Pancreatic beta-cell growth and survival in the onset of type 2 diabetes: a role for protein kinase B in the Akt?
The control of pancreatic beta-cell growth and survival in the adult plays a pivotal role in the pathogenesis of type 2 diabetes. In certain insulin-resistant states, such as obesity, the increased insulin-secretory demand can often be compensated for by an increase in beta-cell mass, so that the onset of type 2 diabetes is avoided. This is why approximately two-thirds of obese individuals do not progress to type 2 diabetes. However, the remaining one-third of obese subjects that do acquire type 2 diabetes do so because they have inadequate compensatory beta-cell mass and function. As such, type 2 diabetes is a disease of insulin insufficiency. Indeed, it is now realized that, in the vast majority of type 2 diabetes cases, there is a decreased beta-cell mass caused by a marked increase in beta-cell apoptosis that outweighs rates of beta-cell mitogenesis and neogenesis. Thus a means of promoting beta-cell survival has potential therapeutic implications for treating type 2 diabetes. However, understanding the control of beta-cell growth and survival at the molecular level is a relatively new subject area of research and still in its infancy. Notwithstanding, recent advances have implicated signal transduction via insulin receptor substrate-2 (IRS-2) and downstream via protein kinase B (PKB, also known as Akt) as critical to the control of beta-cell survival. In this review, we highlight the mechanism of IRS-2, PKB, and anti-apoptotic PKB substrate control of beta-cell growth and survival, and we discuss whether these may be targeted therapeutically to delay the onset of type 2 diabetes.
Pacific Northwest Research Institute, 720 Broadway, Seattle, WA 98122, USA.
Lorna M
LM
Dickson
Christopher J
CJ
Rhodes
D000328:Adult; D000818:Animals; D017209:Apoptosis / Q000502:physiology; D002470:Cell Survival; D003924:Diabetes Mellitus, Type 2 / Q000150:complications / Q000503:physiopathology* / Q000628:therapy; D006801:Humans; D055504:Insulin Receptor Substrate Proteins; D047908:Intracellular Signaling Peptides and Proteins; D007515:Islets of Langerhans / Q000201:enzymology* / Q000254:growth & development* / Q000473:pathology; D051379:Mice; D009765:Obesity / Q000150:complications / Q000503:physiopathology*; D010750:Phosphoproteins / Q000378:metabolism*; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism* / Q000627:therapeutic use; D011505:Protein-Tyrosine Kinases / Q000378:metabolism*; D011518:Proto-Oncogene Proteins / Q000378:metabolism* / Q000627:therapeutic use; D051057:Proto-Oncogene Proteins c-akt; D051381:Rats; D015398:Signal Transduction
C526297:IRS2 protein, human; D055504:Insulin Receptor Substrate Proteins; D047908:Intracellular Signaling Peptides and Proteins; C526298:Irs2 protein, mouse; C526299:Irs2 protein, rat; D010750:Phosphoproteins; D011518:Proto-Oncogene Proteins; D011505:Protein-Tyrosine Kinases; C494918:AKT1 protein, human; C494920:Akt1 protein, rat; D017346:Protein Serine-Threonine Kinases; D051057:Proto-Oncogene Proteins c-akt