Effects of hypertriglyceridemia with or without NEFA elevation on ß-cell function and insulin clearance and sensitivity.

AIMS: Hypertriglyceridemia is a risk factor for developing type 2 diabetes (T2D) and might contribute to its pathogenesis either directly or through elevation of non-esterified fatty acids (NEFAs). This study aimed at comparing the glucometabolic effects of acute hypertriglyceridemia alone or combined with NEFA elevation in non-diabetic subjects. METHODS: Twenty-two healthy lean volunteers underwent two 5-h intravenous infusions of either saline or Intralipid, without (n=12) or with heparin (I+H; n=10) to activate the release of NEFAs. Oral glucose tolerance tests (OGTTs) were performed during the last 3h of infusion. Insulin sensitivity, insulin secretion rate (ISR), model-derived ß-cell function, and insulin clearance were measured after 2h of lipid infusion and during the OGTTs. RESULTS: In fasting conditions, both lipid infusions increased plasma insulin and ISR and reduced insulin clearance, without affecting plasma glucose and insulin sensitivity. These effects on insulin and ISR were more pronounced for I+H than Intralipid alone. During the OGTT, the lipid infusions markedly impaired glucose tolerance, increased plasma insulin and ISR, and decreased insulin sensitivity and clearance, without significant group differences. Intralipid alone inhibited glucose-stimulated insulin secretion (i.e. ß-cell glucose sensitivity) and increased ß-cell potentiation, whereas I+H had neutral effects on these ß-cell functions. CONCLUSION: In healthy non-obese subjects, mild acute hypertriglyceridemia directly reduces glucose tolerance, insulin sensitivity and clearance, and has selective and opposite effects on ß-cell function that are neutralized by NEFAs. These findings provide new insight into plausible biological signals that generate and sustain insulin resistance and chronic hyperinsulinemia in the development of T2D.

Role of Glycosuria in SGLT2 Inhibitor-Induced Cardiorenal Protection: A Mechanistic Analysis of the CREDENCE Trial.

SGLT2 inhibitors have been shown to provide pronounced reductions in cardiorenal outcomes, including cardiovascular death, heart failure, and renal failure. The mechanisms underlying these benefits remain uncertain. We hypothesized that the effects could be attributed to the elevated glycosuria induced by these drugs. Urine concentrations of glucose, creatinine, and ketones were measured at baseline and after 1 year of treatment with either placebo or canagliflozin 100 mg/day, in approximately 2,600 individuals from the Canagliflozin and Renal Events in Diabetes with Established Nephropathy Clinical Evaluation (CREDENCE) trial (enrolling patients with type 2 diabetes, chronic kidney disease (CKD), and albuminuria). Associations between glycosuria and the primary composite end point from CREDENCE, and secondary outcomes were assessed using Cox proportional hazards models. Canagliflozin treatment increased fractional urinary glucose excretion (± SD) from 3 ± 9% at baseline to 30 ± 26% at year 1 (vs. 5 ± 19% with placebo; P < 0.001). Patients in the canagliflozin arm and in the top quartile of urine glucose to creatinine ratio at year 1 were significantly protected for the primary end point (hazard ratio [HR] 0.42; 95% CI 0.30-0.61); similar results were seen for cases of hospitalized heart failure (HR 0.45; 95% CI 0.27-0.73) and all-cause death (HR 0.56; 95% CI 0.39-0.80). These associations persisted when adjustments were made for multiple conventional risk factors. Among patients with type 2 diabetes and CKD treated with canagliflozin, individuals with the highest glycosuria levels had the strongest protection against multiple cardiorenal outcomes.

Fasting Substrate Concentrations Predict Cardiovascular Outcomes in the CANagliflozin cardioVascular Assessment Study (CANVAS).

OBJECTIVE: To examine whether the circulating substrate mix may be related to the incidence of heart failure (HF) and cardiovascular (CV) mortality and how it is altered by canagliflozin treatment. RESEARCH DESIGN AND METHODS: We measured fasting glucose, free fatty acids (FFA), glycerol, ß-hydroxybutyrate, acetoacetate, lactate, and pyruvate concentrations in 3,581 samples from the CANagliflozin cardioVascular Assessment Study (CANVAS) trial at baseline and at 1 and 2 years after randomization. Results were analyzed by univariate and multivariate Cox proportional hazards models. RESULTS: Patients in the lowest baseline FFA tertile were more often men with a longer duration of type 2 diabetes (T2D), higher urinary albumin excretion, lower HDL-cholesterol levels, higher history of CV disease (CVD), and higher use of statins and insulin. When all seven metabolites were used as predictors, FFA were inversely associated with incident hospitalized HF (hazard ratio [HR] 0.33 [95% CI 0.21-0.55]), while glycerol was a positive predictor (2.21 [1.45-3.35]). In a model further adjusted for 16 potential confounders, including prior HF and CVD and pharmacologic therapies, FFA remained a significant negative predictor. FFA and glycerol also predicted CV mortality (HR 0.53 [95% CI 0.35-0.81] and 1.81 [1.26-2.58], respectively) and all-cause death (0.50 [0.36-0.70] and 1.64 [1.22-2.18]). When added to these models, background insulin therapy was an independent positive predictor of risk of death. Canagliflozin treatment significantly increased plasma FFA and ß-hydroxybutyrate regardless of background antihyperglycemic therapy. CONCLUSIONS: A constitutive metabolic setup consisting of higher lipolysis may be beneficial in delaying or preventing hospitalized HF; a further stimulation of lipolysis by canagliflozin may reinforce this influence.