Impaired glucagon suppression and reduced insulin sensitivity in subjects with prediabetes undergoing atorvastatin therapy

Abstract

Objective Statin therapy has been linked to an increased risk of type 2 diabetes in high-risk populations; however, the pathophysiology of this association remains to be clarified. We investigated glucagon suppression and its relationship with insulin resistance in prediabetic subjects undergoing atorvastatin therapy; in addition, we studied molecular insulin signaling in pancreatic α-cells exposed to atorvastatin in vitro. Design and methods Fifty subjects with prediabetes were divided into two groups based on atorvastatin therapy. All subjects underwent an oral glucose tolerance test. Early (0–30 min), late (30–120 min) and overall (0–120 min) glucagon suppression were evaluated. Insulin sensitivity was estimated by the insulin sensitivity index (ISI0–120). Insulin signaling pathway and insulin-mediated glucagon suppression were investigated in pancreatic αTC1-6 cells chronically exposed (24 or 48 h) to atorvastatin (100 ng/mL). Results Individuals on statin therapy (n = 26) showed a significantly reduced early (0–30 min) (P = 0.003) and overall (0–120 min) (P = 0.01) glucagon suppression compared with controls (n = 24). In multivariate regression analysis, early glucagon suppression (0–30 min) exhibited a significant correlation with statin therapy. Regression analysis showed a significant association between ISI 0-120 and early0-30 (r = 0.33, P < 0.05) and overall0-120 (r = 0.38, P < 0.05) glucagon suppression. Moreover, in αTC1-6 cells atorvastatin treatment affected insulin-mediated glucagon suppression, insulin receptor phosphorylation and IRS-1-AKT pathway signaling. Conclusions Prediabetic patients undergoing statin therapy exhibit impaired glucagon suppression associated with lower insulin sensitivity. Our data revealed a new molecular aspect behind the deregulation of insulin sensitivity secondary to statin exposure.

Effect of PCSK9 inhibitors on pulse wave velocity and monocyte-to-HDL-cholesterol ratio in familial hypercholesterolemia subjects: results from a single-lipid-unit real-life setting

“…Non-statin lipid-lowering therapy was defined as the intake of lipid-lowering treatments other than statins (niacin, bile acid sequestrants, fibrates, nutraceuticals) [24]. Type 2 diabetes (T2D) was defined as a fasting plasma glucose ≥ 126 mg/dL on two consecutive readings or a glycated hemoglobin (HbA1c) ≥ 6.5% or the use of antidiabetic medications [25]. Smokers were divided into either current smoker (defined as any cigarette in the last month) or past smoker [26].…”

Subjects with high fasting insulin also have higher postprandial GLP-1 and glucagon levels than controls with lower insulin

“…These findings could suggest that physiological elevations of GLP-1 do not strongly suppress glucagon release in early stages of insulin resistance, in contrast to what has been found in later stages [14,15]. Indeed, Glucagon suppression has been shown to be affected by insulin resistance [5,14,23,25]. However, it is possible that early stages of the metabolic syndrome, before overt diabetes, presents with a different incretin release pattern than in patients with overt type 2 diabetes [5,7,8,15,26].…”

Direct Effects of D-Chiro-Inositol on Insulin Signaling and Glucagon Secretion of Pancreatic Alpha Cells

“…Cells were then washed and incubated for 2 h in Krebs–Ringer buffer (KRB) containing 16.7 mmol/L glucose and 0.5% BSA (pH 7.4) in the presence or absence of insulin 10 −9 M. Afterwards, media were collected in tubes containing aprotinin (0.1 mg/L) (Sigma-Aldrich, Saint Louis, MO, USA) and kept frozen at –20 °C for subsequent analysis. The cells were lysed in a radio-immunoprecipitation assay (RIPA) buffer and the lysates were analyzed for total protein content to control for the number of cells, as previously reported [ 36 ]. Glucagon levels were measured using a specific ELISA kit (Mercodia Glucagon, Uppsala, Sweden) according to the manufacturer’s instructions.…”