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β-cell failure as a complication of diabetes

  • K. J. Chang-Chen
  • R. Mullur
  • E. Bernal-MizrachiEmail author
Article

Abstract

Type 2 diabetes mellitus is a complex disease characterized by β-cell failure in the setting of insulin resistance. In early stages of the disease, pancreatic β-cells adapt to insulin resistance by increasing mass and function. As nutrient excess persists, hyperglycemia and elevated free fatty acids negatively impact β-cell function. This happens by numerous mechanisms, including the generation of reactive oxygen species, alterations in metabolic pathways, increases in intracellular calcium and the activation of endoplasmic reticulum stress. These processes adversely affect β-cells by impairing insulin secretion, decreasing insulin gene expression and ultimately causing apoptosis. In this review, we will first discuss the regulation of β-cell mass during normal conditions. Then, we will discuss the mechanisms of β-cell failure, including glucotoxicity, lipotoxicity and endoplasmic reticulum stress. Further research into mechanisms will reveal the key modulators of β-cell failure and thus identify possible novel therapeutic targets. Type 2 diabetes mellitus is a multifactorial disease that has greatly risen in prevalence in part due to the obesity and inactivity that characterize the modern Western lifestyle. Pancreatic β-cells possess the potential to greatly expand their function and mass in both physiologic and pathologic states of nutrient excess and increased insulin demand. β-cell response to nutrient excess occurs by several mechanisms, including hypertrophy and proliferation of existing β-cells, increased insulin production and secretion, and formation of new β-cells from progenitor cells [1, 2]. Failure of pancreatic β-cells to adequately expand in settings of increased insulin demand results in hyperglycemia and diabetes. In this review, we will first discuss the factors involved in β-cell growth and then discuss the mechanisms by which β-cell expansion fails and leads to β-cell failure and diabetes (Fig. 1).
Fig. 1

The mechanisms by which -cell failure and apoptosis occur are complex, not completely unraveled and involve the interplay of numerous factors and conditions. These factors are summarized in this figure. Glucotoxicity and lipotoxicity lead to the production of ROS, which activate JNK. JNK activity leads to a decrease in IRS signaling and may directly be involved in decreased Pdx-1 activity by translocation from the nucleus to the cytoplasm [183]. In addition, glucose and FA have both been found to induce ER stress. Chronic glucose elevation inhibits FA oxidation and favors the generation of ceramide and lipid partitioning, which ultimately results in β-cell dysfunction and apoptosis. AMPK activation promotes fatty acid oxidation by phosphorylation and inhibition of acetyl-CoA carboxylase or via down regulation of the transcription factor sterol-regulatory-element-binding-protein-1c (SREBP1c) and subsequent decreases in acetyl-CoA carboxylase. Glucose and FA also activate the UPR response and induce ER stress. The ER stress response and its effectors are activated in response to misfolded proteins in order to protect β-cells from apoptosis; however, activation of these processes under conditions of long-term elevation of FFA and glucose can lead to β-cell dysfunction and ultimately apoptosis. Activation of ER stress leads to inhibition of insulin mRNA and protein expression and may also be pro-apoptotic. The mechanisms for induction of apoptosis by ER stress are not completely known, but induction of CHOP is an important component. In addition, induction of ATF3 and SREBP can downregulate IRS signaling by repressing IRS2 transcription. One interesting finding is that inhibition of IRS signaling seems to be a common pathway induced by the majority of the mechanisms described for β-cell failure. An additional event is the increase in mTOR signaling by nutrient excess (glucose). This results in negative feedback inhibition on IRS1 and possibly IRS2 by activation of S6K signaling. The decrease in IRS signaling induces GSK3β and Foxo1 function. Activation of these molecules ultimately reduces Pdx1 levels and increases the levels of the cell cycle inhibitor p27

Keywords

β-cell failure Lipotoxicity Glucotoxicity Glucolipotoxicity Diabetes 

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Copyright information

© Springer Science+Business Media, LLC 2008

Authors and Affiliations

  • K. J. Chang-Chen
    • 1
  • R. Mullur
    • 2
  • E. Bernal-Mizrachi
    • 3
    Email author
  1. 1.Division of Endocrinology, Metabolism and Lipid ResearchWashington University School of MedicineSt. LouisUSA
  2. 2.Division of Medical Education, Department of Internal MedicineWashington University School of MedicineSt. LouisUSA
  3. 3.Washington University School of MedicineSt. LouisUSA

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