Pioglitazone Acutely Reduces Insulin Secretion and Causes Metabolic Deceleration of the Pancreatic β-Cell at Submaximal Glucose Concentrations

Abstract

Thiazolidinediones (TZDs) have beneficial effects on glucose homeostasis via enhancement of insulin sensitivity and preservation of beta-cell function. How TZDs preserve beta-cells is uncertain, but it might involve direct effects via both peroxisome proliferator-activated receptor-gamma-dependent and -independent pathways. To gain insight into the independent pathway(s), we assessed the effects of short-term (<or=90 min) exposure to pioglitazone (Pio) (10 to 50 microM) on glucose-induced insulin secretion (GIIS), AMP-activated protein kinase (AMPK) activation, and beta-cell metabolism in INS 832/13 beta-cells and rat islets. Pio caused a right shift in the dose-dependence of GIIS, such that insulin release was reduced at intermediate glucose but unaffected at either basal or maximal glucose concentrations. This was associated in INS 832/13 cells with alterations in energy metabolism, characterized by reduced glucose oxidation, mitochondrial membrane polarization, and ATP levels. Pio caused AMPK phosphorylation and its action on GIIS was reversed by the AMPK inhibitor compound C. Pio also reduced palmitate esterification into complex lipids and inhibited lipolysis. As for insulin secretion, the alterations in beta-cell metabolic processes were mostly alleviated at elevated glucose. Similarly, the antidiabetic agents and AMPK activators metformin and berberine caused a right shift in the dose dependence of GIIS. In conclusion, Pio acutely reduces glucose oxidation, energy metabolism, and glycerolipid/fatty acid cycling of the beta-cell at intermediate glucose concentrations. We suggest that AMPK activation and the metabolic deceleration of the beta-cell caused by Pio contribute to its known effects to reduce hyperinsulinemia and preserve beta-cell function and act as an antidiabetic agent.

The Pancreatic β-Cell: A Bioenergetic Perspective

“…In low glucose, INS-1 832/13 cells oxidized labeled palmitate to CO 2 at rates of 0.2-0.4 nmol·min Ϫ1 ·mg protein Ϫ1 (279,332,407). These rates are comparable to those for the utilization of 2.8 mM glucose by these cells (332).…”

“…Interestingly, pioglitazone, a member of the thiazolidinedione class of antidiabetic agents that had previously been shown to restrict ␤-cell mitochondrial metabolism (278,279), was reported to act as a selective inhibitor of the pyruvate transporter (125).…”

“…In the fasting state, ⌬G p is maintained by fatty acid oxidation and glucose is spared, most potently by inhibition of pyruvate dehydrogenase by a combination of raised AcCoA and NADH and activation of the inhibitory pyruvate dehydrogenase kinase (493). ␤-Cells oxidize exogenous fatty acids provided as albumin buffers with typical, physiologically relevant, fatty acid/albumin molar ratios not exceeding 3:1 (127,279,407,446). The cells also possess endogenous triglyceride stores (328) together with low levels of hormone-sensitive lipase activity (363,545).…”

Anti-inflammatory Effects of Thiazolidinediones in Human Airway Smooth Muscle Cells

“…Both antagonists prevented the AICAR-induced activation of AMPK, as assessed by the Thr 172 phosphorylation of AMPK ( Figure 7A), indicating that they were active at the concentrations administered. Both compounds were also shown to inhibit the TZD-induced activation of AMPK in other cell types (72,73). However, they did not reverse the effects of TZDs on the release of inflammatory mediators from HASM cells (Figures 7B and 7C).…”

Activation of the AMP-activated protein kinase enhances glucose-stimulated insulin secretion in mouse β-cells

“…For this purpose compound C is often used. [31][32][33] Unfortunately, the drug is inappropriate for application in b-cells because it stimulates insulin secretion per se (reviewed in ref. 33).…”