Chronic inflammation is postulated to be involved in development of end stage renal disease (ESRD) in diabetes, but which specific circulating inflammatory proteins contribute to this risk remains unknown. To study this we examined 194 circulating inflammatory proteins in subjects from three independent cohorts with Type 1 and Type 2 diabetes. In each cohort we identified an extremely robust K idney R isk I nflammatory S ignature (KRIS) consisting of 17 novel proteins enriched for TNF Receptor Superfamily members that was associated with a 10-year risk of ESRD. All these proteins had a systemic, non-kidney source. Our prospective study findings provide strong evidence that KRIS proteins contribute to the inflammatory process underlying ESRD development in both types of diabetes. These proteins may be used as new therapeutic targets, new prognostic tests for high risk of ESRD and as surrogate outcome measures where changes in KRIS levels during intervention can reflect the tested therapy’s effectiveness.

To determine the effect of tirzepatide, a dual agonist of glucose-dependent insulinotropic polypeptide and glucagon-like peptide 1 receptors, on biomarkers of nonalcoholic steatohepatitis (NASH) and fibrosis in patients with type 2 diabetes mellitus (T2DM). RESEARCH DESIGN AND METHODSPatients with T2DM received either once weekly tirzepatide (1, 5, 10, or 15 mg), dulaglutide (1.5 mg), or placebo for 26 weeks. Changes from baseline in alanine aminotransferase (ALT), aspartate aminotransferase (AST), keratin-18 (K-18), procollagen III (Pro-C3), and adiponectin were analyzed in a modified intentionto-treat population. RESULTSSignificant (P < 0.05) reductions from baseline in ALT (all groups), AST (all groups except tirzepatide 10 mg), K-18 (tirzepatide 5, 10, 15 mg), and Pro-C3 (tirzepatide 15 mg) were observed at 26 weeks. Decreases with tirzepatide were significant compared with placebo for K-18 (10 mg) and Pro-C3 (15 mg) and with dulaglutide for ALT (10, 15 mg). Adiponectin significantly increased from baseline with tirzepatide compared with placebo (10, 15 mg). CONCLUSIONSIn post hoc analyses, higher tirzepatide doses significantly decreased NASH-related biomarkers and increased adiponectin in patients with T2DM.The prevalence of nonalcoholic fatty liver disease (NAFLD) is ;25% globally and ;60-75% in patients with type 2 diabetes mellitus (T2DM) (1,2). Nonalcoholic steatohepatitis (NASH) (NAFLD with inflammation and hepatocyte injury, with or without fibrosis) can progress to cirrhosis, liver failure, hepatocellular carcinoma, and increased cardiovascular risk (3,4). T2DM increases the risk of NASH twofold (5). Weight loss through lifestyle modification reduces liver fat; weight reductions $10% can induce NASH resolution in most patients (6).Glucagon-like peptide 1 receptor agonists (GLP-1 RAs) promote weight loss and may have efficacy in NASH (7). Tirzepatide, a 39-amino acid synthetic peptide, has agonist activity at both glucose-dependent insulinotropic polypeptide (GIP) and GLP-1

Context Novel dual GIP and GLP-1 receptor agonist (RA) tirzepatide demonstrated substantially greater glucose control and weight loss (WL) compared with selective GLP-1RA dulaglutide. Objective Explore mechanisms of glucose control by tirzepatide. Design Post-hoc analyses of fasting biomarkers and multiple linear regression analysis. Setting 47 sites in 4 countries. Patients or other Participants: 316 subjects with Type 2 diabetes. Interventions Tirzepatide (1, 5, 10, 15 mg), dulaglutide (1.5 mg), placebo. Main Outcome Measures Analyze biomarkers of beta-cell function and insulin resistance (IR) and evaluate WL contributions to IR improvements at 26 weeks. Results HOMA2-B significantly increased with dulaglutide and tirzepatide 5, 10, and 15 mg compared with placebo (p&lt;0.02). Proinsulin/insulin and proinsulin/C-peptide ratios significantly decreased with tirzepatide 10 and 15 mg compared with placebo and dulaglutide (p&lt;0.007). Tirzepatide 10 and 15 mg significantly decreased fasting insulin (p&lt;0.033) and tirzepatide 10 mg significantly decreased HOMA2-IR (p=0.004) compared with placebo and dulaglutide. Markers of improved insulin sensitivity (IS) adiponectin, IGFBP-1, and IGFBP-2 significantly increased by one or more doses of tirzepatide (p&lt;0.05). To determine whether improvements in IR were directly attributable to WL, multiple linear regression analysis with potential confounding variables age, sex, metformin, triglycerides, and HbA1c was conducted. WL significantly (p&lt;0.028) explained only 13% and 21% of improvement in HOMA2-IR with tirzepatide 10 and 15 mg, respectively. Conclusions Tirzepatide improved markers of IS and beta-cell function to a greater extent than dulaglutide. IS effects of tirzepatide were only partly attributable to WL, suggesting dual receptor agonism confers distinct mechanisms of glycemic control.

The FGF23 coreceptor αKlotho (αKL) is expressed as a membrane-bound protein (mKL) that forms heteromeric complexes with FGF receptors (FGFRs) to initiate intracellular signaling. It also circulates as an endoproteolytic cleavage product of mKL (cKL). Previously, a patient with increased plasma cKL as the result of a translocation [t(9;13)] in the αKLOTHO (KL) gene presented with rickets and a complex endocrine profile, including paradoxically elevated plasma FGF23, despite hypophosphatemia. The goal of this study was to test whether cKL regulates phosphate handling through control of FGF23 expression. To increase cKL levels, mice were treated with an adeno-associated virus producing cKL. The treated groups exhibited dose-dependent hypophosphatemia and hypocalcemia, with markedly elevated FGF23 (38 to 456 fold). The animals also manifested fractures, reduced bone mineral content, expanded growth plates, and severe osteomalacia, with highly increased bone Fgf23 mRNA (>150 fold). cKL activity in vitro was specific for interactions with FGF23 and was FGFR dependent. These results demonstrate that cKL potently stimulates FGF23 production in vivo, which phenocopies the KL translocation patient and metabolic bone syndromes associated with elevated FGF23. These findings have important implications for the regulation of αKL and FGF23 in disorders of phosphate handling and biomineralization. IntroductionThe bone-derived hormone FGF23 and its coreceptor αKlotho (αKL) are critical regulators of systemic phosphate metabolism. The αKL gene product is expressed as multiple species; the membrane-bound form (mKL) associates with FGF23 and FGF receptors (FGFRs) to signal through the MAPK cascade (1, 2). Two soluble species have also been reported, an alternatively spliced secreted form (sKL) (exons 1-3 of the 5-exon KL gene) and an endoproteolytic cleavage product of mKL (cKL) (3). Although sKL was identified as a potential αKL variant, only cKL protein was detectable in human and rodent plasma and cerebrospinal fluids (4). The cKL form has been implicated in directly mediating renal phosphate handling through paracrine activity (5); however, whether endocrine effects of cKL occur remains unclear. This possibility is highlighted by findings in a patient with a translocation in the αKLOTHO (KL) gene (t9;13), who presented with elevated plasma cKL and a ricketic phenotype (6). The biochemical and endocrine abnormalities were complex and included hypophosphatemia, hypocalcemia, inappropriately normal 1,25(OH) 2 vitamin D (1,25D), and severe hyperparathyroidism requiring surgical intervention. Of note, this patient also had sustained, highly elevated plasma FGF23 (>12 times the upper limit of normal), despite marked hypophosphatemia on or off calcitriol treatment (6). The paradoxically elevated FGF23 in this patient, together with a clinical phenotype resembling that of patients with severe autosomal dominant hypophosphatemic rickets, X-linked

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