There is currently a revolution in the pharmacologic treatment of obesity and diabetes with newly available agonists of incretin receptors. The health benefits of these novel treatments include not only metabolic effects but also improvements in brain neurodegenerative conditions. Receptors for incretins have been described in the hypothalamic appetite regulatory center; however, their expression in the peripheral nervous system (PNS) has been largely overlooked, despite likely contributing important effects. For example, the PNS is essential for the control of numerous metabolically relevant pathways in tissues such as liver, adipose, intestine, and muscle, and incretin receptors are found on nerves innervating some, if not all, of these metabolically important tissues. In this article, we summarize the knowledge to date regarding incretin receptors and incretin drug actions in the PNS, as well as PNS control over incretin release, and the related implications for metabolic disease states that are accompanied by peripheral neuropathy.

We undertook this study to estimate the causal role of circulating branched-chain amino acids (BCAAs) in metabolic health using genetics. Are circulating BCAAs a cause or consequence of metabolic health? We found that a higher circulating level of BCAAs likely reflects poorer metabolic health. There is a potential bidirectional causal link between BCAAs and dyslipidemia that warrants further tissue-specific functional studies. Our findings suggest that BCAAs may causally affect lipid metabolism, with adipocytes as a key site. Understanding tissue-specific pathways of BCAA-induced lipid dysregulation could guide BCAAs' potential as a clinical intervention target.

FoxO1 and PPARα share significant DNA binding sites, regulating a coordinated transcriptional network in hepatic metabolism. FoxO1 and PPARα orchestrate distinct yet overlapping roles in gluconeogenesis and fatty acid/lipid metabolism. High-fat diet amplifies the metabolic interplay between FoxO1 and PPARα, with implications for insulin resistance management. Targeting the FoxO1-PPARα interplay offers novel strategies for treating selective insulin resistance and metabolic disorders.

Sodium-glucose cotransporter 2 inhibitors (SGLT2i) cause an increase in hepatic glucose production (HGP). We previously showed that SGLT2i cause a rapid (within 4 h) increase in the total-body norepinephrine (NE) turnover rate, which could explain the increase in HGP. Because the increase in HGP caused by SGLT2i is long-lasting, we examined the long-term effect of SGLT2i on the NE turnover rate. Empagliflozin caused a decrease in total-body NE turnover at 1 day and at 12 weeks after starting therapy, despite an increase in glucose production, and the magnitude of decrease in NE turnover inversely correlated with the increase in HGP caused by empagliflozin.

Hypercortisolism as a causative factor in the development of type 2 diabetes has received scant attention. Studies from Europe, South America, and the U.S. have demonstrated that a significant percentage of individuals with poorly managed type 2 diabetes, despite treatment with multiple glucose-lowering agents, have endogenous hypersecretion of cortisol as a causative factor for their hyperglycemia. In vivo and in vitro studies in animals and humans have demonstrated that excess exposure to glucocorticoids can promote insulin resistance in muscle, liver, and adipocytes and impair insulin secretion. We propose a reverberating cycle in which hypercortisolism disrupts the normal circadian rhythm causing insulin resistance and hyperinsulinemia, which in turn further disrupts the hypothalamic-pituitary-adrenal axis.

Metabolic and energy reprogramming significantly affects renal cell function in diabetic kidney disease (DKD). We developed unique metabolic mouse models with varying levels of lipoic acid synthase (Lias) gene expression and correspondingly varying levels of protein lipoylation and metabolic activity. Using these metabolic mouse models, our study demonstrates that increased protein lipoylation can alleviate DKD through metabolic and energetic regulation. Our unique metabolic mouse models can serve as a preclinical platform to evaluate new therapeutic strategies, ultimately guiding translational studies for patients with DKD.

Glucagon-like peptide-1 receptor agonists are promising therapies in treating various obesity-associated diseases; however, the mechanisms are convoluted with the benefits of weight loss. Dulaglutide has weight-independent therapeutic effects on the liver, reducing hepatic steatosis and improving liver function. Dulaglutide reduces de novo lipogenesis, lipid droplet stability, inflammation, and oxidative stress in the liver and lipolysis in adipose tissue. Weight loss may play an important role in glucagon-like peptide-1 receptor agonists' effect on decreasing coronary vascular disease risk.

Current research and development are ushering in a new era of novel islet β-cell replacement therapies that can no longer be considered solely a rescue treatment for those with unstable glucose management. Clinical trial design must ensure that the application of islet β-cell replacement is broadened beyond the indication of severe hypoglycemia given the potential for establishing insulin-independent normoglycemia. It is imperative that people with type 1 diabetes and their clinicians are at the center of the risk-benefit equipoise as evidence for the safety of cellular products, transplant sites, and immune protection strategies accumulates and an increasing number of options for intervention become available.

The dorsal raphe nucleus (DRN) is a key regulator of food intake and body weight. The DRN has historically been associated with feeding, as it houses the single largest population of serotonergic neurons in the mammalian brain. Few studies have demonstrated a direct role for DRN serotonergic neurons in regulating feeding; none of these studies have demonstrated effects near those elicited by serotonin, itself. There are many nonserotonergic cell types in the DRN that play an integral role in feeding. These DRN cell types play important roles in both hunger and satiation.

The underlying molecular pathogenesis of the Asian phenotype of insulin resistance remains to be understood. We carried out metabolic phenotyping of study participants without diabetes according to insulin sensitivity indices derived from hyperinsulinemic-euglycemic clamp procedures. We identified lipidomic signatures of insulin resistance and metabolic plasticity. These lipidomic signatures have the potential to help in risk stratification of insulin resistance and metabolic dysfunction for early intervention.

Sarcopenic obesity, a subtype of obesity, is marked by reduced skeletal muscle mass and function, or sarcopenia, and poses a significant health challenge to older adults as it affects an estimated 28.3% of people aged >60 years. This subtype is unique to older adults as aging exacerbates sarcopenia and obesity due to changes in energy metabolism, hormones and inflammatory markers, and lifestyle factors. Traditional treatments for sarcopenic obesity have been focused on exercise and dietary modifications to reduce fat while maintaining muscle mass. Newer glucagon-like peptide 1 receptor agonists (GLP-1RA) and dual gastric inhibitory polypeptide/GLP-1 receptor agonists (GIP/GLP-1RAs), including liraglutide, semaglutide, and tirzepatide, have shown great promise to reduce weight, treat obesity-related complications, improve physical function, and improve quality of life, in younger clinical trial populations. However, the use of GLP-1RAs and GIP/GLP-1RAs has not been exhaustively evaluated in older adults with sarcopenic obesity. These medications come with the risk of loss of muscle mass and an increased rate of adverse events. Thus, clinicians should use them cautiously by weighing the potential benefits against their risks. Herein, we discuss a possible approach to using GLP-1RAs and GIP/GLP-1RAs in patients with sarcopenic obesity, including considerations for patient identification, monitoring, maintenance, and discontinuation. In this article we also discuss the emerging treatments that will be available, which may include activin type II receptor antibodies and selective androgen receptor agonists. We conclude by highlighting the advancement of geroscience as a promising field for individualizing treatments in the future.

Although imeglimin promotes β-cell proliferation and ameliorates β-cell apoptosis, the detailed metabolic changes induced by imeglimin in β-cells are unknown. Imeglimin increases adenylosuccinate (S-AMP), which is produced by adenylosuccinate synthase (ADSS) from inosine monophosphate and aspartate, and imeglimin also increases amino acid content, including aspartate, in mouse islets. Inhibition of S-AMP production by an ADSS inhibitor reduces the ability of imeglimin to increase β-cell proliferation and ameliorate β-cell apoptosis in mouse islets, human islets, porcine islets, and human pluripotent stem cell-derived β-cells. Imeglimin increases S-AMP to promote β-cell proliferation and ameliorate β-cell apoptosis.

The present study reveals a previously unknown molecular mechanism linking prediabetes to neurodegeneration, addressing a critical gap in understanding metabolic-neurological interplay. We investigated whether PTP1B mediates prediabetes-induced cognitive impairment. PTP1B impaired synaptic signaling and synaptic ultrastructure in hippocampal neurons, contributing to cognitive decline in prediabetes. PTP1B is a novel therapeutic target for prediabetes-associated neurodegeneration.

Cerebral microvascular disease can be triggered in people with diabetes who have chronic hyperglycemia. The aim of our study was to understand what effect diabetes has on the cerebral vasculature. In a rodent model, diabetes caused varying degrees of reduced cerebral vascular density and slowed cerebral blood flow in the brain striatum, basal forebrain, thalamus, hypothalamus, and hippocampus. There is a correlation between vessel density and blood flow velocity and the correlation changes in the diabetic state.

We aimed to explore sustainability of lowered glycated hemoglobin (HbA1c) and weight with tirzepatide in a post hoc analysis. The question we wanted to answer was what predicted achieving and sustaining HbA1c and weight reduction in A Study of Tirzepatide (LY3298176) Once a Week Versus Insulin Glargine Once a Day in Participants With Type 2 Diabetes and Increased Cardiovascular Risk (SURPASS-4). We found greater weight loss and improved β-cell function were the main predictors for sustained glycemic control with tirzepatide therapy. No clinically relevant predictor was identified for sustained weight loss. Simple clinical measures may predict initial and sustained glycemic control and initial weight loss with tirzepatide.

Type 1 diabetes-associated autoimmune mechanisms have not been thoroughly examined in pancreatitis-associated diabetes. We assessed the prevalence of four islet autoantibodies in serum from a large prospective cohort of patients with acute, recurrent acute, or chronic pancreatitis. Diabetes was present in 11 (12%) of 94 participants with acute pancreatitis, 69 (27%) of 273 with recurrent acute pancreatitis, and 235 (43%) of 560 with chronic pancreatitis. Excluding those with only insulin autoantibody positivity, which is confounded by insulin treatment, islet autoantibodies were identified in 51 (5.5%) of 927 participants, and 30 (3.2%) of 297 were positive for two or more autoantibodies. Our findings suggest pancreatitis may elicit islet autoimmunity in a subset of patients, necessitating prospective longitudinal follow-up.

High-quality weight loss, i.e., a high proportion of fat to skeletal muscle lost during the treatment of obesity, is advantageous for metabolic and physical health. Precise and accurate determinations of skeletal muscle mass in clinical settings are often challenging. In prevention of excessive loss of skeletal muscle during weight loss, advantages include minimization of metabolic adaptation that makes it difficult to sustain weight loss, improved glucose homeostasis and metabolic flexibility, and better mobility and strength. Effective approaches to preserving skeletal muscle include sufficient dietary protein and inclusion of exercise (especially resistance exercise) during weight loss; new pharmacological approaches are under development.

The primary treatment for obesity involves calorie restriction (CR) to promote dietary weight loss achieved through interventions including behavioral modification, bariatric surgery, and antiobesity medications. In adults with obesity, CR-induced weight loss enhances physical function and improves quality of life, while also reducing the burden of various obesity-related chronic conditions, including hypertension, diabetes, obstructive sleep apnea, and atherosclerotic heart disease. However, it is also associated with a decline in lean mass and bone mineral density, which increases the risk of sarcopenia and osteoporosis. When performed alongside CR, progressive resistance training (RT) attenuates this loss of lean mass and bone mass, while the addition of aerobic training (AT) further improves cardiorespiratory fitness. The individual benefits of RT and AT are complementary, and combining both exercise training modalities during CR provides the most optimal benefits for body composition and physical function. The World Health Organization recommends that adults engage in at least 150 min of moderate-intensity or 75 min of vigorous-intensity AT weekly and participate in RT activities involving major muscle groups at least 2 days per week. While this recommendation applies to the general adult population, regular exercise training that incorporates both RT and AT is particularly crucial for adults with obesity undergoing weight loss interventions. This clinical perspective highlights the benefits of exercise training alongside current weight loss strategies, such as lifestyle changes, bariatric surgery, and pharmacotherapy, with a focus on incretin-based therapies.

Roux-en-Y gastric bypass improves glycemic control in patients with type 2 diabetes, but the impact of the improved glycemic control on β-cell sensitivity to glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic peptide (GIP) is sparsely described. GLP-1 and GIP potentiated insulin secretion during clamped hyperglycemia before and after surgery, but, when related to the response to glucose alone, the relative potentiating effects of GIP (on first-phase insulin secretion) and GLP-1 (on first- and second-phase insulin secretion) were reduced postoperatively. The improvement in β-cell function after Roux-en-Y gastric bypass in patients with type 2 diabetes is not driven by improved β-cell sensitivity to incretins but rather other factors, including improved β-cell sensitivity to the changed glucose response and exaggerated postprandial GLP-1.

Vesicle-associated membrane protein 8 (VAMP8) localizes to endosomal vesicles and mediates their exocytosis in pancreatic β-cells. VAMP8-dependent vesicle fusion delivers glucagon-like peptide 1 receptor and GLUT2 to the plasma membrane. VAMP8 overexpression inhibits insulin granule exocytosis. "Newcomer" exocytosis likely involves endosomal compartments, not insulin granules.