Pioglitazone Acutely Reduces Energy Metabolism and Insulin Secretion in Rats

Our objective was to determine if the insulin-sensitizing drug pioglitazone acutely reduces insulin secretion and causes metabolic deceleration in vivo independently of change in insulin sensitivity. We assessed glucose homeostasis by hyperinsulinemic-euglycemic and hyperglycemic clamp studies and energy expenditure by indirect calorimetry and biotelemetry in male Wistar and obese hyperinsulinemic Zucker diabetic fatty (ZDF) rats 45 min after a single oral dose of pioglitazone (30 mg/kg). In vivo insulin secretion during clamped hyperglycemia was reduced in both Wistar and ZDF rats after pioglitazone administration. Insulin clearance was slightly increased in Wistar but not in ZDF rats. Insulin sensitivity in Wistar rats assessed by the hyperinsulinemic-euglycemic clamp was minimally affected by pioglitazone at this early time point. Pioglitazone also reduced energy expenditure in Wistar rats without altering respiratory exchange ratio or core body temperature. Glucose-induced insulin secretion (GIIS) and oxygen consumption were reduced by pioglitazone in isolated islets and INS832/13 cells. In conclusion, pioglitazone acutely induces whole-body metabolic slowing down and reduces GIIS, the latter being largely independent of the insulin-sensitizing action of the drug. The results suggest that pioglitazone has direct metabolic deceleration effects on the β-cell that may contribute to its capacity to lower insulinemia and antidiabetic action.Major drugs developed to treat type 2 diabetes aim at either increasing insulin secretion or reducing insulin resistance (1–4). Two classes of insulin-sensitizing agents are currently used, the biguanides (metformin) and the thiazolidinediones (TZDs), of which the only one still recommended for use in some countries is pioglitazone (5). TZDs are peroxisome proliferator–activated receptor-γ (PPARγ) agonists. They stimulate adipocyte differentiation, relieving other tissues from fat excess, thereby reducing their resistance to insulin (6,7). The beneficial effects of TZDs are not limited to increased insulin sensitivity and also include preservation of β-cell function (8). It is thought that the beneficial effect of TZDs on β-cell function in vivo is indirect and occurs via a relief of the need for insulin hypersecretion because of their insulin sensitizing action. We should, however, consider the possibility that the classical antidiabetic insulin sensitizers, pioglitazone and metformin, might also have beneficial effects on glucose homeostasis via direct reduction of insulin hypersecretion independently of insulin resistance.We previously demonstrated in vitro that pioglitazone acutely slows down glucose and lipid metabolism in the β cell and inhibits glucose-induced insulin secretion (GIIS) primarily at submaximal and much less at maximal glucose concentrations (right shift in the glucose dose response) via a PPARγ-independent mechanism (9). These acute effects of pioglitazone are likely attributable to complex I inhibition of the electron transport chain (10) and involve reduced glucose oxidation, decreased ATP levels, and increased AMPK activation (9). Interestingly, metformin causes similar effects (J.L. and M.P., unpublished data). Hence, we proposed the novel concept of “metabolic deceleration” as a mode of action of some antidiabetic drugs and suggested that the action of pioglitazone to reduce glucose metabolism and insulin secretion in the β-cell may partly explain its beneficial effects (9). The concept that metabolic deceleration protects the β-cell from both oxidative and endoplasmic reticulum stress has recently been reviewed (11,12).In the current study we performed in vivo experiments in normal Wistar and obese Zucker diabetic fatty (ZDF) rats to better understand how acute treatment with pioglitazone alters glucose homeostasis, with particular focus on how it reduces hyperinsulinemia. The following questions were asked: 1) Can we confirm in vivo our previous in vitro findings in isolated rat islet and β-cell line that pioglitazone acutely reduces insulin secretion? 2) Is this acute effect of pioglitazone on insulin secretion independent of its effects on insulin sensitivity? and 3) Does pioglitazone acutely slow down whole-body energy metabolism?