The intestinal farnesoid X receptor (FXR)/fibroblast growth factor 19 (FGF19) axis is involved in maintaining glucose homeostasis and gut barrier function in animals. Do individuals with prediabetes and type 2 diabetes exhibit a compromised intestinal FXR/FGF19/barrier integrity axis? Can obeticholic acid (OCA) treatment counteract diabetes-related gut mucosa dysfunction? A downregulation of ileal FXR/FGF19/tight-junctions signaling occurs in individuals with hyperglycemia. OCA-mediated FXR activation reverts diabetes-related alterations. OCA-mediated intestinal FXR activation in individuals with hyperglycemia may represent a strategy for restoring FGF19 synthesis with positive effects on gut barrier.

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 GIP and 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.

Evidence of retinal vascular inflammation accompanies diabetic retinopathy (DR) progression, and inflammatory cytokines TNFα and IL-1β are experimentally linked to several hallmark DR features, including retinal leukostasis. Cannabinoid receptor 2 (CB2) agonism has been shown to decrease inflammatory cytokine production and leukocyte recruitment and adhesion in nonocular inflammation models, suggesting CB2 agonism could have therapeutic potential in DR. We tested the efficacy of two CB2-selective agonists, HU-308 and CB65, to attenuate leukocyte adhesion to human retinal microvascular endothelial cells (hRMEC) in response to diabetes-relevant inflammatory stimuli and to the walls of retinal capillaries in murine models of DR. In vitro, HU-308 and CB65 significantly reduced TNFα-induced and IL-1β-induced gene expression of the adhesion molecules ICAM1, VCAM1, and SELE and protein expression of ICAM-1 and VCAM-1 in hRMEC. Additionally, HU-308 and CB65 inhibited TNFα-induced and IL-1β-induced leukocyte adhesion to hRMEC monolayers, aligning with their effects on adhesion protein levels. HU-308 and CB65 reduced TNFα-induced and IL-1β-induced nuclear factor κB translocation and activation, suggesting downstream mechanisms of CB2 receptor activation. In vivo, both intraocular and systemic HU-308 administration significantly decreased retinal leukostasis in cytokine-induced inflammation and streptozotocin-induced diabetes. Therefore, CB2 agonism demonstrates potential for mitigating leukostasis and its pathogenic consequences in 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 in young children. We performed a longitudinal study using brain MRI (diffusion tensor imaging) and cognitive assessments in 4- to 9-year-old children, control participants without diabetes (n = 71) and with type 1 diabetes (n = 143), plus continuous glucose monitoring, to assess changes at four time points as children grow over 6-8 years. White matter myelination and fiber integrity were assessed using axial diffusivity, which was decreased in the diabetes versus control group, less so during puberty, and fractional anisotropy was reciprocally related to hyperglycemia. Data suggest continued negative impact of chronic hyperglycemia in the developing brain.

Administration of the gut hormone glucose-dependent insulinotropic polypeptide (GIP) increases splanchnic blood flow. We investigated the role of endogenous GIP in splanchnic blood flow regulation using a receptor antagonist in humans. Oral glucose ingestion increased blood flow in the superior mesenteric artery by ∼70%, and the increase was significantly lower during concurrent infusion of the GIP receptor antagonist. Thus, endogenous GIP contributed ∼22% of the postprandial increase in superior mesenteric artery blood flow. We have identified a novel physiological aspect of vascular biology related to the GIP receptor in humans. Treatments targeting the GIP receptors are likely to affect splanchnic blood flow.

Instant blood-mediated inflammatory reactions (IBMIRs) and low extracellular matrix (ECM) concentrations hinder islet implantation and survival in the spleen. Islets were encapsulated in hepatocytes and fibroblasts. The low expression of von Willebrand factor in hepatocytes enables them to form a protective coating with fibroblasts. This coating reduces IBMIRs and supports islet survival through ECM production by fibroblasts. The hepatocyte-fibroblast encapsulation significantly reduces islet mortality during the posttransplantation stress period, enabling rapid engraftment and vascularization in the spleen.

This study was conducted to assess splanchnic and leg glucagon metabolism in humans using stable glucagon isotopes. We wanted to evaluate whether splanchnic and leg glucagon metabolism differed between participants with no diabetes (ND) and those with type 1 diabetes (T1D) at glucagon concentrations spanning the physiological range. Whereas splanchnic glucagon extraction did not differ between participants with ND and those with T1D, leg glucagon extraction fell in those with ND but did not change in those with T1D as glucagon concentrations increased. Net splanchnic glucagon production did not change with exogenous glucagon infusion. Our study has implications for dual hormone closed loop control in T1D where glucagon is infused for prevention of hypoglycemia and for investigating the effects of emerging GLP-1, glucose-dependent insulinotropic polypeptide, and glucagon receptor agonists on endogenous glucagon secretion and clearance.

We aimed to develop a dual-targeted mRNA-based therapy to address both neural degeneration and vascular insufficiency in diabetic peripheral neuropathy. We identified NGFR100W as a mutation that enhances neuritogenic activity without pain sensitization and investigated its transcriptome to explore its ability to uncouple neuroprotective and nociceptive pathways. Combination therapy using lipid nanoparticles for codelivery of NGFR100W and VEGFA mRNA improved blood flow, increased microvessel formation, and preserved nerve function in a diabetic mouse model. This approach, which combines structure-based design and mRNA therapy, offers a novel strategy for decoupling protein functions and developing therapeutic molecules with specific functionalities.

The effects of acute atmospheric pressure changes on glucose metabolism in type 1 diabetes remain controversial and may have safety implications for pilots and travelers alike. What are the differences in glucose kinetics and hormones between ground and simulated flight environments? Glucose disposal and insulin concentration are increased in response to a meal during flight, without associated changes in endogenous glucose production or meal glucose appearance rates. Pressure-related changes in insulin pump performance and hypoxia may explain these findings. Because glucose concentrations were unaffected, there is no evidence that insulin pump therapy is a risk factor in flight.

Individuals with type 1 diabetes (T1D) have a markedly smaller pancreas, but the mechanism responsible for the reduction in size is unknown. How pancreas volume differs in individuals with specific forms of monogenic diabetes and how pancreas volume relates to the severity of insulin deficiency are unknown. Measured by MRI, individuals with permanent neonatal diabetes due to an INS gene mutation (INS-PND) or the HNF1B gene associated with maturity onset diabetes of the young had smaller pancreas than individuals without diabetes. Across all types of monogenic diabetes, individuals receiving insulin replacement therapy had smaller pancreas than individuals not using insulin. These results support the conclusion that insulin deficiency is a major factor contributing to changes in pancreas volume in T1D, INS-PND, and other forms of monogenic diabetes.