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.

Liver-expressed antimicrobial peptide 2 (LEAP2) is an endogenous ghrelin receptor (GHSR) antagonist and inverse agonist, and represents a novel strategy to modulate the GHSR system for treatment of cardiometabolic disease. A long-acting LEAP2 (LA-LEAP2) analog induces significant weight reduction in rodent models without causing aversion. LA-LEAP2-mediated weight loss is driven by decreased energy intake alongside preservation of energy expenditure during weight loss. Combined LA-LEAP2 and semaglutide therapy supports durable weight loss, addressing a critical gap in obesity treatment.

Fasting is associated with increased risk of hypoglycemia in patients with type 1 diabetes (T1D); however, little is known about how the counterregulatory responses to low blood sugar are affected under these metabolic conditions. During insulin-induced hypoglycemia, fasting (compared with eating normal meals for breakfast and lunch) glucagon concentrations were lower by 42% and endogenous glucose production by 47% in individuals with T1D. The secretion of other counterregulatory hormones during hypoglycemia was not affected by fasting (e.g., epinephrine, norepinephrine, cortisol). Fasting diminishes glucagon levels under hypoglycemic conditions in those with T1D, which may increase their susceptibility to hypoglycemia.

It has been hypothesized that dietary proteins act as environmental factors in type 1 diabetes pathogenesis. This study investigated whether gliadin-specific T cells are present in the small intestine of children with type 1 diabetes, without or with celiac disease comorbidity. No sign of gliadin-reactive T cells, either proinflammatory or regulatory, was observed in the gut mucosa of children with type 1 diabetes negative for celiac disease autoimmunity. Interferon-γ-producing T cells were detected in gut mucosa biopsy specimens of children with diabetes seropositive for antitissue transglutaminase antibodies. Our study does not support a pathogenic role of intestinal T cell-mediated immunity to gluten in type 1 diabetes pathogenesis.

Abnormal glucose tolerance (AGT) in youth has become an alarming global public health issue; however, approaches to identify high-risk population among young people have not been well-established. Can the long-term risk of AGT be stratified by the subclasses of glucose trajectories defined in childhood? Subclasses defined in childhood can efficiently stratify the risk of AGT in adolescence and young adulthood. The subclass membership was strongly associated with cardiometabolic disorders in childhood and maternal cardiometabolic disorders during pregnancy. This subclass method provides a potential strategy to identify those at risk of later cardiometabolic disorders from childhood for more intensive evaluation of intervention. The close relationship between maternal cardiometabolic disorders and subclass membership of children highlighted the potential influence of gestational cardiometabolic health on the development of cardiometabolic disorders in offspring.

Understanding the role of micropeptides (miPs) in metabolic regulation could enhance insights into metabolic diseases and open new pathways for treatment. Small integral membrane protein 30 (Smim30), an adipose tissue macrophage-expressed miP, maintains insulin sensitivity and safeguards systemic metabolic homeostasis. Smim30 modulates inflammatory responses and macrophage-adipocyte communication in adipose tissue. Smim30 could serve as a potential diagnostic biomarker and therapeutic target for metabolic disorders.

The farnesoid X receptor (FXR)-fibroblast growth factor 19 (FGF19) axis is involved in maintaining glucose homeostasis and gut tight-junction (TJ) integrity. We evaluated whether individuals with prediabetes or type 2 diabetes (T2D) have altered intestinal FXR-FGF19 signaling and barrier function and whether high-glucose (HG) exposure may cause these aberrations. Moreover, we tested beneficial effects of the FXR agonist obeticholic acid (OCA) on intestinal FXR signaling in individuals with prediabetes or T2D. Included were 60 individuals with different glucose tolerance (normal glucose tolerance [NGT; n = 25], prediabetes [n = 19], or T2D [n = 16]) who underwent ileocolonoscopy with collection of ileal mucosa biopsy specimens, which were used for expression profiling analysis of the FXR/FGF19/TJ axis and tissue culture experiments. Individuals with prediabetes or T2D displayed lower ileal levels of FXR and its target genes FGF19 and TJ proteins zonula, occludens-1, occludin, and claudin-1, along with increased proinflammatory nuclear factor-κB (NF-κB) activity and cytokines expression compared with those with NGT. HG exposure on ileal explants collected from NGT individuals hampered the FXR/FGF19/TJ axis. OCA treatment on ileal fragments of individuals with prediabetes/T2D was able to restore FGF19 synthesis and secretion, TJ expression, and counteract NF-κB activity and cytokines expression. In conclusion, OCA treatment counteracts T2D-related intestinal abnormalities in the FXR/FGF19/TJ axis.

The diabetic heart has reduced ketone utilization due to impaired ketolytic enzyme activity. In a randomized controlled crossover trial, we investigated whether the cardiac response to 3-hydroxybutyrate infusion is impaired in type 1 diabetes. The response on cardiac output was blunted by 80% in type 1 diabetes, with no improvement in systolic function and left ventricular work efficiency was reduced. These findings suggest impaired cardiac ketone metabolism may have clinical significance and could contribute to diabetic cardiomyopathy.

This study was undertaken to establish a temporal link between an increase in intracellular Ca2+ concentration and the loss of pancreatic β-cell identity. We profiled the alterations in Ca2+ dynamics and gene transcription that occur in freshly isolated islets following membrane depolarization. We show that initially adaptive Ca2+-dependent transcription changes, mediated largely by CREB and CREB-dependent transcription factors, rapidly become maladaptive, causing the loss of β-cell identity and function. We also show that many effector genes linked to nearby human type 2 diabetes susceptibility loci are regulated by Ca2+-dependent mechanisms.

In combatting the obesity crisis, leveraging mechanisms that lower body weight is critical. The finding that treatment with tirzepatide, a glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide 1 (GLP-1) receptor agonist, produces profound weight loss highlights the value of activating the incretin receptors. Supporting this, recent studies have revealed mechanisms by which GIP receptor (GIPR) activation is beneficial in pancreatic islets, the central nervous system (CNS), and adipose tissue. Paradoxically, a hypothesis has emerged that GIPR antagonism could be an additional option in treating obesity. This concept stems from concern that GIP facilitates lipid uptake and storage in adipose tissue, although the lipid-buffering capacity of adipocytes versus other cell types is metabolically favorable. In this article, we highlight the natural physiology of the incretins, noting GIP as the primary incretin. In the CNS, GIPR agonism attenuates nausea and suppresses appetite, features that also help GLP-1 receptor agonism promote a negative energy balance. Further, we provide rationale that, in protecting against ectopic fat distribution and augmenting substrate utilization to promote insulin sensitivity, GIPR activity in adipose tissue is advantageous. Collectively, these attributes support GIPR agonism in the treatment of obesity and metabolic disease.

Current and emerging strategies to therapeutically target weight management include pairing agonism of the glucagon-like peptide 1 receptor (GLP-1R) with either agonism or antagonism of the glucose-dependent insulinotropic polypeptide receptor (GIPR). On the surface, these two approaches seem contradictory, yet they have produced similar effects for weight loss in clinical studies. Arguments that support the rationale for both approaches are made in these point-counterpoint articles, founded on preclinical studies, human genetics, and clinical outcomes. Here, we attempt to reconcile how two opposing approaches can produce similar effects on body weight by evaluating the leading hypotheses derived from the available evidence.

Obesity is a prevalent disease that also contributes to the incidence and severity of many other chronic diseases and health conditions. Treatment approaches include lifestyle intervention, bariatric surgery, and pharmacological approaches, with glucagon-like peptide 1 (GLP-1) receptor agonists approved specifically for weight loss having changed the treatment landscape significantly in the last 5 years. Targeting the glucose-dependent insulinotropic polypeptide (GIP) receptor may enhance the metabolic benefits of GLP-1 receptor agonism. These beneficial effects are seen with both GIP receptor antagonism and GIP receptor agonism, although the mechanisms underlying this apparent paradox remain unknown. Here, we summarize the physiologic, genetic, and clinical evidence for pursuing GIP receptor antagonism to achieve metabolic and weight benefits. Both global and central nervous system knockout of GIP receptors protects mice fed a high-fat diet from obesity and insulin resistance. Genome-wide association studies in humans support this notion, correlating lower BMI with GIP receptor genetic variants with reduced function. Pharmacologic approaches in mice and monkeys confirm that GIP receptor antagonism enhances GLP-1-induced weight reduction and other metabolic benefits, and a phase 1 study provides proof of principle that beneficial effects extend to humans. GIP receptor antagonism may represent an important new mechanism to expand the treatment options available to individuals living with obesity.

An effective treatment strategy for early-stage diabetic retinopathy (DR) could delay or prevent disease progression and limit or eliminate irreparable retinal damage and vision loss associated with progression to later stages of DR. Cannabinoid receptor 2 (CB2) activation strategies may provide a promising therapeutic approach to address the chronic retinal inflammation that encourages DR progression. CB2 activation therapeutically addresses leukocyte binding in human retinal microvascular endothelial cells and retinal leukostasis in diabetic mice, presumably by inhibiting nuclear factor κB-dependent transcription of adhesion molecules VCAM-1 and ICAM-1. CB2 agonism constitutes a rational therapeutic approach for clinical application to patients with early-stage DR.