Insulin-sparing effects of troglitazone in rat pancreatic islets

Abstract

Thiazolidinediones (TZDs) have been suggested to act beneficially on pancreatic islet function and on beta-cell viability but data concerning direct effects on isolated islets are controversial. Therefore, we have examined parameters of pancreatic insulin and glucagon secretion and biosynthesis in TZD-exposed rat pancreatic islets under physiological glucose level conditions and under conditions of glucolipotoxicity.Primary rat islets were incubated for 2·5 h with or without troglitazone (10 µM) in 5·6 mM glucose (standard glucose levels) and 16·7 mM glucose (high glucose levels); a subgroup was additionally treated with oleate (200 µM) to simulate acute glucolipotoxicity. Insulin and glucagon secretion, intracellular content and their respective mRNAs were quantified. Newly synthesized insulin was determined by pulse-labeling experiments.Troglitazone reduced insulin secretion at standard and high glucose levels by about one-third (P≤0·05). Insulin content was decreased at 5·6 mM glucose but increased at 16·7 mM glucose by the presence of troglitazone (P≤0·05). Newly synthesized insulin mRNA and preproinsulin mRNA decreased by about 20% at standard glucose levels (P≤0·05). Glucagon secretion was augmented by troglitazone in islets under high glucose conditions by an additional 50% (P≤0·05). No clear beneficial troglitazone effects were observed under glucolipotoxic conditions.The reduced insulin secretion and biosynthesis at standard glucose levels can be interpreted as an insulin-sparing effect. Troglitazone effects were less pronounced at high glucose alone or in combination with oleate. From a clinical point of view, these results indicate a greater benefit of troglitazone for beta-cell function in hyperinsulinemic, but normoglycemic patients with insulin resistance or early type 2 diabetes without major insulin secretion deficits and/or pronounced hyperglycemia.

Intracellular lipid metabolism impairs β cell compensation during diet-induced obesity

“…We demonstrate this directly with the β cell-specific overexpression mouse model. This can also provide more insights into the insulin-sparing effects of the thiazolidinediones (TZDs), which are PPARγ agonists (58). Activation of PPARγ in peripheral tissues, such as adipose tissue, can improve systemic lipid metabolism and insulin sensitivity through its beneficial effectors, e.g., adiponectin (5,6).…”

Defining high-fat-diet rat models: metabolic and molecular effects of different fat types

“…The formation of primer dimers was ruled out in all LightCycler experiments by melting curve analysis. The cDNA content for a specific gene in each sample was semiquantitatively assessed by comparing the experimentally determined crossing point with the crossing points and respective concentrations of a pooled standard cDNA, as described previously (Bollheimer et al 2003). All results were normalized by the 18s-rRNA content to ensure comparability.…”

“…Pancreatic islets were isolated separately from individual animals treated with the different diet types by collagenase digestion and Histopaque-Ficoll density gradient centrifugation, as previously described (Bollheimer et al 2003). Batches of 10 islets were placed into 150 µl Krebs-Ringer bicarbonate buffer, 0·1% (w/v) fatty acid-free BSA, 5·6 mM glucose and 16 mM Hepes (pH 7·4).…”

Impact of PPARγ overexpression and activation on pancreatic islet gene expression profile analyzed with oligonucleotide microarrays

“…First, of four morbidly obese individuals carrying a rare activating mutation (Pro 113 Glu) of PPAR␥2 (38), three were diabetic with decreased circulating insulin levels. Second, activation of PPAR␥1 has been shown to inhibit glucose-stimulated insulin release ex vivo both from a tumoral ␤-cell line (34) and from primary islets (3). Third, PPAR␥ expression is increased more than fivefold in islets from ZDF rats (53), suggesting that PPAR␥ induction may also negatively regulate insulin release in this model.…”