Daily Endocrinology Research Analysis

Metabolic dysfunction-associated steatohepatitis (MASH) is an important phase in the progression of metabolic dysfunction-associated steatotic liver disease to end-stage liver diseases, posing an increasing threat to public health worldwide with limited treatment options. Here we show that GPR110 is a liver-selective G-protein-coupled receptor closely associated with MASH in a sex-specific manner. Hepatocyte-specific Gpr110 knockout protects against MASH in female, but not male mice. The GPR110 variant rs937057 T > C is associated with a higher prevalence of metabolic dysfunction-associated steatotic liver disease in women. The improved liver phenotypes in female mice are abrogated by knocking down the expression of hepatic oestrogen receptor alpha (Esr1). Mechanistically, GPR110 couples to Gα

BACKGROUND: Adiponectin, an adipocyte-derived protein, has diverse organ-protective effects, which are associated with its accumulation in vascular endothelial cells (VECs) as well as in various extravascular cell types, including skeletal muscle cells and cardiomyocytes. T-cadherin, a high-affinity binding partner for multimeric adiponectin, facilitates this accumulation; however, the mechanism by which high-molecular-weight (HMW) adiponectin transverses the endothelium remains unclear. METHOD AND RESULTS: We showed that tamoxifen-induced T-cadherin deficiency in VECs alone significantly increased plasma adiponectin levels, similar to inducible systemic T-cadherin deletion. The intravenous administration of adiponectin to adiponectin-deficient VEC-specific T-cadherin knockout mice markedly impaired the clearance of intravenously injected adiponectin, resulting in significant reductions in the accumulation of hexameric and HMW adiponectin, particularly the octadecameric (18-mer) form, not only in VECs, to note, but also in skeletal muscle and heart tissues. Furthermore, endothelial T-cadherin deficiency led to activation of innate immune signaling and cardiac remodeling, even under physiological conditions. In vitro experiments using MDCK II cells demonstrated that T-cadherin mediated the apical-to-basolateral transport of 18-mer adiponectin, largely preserving its HMW form. Additionally, intracellular adiponectin colocalized with the recycling endosome marker RAB11, and Rab11 deficiency significantly impaired its transcytosis. Similarly, in human VECs, T-cadherin knockdown significantly reduced basolateral adiponectin transport. CONCLUSIONS: These findings identify vascular endothelial T-cadherin as a key mediator of HMW adiponectin transcytosis via the recycling endosome pathway, enabling its traversal from the circulation to sub-vascular tissues/cells and offering a mechanistic basis for the systemic organ-protective effects of adiponectin.

BACKGROUND: The effects of sodium-glucose cotransporter-2 inhibitors (SGLT-2is) on diabetic foot disease have been mixed in prior trials of SGLT-2is compared with placebo. The comparative risk for diabetic foot disease with SGLT-2is compared with glucagon-like peptide-1 receptor agonists (GLP-1RAs) is unknown. OBJECTIVE: To compare risks for foot disease in new users of SGLT-2is and GLP-1RAs. DESIGN: Cohort study using target trial emulation. SETTING: Danish population-based study. PARTICIPANTS: Patients with type 2 diabetes initiating SGLT-2i or GLP-1RA treatment, identified using national health care registry data from 2013 to 2023, and a convenience sample enrolled in a research cohort study with additional behavioral and clinical assessments. MEASUREMENTS: Incident diagnosis of foot disease outcomes (peripheral neuropathy, peripheral artery disease, foot ulcers, or lower-limb amputation) as defined by the International Working Group on the Diabetic Foot. Inverse probability of treatment-weighted risk ratios (RRs) were estimated, with adjustment for 45 demographic, clinical, and other factors. RESULTS: The registry cohort included 53 769 new users of SGLT-2is and 30 380 of GLP-1RAs. During 6 years of follow-up, any foot disease occurred in 10.8% of SGLT-2i users and 12.0% of GLP-1RA users, corresponding to an RR of 0.90 (95% CI, 0.84 to 0.97) in an intention-to-treat analysis; differences did not emerge until after year 3, when 40% of SGLT-2i users and 32% of GLP-1RA users had discontinued initial treatment. The modest reduction in risk among SGLT-2i users was driven by lower risk for neuropathy (RR, 0.78 [CI, 0.68 to 0.87]). Users of SGLT-2is and GLP-1RAs had similar risks for peripheral artery disease, foot ulcers, amputations, and all-cause mortality. LIMITATION: Residual confounding; exposure and outcome misclassification. CONCLUSION: New SGLT-2i users had a modestly lower risk for foot disease largely driven by a lower risk for neuropathy than GLP-1RA users. PRIMARY FUNDING SOURCE: Aarhus University and Center for Population Medicine.