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Body fat distribution is a predictor of metabolic health in obesity. In this Classics in Diabetes article, we revisit a 1985 Diabetes article by Swedish investigators Ohlson et al. This work was one of the first prospective population-based studies that established a relationship between abdominal adiposity and the risk for developing diabetes. Here, we discuss evolving concepts regarding the link between regional adiposity and diabetes and other chronic disorders. Moreover, we highlight fundamental questions that remain unresolved ..read more

I recently read the article by Ren et al. (1) and think it is valuable work but could have gone further in investigating glucokinase variant-induced maturity-onset diabetes of the young (GCK-MODY). The authors are to be commended for their use of a cross-sectional case-control study design to compare glucose control for participants with GCK-MODY, type 2 diabetes, and normal glucose tolerance (25 participants per group) using masked glucose readings and encouraging others to further this work. The authors showed that GCK-MODY and type 2 diabetes could be differentiated on the basis of glu ..read more

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The beneficial effects of sodium–glucose cotransporter 2 (SGLT2) inhibitors on kidney function are well-known; however, their molecular mechanisms are not fully understood. We focused on 78-kDa glucose-regulated protein (GRP78) and its interaction with SGLT2 and integrin-β1 beyond the chaperone property of GRP78. In streptozotocin (STZ)-induced diabetic mouse kidneys, GRP78, SGLT2, and integrin-β1 increased in the plasma membrane fraction, while they were suppressed by canagliflozin. The altered subcellular localization of GRP78/integrin-β1 in STZ mice promoted epithelial mesenchymal transitio ..read more

Nonalcoholic fatty liver disease (NAFLD) is considered a risk factor for cardiovascular and cerebrovascular disease owing to its close association with coagulant disturbances. However, the precise biological functions and mechanisms that connect coagulation factors to NAFLD pathology remain inadequately understood. Herein, with unbiased bioinformatics analyses followed by functional testing, we demonstrate that hepatic expression of coagulation factor VII (FVII) decreases in patients and mice with NAFLD/nonalcoholic steatohepatitis (NASH). By using adenovirus-mediated F7-knockdown and hepatocy ..read more

Increasing evidence implicates chronic inflammation as the main pathological cause of diabetic nephropathy (DN). Exploration of key targets in the inflammatory pathway may provide new treatment options for DN. We aimed to investigate the role of Src homology 2–containing protein tyrosine phosphatase 2 (SHP2) in macrophages and its association with DN. The upregulated phosphorylation of SHP2 was detected in macrophages in both patients with diabetes and in a mouse model. Using macrophage-specific SHP2-knockout (SHP2-MKO) mice and SHP2fl/fl mice injected with streptozotocin (STZ), we showed that ..read more

Type 1 diabetes (T1D) is an autoimmune disease in which pathogenic lymphocytes target autoantigens expressed in pancreatic islets, leading to the destruction of insulin-producing β-cells. Zinc transporter 8 (ZnT8) is a major autoantigen abundantly present on the β-cell surface. This unique molecular target offers the potential to shield β-cells against autoimmune attacks in T1D. Our previous work showed that a monoclonal antibody (mAb43) against cell-surface ZnT8 could home in on pancreatic islets and prevent autoantibodies from recognizing β-cells. This study demonstrates that mAb43 binds to ..read more

Reactive oxygen species (ROS) are formed by virtually all tissues. In normal concentrations they facilitate many physiologic activities, but in excess they cause oxidative stress and tissue damage. Local antioxidant enzyme synthesis in cells is regulated by the cytoplasmic KEAP-1/Nrf2 complex, which is stimulated by ROS, to release Nrf2 for entry into the nucleus, where it upregulates antioxidant gene expression. Major antioxidant enzymes include glutathione peroxidase (GPx), catalase (CAT), superoxide dismutases (SOD), hemoxygenases (HO), and peroxiredoxins (Prdx). Notably, the pancreatic isl ..read more

Bile acids (BAs) are pleiotropic regulators of metabolism. Elevated levels of hepatic and circulating BAs improve energy metabolism in peripheral organs, but the precise mechanisms underlying the metabolic benefits and harm still need to be fully understood. In the current study, we identified orosomucoid 2 (ORM2) as a liver-secreted hormone (i.e., hepatokine) induced by BAs and investigated its role in BA-induced metabolic improvements in mouse models of diet-induced obesity. Contrary to our expectation, under a high-fat diet (HFD), our Orm2 knockout (Orm2-KO) exhibited a lean phenotype compa ..read more