How pioglitazone affects glucose and lipid metabolism

Abstract

The two primary perturbations resulting in hyperglycaemia in type 2 diabetes are insulin resistance and insulin deficiency. Insulin resistance occurs in peripheral organs (muscle and fat) leading to decreased glucose uptake and utilisation and in liver leading to increased hepatic glucose production. Thiazolidinediones, synthetic ligands for peroxisome proliferator-activated receptor gamma (PPARg) can modulate the expression of genes influencing carbohydrate and lipid metabolism. Pioglitazone, a recently introduced thiazolidinedione, improves glycaemic control and lipid profiles in people with type 2 diabetes. Some of the possible mechanisms of improving glycaemic control include increases in glucose transporters 1 and 4, enhancement of insulin signalling, decrease in tumour necrosis factor-a, reduction of plasma free fatty acid, and decrease in phosphoenolpyruvate carboxykinase. Together, these can increase glucose uptake and utilisation in the peripheral organs and decrease gluconeogenesis in the liver. Possible mechanisms resulting in more desirable lipid profiles include an increase in phosphodiesterase 3B, resulting in reduced intracellular lipolysis in adipocytes, and an increase in lipoprotein lipase resulting in enhanced clearance of triglyceriderich lipoproteins. In brief, pioglitazone reduces hepatic and peripheral insulin resistance.

Pioglitazone Increases Serum Magnesium Levels in Glucose-Intolerant Subjects. A Randomized, Controlled Trial

“…However, in view of the fact that thiazolidinediones reduce plasma glucose levels (Tan, 2000), it is likely that the elevation of serum magnesium concentration that we documented, was linked to reduction in the urinary magnesium excretion that hyperglycemia promotes. In addition, the decrease in TNF-a levels that thiazolidinediones promotes, reduces the inflammatory response (Tan, 2000) and might influence the release of neuro-peptide substance P, which has been related to magnesium-deficiency in animals (Malpuech-Brugre, et al, 1999), and in this way thiazolidinediones could improve magnesium levels. Finally, increased serum magnesium concentration may be a secondary effect of the improvement in insulin sensitivity induced by Pioglitazone.…”

“…Decreased magnesium levels result in malfunctioning tyrosinekinase activity of the insulin receptor (Paolisso et al, 1990;Paolisso et al, 1997;Resnick, 1993), development of insulin resistance (Humphries et al, 1999;Rosolova et al, 1997;Nadler et al, 1993), and is related to decreased HDL-cholesterol levels (Guerrero and Rodriguez, 2000). In addition, magnesium supplementation improves the insulin action by reducing glycemic levels and increasing HDL-cholesterol (Lefbvre et al, 1995;Itoh et al, 1997), similar to the well-known effects of Pioglitazone (Tan, 2000;Eckland and Danhof, 2000;Schneider et al, 1999;Buse, 2000). So, based on the similar effects of Pioglitazone and magnesium supplementation on insulin and lipid metabolism, and the significant increase of serum magnesium levels in the subjects that received Pioglitazone, we hypothesize that Pioglitazone and magnesium actions on insulin metabolism are linked.…”

Oral hypoglycemic agents: insulin secretagogues, α-glucosidase inhibitors and insulin sensitizers

“…The glucose-lowering effects of the thiazolidinediones are related to their ability to increase insulin effects on liver, skeletal muscle and adipose tissue (increase insulin sensitivity) (Fujiwara et al, 1988;Saltiel and Olefsky, 1996;Spencer and Markham, 1997;Barman Balfour and Plosker, 1999;Tan, 2000). On liver cells, troglitazone has been shown to decrease the rates of glucose production by inhibiting gluconeogenesis (Ciaraldi et al, 1990).…”

Type 2 diabetes: Are current oral treatment options sufficient?

“…Increased expression of insulin-sensitive genes is thought to be the primary mechanism for reduction of insulin resistance by thiazolidinediones. Additional mechanisms are described elsewhere in this supplement (Tan et al, 2000), but include lipid-lowering effects (e.g., lowering triglyceride and nonesterified fatty acid concentrations), increasing GLUT-4 production, increasing hepatic glucose disposal, decreasing hepatic glucose production, correcting TNF-a overproduction, and possibly altering leptin gene expression (Spiegelman, 1998;Ciaraldi et al, 1995;Bahr et al, 1996). Thiazolidinediones can cause weight gain over time, which has been associated with improved glycaemic control.…”