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.

Senescence is a β-cell stress response in type 1 diabetes (T1D), the origins of which are not understood. We wanted to determine the role of the T cell-mediated autoimmune process in β-cell senescence during T1D. In the nonobese diabetic mouse model, β-cell senescence largely depended on damage inflicted by autoreactive CD4+ and CD8+ T cells during the development of T1D. Chronic exposure to sublethal doses of proinflammatory cytokines associated with the diabetogenic process was sufficient to elicit stable senescence phenotypes in human islets in culture. Our findings suggest that autoreactive T cells trigger not only β-cell death but also β-cell senescence, potentially via cytokine-dependent mechanisms in T1D. This finding has implications for understanding the mechanisms of action and beneficial impacts of immunotherapy using CD3 antibodies in T1D.

Type 1 diabetes has detrimental effects in white matter microstructure. In a longitudinal study, we investigated whether these reported findings change as children grow and enter puberty. At study entry, there were 143 children with type 1 diabetes and 71 control participants without diabetes, 4-9 years old. Brain MRI using diffusion tensor imaging, neurocognitive, and glycemic assessments were performed four times across 6-8 years of follow-up. Longitudinal mixed-effects modeling was used to examine changes in fractional anisotropy (FA), axial diffusivity (AD) (measures of myelination and fiber integrity), radial diffusivity (RD) (axonal leakage), and mean diffusivity (MD) (average diffusion). Associations with glycemic and cognitive measures were assessed. We observed in 182 children (121 type 1 diabetes vs. 61 control participants) who had testing at time 4 that FA increased, and RD, AD, and MD decreased significantly in both groups, with no differences between groups for FA, RD and MD over time. However, children with diabetes had lower AD than control participants at 6-10 years. Differences were not detected at 12 years (age imputed from data), when in puberty. Higher blood glucose levels are associated with lower FA and higher RD and MD. Higher glucose percentage time-in-range was associated with higher FA, reflecting better fiber integrity and myelination and higher cognitive metrics. Within the diabetes group, AD and MD showed no association with neurocognitive outcomes. In summary, white matter AD was decreased in children with diabetes, less so during puberty, and FA was reciprocally related to hyperglycemia. These data suggest continued negative impact of chronic hyperglycemia in the developing brain.

Gastrointestinal hormones are essential for nutrient handling and regulation of glucose metabolism and may affect postprandial blood redistribution. In a randomized cross-over design in 10 healthy men, the involvement of glucose-dependent insulinotropic polypeptide (GIP) in splanchnic blood flow regulation was investigated using an infusion of GIP receptor antagonist (GIPR-An) GIP(3-30)NH2 during ingestion of oral glucose (75 g). In five separate sessions, we investigated GIP(1-42), GIPR-An with and without oral glucose, oral glucose alone, and a control saline infusion. Blood flow was assessed by phase contrast MRI, hepatic oxygen consumption by T2*, and plasma glucose, insulin, C-peptide, glucagon, GIP, GIPR-An, glucagon-like peptide 2, and bone metabolism markers by frequent blood sampling during all sessions. We found GIP(1-42) to stimulate blood flow in the superior mesenteric artery by ∼10% in the fasting state. Oral glucose alone increased mean blood flow in the superior mesenteric artery by ∼70% and portal vein by ∼40% of baseline. During oral glucose ingestion with concurrent infusion of GIPR-An, blood flow in the superior mesenteric artery was ∼22% lower. The hormone infusions did not affect blood flow in the hepatic artery and the celiac artery. Infusion of GIPR-An during oral glucose ingestion resulted in lower insulin secretion and higher levels of carboxy-terminal collagen crosslinks (bone resorption biomarker) compared with saline infusion, whereas glucagon levels were unaffected by both the injection of GIP and the GIPR-An infusions. We conclude that endogenous GIP increases splanchnic blood flow and contributes to postprandial intestinal hyperemia in healthy men.

Intraportal islet transplantation to treat insulin-dependent diabetes has been clinically validated. However, the hypoxic environment and sinusoidal architecture of the liver are unsuitable for the long-term survival of transplanted islets, leading to the loss of therapeutic effects within 1 year. The spleen has oxygen levels that meet islet needs, but intense instant blood-mediated inflammatory reactions (IBMIRs) and low extracellular matrix (ECM) concentrations hinder islet engraftment and survival. In this study, we developed constructs of islets encapsulated by hepatocytes and fibroblasts. The hepatocytes and fibroblasts create a protective coating that reduces IBMIRs because of the low expression of von Willebrand factor in hepatocytes and supports normal islet survival through ECM production by fibroblasts. These constructs can be easily injected into the mouse spleen. The hepatocyte-fibroblast encapsulation significantly reduces islet mortality during the posttransplantation stress period, enabling rapid engraftment and vascularization in the spleen. The high-oxygen environment of the spleen then supports long-term (>1 year) islet survival and sustained glycemic regulation. Additionally, this method significantly lowers the critical islet dose required for transplantation. The live cell-shielding strategy developed in this study represents a novel approach in islet transplantation and functional regeneration, demonstrating promising clinical potential.

Circulating glucagon concentrations differ between individuals with no diabetes (ND) and those with type 1 diabetes (T1D). We combined an isotope dilution technique using stable tracers [6,22-13C9,15N1]glucagon and [6,14,19,22-13C9,15N1]glucagon with splanchnic and leg catheterization in participants with ND (n = 8; age 23.1 ± 2.9 years, BMI 26.6 ± 3.5 kg/m2, HbA1c 5.0 ± 0.2% [31 ± 2 mmol/mol]) and T1D (n = 6; 29.0 ± 8.8 years, BMI 26.3 ± 5.0 kg/m2, HbA1c 7.9 ± 0.8% [63 ± 8 mmol/mol]) in the overnight fasted state. After baseline period, exogenous glucagon was infused at rates designed to achieve plasma glucagon concentrations spanning the physiological ranges, to determine the effects of rising glucagon concentrations on splanchnic and leg glucagon balance. At baseline, splanchnic glucagon extraction (SGE) was similar (30.7 ± 2.7 vs. 29.1 ± 2.9%) but leg glucagon extraction (LGE) was lower (27.0 ± 4.2 vs. 40.6 ± 3.1%) in participants with T1D versus those with ND. However, with increasing plasma glucagon concentrations, while SGE remained unchanged within and between groups, LGE fell in participants with ND (41 vs. 31 vs. 24%) but did not change in those with T1D. Despite a numerically lower net splanchnic glucagon production in participants with T1D than in those with ND, no changes were observed with increasing glucagon concentrations within the physiological range in both groups. This is the first human study applying novel glucagon isotopes that describes regional glucagon metabolism in participants with ND and T1D. Our observations provide translational relevance for dual hormone closed-loop systems and provide tools for probing the effects of GLP-1, dual, and triple receptor agonists on pancreatic α-cell functions.

Diabetic peripheral neuropathy (DPN) poses significant clinical challenges due to progressive nerve degeneration and vascular insufficiency. To address both neural and vascular complications simultaneously, we employed an mRNA-based protein replacement therapy. In this study, leveraging mRNA template design, structure-based screening identified NGFR100W as a variant dissociating neuroprotective and nociceptive functions, demonstrating enhanced neuritogenic activity without pain sensitization. Additionally, transcriptome analysis of NGF mutants versus wild type further reveals the potential mechanism by which NGFR100W uncouples neuroprotective and nociceptive pathways. We cotransfected chemically modified NGFR100W mRNA and vascular endothelial growth factor A (VEGFA) mRNA, and the conditioned media collected from this transfection promoted endothelial cell migration, tubulogenesis, and neurite outgrowth. In a diabetic mouse model, combination therapy with lipid nanoparticle codelivery of NGFR100W and VEGFA mRNA significantly improved blood flow in the plantar region and mitigated nerve function decline compared with monotherapy. Histological analysis showed increased microvessel formation and higher intraepidermal nerve fiber density in treated mice. Our findings highlight the therapeutic potential of NGFR100W and VEGFA mRNA coadministration for DPN, suggesting that protein supplementation via mRNA could offer a novel strategy for clinical intervention in some chronic medical conditions.

The impact of atmospheric pressure changes on glucose metabolism encountered in aviation on people with type 1 diabetes is controversial. A dual-isotope study was performed in a hypobaric chamber to simulate pressure changes experienced on commercial flights. The fasting and postprandial glucose kinetics of individuals with type 1 diabetes were evaluated across simulated in-flight cabin pressures (550 mmHg; experimental arm) and ground level (750 mmHg; control arm). The impact of ambient pressure on glucose disposal (Rd), endogenous glucose production (EGP), meal glucose appearance (Ra), and insulin concentrations were evaluated. Six male participants, aged 20-61 years, with a median BMI of 26.6 kg/m2, were studied. Baseline glucose Rd, EGP, and meal Ra values were not affected by ambient pressure changes. Postprandial glucose Rd was higher in hypobaric conditions than ground, the percent change in postprandial glucose concentration was lower, but postprandial EGP and meal Ra were not affected. Insulin concentration between 120 and 180 min was higher in the hypobaric simulation. The observed increase in glucose Rd for individuals with type 1 diabetes who were using insulin pumps may be related to the hypoxia and pressure changes experienced during flight. Because glucose profiles were unaffected, there is no evidence that insulin pump therapy is a risk factor in flight.

Individuals with type 1 diabetes (T1D) or permanent neonatal diabetes (PND) due to an INS gene mutation (INS-PND) have a marked reduction in pancreas volume by MRI compared with control individuals with no diabetes (ND). One possible explanation for this is loss of islet-acinar insulin signaling in these forms of severe insulin deficiency. To test the hypothesis that insulin deficiency drives the loss of pancreas volume in diabetes, we used a standardized and validated MRI protocol to measure pancreas volumes in individuals with various forms of monogenic diabetes, including maturity-onset diabetes of the young (MODY) and PND (HNF4A-MODY, GCK-MODY, HNF1A-MODY, HNF1B-MODY, INS-MODY, or INS-PND; n = 37), and compared their pancreas volumes with those of previously reported individuals with T1D (n = 93) or healthy control participants with ND (n = 90). Across all monogenic diabetes groups, individuals receiving insulin therapy had significantly smaller pancreas volume compared with those not requiring insulin. These results support the hypothesis that insulin signaling to the exocrine pancreas determines pancreas volume in multiple types of diabetes.