OBJECTIVEThe aim of this study was to investigate tissue-specific effects of dapagliflozin on insulin sensitivity and liver and body fat in patients with type 2 diabetes. RESEARCH DESIGN AND METHODSThis randomized, double-blind, parallel group, placebo-controlled study recruited 32 patients with type 2 diabetes. Enrolled patients were to have HbA 1c 6.5-10.5% (48-91 mmol/mol) and ‡3 months of stable treatment with metformin, dipeptidyl peptidase 4 inhibitor, or their combination. Patients were randomized 1:1 to receive 10 mg dapagliflozin or placebo daily for 8 weeks. Before and after the intervention, tissue insulin sensitivity was measured using [ 18 F]-fluorodeoxyglucose and positron emission tomography during hyperinsulinemic-euglycemic clamp. Liver proton density fat fraction (PDFF) and adipose tissue volumes were assessed using MRI, and blood biomarkers were analyzed. RESULTSAfter 8 weeks, glycemic control was improved by dapagliflozin (placebo-corrected change in HbA 1c 20.39%, P < 0.01), but whole-body glucose uptake was not increased (P = 0.90). Tissue-specific insulin-stimulated glucose uptake did not change in skeletal muscle, liver, myocardium, or white and brown adipose tissue, and endogenous glucose production remained unaffected. However, there were significant placebo-corrected decreases in liver PDFF (23.74%, P < 0.01), liver volume (20.10 L, P < 0.05), visceral adipose tissue volume (20.35 L, P < 0.01), interleukin-6 (21.87 pg/mL, P < 0.05), and N-terminal prohormone of brain natriuretic peptide (296 ng/L, P = 0.03). CONCLUSIONSIn this study, 8 weeks of treatment with dapagliflozin reduced liver PDFF and the volume of visceral adipose tissue in obese patients with type 2 diabetes. Although glycemic control was improved, no effect on tissue-level insulin sensitivity was observed.Clinical trial reg. no. NCT02426541, clinicaltrials .gov This article contains Supplementary Data online at

ObjectiveInsulin resistance is reflected by the rates of reduced glucose uptake (GU) into the key insulin-sensitive tissues, skeletal muscle, liver and adipose tissue. It is unclear whether insulin resistance occurs simultaneously in all these tissues or whether insulin resistance is tissue specific.Design and methodsWe measured GU in skeletal muscle, adipose tissue and liver and endogenous glucose production (EGP), in a single session using 18F-fluorodeoxyglucose with positron emission tomography (PET) and euglycemic–hyperinsulinemic clamp. The study population consisted of 326 subjects without diabetes from the CMgene study cohort.ResultsSkeletal muscle GU less than 33 µmol/kg tissue/min and subcutaneous adipose tissue GU less than 11.5 µmol/kg tissue/min characterized insulin-resistant individuals. Men had considerably worse insulin suppression of EGP compared to women. By using principal component analysis (PCA), BMI inversely and skeletal muscle, adipose tissue and liver GU positively loaded on same principal component explaining one-third of the variation in these measures. The results were largely similar when liver GU was replaced by EGP in PCA. Liver GU and EGP were positively associated with aging.ConclusionsWe have provided threshold values, which can be used to identify tissue-specific insulin resistance. In addition, we found that insulin resistance measured by GU was only partially similar across all insulin-sensitive tissues studied, skeletal muscle, adipose tissue and liver and was affected by obesity, aging and gender.

Aim: To explore the early effects of dapagliflozin on myocardial function and metabolism in patients with type 2 diabetes without heart failure.Materials and Methods: Patients with type 2 diabetes on metformin treatment were randomized to double-blind, 6-week placebo or dapagliflozin 10 mg daily treatment.Investigations included cardiac function and structure with myocardial resonance imaging; cardiac oxygen consumption, perfusion and efficiency with [ 11 C]-acetate positron emission tomography (PET); and cardiac and hepatic fatty acid uptake with [ 18 F]-6-thia-heptadecanoic acid PET, analysed by ANCOVA as least square means with 95% confidence intervals.Results: Evaluable patients (placebo: n = 24, dapagliflozin: n = 25; 53% males) had a mean age of 64.4 years, a body mass index of 30.2 kg/m 2 and an HbA1c of 6.7%.Body weight and HbA1c were significantly decreased by dapagliflozin versus placebo. Dapagliflozin had no effect on myocardial efficiency, but external left ventricular (LV) work (−0.095 [−0.145, −0.043] J/g/min) and LV oxygen consumption were significantly reduced (−0.30 [−0.49, −0.12] J/g/min) by dapagliflozin, although the changes were not statistically significant versus changes in the placebo group.Change in left atrial maximal volume with dapagliflozin versus placebo was −3.19 (−6.32, −0.07) mL/m 2 (p = .056). Peak global radial strain decreased with dapagliflozin versus placebo (−3.92% [−7.57%, −0.28%]; p = .035), while peak global longitudinal and circumferential strains were unchanged. Hepatic fatty acid uptake