AMP-Activated Protein Kinase (AMPK) Mediates Nutrient Regulation of Thioredoxin-Interacting Protein (TXNIP) in Pancreatic Beta-Cells

Thioredoxin-interacting protein (TXNIP) regulates critical biological processes including inflammation, stress and apoptosis. TXNIP is upregulated by glucose and is a critical mediator of hyperglycemia-induced beta-cell apoptosis in diabetes. In contrast, the saturated long-chain fatty acid palmitate, although toxic to the beta-cell, inhibits TXNIP expression. The mechanisms involved in the opposing effects of glucose and fatty acids on TXNIP expression are unknown. We found that both palmitate and oleate inhibited TXNIP in a rat beta-cell line and islets. Palmitate inhibition of TXNIP was independent of fatty acid beta-oxidation or esterification. AMP-activated protein kinase (AMPK) has an important role in cellular energy sensing and control of metabolic homeostasis; therefore we investigated its involvement in nutrient regulation of TXNIP. As expected, glucose inhibited whereas palmitate stimulated AMPK. Pharmacologic activators of AMPK mimicked fatty acids by inhibiting TXNIP. AMPK knockdown increased TXNIP expression in presence of high glucose with and without palmitate, indicating that nutrient (glucose and fatty acids) effects on TXNIP are mediated in part via modulation of AMPK activity. TXNIP is transcriptionally regulated by carbohydrate response element-binding protein (ChREBP). Palmitate inhibited glucose-stimulated ChREBP nuclear entry and recruitment to the Txnip promoter, thereby inhibiting Txnip transcription. We conclude that AMPK is an important regulator of Txnip transcription via modulation of ChREBP activity. The divergent effects of glucose and fatty acids on TXNIP expression result in part from their opposing effects on AMPK activity. In light of the important role of TXNIP in beta-cell apoptosis, its inhibition by fatty acids can be regarded as an adaptive/protective response to glucolipotoxicity. The finding that AMPK mediates nutrient regulation of TXNIP may have important implications for the pathophysiology and treatment of diabetes

Apoptotic, Regenerative, And Immune-Related Signaling in Human Islets from Type 2 Diabetes Individuals

Islet dysfunction is a primary cause of developing type 2 diabetes mellitus (T2DM). Events leading to islet failure are still poorly defined due to the complexity of the disease and scarcity of human T2DM islets. The aim of the present study was to identify cellular mechanisms involved in the T2DM pathophysiology by protein profiling islets obtained from T2DM individuals and age- and weight-matched controls using liquid chromatography Fourier transform ion cyclotron resonance mass spectrometry and surface enhanced laser desorption/ionization time-of-flight mass spectrometry. In T2DM islets, multiple differentially expressed proteins correlated with insulin secretion. When these T2DM islet proteins were analyzed for differential pathway activation, three of the five most activated pathways were pathways of cell arrest and apoptosis (p53, caspase, stress-activated), one represented immune-response (Fas), and the most activated pathway was connected with proliferation and regeneration (E2F). Among the inactivated pathways, three out of five were pathways of proliferation and regeneration (insulin, PRL, PDGF). The present study is the first to report differential activation of specific pathways during T2DM islet deterioration. The information about alterations in pathway signaling patterns may open new ways to develop strategies aimed at restoring islet cell function and survival

The β-cell in human type 2 diabetes

β-cell dysfunction is central to the onset and progression of type 2 diabetes. Reduced islet number and/or diminished β-cell mass/volume in the pancreas of type 2 diabetic subjects have been reported by many authors, mainly due to increased apoptosis not compensated for by adequate regeneration. In addition, ultrastructural analysis has shown reduced insulin granules and morphological changes in several β-cell organelles, including mitochondria and endoplasmic reticulum. Several quantitative and qualitative defects of β-cell function have been described in human type 2 diabetes using isolated islets, including alterations in early phase and glucose-stimulated insulin release. These survival and functional changes are accompanied by modifications of islet gene and protein expression. The impact of genotype in affecting β-cell function and survival has been addressed in a few studies, and a number of gene variants have been associated with β-cell dysfunction. Among acquired factors, the role of glucotoxicity and lipotoxicity could be of particular importance, due to the potential deleterious impact of elevated levels of glucose and/or free fatty acids in the natural history of β-cell damage. More recently, it has been proposed that inflammation might also play a role in the dysfunction of the β-cell in type 2 diabetes. Encouraging, although preliminary, data show that some of these defects might be directly counteracted, at least in part, by appropriate in vitro pharmacological intervention

AMP-activated protein kinase and metabolic control.

28 pagesInternational audienceAMP-activated protein kinase AMP-activated protein kinase (AMPK AMPK ), a phylogenetically conserved serine/threonine protein kinase, is a major regulator of cellular and whole-body energy homeostasis that coordinates metabolic pathways in order to balance nutrient supply with energy demand. It is now recognized that pharmacological activation of AMPK improves blood glucose homeostasis, lipid profile, and blood pressure in insulin-resistant rodents. Indeed, AMPK activation mimics the beneficial effects of physical activity or those of calorie restriction calorie restriction by acting on multiple cellular targets. In addition, it is now demonstrated that AMPK is one of the probable (albeit indirect) targets of major antidiabetic drugs drugs including the biguanides (metformin metformin ) and thiazolidinedione thiazolidinedione s, as well as of insulin-sensitizing adipokines (e.g., adiponectin adiponectin ). Taken together, such findings highlight the logic underlying the concept of targeting the AMPK pathway for the treatment of metabolic syndrome and type 2 diabetes