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Objective: Endogenous insulin clearance (EIC) is physiologically reduced at increasing insulin secretion rate (ISR). Computing EIC at the prevailing ISR does not distinguish the effects of hypersecretion from those of other mechanisms of glucose homeostasis. We aimed to measure EIC in standardized ISR conditions (i.e., at fixed ISR levels) and to analyze its associations with relevant physiologic factors., Research Design and Methods: We estimated standardized EIC (EIC ISR ) by mathematical modeling in nine different studies with insulin and glucose infusions ( N = 2,067). EIC ISR association with various traits was analyzed by stepwise multivariable regression in studies with both euglycemic clamp and oral glucose tolerance test (OGTT) ( N = 1,410). We also tested whether oral glucose ingestion, as opposed to intravenous infusion, has an independent effect on EIC ( N = 1,555)., Results: Insulin sensitivity (as M/I from the euglycemic clamp) is the strongest determinant of EIC ISR , approximately four times more influential than insulin resistance-related hypersecretion. EIC ISR independently associates positively with M/I, fasting and mean OGTT glucose or type 2 diabetes, and β-cell glucose sensitivity and negatively with African American or Hispanic race, female sex, and female age. With oral glucose ingestion, an ISR-independent ∼10% EIC reduction is necessary to explain the observed insulin concentration profiles., Conclusions: Based on EIC ISR , we posit the existence of two adaptive processes involving insulin clearance: the first reduces EIC ISR with insulin resistance (not with higher BMI per se) and is more relevant than the concomitant hypersecretion; the second reduces EIC ISR with β-cell dysfunction. These processes are dysregulated in type 2 diabetes. Finally, oral glucose ingestion per se reduces insulin clearance., (© 2021 by the American Diabetes Association.)

Objective: To assess the effects of empagliflozin, a selective sodium-glucose cotransporter 2 (SGLT2) inhibitor, on broad biological systems through proteomics., Research Design and Methods: Aptamer-based proteomics was used to quantify 3,713 proteins in 144 paired plasma samples obtained from 72 participants across the spectrum of glucose tolerance before and after 4 weeks of empagliflozin 25 mg/day. The biology of the plasma proteins significantly changed by empagliflozin (at false discovery rate-corrected P < 0.05) was discerned through Ingenuity Pathway Analysis., Results: Empagliflozin significantly affected levels of 43 proteins, 6 related to cardiomyocyte function (fatty acid-binding protein 3 and 4 [FABPA], neurotrophic receptor tyrosine kinase, renin, thrombospondin 4, and leptin receptor), 5 to iron handling (ferritin heavy chain 1, transferrin receptor protein 1, neogenin, growth differentiation factor 2 [GDF2], and β2-microglobulin), and 1 to sphingosine/ceramide metabolism (neutral ceramidase), a known pathway of cardiovascular disease. Among the protein changes achieving the strongest statistical significance, insulin-like binding factor protein-1 (IGFBP-1), transgelin-2, FABPA, GDF15, and sulphydryl oxidase 2 precursor were increased, while ferritin, thrombospondin 3, and Rearranged during Transfection (RET) were decreased by empagliflozin administration., Conclusions: SGLT2 inhibition is associated, directly or indirectly, with multiple biological effects, including changes in markers of cardiomyocyte contraction/relaxation, iron handling, and other metabolic and renal targets. The most significant differences were detected in protein species (GDF15, ferritin, IGFBP-1, and FABP) potentially related to the clinical and metabolic changes that were actually measured in the same patients. These novel results may inform further studies using targeted proteomics and a prospective design., (© 2020 by the American Diabetes Association.)

Objective: Pharmacologically induced glycosuria elicits adaptive responses in glucose homeostasis and hormone release, including decrements in plasma glucose and insulin levels, increments in glucagon release, enhanced lipolysis, and stimulation of ketogenesis, resulting in an increase in ketonemia. We aimed at assessing the renal response to these changes., Research Design and Methods: We measured fasting and postmeal urinary excretion of glucose, β-hydroxybutyrate (β-HB), lactate, and sodium in 66 previously reported patients with type 2 diabetes and preserved renal function (estimated glomerular filtration rate ≥60 mL · min -1 · 1.73 m -2 ) and in control subjects without diabetes at baseline and following empagliflozin treatment., Results: With chronic (4 weeks) sodium-glucose cotransporter 2 inhibition, baseline fractional glucose excretion (<2%) rose to 38 ± 12% and 46 ± 11% (fasting vs. postmeal, respectively; P < 0.0001) over a range of BMIs (range 23-41 kg/m 2 ) and creatinine clearance (65-168 mL · min -1 · m -2 ). Excretion of β-HB (median [interquartile range]: 0.08 [0.10] to 0.31 [0.43] µmol · min -1 ), lactate (0.06 [0.06] to 0.28 [0.25] µmol · min -1 ), and sodium (0.27 [0.22] to 0.36 [0.16] mEq · min -1 ) all increased ( P ≤ 0.001 for all) and were each positively related to glycosuria ( P ≤ 0.001). These parameters changed in the same direction in subjects without diabetes, but changes were smaller than in the patients with diabetes. Although plasma N-terminal pro-B-type natriuretic peptide levels were unaltered, plasma erythropoietin concentrations increased by 31 (64)% ( P = 0.0078)., Conclusions: We conclude that the sodium-glucose cotransporter 2 inhibitor-induced increase in β-HB is not because of reduced renal clearance but because of overproduction. The increased lactate excretion contributes to lower plasma lactate levels, whereas the increased natriuresis may help in normalizing the exchangeable sodium pool. Taken together, glucose loss through joint inhibition of glucose and sodium reabsorption in the proximal tubule induces multiple changes in renal metabolism., (© 2017 by the American Diabetes Association.)