Effects of Age and Sex on Systemic Inflammation and Cardiometabolic Function in Individuals with Type 2 Diabetes.

Objective: Systemic inflammation, aging, and type 2 diabetes (T2DM) all contribute to the development of cardiovascular dysfunction and impaired aerobic exercise capacity but their interplay remains unclear. This study evaluates the impact of age, sex, and inflammation on coronary and peripheral vascular function and exercise capacity in elderly individuals with and without type 2 diabetes (T2DM). Research Design and Methods: Elderly individuals (age ≥65 years) underwent biochemical and tissue inflammatory phenotyping, cardiopulmonary exercise testing (CPET), cardiovascular magnetic resonance (CMR) imaging, and vascular reactivity testing. Correlation and regression analyses determined the effects of systemic inflammation, older age, and sex on cardiovascular health, stratified by T2DM status. Results: For the 133 recruited individuals (44% female; median age 71, IQR=7 years, 41% with T2DM) the presence of T2DM did not have an effect on most blood serum inflammatory markers and skin biopsies. Hyperemic myocardial blood flow (hMBF), flow-mediated, and flow-independent nitroglycerin induced brachial artery dilation were significantly impaired in males, but not females with T2DM. Peak VO2 was lower with T2DM (p=0.022), mostly because of the effect of T2DM in females. Females showed more adverse myocardial remodeling assessed by extracellular volume (p=0.008), independent of T2DM status. Conclusions: Our findings suggest that the pathophysiological manifestations of T2DM on vascular function and aerobic exercise capacity are distinct in elderly males and females and this may reflect underlying differences in vascular and myocardial aging in the presence of T2DM.

Weight Loss Outcomes Among Early High Responders to Exenatide Treatment: A Randomized, Placebo Controlled Study in Overweight and Obese Women.

Objective: As there is significant heterogeneity in the weight loss response to pharmacotherapy, one of the most important clinical questions in obesity medicine is how to predict an individual's response to pharmacotherapy. The present study examines patterns of weight loss among overweight and obese women who demonstrated early robust response to twice daily exenatide treatment compared to those treated with hypocaloric diet and matched placebo injections. Methods: We randomized 182 women (BMI 25-48 kg/m2) to treatment with exenatide alone or matched placebo injections plus hypocaloric diet. In both treatment groups, women who demonstrated ≥ 5% weight loss at 12 weeks were characterized as high responders and those who lost ≥10% of body weight were classified as super responders. Our primary outcome was long-term change in body weight among early high responders to either treatment. An exploratory metabolomic analysis was also performed. Results: We observed individual variability in weight loss with both exenatide and hypocaloric diet plus placebo injections. There was a trend toward a higher percentage of subjects who achieved ≥ 5% weight loss with exenatide compared to diet (56% of those treated with exenatide, 76% of those treated with diet, p = 0.05) but no significant difference in those who achieved ≥ 10% weight loss (23% of individuals treated with exenatide and 36% of those treated with diet, p = 0.55). In both treatment groups, higher weight loss at 3 months of treatment predicted super responder status (diet p=0.0098, exenatide p=0.0080). Both treatment groups also demonstrated similar peak weight loss during the study period. We observed lower cysteine concentrations in the exenatide responder group (0.81 vs 0.48 p < 0.0001) and a trend toward higher levels of serotonin, aminoisobutyric acid, anandamide, and sarcosine in the exenatide super responder group. Conclusion: In a population of early high responders, longer term weight loss with exenatide treatment is similar to that achieved with a hypocaloric diet. Clinical Trial Registration: www.clinicaltrialsgov, identifier NCT01590433.

Multi-sensor ecological momentary assessment of behavioral and psychosocial predictors of weight loss following bariatric surgery: study protocol for a multicenter prospective longitudinal evaluation.

BACKGROUND: Bariatric surgery is currently the most effective strategy for producing significant and durable weight loss. Yet, not all patients achieve initial weight loss success and some degree of weight regain is very common, sometimes as early as 1-2 years post-surgery. Suboptimal weight loss not fully explained by surgical, demographic, and medical factors has led to greater emphasis on patient behaviors evidenced by clinical guidelines for appropriate eating and physical activity. However, research to inform such guidelines has often relied on imprecise measures or not been specific to bariatric surgery. There is also little understanding of what psychosocial factors and environmental contexts impact outcomes. To address research gaps and measurement limitations, we designed a protocol that innovatively integrates multiple measurement tools to determine which behaviors, environmental contexts, and psychosocial factors are related to outcomes and explore how psychosocial factors/environmental contexts influence weight. This paper provides a detailed description of our study protocol with a focus on developing and deploying a multi-sensor assessment tool to meet our study aims. METHODS: This NIH-funded prospective cohort study evaluates behavioral, psychosocial, and environmental predictors of weight loss after bariatric surgery using a multi-sensor platform that integrates objective sensors and self-report information collected via smartphone in real-time in patients' natural environment. A target sample of 100 adult, bariatric surgery patients (ages 21-70) use this multi-sensor platform at preoperative baseline, as well as 3, 6, and 12 months postoperatively, to assess recommended behaviors (e.g., meal frequency, physical activity), psychosocial indicators with prior evidence of an association with surgical outcomes (e.g., mood/depression), and key environmental factors (e.g., type/quality of food environment). Weight also is measured at each assessment point. DISCUSSION: This project has the potential to build a more sophisticated and valid understanding of behavioral and psychosocial factors contributing to success and risk after bariatric surgery. This new understanding could directly contribute to improved (i.e., specific, consistent, and validated) guidelines for recommended pre- and postoperative behaviors, which could lead to improved surgical outcomes. These data will also inform behavioral, psychosocial, and environmental targets for adjunctive interventions to improve surgical outcomes. TRIAL REGISTRATION: Registered trial NCT02777177 on 5/19/2016.

Elevated Serum Fibroblast Growth Factor 21 in Humans with Acute Pancreatitis.

BACKGROUND: The metabolic regulator Fibroblast Growth Factor 21 (FGF21) is highly expressed in the acinar pancreas, but its role in pancreatic function is obscure. It appears to play a protective role in acute experimental pancreatitis in mice. The aim of this study was to define an association between FGF21 and the course and resolution of acute pancreatitis in humans. METHODS AND PRINCIPAL FINDINGS: Twenty five subjects with acute pancreatitis admitted from May to September 2012 to the Beth Israel Deaconess Medical Center (BIDMC) were analyzed. Serial serum samples were collected throughout hospitalization and analyzed for FGF21 levels by ELISA. Twenty healthy subjects sampled three times over a four week period were used as controls. We found that, in patients with pancreatitis, serum FGF21 rises significantly and peaks four to six days after the maximum lipase level, before slowly declining. Maximum FGF21 levels were significantly greater than baseline levels for acute pancreatitis subjects (1733 vs. 638 pg/mL, P = 0.003). This maximum value was significantly greater than the highest value observed for our control subjects (1733 vs. 322 pg/mL, P = 0.0002). The ratio of active to total FGF21 did not change during the course of the disease (42.5% vs. 44.4%, P = 0.58). Fold increases in FGF21 were significantly greater in acute pancreatitis subjects than the fold difference seen in healthy subjects (4.7 vs. 2.0, P = 0.01). Higher fold changes were also seen in severe compared to mild pancreatitis (18.2 vs. 4.4, P = 0.01). The timing of maximum FGF21 levels correlated with day of successful return to oral intake (R2 = 0.21, P = 0.04). CONCLUSIONS: Our results demonstrate that serum FGF21 rises significantly in humans with acute pancreatitis. The pancreas may be contributing to increased FGF21 levels following injury and FGF21 may play a role in the recovery process.

Effect of Linagliptin on Vascular Function: A Randomized, Placebo-controlled Study.

CONTEXT: The dipeptidyl peptidase-4 inhibitor, linagliptin, possesses pleiotropic vasodilatory, antioxidant, and anti-inflammatory properties in animals, independent of its glucose-lowering properties. Although large, randomized clinical trials are being conducted to better evaluate the efficacy and safety of linagliptin on cardiovascular outcomes, little is known about its effects on vascular function in humans. OBJECTIVE: This study sought to evaluate the effect of linagliptin on surrogates of vascular and mitochondrial function. DESIGN AND SETTING: This was a randomized, double-blind, placebo-controlled trial at a tertiary care center with a large type 2 diabetes referral base. PATIENTS AND INTERVENTION: Forty participants with type 2 diabetes were included in a 12-wk treatment of either linagliptin 5mg/d or placebo. MAIN OUTCOME MEASURES: Micro- and macrovascular functions were assessed using laser Doppler coupled with iontophoresis and with brachial flow-mediated dilation, respectively. Mitochondrial function was assessed by phosphorus-31 metabolites changes in the calf muscle measured by magnetic resonance spectroscopy. Circulating endothelial progenitor cells, as well as inflammatory cytokines, growth factors, and biomarkers of endothelial function were also quantified. RESULTS: Linagliptin was associated with an increase in axon reflex-dependent vasodilation, a marker of neurovascular function (P = .05). A trend indicating increased endothelium-dependent microvascular reactivity was observed (P = .07). These were associated with decreases in concentrations of IFNγ (P < .05), IL-6 (P = .03), IL-12 (P < .03), and MIP-1 (P < .04) following linagliptin treatment when compared with placebo. CONCLUSIONS: This study demonstrates that linagliptin tends to improve endothelial and neurovascular microvascular function and is associated with decreased markers of inflammation in patients with type 2 diabetes. There was no significant effect of linagliptin on mitochondrial function, macrovascular function, or endothelial progenitor cells.

Fructose ingestion acutely stimulates circulating FGF21 levels in humans.

OBJECTIVE: Fibroblast growth factor 21 (FGF21) is a hormone with pleiotropic metabolic activities which, in rodents, is robustly regulated by fasting and ketogenic diets. In contrast, similar dietary interventions have either no or minimal effects on circulating FGF21 in humans. Moreover, no intervention or dietary challenge has been shown to acutely stimulate circulating FGF21 in either humans or animals. Recent animal data suggest that the transcription factor Carbohydrate Responsive-Element Binding Protein (ChREBP) stimulates hepatic FGF21 expression and that fructose may activate hepatic ChREBP more robustly than glucose. Here, we examined whether fructose ingestion can acutely stimulate FGF21 in humans. METHODS: We measured serum FGF21, glucose, insulin, and triglyceride levels in ten lean, healthy adults and eleven adults with the metabolic syndrome following oral ingestion of 75 g of glucose, fructose, or a combination of the two sugars. RESULTS: FGF21 levels rose rapidly following fructose ingestion, achieved a mean 3.4-fold increase at two hours (P < 0.01), and returned to baseline levels within five hours. In contrast, FGF21 did not increase in the first two hours following ingestion of a glucose load, although more modest increases were observed after three to four hours. Both baseline and fructose-stimulated FGF21 levels were 2-3 fold elevated in subjects with metabolic syndrome. CONCLUSIONS: Fructose ingestion acutely and robustly increases serum FGF21 levels in humans in a pattern consistent with a hormonal response. While FGF21 appears to be critical for the adaptive response to fasting or starvation in rodents, these findings suggest that in humans, FGF21 may play an important role in fructose metabolism.

Aliskiren improves vascular smooth muscle function in the skin microcirculation of type 2 diabetic patients with normal renal function.

OBJECTIVE: The objective of this paper is to study the effect of aliskiren on metabolic parameters and micro- and macrovascular reactivity in individuals diagnosed with or at high risk for developing type 2 diabetes mellitus (T2DM). RESEARCH DESIGN AND METHODS: We studied 47 T2DM and 41 at-risk individuals in a randomized, double-blinded, placebo-controlled trial. All subjects were treated with 150 mg aliskiren or placebo daily for 12 weeks. Twenty-six (55%) of T2DM and four (8%) at-risk subjects were also treated with angiotensin-converting enzyme (ACE) inhibitors or angiotensin II receptor blockers. RESULTS: Aliskiren treatment was associated with improvement in systolic and diastolic blood pressure and endothelium-independent vasodilation at the skin microcirculation in those with T2DM but not in those at risk. There were no incidences of hypotension and no significant changes in serum potassium or creatinine levels with aliskiren treatment in either study group. CONCLUSIONS: Aliskiren improves blood pressure and vascular smooth muscle function in the skin microcirculation of T2DM patients.

Short-term exenatide treatment leads to significant weight loss in a subset of obese women without diabetes.

OBJECTIVE: To investigate the effect of treatment with the glucagon-like peptide 1 receptor agonist exenatide on weight loss and metabolic parameters in obese nondiabetic women. RESEARCH DESIGN AND METHODS: Forty-one obese women (aged 48 ± 11 years and BMI 33.1 ± 4.1 kg/m(2)) participated in a 35-week randomized, double-blind, placebo-controlled, crossover study, including two 16-week treatment periods separated by a 3-week washout period. There was no lifestyle intervention. The primary outcome was change in body weight. RESULTS: Subjects treated with exenatide lost an average of 2.49 ± 0.66 kg compared with a 0.43 ± 0.63 kg weight gain during placebo treatment. Weight loss with exenatide treatment was noted at 2 weeks. The degree of weight loss could be stratified. A total of 30% of subjects were high responders who lost ≥5% body weight (-7.96 ± 0.52%), 39% were moderate responders who lost <5% body weight (-2.43 ± 0.45%), and 31% were nonresponders who gained weight (1.93 ± 0.53%). Waist circumference also decreased significantly with exenatide treatment. Subjects experienced more nausea during exenatide treatment compared with placebo, but the severity decreased over time and did not correlate with weight loss. CONCLUSIONS: Short-term exenatide treatment was associated with modest weight loss and decreased waist circumference in a cohort of obese nondiabetic women. A subset of individuals demonstrated robust weight loss that was detected very early in the course of treatment.

Increased fibroblast growth factor 21 in obesity and nonalcoholic fatty liver disease.

BACKGROUND & AIMS: Fibroblast growth factor 21 (FGF21) is an hepatic protein that plays a critical role in metabolism, stimulating fatty acid oxidation in liver and glucose uptake in fat. Systemic administration to obese rodents and diabetic monkeys leads to improved glucose homeostasis and weight loss. In rodents, FGF21 increases with fasting and consumption of a ketogenic diet (KD). In humans, FGF21 correlates with body mass index (BMI), but studies evaluating other parameters show inconsistent results. We examined FGF21 serum levels in lean and obese individuals and in response to dietary manipulation. We also evaluated FGF21 serum levels and liver messenger RNA (mRNA) expression in nonalcoholic fatty liver disease (NAFLD) and nonalcoholic steatohepatitis (NASH). METHODS: Serum FGF21 was measured after an overnight fast in individuals with BMI ranging from normal to obese. Volunteers fasted for 16 or 72 hours and then ate a standard meal. Another group consumed KD for 12 days. Serum FGF21 and hepatic mRNA expression were measured in obese individuals with NAFLD or NASH. RESULTS: There was a positive correlation between BMI and FGF21. There was no change in FGF21 in response to a short fast or KD. A nonstatistically significant fall in FGF21 levels was seen after a 72-hour fast. Hepatic FGF21 mRNA expression was significantly elevated in NAFLD, which correlated with a substantial increase in serum FGF21. In NASH, serum FGF21 but not liver mRNA was increased. CONCLUSIONS: FGF21 correlates with BMI and may be a novel biomarker for NAFLD, but is not nutritionally regulated in humans.