward value of food, while simultaneously reversing adipose tissue expansion in diet-induced mice with obesity. Additionally, fat thermogenesis and sympathetic nervous system signaling increased in olfactory deficient animals, which suggests that olfactory sensory neurons play a role in regulating energy homeostasis and adipose tissue thermogenesis. Therefore, Dr. Riera concluded that the olfactory system has significant implications for our understanding of feeding behavior, energy balance, communication with the nervous system, and the resultant impact on body weight and food preference.

Shared Genetic Determinants of Glycemic Traits In and Outside of Pregnancy

Marie-France Hivert, MD (Harvard Pilgrim Health Care Institute, Boston, MA)

Dr. Marie-France Hivert compared the genetic determinants of glycemic traits during and outside of pregnancy, highlighting the impact of gestational hormones on glycemia and birth outcomes. In a study of 1,024 pregnant women, Dr. Hivert found that genetic risk was highly associated with fasting glucose but was not associated with fasting insulin, suggesting that fasting insulin is influenced heavily by pregnancy hormones. In addition, Dr. Hivert found that genetic risk scores for type 2 diabetes predicted the development of gestational diabetes. These findings have significant implications for identifying risk for type 2 diabetes and birth complications.

Targeting LMPTP for Obesity-Associated Diabetes Therapy

Stephanie Stanford, PhD (La Jolla Institute for Allergy and Immunology, La Jolla, CA)

Dr. Stephanie Stanford presented her examination of low molecular weight protein tyrosine phosphatase (LMPTP) as a target for obesity and type 2 diabetes. Currently, insulin-sensitizing agents that minimize the need for injectable insulin are an unmet medical need in type 2 diabetes and obesity treatment, a fact that lead Dr. Stanford to explore a LMPTP inhibitor to alter insulin signaling.. The findings indicated that treatment of obese mice with anti-LMPTP antisense oligonucleotides improved insulin sensitivity and decreased hyperglycemia. In addition, the LMPTP inhibitor reduced diabetes in diet-induced obese (DIO) mice through increasing insulin receptor phosphorylation, thereby improving blood glucose and decreasing fasting insulin. This research shows promising new directions for new insulin-sensitizing agents to prevent and control type 2 diabetes.

Symposium: Genetic Analysis of Gut Flora in Diabetes and Metabolic Disease

The Microbiome and Metabolic Disease

Rémy Burcelin, PhD (University of Toulouse, France)

Dr. Rémy Burcelin reviewed some of the recent data around the microbiome’s role in metabolic disease. He opened by noting that upon changes in diet, the microbiome also changes as it maintains and improves the body’s natural defense. Specifically, in this role, Dr. Burcelin shared how the gut microbiota can directly treat intestinal-producing cells – an idea that can be applied to diabetes. He presented results of studies done in the mouse model: over 15 days, the gut microbiota of mice were colonized for glucose intolerance and at the end of the time period, their lymphocytes were resistant to hyperglycemia. In addition, Dr. Burcelin noted that mice showed improved production of IL-17 from their intestinal lymphocytes, along with enhanced glycemic control phenotypes, as these findings suggested that the microbiome is largely responsible for the impairment of intestinal barriers’ function. Additionally, Dr. Burcelin elaborated upon the potential of developing a vaccine that would help the immune system protect itself from gut microbiota dysbiosis in order to benefit diabetes treatment. Certainly, we have heard a range of possible treatment options targeted toward the microbiome from fecal transplantations to vaccines, but we feel that due to the complexity of this system, it’ll likely be several years until these come close to clinical application.

Symposium: The Experts “Weigh-In” on Low-Calorie Sweeteners

The Impact of LCS on Weight Management

John Peters, PhD (University of Colorado, Aurora, CO)

Dr. John Peters offered an overview of the often controversial and confusing relationship between the consumption of low-calorie sweeteners (LCS) and body weight. He noted that there have been no randomized control trials on this topic for people with diabetes, and the handful of observational studies suggest results in line with the general population data. For that reason, he focused on general population studies, which have variously found an association between calorie sweeteners and increase in body weight, decrease in body weight, and even both increases and decreases in body weight within the same study. Looking at meta-analyses, Dr. Peters argued any associations appeared to cancel each other out to zero. Looking for explanations as to why there have been some findings of association, he suggested the reverse causality of how people looking to lose weight might be more likely to choose a diet beverage, or residual confounding variables present in some studies but not in others. After substantial review, Dr. Peters concluded that low-calorie sweeteners can be an effective tool when used as part of an intentional weight management program, and the observed benefits of these sweeteners is consistent with expectations based on the biology of weight control. He challenged future studies to better characterize dieting behaviors among low-calorie sweetener users to gain a fuller understanding of the overall context for their use and to separate physiological, neurobehavioral, and cognitive effects of sweeteners in diet.

  • Dr. Peters shared that what we might expect to see in terms of effects of low-calorie sweeteners on body weight are shaped by several contextual factors. These include whether the evaluation is in terms of weight loss or weight regain, whether the method of use is as an addition or substitution to existing diet, whether the dietary context is ad libitum or as part of intentional caloric restriction, the size of caloric deficit created, the biological compensation for negative energy balance, consumer beliefs, and cognitive intention. Dr. Peters suggested we would expect the largest benefit for weight gain prevention when substituted in diet for a high-calorie option and when used as a tool in intentional weight loss.
  • According to Dr. Peters, potential mechanisms by which low-calorie sweeteners could affect energy balance include: alteration of appetite and food intake, cephalic phase insulin release, osmolality, gut peptide response, palatability, dietary macronutrient shift, and associative learning. However, none of these mechanisms have been substantiated by the available evidence. Dr. Peters did stress though that that doesn’t rule out any of the mechanisms.
  • Dr. Peters pointed to evidence suggesting that LCS could have a stronger role in weight loss maintenance. Specifically he noted a 1997 study that suggested that aspartame in a multidisciplinary weight loss program could have a beneficial effect on weight loss maintenance, as opposed to weight loss itself. In addition, another study found at six months that a diet soda group reported less dessert consumption than a water-drinking group, which Dr. Peters suggested could mean the former group had received satiation for sweetness that the water group had not. He also pointed to a recent study indicating that drinkers of zero-calorie diet beverages had significantly better weight loss after one year and less weight regain than a water-drinking group; Dr. Peters suggested this could hypothetically be due to water drinkers struggling to adhere to a diet without the sweetness provided by diet beverages. These murky, uncertain findings were indicative of the overall review of the current science on low-calorie sweeteners.

Are We Giving People with Diabetes Evidence-based, Practical Advice for Using LCS?

Hope Warshaw (Hope Warshaw Associates, Alexandria, VA)

Ms. Hope Warshaw offered an overview of the current state of knowledge for low-calorie sweeteners with respect to diabetes. After pointing out the latest dietary guidelines’ call for the reduction of sugars to less than 10% of daily intake, Warshaw noted 20%-30% of the general population consumes low-calorie sweeteners daily, with the highest use among 55- to 74-year-olds, non-Hispanic whites, and overweight and obese adults. She then provided a detailed breakdown of the FDA process for ensuring the safety of low-calorie sweeteners. She acknowledged that her discussion of low-calorie sweeteners’ relationship with body weight largely reiterated the preceding talk. She emphasized that there are four main potential goals with weight control: weight loss, prevention of weight regain after weight loss, maintenance of healthy weight over time, and slowing of a weight gain trajectory. Ms. Warshaw argued sweeteners likely have little to offer with weight loss – the goal that gains the most attention – but that they could be effective for the other three weight control goals. Ms. Warshaw closed by repeating the title of her talk, “Are we giving people with diabetes evidence-based, practical advice for using LCS?” She said that, in the absence of a credible survey, there was no way to provide a scientifically correct answer to the question, but her suspicion is that practitioners do not always provide scientifically based statements to patients on low-calorie sweeteners. She thus modified the question: “Should we be giving people with diabetes evidence-based, practical advice for using LCS?” On this point, she gave a strong affirmative answer to close the session.

  • On the topic of safety, Ms. Warshaw pointed out that the vast chemical differences between various low-calorie sweeteners suggest that it is impossible to make general statements about potential health risk. She said that the only commonality of them is that they all impart sweetness and have a higher sweetening potency by weight compared with sugar, but they don’t share origins, chemical structures, or taste profiles.
  • Ms. Warshaw noted that as food additives, all low-calorie sweeteners must receive FDA approval to be present in the American food supply. Ms. Warshaw pointed out that all sweeteners follow an established, rigorous protocol for safety review and that they generally must meet the safety standard of “reasonable certainty of no harm.” As part of the general food supply, sweeteners must be judged safe for children, pregnant and lactating women, and people with diabetes.

Symposium: Fifty Winks of Diabetes

The Molecular Clock as a Metabolic Rheostat

Joseph Bass, MD, PhD (Northwestern University Feinberg School of Medicine, Chicago, IL)

With a focus on basic science, Dr. Joseph Bass discussed how circadian rhythm aligns physiologic functions – including insulin secretion – with environmental cues. In opening, he noted that different states of energy metabolism – e.g., energy storage vs. use – alternate within a 24-hour cycle. Convergence of the circadian cycle with the energetic system occurs in the hypothalamus, as well as in peripheral organs such as the pancreas. Dr. Bass presented data showing that islet cells have autonomous clocks and produce different amounts of insulin in response to iso-caloric meals given at varying times of day. Studies on the differential expression of RNA indicate that disruption of the clock leads to both gene activation and gene repression, and that clock-mediated regulation differs between cell types (e.g., islet cells vs. hepatocytes). Dr. Bass expounded on CLOCK and BMAL, two transcription factors that heterodimerize to regulate rhythmic gene expression in response to the clock. In islet cells, they influence the transcription of genes involved in priming vesicles and releasing insulin, as well genes that promote beta cell development and health. We would be curious to see how meal timing is involved in this molecular clock, as this more clinical perspective of diabetes and obesity care can potentially be actionable.

Questions and Answers

Q: Did you get the chance to look at other transcription factors that bind to site enhancers? Are there transcription factors that bind chronically to the sites and keep them open, and which are influenced by CLOCK and BMAL?

A: We also looked at PDX1. But the question you’re asking is an experiment that we haven’t done. I don’t know the answer to it; however, we’re looking more at PDX1 and some other factors, as well as a number of additional markers.

Q: Did you do RNAseq on the islet cells? Did you see any hint of rhythmic gene expression in alpha cells, and do you think that some of the principles observed in beta cells might be present in alpha cells? For example, the counter-regulatory hormonal response may be regulated by circadian rhythm.

A: With regard to the rhythmic RNA analyses, those were done without separating alpha and beta cells. The chromatin IP experiments were in beta-cell lines, so this data is all anchored on the beta cell. I think that the evidence would suggest that there are similar aspects in the alpha cell. We didn’t have that technical setup for this analysis; however, it is a good point.

Q: I realize it’s impossible to know the real answer, but can you comment on teleology? I would think of the beta cell as the prototypical responsive kind of cell. What is the teleological reason for the cell to secret more insulin at one time of day versus another? Why would its response be controlled by circadian rhythm?

A: I think that these are vestiges, and that the embedded clock mechanism is a very primitive feature of the genome. I view the beta cell as homologous to hypothalamic neurons and all neurons, as it has polarizing and depolarizing functions. The clock mechanism is a vestigial function, and the selection was probably for behavior; however, I think it clearly has an impact on health. A big feature of neurons is that they clearly know what time of day it is. I don’t know whether there is a teleological explanation for beta cells. 

Q: So type 1 diabetes is an autoimmune attack on the beta cells. Do you have any thoughts on the interface between autoimmunity and the circadian clock mechanism?

A: There are two different ways to address the question. One is from the perspective of immune-cell biology and the other is from the perspective of beta-cell biology. I think that in the type 1 community, there’s a similar dichotomy. It is believed that type 1 diabetes is due to a non-viral intrinsic defect in the beta cell function that occurs early in development. The thinking is that there are remaining islet dendritic cells that are presented with an antigen early in development, and the problem is related to errors in protein trafficking. One concept from the standpoint of the beta cell is that if we understand the machinery and regulation of peptide trafficking in these cells, it will give us insight into the mechanisms that are perturbed in the antigen presentation to beta cells. On the other hand, immune cells are also controlled by transcription factors that are convergent with this area.

Symposium: Metabolic Surgery – Is it Ready for Prime Time?

What is the Cost Effectiveness of Metabolic Surgery for the Treatment of Type 2 Diabetes?

William Herman, MD (University of Michigan, Ann Arbor, MI)

Dr. William Herman presented data demonstrating the “clear” financial argument for metabolic surgery over failed conventional treatment. He cited a number of studies in general obese populations and type 2 diabetes, demonstrating that surgery was either “cost effective” (good value of resources spent) or “cost saving.” He attributed this benefit to three major points: (i) surgery is safe and effective; (ii) the impact on the outcomes is large; and (iii) the time to positive outcomes is short. While he spoke in glowing terms about these benefits, he did acknowledge that the long-term effects of surgery remain unknown – in particular, he noted that the BIG assumption is that the positive effects of surgery will persist over time without negative comorbidities.

  • Dr. Herman presented data demonstrating that surgery is more cost effective earlier in the course of type 2 diabetes and when surgery is performed laparoscopically. Other trends he highlighted including the greater success of surgery: (i) in women vs. men; (ii) in patients who were more obese; and (iii) in patients with more obesity-related comorbidities. Additionally, data seemed to suggest greater cost-effectiveness when studies were funded by industry – though Dr. Herman did not spend too much time on this this, it’s certainly interesting and we believe warrants independent research in the future.
  • Dr. Herman also pointed out additional limitations in our understanding of surgery: i) a lack long-term RCTs; ii) the assumption that BMI will remain stable following surgery; and iii) and a lack of data examining the costs associated with negative long-term consequences surgery (e.g., nutrient deficiency, etc.).

What is the Evidence in Support of Metabolic Surgery for the Treatment of Type 2 Diabetes?

Philip Schauer, MD (Cleveland Clinic, Cleveland, OH)

Dr. Philip Schauer concluded his talk with an emphatic “Yes!” to the question of whether metabolic surgery is ready for the prime time. He spent the majority of his presentation reviewing 11 randomized controlled trials (surgery vs. medication), highlighting that research on bariatric surgery has consistently shown a significant reduction in A1c, with all but one study favoring surgery over medication. In these studies, Dr. Schauer pointed out that the number of major adverse events has been small; minor adverse events have included cases of micronutrient deficiencies and mild anemia, with less than 1% of patients experiencing severe hypoglycemia. He also reviewed the new 2016 guidelines for bariatric surgery that recommend surgery to treat type 2 diabetes in patients with BMI ≥40 kg/m² and those with BMI of 35-39.9 kg/m² when hyperglycemia is inadequately controlled by lifestyle and medical therapy. Dr. Schauer stressed that the more important addition to the guidelines concerned the recommendation of surgery for people who have a BMI between 30 and 34.9 kg/m² if hyperglycemia is inadequately controlled – a big paradigm shift considering that surgery has typically been perceived as an option for only those with more severe forms of obesity. We will be very curious to see how the uptake of metabolic surgery changes following the publication of these guidelines and whether payers will get on board in covering surgery for those with a lower BMI.

  • Dr. Schauer also discussed evidence gaps in metabolic surgery, highlighting the lack of research into the long-term effects of the procedures. Along these lines, he praised the ongoing observational ARMMS study that will be begin to provide some answers on this front.

Symposium: Exercise as the Afterburner for the Post-Bariatric Surgery Patient

Metabolic Adaptations that Alter Bioenergetics and Body Composition

Kevin Hall, PhD (NIDDK, Bethesda, MD)

Dr. Kevin Hall gave a phenomenal presentation on the persistence of metabolic adaption in contestants from season 8 of The Biggest Loser, noting that he is “still a little surprised” by the results. He opened by noting that fat free mass is the most significant driver of resting metabolic rate, and that metabolic adaption represents the difference between predicted vs. actual metabolic rate. Dr. Hall focused on his highly-publicized study, which followed the 14 contestants during the 30-week TV show, and for six years afterwards. On the show, the contestants experienced relative preservation of fat-free mass despite rapid weight loss, with >80% of weight loss coming from body fat in the setting of substantial, diet/exercise-induced weight loss. They had a significant negative metabolic adaption at the end of the show, meaning that the metabolic rate slowed to a degree greater than expected for their smaller body size and lower fat free mass. Metabolic adaptation has often been observed with active weight loss, including that achieved with Roux-en-Y gastric bypass (RYGB). However, while metabolic adaption disappeared after 1 year in surgery patients, it persisted for six years in the Biggest Loser contestants, even as they regained, on average, about two-thirds of the weight lost during the competition. Dr. Hall concluded by positing that metabolic adaption represents a response by the body to reach its former, heavier weight. For more on this study, please see our full coverage

  • Dr. Hall highlighted that fat free mass is the most significant driver of metabolic rate. Thus, maintaining fat free mass during substantial weight loss would be expected to counteract the compensatory decrease in metabolic rate. Data from The Biggest Loser contestants revealed two interesting findings: first, the participants were able to achieve a relative preservation of fat free mass in the setting of drastic weight loss, a finding not observed in bariatric surgery patients. Second, these contestants had much lower resting metabolic rates after weight loss than would be expected for their amount of fat free mass. Dr. Hall explained that the difference between the predicted value and actual measurement of metabolic rate is termed metabolic adaption. For the contestants, this was a difference of several hundred calories per day.
  • Dr. Hall’s team used their simulation model to predict how the contestants would have responded if they had only dieted or only exercised while on the show. The model predicted greater reductions in total body weight from a theoretical regimen of dieting alone (~34 kg [75lbs]) vs. an exercise-only regimen (~27 kg [60 lbs]). However, greater reductions in fat mass were predicted with the exercise-only vs. the diet only regimen (~27 [60 lbs] kg vs. ~22 kg [49 lbs], respectively). We find these results interesting in the context of the exercise vs. diet debate, as we have heard that diet is critical in the weight loss period while exercise is more important in the weight maintenance period.
  • In an interesting study, Dr. Hall’s team compared metabolic parameters between 13 Biggest Loser contestants and 13 pair-matched patients of RYGB. Both groups experienced a metabolic adaption while actively losing weight. However, the metabolic adaption disappeared after one year in the surgery patients. In contrast, it persisted in the Biggest Loser contestants through the six-year follow-up, despite the fact that these participants had gained back significant amounts of weight, and were no longer in the active phase of weight loss.
  • While one would expect that a high level of metabolic adaption would result in a greater amount of weight gain following the show, no such relationship was observed. In contrast, the highest levels of adaption were observed in the contestants who had lost and maintained the greatest amount of weight during the six-year follow up. Per Dr. Hall, these results suggest that metabolic adaption is a response to weight loss – i.e., a tool used by the body to reach its former, heavier weight. Of note, this response was absent in patients who lost weight via bariatric surgery, indicating that RYGB may lead to physiologic changes that do not occur in people who lose weight via diet and exercise – indeed, the new framework for surgery has shifted more toward physiological rather than mechanical mechanisms.
  • As background, The Biggest Loser brings 16 obese contestants (average BMI of 50 kg/m2) to a ranch in California, where they are placed on a rigorous diet and exercise regimen. Participants are sent home each week, with the knowledge that they will reappear on the show during its finale on week 30. Dr. Hall and his team followed the 16 contestants throughout the show, and 14 during the six years afterwards.
  • The show contestants lost an average of one pound per day while at the ranch, followed by an average of a half-pound per day while at home preparing for the show’s finale. Measures of energy expenditure rate (using doubly-labeled water), as well as indirect measures of calorie intake (using the team’s model) indicate that while on the ranch, the contestants were expending roughly 4,500 calories per day (corresponding to three hours of vigorous exercise) while taking in 1,300 calories per day. After being sent home from the show, the contestants had an energy expenditure that corresponded to roughly one hour of vigorous exercise daily, with a daily calorie intake of roughly 2,000. These numbers indicate the substantial energy imbalance experienced by the contestants.

Questions and Answers

Q: These are amazing results. Which kind of diet did the contestants have while on the show? Did it consist of protein?

A: We did not control their diets. They basically had a fridge stocked with food and they were given instructions to not eat less than their calculated resting metabolic rate. They were encouraged to eat greater amounts of protein and whole foods, but the show didn’t measure it, and it was not feasible for us to measure it. After the contestants went home, we didn’t know what they ate.

Q: So there was no integration of protein? You hear of people taking protein powder after going to the gym.

A: I don’t think they had protein power. The show does have an educational component that tries to educate the contestants on how to prepare different healthy meals for themselves. Part of the process is to stock the ingredients in the fridge and hope that the contestants will use them.

Q: This is hugely interesting. I was wondering – is it more of a surprise that their resting metabolic rate was so low after their regained weight, or that it wasn’t even lower given the physiologic changes that occur?

A: That’s a good question. I am not surprised by the results that we got during the competition or at the end of it. What I’m surprised about is how the metabolic rate was still so low in a state of weight maintenance at a higher weight. During the competition, I think our models worked beautifully.

Q: The biggest losers are like professional athletes, really. They are really clued into all the aspects of weight loss, including stimulants and other things. Were you able to control for that, and was that a factor in some of the metabolic changes that were measured?

A: [Jokingly]: Sounds like you’ve been reading the NY Post. It’s a good question. The ranch is basically a sports rehab facility. I was not aware of – and have no reason to believe – that there was any use of stimulants in the people who were studied. The fact that the metabolic rate was lower than expected – not higher than expected – seems to go along with this assessment.  Once we publish the data, it may influence what people use to counter the metabolic adaption with weight loss, but that won’t affect our study and I have no knowledge of it.

Q: In the gastric bypass group, did you have outliers, and did you measure sympathetic tone or norepinephrine in the urine to see whether the decrease in metabolic adaption is driven by the sympathetic nervous system?

A: We only looked at the common measures between the Biggest Loser contestants and the surgery patients. Leptin seemed to be the only predictor of metabolic rate in these two groups, and that may even be an artifact because the contestants had immeasurable levels of leptin while the bariatric patients had measurable levels. Like I said, the physiologic mechanisms underlying this effect are still not well determined.

Q: In terms of brainstorming mechanisms, I am curious if the amount of exercise matters for the amount of metabolic adaption for this population. If you were to take a subgroup and have them exercise only 20 minutes a day, and eat 500 calories less, maybe their body’s response to exercise-induced weight loss would be different with regard to resting metabolic energy.

A: That’s a great question. I presented the lack of metabolic adaption after bariatric surgery as a possible indication of resetting the set point. Alternatively, you can say that the contestants did such extreme exercise and calorie restriction that they are the outliers – i.e., that as a result of this crazy intervention, some permanent change has occurred that makes them an outlier. That is also a perfectly reasonable interpretation of the data.

Symposium: When Food Access Is the Problem – Improving Diabetes Care and Outcomes in Low-Income Populations in the US

Diabetes Nutrition Messaging and Educational Strategies for Low-Income Populations

Kate Hilliard (Food Bank of Corpus Christi, Corpus Christi, TX)

Ms. Kate Hilliard introduced a spectrum of nutritional education programs and food messaging techniques that operate in conjunction with the Food Bank of Corpus Christi, located in a region of Southern Texas with a 25% prevalence diabetes and a poorly insured population. Ms. Hilliard is a field worker, and we found it fascinating to hear her first-hand experiences with food insecurity and diabetes management. She spoke in particular to the challenge of eating healthy for families in which parents are working multiple jobs and in which the purchase of unhealthy and inexpensive food is a necessity, not a choice – of course, she noted that this challenge is only magnified for patients also living with diabetes. With this in mind, the Food Bank of Corpus Christi aims to help food insecure populations by providing more easily accessible nutritious produce, cooking classes, and more. For patients with diabetes specifically, the organization also holds a program – called Diabetes Hands On – that helps attendees understand the basics of how nutrition affects glucose and how to “balance their plates.” The eight-week program tracks attendees’ A1cs and, in Ms. Hilliard’s words, provides a supportive community for those struggling with the challenges of both food insecurity and diabetes management. We were inspired to hear Ms. Hilliard’s commitment to helping patients with diabetes and came away with a much more nuanced understanding of the challenges of eating healthy on a minimal budget – indeed, if one message were to be taken from Ms. Hilliard’s moving testimony, it would be the need for more people who are willing to work with those who most need it.

  • Ms. Hilliard shared that Feeding America and Bristol Myers Squibb recently piloted a program with the Food Bank of Corpus Christi in which low-income adults with type 2 diabetes are provided monthly food boxes, one-on-one educational screenings, and bi-directional clinic referrals. The three-year program helped over 600 clients and, in one case, helped a patient lower her A1c from 13.0% to 7.4% in one year. We’re not sure if the program has received requisite funding to be extended into the future.
  • Ms. Hilliard stressed the importance of cultural competency in working with her majority Latino population. She acknowledged the strong ties to food in Hispanic culture, noting that conversations around diet have to be approached in a sensitive way. She noted, too, that norms of health are different between cultures, suggesting that dialogue around food has to first be grounded in a shared understanding of what it means to be healthy.

Symposium: Immunobiology of Type 2 Diabetes

NK/NKT Cells in Obesity

Mark Esley, PhD (Brigham and Women’s Hospital, Boston, MA)

The thrust of Dr. Mark Esley’s talk was that what is good for immunity against cancer is often bad for autoimmunity and inflammation, and vice versa. His team has exploited natural killer (NK) and natural killer T (NKT) cells in preclinical models and clinically to elucidate regulatory responses of cellular immunity pathways (e.g. Th1, Th2, Th17). He has found that NK cells, innate lymphoid cells present in human and murine abdominal fat, are increased in count and partly defective in obesity. They confer pro-inflammatory effects on macrophages that are often linked to promotion of obesity and type 2 diabetes. Conversely, NKT cells, which release a large variety of cytokines when activated in both humans and mice, are reversibly depleted in obesity and play a protective role against type 2 diabetes. NKT cells in adipose tissue are superior regulators of inflammation due to their thermogenic properties, which promote higher metabolic rates and are essentially a preventative measure against obesity. However, obesity causes a dramatic reduction in invariant NKT cells and an increase in inflammatory M1 macrophages. In addition, NKT cells are often absent in autoimmune diseases. Dr. Esley noted that a number of phase 1 trials have been started to investigate the reactivity of CD1-reactive NKT cells, mostly in the context of tumor immunity. He also raised the intriguing idea of investigating NKT double defective cells in patients with both obesity and cancer.

Mini-Symposium: The Feasibility of Doing High-Intensity Interval Training (HIIT) in Persons with Diabetes

To HIIT or Not to HIIT?

Sheri Colberg-Ochs, PhD (Old Dominion University, Virginia Beach, VA)

“Who wouldn’t want to just exercise for just one minute rather than 45, right?” began Dr. Sheri Colberg-Ochs, a leading expert and published author on diabetes and exercise science, as well as the 2016 recipient of the ADA Outstanding Educator in Diabetes Award. The most recent fitness craze involves high-intensity interval training (HIIT), which is characterized by short bursts of maximum (or close to maximum) exertion. Although there are significant benefits of such training for some populations – namely young, fit, athletically-minded individuals – for patients with type 2 diabetes and obesity complications, the feasibility of success or even safety of this form of training is incredibly low (as discussed in and cited by Dr. Colberg, Biddle and Batterham, 2015). HIIT marketing is incredibly intriguing, especially as it is currently presented in the media. However, Dr. Colberg emphasized the myths and problems associated with such marketing and subsequent utilization of training strategies. Instead, Dr. Colberg argued that more feasible solutions to increase the physical activity of patients living with type 2 diabetes and obesity are required.. For this population, increasing physical activity by creating daily opportunities to break from one’s sedentary lifestyle, such as sitting less and walking more, is much more effective in long-term weight management and health regulation. Thus, when dealing with the bottom of the pyramid of health among individuals, the best way to approach weight loss and health maintenance is personalizing treatment in more ways than just pharmacotherapy.

  • Dr. Colberg exposed the lack of understanding about HIIT and its resulting success. First, there is no universal understanding of exactly what “high-intensity” physiologically entails. Second, the enticing headlines are misleading in their exclamatory promise of short duration. In reality, most proper HIIT workouts require at least 25 minutes of dedication. Third, for those who are not well-seasoned athletes, HIIT workouts are simply not enjoyable, which reduces the likelihood of consistency in or commitment to a training program. Most importantly, the population most necessary to reach with health interventions do not have the same physical capacity as those who dominate the HIIT scene.
  • As Dr. Colberg asserted, older people who are severely overweight, suffer from type 2 diabetes complications, and lead a sedentary lifestyle are generally not able to follow or stick with the demands of such an intense exercise program, especially at the beginning of their physical activity training regimen – “If you can’t imagine your elderly, overweight grandma with type 2 diabetes doing HIIT regularly (or at all), then it’s probably not the right exercise to recommend for everyone to do as a lifelong activity for disease management,” (i.e. “The ‘Grandma’ Test”).

Corporate Symposium: Options and Outcomes – Individualizing Therapy To Help Your Patients With T2DM Successfully Achieve Their Weight Loss Goals (Sponsored by the Institute for Medical and Nursing Education, Inc. and supported by Novo Nordisk)

Summary

W. Timothy Garvey, MD (University of Alabama, Birmingham, AL); Davida Kruger (Henry Ford Health System, Detroit, MI); Donna Ryan, MD (Pennington Biomedical Research Center, Baton Rouge, Louisiana)

The focus of this corporate symposium was on the relationship between type 2 diabetes and obesity and using weight loss as a form of treatment therapy. Speakers explored the complex nature of obesity as a chronic disease and the various forms of novel treatment as a result of changing paradigms. Through individual presentations by Dr. W. Timothy Garvey and Ms. Davida Kruger and discussion panels based on real-life case studies, the session focused on the necessity for obesity to be viewed as a chronic disease and treated as such. One focus of the discussion was an emphasis on the combination of obesity-related medications and behavioral therapies. According to the speakers, for doctors who care for type 2 diabetes patients, it is crucial that they are trained and continually educated in in treating obesity, as it is often a deciding factor in patient outcome. Furthermore, the speakers emphasized that doctors treat obesity and diabetes on a case-by-case basis, as patient values and needs are different. Dr. Ryan ended the symposium by expressing her hope that the diabetes field will be a leader in focusing on weight management as a therapeutic approach and leverage weight management as a tool to better help patients. Please see below for the symposium’s panel discussion.

Panel Discussion

Q: What is the best intervention or therapy? The first option is to start a stricter drug regimen and the second is to enroll in a medical management program for obesity that includes behavioral therapy.

Dr. Garvey: I think a medical management program is right. We’re used to using diabetes meds to treat diabetes, but there are new evidence-based guidelines that can really affect weight loss. We’ve started to realize these new benefits and not just for glucose lowering medicines.

Q: What are some barriers that you typically explore with patients that struggle to lose weight?

Dr. Ryan: I think a big one is the extra meal between dinner and bed. Medication-giving doesn’t help getting to bed with higher blood sugars. What about choosing better snacks and finding how to stay away from the kitchen? Talk about what your patient can do to reduce food in evenings.

Type 2 diabetes is an obesity-associated disease. It’s not just that they have common drivers; it’s that obesity is a driver of beta cell dysfunction. For every patient with BMI over 25, you must address weight management because it’s a key to good diabetes management. It’s appropriate for every obese and diabetic patient you’re seeing. You don’t need to normalize weight. We don’t have the tools to treat to a BMI of 25 or often even 3o, but we can achieve weight loss of 5%, 10%, 15%. Tim described how to use different approaches to reach different degrees of weight loss. More weight loss is, of course, better.

Q: How can we predict who is going to gain weight after bariatric surgery?

Dr. Garvey: Since we all have different mechanisms of action, combos are a good approach? Naltrexone, phentermine, etc. drive weight gain in patients with obesity. The future is combining these medications for weight loss. Right now, we are lacking a lot of data and the FDA cautions only use where safety data exists. We just need to wait for some trials to guide rational therapy. There are surely more options in the future that are not too far off.

Q: What is your physical activity prescription to patients with diabetes?

Ms. Kruger: Well, it’s not running marathons. I’d ask for them to do more than what they’ve been doing so if they’ve not been doing anything, then have them start with 15 minute walks, something like that.

Q: What about weight training?

Ms. Kruger: In the older patients, that helps them when their body fat changes to sustain whatever muscle they can

Q: Two related questions here are if the patient has a history of gastric-bypass and regains weight, can they take a weight-loss medication? Which one might it be and are weight-loss medications FDA-approved for those who have had bariatric surgery?

Dr. Garvey: You know, we are really lacking data in the use of weight-loss medications in patients following bariatric surgery either to promote more weight loss or prevent weight regain or to address weight regain in those patients where that happens. There is a little data with liraglutide, which was shown in a small study that it was effective and safe; there’s no reason to assume that patients wouldn’t do well on these medications, except with the exception of orals in patients whose GI tracts have been manipulated in that way, but just like the data, there are studies being performed right now. But I think there will certainly be a place for weight-loss medications, particularly in patients with weight regain following bariatric surgery.

Q: What do you do about the cost of the therapies?

Ms. Kruger: We all know it’s an issue and we’re hoping that by documenting the needs of these patients, the fact that the FDA will take note of the importance of weight reduction will change some of their stances. I think there are some generic combinations that can be done, but in general, you have to write a prescription to see what coverage we can get.

Q: Why is 5%-10% weight loss so effective in individuals who are obese and remain obese after just 5%-10% weight loss?

Dr. Ryan: This weight loss can have dramatic health benefits. A study showed that people who achieved 5%, 11%, 16% weight loss – they showed that different tissues and different organs respond differently to these weight losses, and that you probably maximize liver and adipose tissue insulin sensitivity at just 5% weight loss. But interestingly, it took about 15-16% weight loss to see significant changes in many inflammatory factors.

Q: How about diabetes drugs for obesity?

Dr. Garvey: Here’s a recommendation that the best thing to do in these situations is to have metformin, SGLT2 inhibitors, and glucose-receptor agonists all combined, and I think there’s nothing wrong with that, but when you have a hammer, if you’re going to use it to hit the nail, if you have other tools, you’re going to use those. And I think it just happens that we’re just used to using glucose-lowering medications. If we’re really treating obesity, body weight to reduce adipose to improve health, I think just relying on glucose-lowering medications, even if they lead to modest weight loss, why not use evidence-based treatments for that weight reduction, because we’ve seen the evidence and the benefits in patients across the board with many cardiovascular factors, so it just reflects a reliance on doing what we do best instead of learning new approaches to treating patients with type 2 diabetes.

Ms. Kruger: I think you’re right, and another comment on top of that is that people have to come out of their comfort level in that obesity doesn’t go away, it’s not going to go away, and it continues to get worse. If we really are going to find the best-quality care, then we need to use medicines for both obesity and diabetes.

-- by Melissa An, Lucy Chu, Abigail Dove, Emily Fitts, Helen Gao, Varun Iyengar, Nancy Liu, Hannah Martin, Sarah Odeh, Nina Ran, Emily Regier, Ava Runge, Barbara Troupin, Tony Thaweethai, Alasdair Wilkins, Sarah Wilkins, Yrenly Yuan, and Kelly Close