Uncoupling Protein 2 and Islet Function

Abstract

Stressors such as chronic hyperglycemia or hyperlipidemia may lead to insufficient insulin secretion in susceptible individuals, contributing to type 2 diabetes. The molecules mediating this effect are just beginning to be identified. Uncoupling protein (UCP)-2 may be one such negative modulator of insulin secretion. Accumulating evidence shows that ␤-cell UCP2 expression is upregulated by glucolipotoxic conditions and that increased activity of UCP2 decreases insulin secretion. Mitochondrial superoxide has been identified as a posttranslational regulator of UCP2 activity in islets; thus, UCP2 may provide protection to ␤-cells at one level while simultaneously having detrimental effects on insulin secretion. Interestingly, the latter appears to be the dominant outcome, because UCP2 knockout mice display an increased ␤-cell mass and retained insulin secretion capacity in the face of glucolipotoxicity. Diabetes 53 (Suppl. 1):S136 -S142, 2004 H ealthy pancreatic ␤-cells are poised to respond rapidly and efficiently to acute changes in circulating nutrient availability to maintain metabolic homeostasis. However, it is well recognized that chronic exposure to overnutrition, such as what occurs in obesity, results in a blunting of the insulin response to an acute stimulus. The mechanisms by which this adaptation occurs are hotly debated but, based on recent analyses of gene expression using oligonucleotide microarray technology, include multiple enzymes involved in glucose and fat metabolism (1,2). Key rate-limiting enzymes, such as carnitine palmitoyl transferase (CPT)-1, have been identified as crucial mediators of altered metabolism of fat and glucose leading to impaired insulin secretion (3). Until recently, regulatory proteins that participate specifically in downregulation of insulin secretion have received little attention. The discovery that uncoupling protein (UCP)-2 is present in pancreatic islets and ␤-cell lines (4) has led to the suggestion that such molecules can participate in the long-term adaptation of the ␤-cell to increased nutrient availability and contribute to the suppression of glucose-stimulated insulin secretion (GSIS) (5). UCP2The existence of UCP2 was first described in 1997 in multiple tissues (6 -8), including the pancreas (6). It was subsequently localized in rat (4,5) and human pancreatic (9,10) islets. In general, UCPs function to decrease metabolic efficiency by dissociating substrate oxidation in the mitochondrion from ATP synthesis. This is thought to be accomplished by promoting net translocation of protons from the intermembrane space, across the inner mitochondrial membrane to the matrix, thereby dissipating the potential energy available for conversion of ADP to ATP despite continued oxidation of fuels (11). This uncoupling effect then leads to homologue-and tissue-specific functions such as thermogenesis for UCP1 (12), regulation of free fatty acid (FFA) metabolism and transport for UCP2 and UCP3 (11,13,14), decreasing reactive oxygen species (ROS) formation (UCP1 and UCP2) (15,...

Adverse physicochemical properties of tripalmitin in beta cells lead to morphological changes and lipotoxicity in vitro

“…INS1 beta cells (rat insulinoma, passage [9][10][11][12][13][14][15][16][17][18][19] were cultured in RPMI 1640 (Sigma, Poole, UK), 11 mmol/l glucose, 10% fetal bovine serum (FBS), 2 mmol/l L-glutamine, 50 μmol/l β-mercaptoethanol, 10 mmol/l HEPES, 1 mmol/l sodium pyruvate, 50 U/ml penicillin and 50 μg/ ml streptomycin (Gibco, Paisley, UK) in 5% CO 2 . COS7 cells (monkey kidney fibroblasts) were cultured in RPMI 1640, 11 mmol/l glucose, 10% FBS, 2 mmol/l L-glutamine, 50 U/ml penicillin and 50 μg/ml streptomycin (Gibco) in 5% CO 2 .…”

“…Hence, TG accumulation could play a role in inhibition of GSIS. The intermediates of lipid metabolism change expression of beta cell genes and proinsulin biosynthesis [12,13], and NEFA or their metabolites have been proposed to increase uncoupling protein 2 and modulate insulin secretion through decreased production of ATP [14,15]. NEFA have also been shown to reduce cellular viability and induce beta-cell apoptosis [16].…”

Mitochondrial uncoupling protein 2 in pancreatic β‐cells

“…This reduction in protonmotive force will decrease oxidative phosphorylation, ATP/ADP ratio and GSIS. There has, therefore, been a great deal of interest in the possibility that endogenous uncoupling proteins in the β-cell might attenuate GSIS [4][5][6][7][8][9][10][11].Uncoupling protein 2 (UCP2), a member of the uncoupling protein family, is present in native β-cells [11]. Its concentration has been measured in a β-cell model, cultured insulinoma (INS-1E) cells, to be a modest 8 ng/mg mitochondrial protein [12].…”

Asociación de variantes en genes de las proteínas desacoplantes con diabetes mellitus tipo 2 en una población del nordeste colombiano

“…Estas relaciones varían según la proteína particular y su expresión en diferentes tejidos. En diversos estudios se han hallado, principalmente, relaciones entre alteraciones en UCP1 y UCP3, con obesidad y metabolismo de lípidos, en UCP2, con fallas en la secreción de insulina, y en UCP2 y UCP3, con protección contra especies reactivas de oxígeno (6,7,10,11). Además, en el último año, UCP1 y UCP3 se han asociado con la secreción de insulina estimulada por glucosa (5,9).…”