Category: Diabetes

β-Cell maladaptive unfolded protein response is a shared pathogenic feature of type 1 and type 2 diabetes, yet therapeutic strategies that selectively restore β-cell proteostasis remain limited. Zinc transporter 8 (ZnT8) is an islet-restricted endoplasmic reticulum (ER)–resident membrane protein whose folding burden is amplified under inflammatory stress. Here, we show that cell surface–directed ZnT8 antibodies […]

Glucose-dependent insulinotropic polypeptide (GIP) promotes nutrient storage, but its vascular actions in skeletal muscle remain unclear. To determine whether GIP regulates muscle microvascular perfusion, a key determinant of substrate use, we examined GIP receptor (GIPR) expression in vascular endothelium and assessed GIP effects in vivo in chow-fed and high-fat diet (HFD)–fed rats. Overnight-fasted rats received 120-min […]

Endothelial dysfunction contributes to the pathogenesis and progression of diabetes and atherosclerotic cardiovascular diseases (ASCVDs) with sirtuin-6 (SIRT6) downregulation in vascular endothelial cells (ECs). Here, the effects and underlying mechanisms of SIRT6 as a deacetylase were investigated in maintaining EC integrity against diabetes-exacerbated atherogenesis. SIRT6 downregulation was exacerbated in carotid artery ECs of Apoe−/− mice […]

Type 1 diabetes is driven by both β-cell dysfunction and an autoreactive immune system, resulting in β-cell destruction and hyperglycemia. We previously showed that pharmacological modulation of prostaglandin E2 (PGE2) receptor (EP) signaling protects β-cells from cytokine-mediated death ex vivo and relieves oxidative stress and maintains β-cell identity in a mouse model of type 2 […]

The intraislet heparan sulfate (HS) barrier is essential for β-cell survival, yet its role in type 1 diabetes (T1D) remains incompletely understood. We investigated the expression pattern, pathogenic function, and therapeutic potential of the heparanase (HPSE)-HS axis in T1D by integrating single-cell RNA sequencing data sets from human and mouse islets and peripheral immune cells, […]

Hyperglycemia is a hallmark of type 2 diabetes and a key pathogenic driver of diabetes complications. Cullin RING E3 ligases (CRLs) are multisubunit E3 ubiquitin ligases that mediate cellular protein turnover. The activity of CRLs requires cullin neddylation, a posttranslational modification that can be pharmacologically targeted with therapeutic potentials. By using hyperinsulinemic-euglycemic clamp analysis, we […]

Proinflammatory T helper 1 (Th1) CD4 T cells orchestrate β-cell destruction in type 1 diabetes (T1D) by using glycolysis for effector responses. By targeting T-cell metabolism, we may identify novel mechanisms and therapies to effectively delay T cell–mediated autoimmune diseases like T1D. We hypothesized that treatment of prediabetic mice with the glycolysis inhibitor, 2-deoxyglucose (2-DG), […]

Excess adiposity is associated with insulin resistance and pancreatic β-cell dysfunction. We show that palmitoylation cycling in white adipose tissue (WAT) balances insulin sensitivity and insulin secretion. WAT and brown adipose tissue (BAT) ablation of acyl-protein thioesterase 1 (APT1) in APT1-deficient (knockout) mice (APT1-AdipoKO) resulted in increased body weight and exacerbated insulin resistance when the […]

Immunosenescence, characterized by functional decline and altered phenotypes of immune cells with age, can disturb immune tolerance and promote autoreactive responses. Type 1 diabetes (T1D) has traditionally been viewed as a disease of immune dysregulation that leads to the autoimmune destruction of pancreatic β-cells. Emerging evidence suggests that senescence contributes to both the onset and […]