VMP1-related autophagy induced by a fructose-rich diet in β-cells: its prevention by incretins

Abstract

The aim of the present study was to demonstrate the role of autophagy and incretins in the fructose-induced alteration of β-cell mass and function. Normal Wistar rats were fed (3 weeks) with a commercial diet without (C) or with 10% fructose in drinking water (F) alone or plus sitagliptin (CS and FS) or exendin-4 (CE and FE). Serum levels of metabolic/endocrine parameters, β-cell mass, morphology/ultrastructure and apoptosis, vacuole membrane protein 1 (VMP1) expression and glucose-stimulated insulin secretion (GSIS) were studied. Complementary to this, islets isolated from normal rats were cultured (3 days) without (C) or with F and F + exendin-4 or chloroquine. Expression of autophagy-related proteins [VMP1 and microtubule-associated protein light chain 3 (LC3)], apoptotic/antiapoptotic markers (caspase-3 and Bcl-2), GSIS and insulin mRNA levels were measured. F rats developed impaired glucose tolerance (IGT) and a significant increase in plasma triacylglycerols, thiobarbituric acid-reactive substances, insulin levels, homoeostasis model assessment (HOMA) for insulin resistance (HOMA-IR) and β-cell function (HOMA-β) indices. A significant reduction in β-cell mass was associated with an increased apoptotic rate and morphological/ultrastructural changes indicative of autophagic activity. All these changes were prevented by either sitagliptin or exendin-4. In cultured islets, F significantly enhanced insulin mRNA and GSIS, decreased Bcl-2 mRNA levels and increased caspase-3 expression. Chloroquine reduced these changes, suggesting the participation of autophagy in this process. Indeed, F induced the increase of both VMP1 expression and LC3-II, suggesting that VMP1-related autophagy is activated in injured β-cells. Exendin-4 prevented islet-cell damage and autophagy development. VMP1-related autophagy is a reactive process against F-induced islet dysfunction, being prevented by exendin-4 treatment. This knowledge could help in the use of autophagy as a potential target for preventing progression from IGT to type 2 diabetes mellitus.

Pleiotropic Effects of GLP-1 and Analogs on Cell Signaling, Metabolism, and Function

“…It should be noted, however, that GLP-1 induced changes can vary depending on the underling mechanism of stress. For example, while usually promoting autophagy, treatment with GLP-1 analogs in a high fructose fed rat model resulted in apparent inhibition of β-cell autophagy, and increase in β-cell mass and function ( 95 ). The underlying mechanisms and downstream molecular mediators through which GLP-1 influences autophagy remain to be better characterized.…”

Relevance of Autophagy Induction by Gastrointestinal Hormones: Focus on the Incretin-Based Drug Target and Glucagon

“…However, the role of GLP-1 in β-cell autophagy is complex and likely dependent on stress conditions. In a rat model fed with high levels of fructose, GLP-1 analog intervention induced notable inhibition of β cell autophagy and enhanced β cell mass and function (Maiztegui et al, 2017). The detailed molecular regulation of the autophagy system in β cells via GLP-1 receptor signaling requires further investigation.…”

Chronological Appearance of Endocrine and Metabolic Dysfunctions Induced by an Unhealthy Diet in Rats

“…It has been postulated that impairment in glucose metabolism in the liver is one of the earliest reactions to increased flow and availability of fructose [5,[32][33][34]. We previously demonstrated that three weeks-FRD fed rats developed changes in liver glucose and lipid metabolism paralleling endocrine dysfunction (hyperinsulinemia, hyperleptinemia, higher plasminogen activator inhibitor-1 and lower adiponectin levels) and an insulin resistant state [14][15][16][17][18][19][20]. These rats also show increased oxidative stress markers in the liver and pancreatic islets [14,15,20].…”

“…We previously showed that normal rats fed a fructose-rich diet (FRD) for three weeks developed changes in glucose and lipid metabolism together with endocrine dysfunction (hyperinsulinemia, hyperleptinemia, higher plasminogen activator inhibitor-1 and lower adiponectin levels) and an insulin resistant (IR) state [14][15][16][17][18][19][20]. All these changes suggest a complex multi-organ function compromise in animals fed a FRD: adipose tissue (evidenced by increased free fatty acids levels), liver (suggested by several alterations of carbohydrate metabolism and triglyceride levels), and endocrine pancreas (since hyperinsulinemia together with impaired glucose tolerance indicate β-cell functional compromise unable to cope with the enhanced demand for insulin due to IR).…”