High Doses of Exogenous Glucagon Stimulate Insulin Secretion and Reduce Insulin Clearance in Healthy Humans.

Glucagon is generally defined as a counterregulatory hormone with a primary role to raise blood glucose concentrations by increasing endogenous glucose production (EGP) in response to hypoglycemia. However, glucagon has long been known to stimulate insulin release, and recent preclinical findings have supported a paracrine action of glucagon directly on islet ß-cells that augments their secretion. In mice, the insulinotropic effect of glucagon is glucose dependent and not present during basal euglycemia. To test the hypothesis that the relative effects of glucagon on hepatic and islet function also vary with blood glucose, a group of healthy subjects received glucagon (100 ng/kg) during fasting glycemia or experimental hyperglycemia (∼150 mg/dL) on 2 separate days. During fasting euglycemia, administration of glucagon caused blood glucose to rise due to increased EGP, with a delayed increase of insulin secretion. When given during experimental hyperglycemia, glucagon caused a rapid, threefold increase in insulin secretion, as well as a more gradual increase in EGP. Under both conditions, insulin clearance was decreased in response to glucagon infusion. The insulinotropic action of glucagon, which is proportional to the degree of blood glucose elevation, suggests distinct physiologic roles in the fasting and prandial states.

Oxytocin as an Anti-obesity Treatment.

Obesity is a growing health concern, as it increases risk for heart disease, hypertension, type 2 diabetes, cancer, COVID-19 related hospitalizations and mortality. However, current weight loss therapies are often associated with psychiatric or cardiovascular side effects or poor tolerability that limit their long-term use. The hypothalamic neuropeptide, oxytocin (OT), mediates a wide range of physiologic actions, which include reproductive behavior, formation of prosocial behaviors and control of body weight. We and others have shown that OT circumvents leptin resistance and elicits weight loss in diet-induced obese rodents and non-human primates by reducing both food intake and increasing energy expenditure (EE). Chronic intranasal OT also elicits promising effects on weight loss in obese humans. This review evaluates the potential use of OT as a therapeutic strategy to treat obesity in rodents, non-human primates, and humans, and identifies potential mechanisms that mediate this effect.

Metabolic profiles, energy expenditures, and body compositions of the weight regain versus sustained weight loss patients who underwent Roux-en-Y gastric bypass.

BACKGROUND: Weight regain (WR) has been an emerging problem after Roux-en Y gastric bypass (RYGB) and little is known about the mechanisms of WR after RYGB. OBJECTIVE: To evaluate the mechanisms of WR after RYGB through the postprandial gut hormones response, particularly glucagon-like peptide-1 (GLP-1), which regulates appetite control, energy expenditure, body composition, physical activities, dietary intake, and psychological factors. SETTING: Duke University Medical Center, Durham, North Carolina. METHODS: A cross sectional study of 34 patients who underwent RYGB at least 2 years and achieved ≥50% of excess weight loss at 1year was conducted. The subjects were categorized into WR group or sustained weight loss group, based upon whether their WR was ≥15% of postoperative lowest weight. RESULTS: The WR group had less augmented postprandial GLP-1 response but exaggerated hyperinsulinemia. Postprandial peptide YY, ghrelin, and glucose were not different between group. Patients who regained weight required less weight-adjusted energy expenditure and had more percentage body fat and less percentage lean mass. The caloric intake and diet composition were comparable between groups; however, the WR group had higher depression scores, binge eating scales, and hunger rating and spent significantly less time on vigorous exercise. CONCLUSIONS: The mechanisms of WR in patients who were initially successful after RYGB are complex and involved not only the role of postprandial gut hormone response but are also related to energy expenditure adaptation and body composition changes. Moreover, food preference and physical activity may play roles in weight control after bariatric surgery. Further prospective controlled trial is needed to explore the mechanisms of WR.

PREVENT: A Randomized, Placebo-controlled Crossover Trial of Avexitide for Treatment of Postbariatric Hypoglycemia.

CONTEXT: Postbariatric hypoglycemia (PBH), characterized by enteroinsular axis overstimulation and hyperinsulinemic hypoglycemia, is a complication of bariatric surgery for which there is no approved therapy. OBJECTIVE: To evaluate efficacy and safety of avexitide [exendin (9-39)], a glucagon-like peptide-1 antagonist, for treatment of PBH. METHODS: A multicenter, Phase 2, randomized, placebo-controlled crossover study (PREVENT). Eighteen female patients with PBH were given placebo for 14 days followed by avexitide 30 mg twice daily and 60 mg once daily, each for 14 days in random order. The main outcome measures were glucose nadir and insulin peak during mixed-meal tolerance testing (MMTT) and hypoglycemic events captured by self-monitoring of blood glucose (SMBG), electronic diary, and blinded continuous glucose monitoring (CGM). RESULTS: Compared with placebo, avexitide 30 mg twice daily and 60 mg once daily raised the glucose nadir by 21% (P = .001) and 26% (P = .0002) and lowered the insulin peak by 23% (P = .029) and 21% (P = .042), corresponding to 50% and 75% fewer participants requiring rescue during MMTT, respectively. Significant reductions in rates of Levels 1 to 3 hypoglycemia were observed, defined, respectively, as SMBG <70 mg/dL, SMBG <54 mg/dL, and a severe event characterized by altered mental and/or physical function requiring assistance. CGM demonstrated reductions in hypoglycemia without induction of clinically relevant hyperglycemia. Avexitide was well tolerated, with no increase in adverse events. CONCLUSION: Avexitide administered for 28 days was well tolerated and resulted in robust and consistent improvements across multiple clinical and metabolic parameters, reinforcing the targeted therapeutic approach and demonstrating durability of effect. Avexitide may represent a first promising treatment for patients with severe PBH.

Discordance between GLP-1R gene and protein expression in mouse pancreatic islet cells.

The insulinotropic actions of glucagon-like peptide 1 receptor (GLP-1R) in ß-cells have made it a useful target to manage type 2 diabetes. Metabolic stress reduces ß-cell sensitivity to GLP-1, yet the underlying mechanisms are unknown. We hypothesized that Glp1r expression is heterogeneous among ß-cells and that metabolic stress decreases the number of GLP-1R-positive ß-cells. Here, analyses of publicly available single-cell RNA-Seq sequencing (scRNASeq) data from mouse and human ß-cells indicated that significant populations of ß-cells do not express the Glp1r gene, supporting heterogeneous GLP-1R expression. To check these results, we used complementary approaches employing FACS coupled with quantitative RT-PCR, a validated GLP-1R antibody, and flow cytometry to quantify GLP-1R promoter activity, gene expression, and protein expression in mouse α-, ß-, and δ-cells. Experiments with Glp1r reporter mice and a validated GLP-1R antibody indicated that >90% of the ß-cells are GLP-1R positive, contradicting the findings with the scRNASeq data. α-cells did not express Glp1r mRNA and δ-cells expressed Glp1r mRNA but not protein. We also examined the expression patterns of GLP-1R in mouse models of metabolic stress. Multiparous female mice had significantly decreased ß-cell Glp1r expression, but no reduction in GLP-1R protein levels or GLP-1R-mediated insulin secretion. These findings suggest caution in interpreting the results of scRNASeq for low-abundance transcripts such as the incretin receptors and indicate that GLP-1R is widely expressed in ß-cells, absent in α-cells, and expressed at the mRNA, but not protein, level in δ-cells.

Predicting Weight Loss Using Psychological and Behavioral Factors: The POUNDS LOST Trial.

CONTEXT: Eating habits and food craving are strongly correlated with weight status. It is currently not well understood how psychological and behavioral factors influence both weight loss and weight regain. OBJECTIVE: To examine the associations between psychological and behavioral predictors with weight changes and energy intake in a randomized controlled trial on weight loss. DESIGN AND SETTING: The Prevention of Obesity Using Novel Dietary Strategies is a dietary intervention trial that examined the efficacy of 4 diets on weight loss over 2 years. Participants were 811 overweight (body mass index, 25-40.9 kg/m2; age, 30-70 years) otherwise healthy adults. RESULTS: Every 1-point increase in craving score for high-fat foods at baseline was associated with greater weight loss (-1.62 kg, P = .0004) and a decrease in energy intake (r = -0.10, P = .01) and fat intake (r = -0.16, P < .0001) during the weight loss period. In contrast, craving for carbohydrates/starches was associated with both less weight loss (P < .0001) and more weight regain (P = .04). Greater cognitive restraint of eating at baseline was associated with both less weight loss (0.23 kg, P < .0001) and more weight regain (0.14 kg, P = .0027), whereas greater disinhibition of eating was only associated with more weight regain (0.12 kg, P = .01). CONCLUSIONS: Craving for high-fat foods is predictive of greater weight loss, whereas craving for carbohydrates is predictive of less weight loss. Cognitive restraint is predictive of less weight loss and more weight regain. Interventions targeting different psychological and behavioral factors can lead to greater success in weight loss.

Temporal plasticity of insulin and incretin secretion and insulin sensitivity following sleeve gastrectomy contribute to sustained improvements in glucose control.

OBJECTIVE: Bariatric surgery acutely improves glucose control, an effect that is generally sustained for years in most patients. The acute postoperative glycemic reduction is at least partially mediated by enhanced incretin secretion and islet function, and occurs independent of caloric restriction, whereas the sustained improvement in glucose control is associated with increased insulin sensitivity. However, studies in humans with bariatric surgery suggest that these elevations are not static but undergo coordinated regulation throughout the postoperative time course. The studies described here test the hypothesis that incretin secretion, islet function, and peripheral insulin sensitivity undergo temporal regulation following bariatric surgery as a means to regulate glucose homeostasis. METHODS: Incretin secretion, islet function, and insulin sensitivity in mice with vertical sleeve gastrectomy (VSG) were compared to sham-operated controls that were pair-fed for 90d, matching food consumption and body-weight between groups. RESULTS: Glucose clearance and insulin secretion were enhanced in VSG mice compared to controls during mixed-meal tolerance tests (MMTT) at 12 and 80 days postoperatively, as were prandial GLP-1, GIP, and glucagon levels. Insulin sensitivity was comparable between groups 14d after surgery, but significantly greater in the VSG group at day 75, despite similar body-weight gain between groups. Glucose stimulated insulin secretion was greater in VSG mice compared to controls in vivo (I.P. glucose injection) and ex vivo (islet perifusion) indicating a rapid and sustained enhancement of ß-cell function after surgery. Notably, glycemia following a MMTT was progressively higher over time in the control animals but improved in the VSG mice at 80d despite weight regain. However, meal-stimulated incretin secretion decreased in VSG mice from 10 to 80 days postoperative, as did meal-stimulated and I.P. glucose-stimulated insulin secretion. This occurred over the same time period that insulin sensitivity was enhanced in VSG mice, suggesting postoperative islet output is tightly regulated by insulin demand. CONCLUSIONS: These data demonstrate a dynamic, multifactorial physiology for improved glucose control after VSG, whereby rapidly elevated insulin secretion is complimented by later enhancements in insulin sensitivity. Critically, the glucose lowering effect of VSG is demonstrably larger than that of caloric-restriction, suggesting these adaptations are mediated by surgical modification of gastrointestinal anatomy and not weight-loss per se.

The Effects of Bariatric Surgery on Islet Function, Insulin Secretion, and Glucose Control.

Although bariatric surgery was developed primarily to treat morbid obesity, evidence from the earliest clinical observations to the most recent clinical trials consistently demonstrates that these procedures have substantial effects on glucose metabolism. A large base of research indicates that bariatric surgeries such as Roux-en-Y gastric bypass (RYGB), vertical sleeve gastrectomy (VSG), and biliopancreatic diversion (BPD) improve diabetes in most patients, with effects frequently evident prior to substantial weight reduction. There is now unequivocal evidence from randomized controlled trials that the efficacy of surgery is superior to intensive life-style/medical management. Despite advances in the clinical understanding and application of bariatric surgery, there remains only limited knowledge of the mechanisms by which these procedures confer such large changes to metabolic physiology. The improvement of insulin sensitivity that occurs with weight loss (e.g., the result of diet, illness, physical training) also accompanies bariatric surgery. However, there is evidence to support specific effects of surgery on insulin clearance, hepatic glucose production, and islet function. Understanding the mechanisms by which surgery affects these parameters of glucose regulation has the potential to identify new targets for therapeutic discovery. Studies to distinguish among bariatric surgeries on key parameters of glucose metabolism are limited but would be of considerable value to assist clinicians in selecting specific procedures and investigators in delineating the resulting physiology. This review is based on literature related to factors governing glucose metabolism and insulin secretion after the commonly used RYGB and VSG, and the less frequently used BPD and adjustable gastric banding.

Intraislet Ghrelin Signaling Does Not Regulate Insulin Secretion From Adult Mice.

Exogenous ghrelin reduces glucose-stimulated insulin secretion and endogenous ghrelin protects against hypoglycemia during starvation. Islet ε-cells produce ghrelin and δ-cells express growth hormone secretagogue receptor (GHSR), suggesting the possibility of a paracrine mechanism for islet ghrelin to reach high local concentrations and affect insulin secretion. GHSR has high constitutive activity and may act independently of ghrelin. The objective in this study was to determine whether an intraislet ghrelin-GHSR axis modulates insulin secretion and glucose metabolism using mouse models lacking ghrelin (Ghrl-/- ) or GHSR (Ghsr-/- ). Ghsr-/- and Ghsr+/+ mice had comparable islet ghrelin concentrations. Exogenous ghrelin decreased insulin secretion in perifused isolated islets in a GHSR-dependent manner. Islets isolated from Ghrl-/- or Ghsr-/- mice did not differ from controls in glucose-, alanine-, or GLP-1-stimulated insulin secretion during perifusion. Consistent with this finding, Ghrl-/- and Ghsr-/- male mice studied after either 6 or 16 h of fasting had blood glucose concentrations comparable with those of controls following intraperitoneal glucose, or insulin tolerance tests, or after mixed nutrient meals. Collectively, our data provide strong evidence against a paracrine ghrelin-GHSR axis mediating insulin secretion or glucose tolerance in lean, chow-fed adult mice.