Chronic hyperglycemia impairs insulin action, resulting in glucotoxicity, which can be ameliorated in animal models by inducing glucosuria with renal glucose transport inhibitors. Here, we examined whether reduction of plasma glucose with a sodium-glucose cotransporter 2 (SGLT2) inhibitor could improve insulin-mediated tissue glucose disposal in patients with type 2 diabetes. Eighteen diabetic men were randomized to receive either dapagliflozin (n = 12) or placebo (n = 6) for 2 weeks. We measured insulin-mediated whole body glucose uptake and endogenous glucose production (EGP) at baseline and 2 weeks after treatment using the euglycemic hyperinsulinemic clamp technique. Dapagliflozin treatment induced glucosuria and markedly lowered fasting plasma glucose. Insulin-mediated tissue glucose disposal increased by approximately 18% after 2 weeks of dapagliflozin treatment, while placebo-treated subjects had no change in insulin sensitivity. Surprisingly, following dapagliflozin treatment, EGP increased substantially and was accompanied by an increase in fasting plasma glucagon concentration. Together, our data indicate that reduction of plasma glucose with an agent that works specifically on the kidney to induce glucosuria improves muscle insulin sensitivity. However, glucosuria induction following SGLT2 inhibition is associated with a paradoxical increase in EGP. These results provide support for the glucotoxicity hypothesis, which suggests that chronic hyperglycemia impairs insulin action in individuals with type 2 diabetes.

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Patients with coronavirus disease 2019 (COVID-19) are reported to have a greater prevalence of hyperglycaemia. Cytokine release as a consequence of severe acute respiratory syndrome coronavirus 2 infection may precipitate the onset of metabolic alterations by affecting glucose homeostasis. Here we describe abnormalities in glycometabolic control, insulin resistance and beta cell function in patients with COVID-19 without any pre-existing history or diagnosis of diabetes, and document glycaemic abnormalities in recovered patients 2 months after onset of disease. In a cohort of 551 patients hospitalized for COVID-19 in Italy, we found that 46% of patients were hyperglycaemic, whereas 27% were normoglycaemic. Using clinical assays and continuous glucose monitoring in a subset of patients, we detected altered glycometabolic control, with insulin resistance and an abnormal cytokine profile, even in normoglycaemic patients. Glycaemic abnormalities can be detected for at least 2 months in patients who recovered from COVID-19. Our data demonstrate that COVID-19 is associated with aberrant glycometabolic control, which can persist even after recovery, suggesting that further investigation of metabolic abnormalities in the context of long COVID is warranted.

OBJECTIVEInsulin resistance is associated with mitochondrial dysfunction and decreased ATP synthesis. Treatment of individuals with type 2 diabetes mellitus (T2DM) with sodium–glucose transporter 2 inhibitors (SGLT2i) improves insulin sensitivity. However, recent reports have demonstrated development of ketoacidosis in subjects with T2DM treated with SGLT2i. The current study examined the effect of improved insulin sensitivity with dapagliflozin on 1) mitochondrial ATP synthesis and 2) substrate oxidation rates and ketone production.RESEARCH DESIGN AND METHODSThe study randomized 18 individuals with T2DM to dapagliflozin (n = 9) or placebo (n = 9). Before and after 2 weeks, subjects received an insulin clamp with tritiated glucose, indirect calorimetry, and muscle biopsies.RESULTSDapagliflozin reduced fasting plasma glucose (167 ± 13 to 128 ± 6 mg/dL) and increased insulin-stimulated glucose disposal by 36% (P < 0.01). Glucose oxidation decreased (1.06 to 0.80 mg/kg ⋅ min, P < 0.05), whereas nonoxidative glucose disposal (glycogen synthesis) increased (2.74 to 4.74 mg/kg ⋅ min, P = 0.03). Dapagliflozin decreased basal glucose oxidation and increased lipid oxidation and plasma ketone concentration (0.05 to 0.19 mmol/L, P < 0.01) in association with an increase in fasting plasma glucagon (77 ± 8 to 94 ± 13, P < 0.01). Dapagliflozin reduced the ATP synthesis rate, which correlated with an increase in plasma ketone concentration.CONCLUSIONSDapagliflozin improved insulin sensitivity and caused a shift from glucose to lipid oxidation, which, together with an increase in glucagon-to-insulin ratio, provide the metabolic basis for increased ketone production.

A state of subclinical systemic inflammation is characteristically present in obesity/insulin resistance and type 2 diabetes mellitus (T2DM). The aim of the study was to develop an integrated measure of the circulating cytokines involved in the subclinical systemic inflammation and evaluate its relation with whole-body insulin sensitivity and glucose metabolism in T2DM. T2DM patients (n = 17, M/F 13/4, age = 55.0 ± 1.7 years, BMI = 33.5 ± 1.5 kg/m(2), HbA(1c) = 7.7 ± 0.3%) and normal glucose-tolerant (NGT) subjects (n = 15, M/F 7/8, age = 49.1 ± 2.5 years, BMI = 31.8 ± 1.2 kg/m(2), HbA(1c) = 5.6 ± 0.1%) were studied in a cross-sectional design. Whole-body insulin sensitivity was quantified by the euglycemic clamp. Beta-cell function [disposition index (DI)] was calculated using insulin and glucose values derived from an oral glucose tolerance test and the euglycemic clamp. Body fat mass was evaluated by dual-energy X-ray absorptiometry. Plasma cytokine [TNF-α, IL-6, MCP-1, osteopontin, fractalkine and adiponectin] values were divided into quintiles. A score ranging from 0 (lowest quintile) to 4 (highest quintile) was assigned. The inflammatory score (IS) was the sum of each cytokine score from which adiponectin score was subtracted in each study subject. Inflammatory cytokine levels were all higher in T2DM. IS was higher in T2DM as compared to NGT (10.0 ± 1.1 vs. 4.8 ± 0.8; p < 0.001). IS positively correlated with fasting plasma glucose (r = 0.638, p < 0.001), 1-h plasma glucose (r = 0.483, p = 0.005), 2-h plasma glucose (r = 0.611, p < 0.001) and HbA1c (r = 0.469, p = 0.007). IS was inversely correlated with insulin sensitivity (r = -0.478, p = 0.006) and DI (r = -0.523, p = 0.002). IS did not correlate with BMI and body fat mass. IS was an independent predictor of fasting plasma glucose and had a high sensibility and sensitivity to predict insulin resistance (M/I < 4). A state of subclinical inflammation defined and quantifiable by inflammatory score including TNF-α, IL-6, MCP-1, osteopontin, fractalkine and adiponectin is associated with both hyperglycemia and whole-body insulin resistance in T2DM.

Lowering the plasma glucose concentration with dapagliflozin markedly improves β-cell function, providing strong support in man for the glucotoxic effect of hyperglycemia on β-cell function.

OBJECTIVEA gene mutation of the Wnt/b-catenin signaling cascade is present in rare patients with the insulin resistance syndrome. Sclerostin is a circulating peptide inhibiting Wnt/b-catenin signaling. Our aims were to evaluate serum sclerostin in subjects with prediabetes and to analyze its relationship with insulin resistance and b-cell function. RESEARCH DESIGN AND METHODSWe performed a cross-sectional study including 43 healthy normal glucose-tolerant (NGT) individuals and 79 individuals with impaired glucose regulation (IGR), which included subjects with impaired fasting glucose (IFG), impaired glucose tolerance (IGT), and combined IFG-IGT, undergoing oral glucose tolerance test (OGTT) and dual-energy X-ray absorptiometry. A subgroup of 18 with NGT and 30 with IGR also underwent a euglycemic-hyperinsulinemic clamp with tracer. RESULTSSclerostin levels were higher in IGR compared with NGT (50.8 6 2.4 vs. 38.7 6 2.3 pmol/L; P = 0.01), positively correlated with HOMA-insulin resistance (IR) (r = 0.62; P < 0.001), and negatively correlated with insulin-mediated total body glucose disposal (r = 20.40; P < 0.001). Fasting endogenous glucose production (EGP) and hepatic and adipose tissue insulin resistance indexes were positively correlated with sclerostin levels (r = 0.48, r = 0.62, and r = 0.61, respectively; P < 0.001). Fasting and OGTT insulin clearance were inversely correlated with sclerostin serum levels (r = 20.52 and r = 20.44, respectively; both P < 0.001). Sclerostin levels were not correlated with b-cell function parameters. In multiple linear regression analysis, the addition of sclerostin levels to the traditional risk factors for insulin resistance improved the r 2 associated with HOMA-IR (r 2 change: 0.055; F change: 28.893; P = 0.001) and insulin-mediated total body glucose disposal (r 2 change: 0.059; F change: 4.938; P = 0.033). CONCLUSIONSSclerostin levels are increased in individuals with prediabetes and correlated with insulin resistance in skeletal muscle, liver, and adipose tissue. The correlation between sclerostin and insulin clearance at fasting state and during OGTT is novel; thus, studies are needed to explore the potential causal relationship.

Acute EX administration (1) improves Hep-IR, decreases EGP, and enhances HGU and (2) reduces Adipo-IR, improves the antilipolytic effect of insulin, and reduces plasma free fatty acid levels during OGTT. (Hepatology 2016;64:2028-2037).