Oxytocin does not acutely improve glucose tolerance in men with type 2 diabetes.

AIM: To assess oxytocin's acute glucoregulatory impact in men with type 2 diabetes in the context of our previous findings that oxytocin improves ß-cell responsivity in healthy men. METHODS: In a double-blind, crossover comparison, intranasal oxytocin (24 IU) and placebo, respectively, were administered to 25 fasted men with non-insulin-treated type 2 diabetes (age ± standard error of the mean, 63.40 ± 1.36 years; body mass index, 27.77 ± 0.66 kg/m2; HbA1c, 6.86% ± 0.08%; Homeostatic Model Assessment of Insulin Resistance (HOMA-IR, 3.44 ± 0.39) 60 minutes before an oral glucose tolerance test (oGTT). Key outcomes were compared with previous results in men with normal weight or obesity. RESULTS: Oxytocin compared with placebo increased plasma oxytocin concentrations and reduced the heart rate, but did not alter glucose metabolism in the 3 hours after oGTT onset (area under the curve, glucose, 2240 ± 80.5 vs. 2190 ± 69.5 mmol/L × min; insulin, 45 663 ± 4538 vs. 44 343 ± 4269 pmol/L × min; C-peptide, 235 ± 5.1 vs. 231 ± 15.9 nmol/L × min). CONCLUSIONS: This outcome contrasts with the oxytocin-induced attenuation of early postprandial glucose excursions in normal-weight individuals, but is in line with the absence of respective effects in men with obesity. We conclude that insulin resistance in type 2 diabetes is associated with decreased sensitivity to the acute glucoregulatory effect of oxytocin in male individuals.

Obesity-induced inflammation: connecting the periphery to the brain.

Obesity is often associated with a chronic, low-grade inflammatory state affecting the entire body. This sustained inflammatory state disrupts the coordinated communication between the periphery and the brain, which has a crucial role in maintaining homeostasis through humoural, nutrient-mediated, immune and nervous signalling pathways. The inflammatory changes induced by obesity specifically affect communication interfaces, including the blood-brain barrier, glymphatic system and meninges. Consequently, brain areas near the third ventricle, including the hypothalamus and other cognition-relevant regions, become susceptible to impairments, resulting in energy homeostasis dysregulation and an elevated risk of cognitive impairments such as Alzheimer's disease and dementia. This Review explores the intricate communication between the brain and the periphery, highlighting the effect of obesity-induced inflammation on brain function.

Neuroendocrine gut-brain signaling in obesity.

The past decades have witnessed the rise and fall of several, largely unsuccessful, therapeutic attempts to bring the escalating obesity pandemic to a halt. Looking back to look ahead, the field has now put its highest hopes in translating insights from how the gastrointestinal (GI) tract communicates with the brain to calibrate behavior, physiology, and metabolism. A major focus of this review is to summarize the latest advances in comprehending the neuroendocrine aspects of this so-called 'gut-brain axis' and to explore novel concepts, cutting-edge technologies, and recent paradigm-shifting experiments. These exciting insights continue to refine our understanding of gut-brain crosstalk and are poised to promote the development of additional therapeutic avenues at the dawn of a new era of antiobesity therapeutics.

The interactions between energy homeostasis and neurovascular plasticity.

Food intake and energy expenditure are sensed and processed by multiple brain centres to uphold energy homeostasis. Evidence from the past decade points to the brain vasculature as a new critical player in regulating energy balance that functions in close association with the local neuronal networks. Nutritional imbalances alter many properties of the neurovascular system (such as neurovascular coupling and blood-brain barrier permeability), thus suggesting a bidirectional link between the nutritional milieu and neurovascular health. Increasing numbers of people are consuming a Western diet (comprising ultra-processed food with high-fat and high-sugar content) and have a sedentary lifestyle, with these factors contributing to the current obesity epidemic. Emerging pharmacological interventions (for example, glucagon-like peptide 1 receptor agonists) successfully trigger weight loss. However, whether these approaches can reverse the detrimental effects of long-term exposure to the Western diet (such as neurovascular uncoupling, neuroinflammation and blood-brain barrier disruption) and maintain stable body weight in the long-term needs to be clarified in addition to possible adverse effects. Lifestyle interventions revert the nutritional trigger for obesity and positively affect our overall health, including the cardiovascular system. This Perspective examines how lifestyle interventions affect the neurovascular system and neuronal networks.

Global, neuronal or ß cell-specific deletion of inceptor improves glucose homeostasis in male mice with diet-induced obesity.

Insulin resistance is an early complication of diet-induced obesity (DIO)1, potentially leading to hyperglycaemia and hyperinsulinaemia, accompanied by adaptive ß cell hypertrophy and development of type 2 diabetes2. Insulin not only signals via the insulin receptor (INSR), but also promotes ß cell survival, growth and function via the insulin-like growth factor 1 receptor (IGF1R)3-6. We recently identified the insulin inhibitory receptor (inceptor) as the key mediator of IGF1R and INSR desensitization7. But, although ß cell-specific loss of inceptor improves ß cell function in lean mice7, it warrants clarification whether inceptor signal inhibition also improves glycaemia under conditions of obesity. We assessed the glucometabolic effects of targeted inceptor deletion in either the brain or the pancreatic ß cells under conditions of DIO in male mice. In the present study, we show that global and neuronal deletion of inceptor, as well as its adult-onset deletion in the ß cells, improves glucose homeostasis by enhancing ß cell health and function. Moreover, we demonstrate that inceptor-mediated improvement in glucose control does not depend on inceptor function in agouti-related protein-expressing or pro-opiomelanocortin neurons. Our data demonstrate that inceptor inhibition improves glucose homeostasis in mice with DIO, hence corroborating that inceptor is a crucial regulator of INSR and IGF1R signalling.

Loss of GIPR in LEPR cells impairs glucose control by GIP and GIP:GLP-1 co-agonism without affecting body weight and food intake in mice.

OBJECTIVE: The glucose-dependent insulinotropic polypeptide (GIP) decreases body weight via central GIP receptor (GIPR) signaling, but the underlying mechanisms remain largely unknown. Here, we assessed whether GIP regulates body weight and glucose control via GIPR signaling in cells that express the leptin receptor (Lepr). METHODS: Hypothalamic, hindbrain, and pancreatic co-expression of Gipr and Lepr was assessed using single cell RNAseq analysis. Mice with deletion of Gipr in Lepr cells were generated and metabolically characterized for alterations in diet-induced obesity (DIO), glucose control and leptin sensitivity. Long-acting single- and dual-agonists at GIPR and GLP-1R were further used to assess drug effects on energy and glucose metabolism in DIO wildtype (WT) and Lepr-Gipr knock-out (KO) mice. RESULTS: Gipr and Lepr show strong co-expression in the pancreas, but not in the hypothalamus and hindbrain. DIO Lepr-Gipr KO mice are indistinguishable from WT controls related to body weight, food intake and diet-induced leptin resistance. Acyl-GIP and the GIPR:GLP-1R co-agonist MAR709 remain fully efficacious to decrease body weight and food intake in DIO Lepr-Gipr KO mice. Consistent with the demonstration that Gipr and Lepr highly co-localize in the endocrine pancreas, including the ß-cells, we find the superior glycemic effect of GIPR:GLP-1R co-agonism over single GLP-1R agonism to vanish in Lepr-Gipr KO mice. CONCLUSIONS: GIPR signaling in cells/neurons that express the leptin receptor is not implicated in the control of body weight or food intake, but is of crucial importance for the superior glycemic effects of GIPR:GLP-1R co-agonism relative to single GLP-1R agonism.