Amyloid Polypeptide

The Durk Pearson & Sandy Shaw®
Life Extension NewsTM
Volume 6 No. 3 • June 2003

Amyloid Polypeptide Forms in Pancreatic Islet Cells in Type 2 Diabetes: Analogous to Alzheimer’s?

A recent paper1 reports that type 2 diabetes is associated with the formation of pancreatic islet amyloid deposits that are associated with and may cause pancreatic beta-cell failure. Islet amyloid polypeptide (IAPP) is a neuroendocrine peptide hormone that is produced and cosecreted with insulin from beta cells. IAPP aggregates and forms fibrils (like the amyloid beta peptide in Alzheimer’s disease) and is thought to be toxic to beta cells. The paper notes that the normal physiological functions of IAPP are not completely understood, but suggestions have included suppression of food intake, gastric emptying, and arginine-stimulated glucagon secretion from pancreatic beta cells. The authors report that a recent study showed that mice lacking IAPP have modestly enhanced glucose-induced insulin secretion and glucose clearance compared to wild-type mice.

Islet amyloid deposits are reported to be found in up to 90% of patients with type 2 diabetes at autopsy, and the degree of amyloid deposition correlates with the severity of the disease in humans. Islet amyloid formation is also said to be associated with reduced beta-cell mass in both diabetic humans and nonhuman primates. Also, amyloid formation is reported to precede the onset of hyperglycemia in monkeys.

Similarly to the aggregated (fibrillar) amyloid deposits in Alzheimer’s that kill neurons, the aggregated (fibrillar) form of IAPP kills beta cells. Also just as in Alzheimer’s, the soluble form of the polypeptide is not toxic. Moreover, the amyloid beta peptides in the brain are direct competitive inhibitors of insulin binding and action;2 it would obviously be a serious problem if the IAPP were also to be doing this in pancreatic beta cells. Thus, there may be a parallel process taking place both in the brains of Alzheimer’s patients and in the pancreatic beta cells of type 2 diabetics. One has to wonder whether substances that may remove aggregated amyloid from the brain or slow its buildup—such as nonsteroidal anti-inflammatory substances,3 melatonin,4 restoring normal cholinergic function,5 the green tea polyphenol epigallocatechin-3-gallate,6 and therapeutic levels of lithium7—would also do the same to the aggregated amyloid in the pancreatic islets.

  1. Marzban et al. Islet amyloid polypeptide and type 2 diabetes. Exp Gerontol 38:347-51 (2003).
  2. Xie Ling et al. Amyloid beta antagonizes insulin-promoted secretion of the amyloid beta protein precursor. J Alz Dis 4:369-74 (2002). “. . . recent findings have demonstrated upregulation of insulin receptors and defective insulin-receptor signal transduction in AD brains.” “. . . [insulin] also reduces intracellular amyloid beta accumulation in neuronal cells.” “In fact the insulin-degrading enzyme (IDE), which is known to degrade both insulin and amyloid beta, may be extremely important for maintaining normal insulin signaling.”
  3. Weggen et al. A subset of NSAIDs lowers amyloidogenic Abeta42 independently of cyclooxygenase activity. Nature 414:212-16 (2001). The paper reports that the NSAIDs ibuprofen, indomethacin, and sulindac sulphide preferentially decrease the highly amyloidogenic Abeta42 peptide produced from a variety of cultured cells by as much as 80%.
  4. Soto et al. Beta-sheet breaker peptides inhibit fibrillogenesis in a rat-brain model of amyloidosis: implications for Alzheimer’s therapy. Nature Med 4(7):822-6 (1998).
  5. Georgievska et al. Cognitive changes and modified processing of amyloid precursor protein in the cortical and hippocampal system after cholinergic synapse loss and muscarinic receptor activation. Proc Natl Acad Sci 96(21):12108-13 (1999).
  6. Levites et al. Neuroprotection and neurorescue against Abeta toxicity and PKC-dependent release of nonamyloidogenic soluble precursor protein by green tea polyphenol epigallocatechin-3-gallate. FASEB J, March 28, 2003.
  7. Phiel et al. GSK-3alpha regulates production of Alzheimer’s disease amyloid-beta peptides. Nature 423:435-9 (2003). “Here we show that therapeutic concentrations of lithium, a GSK-3 [glycogen synthase kinase-3] inhibitor, block production of amyloid beta peptides by interfering with APP [amyloid precursor protein] cleavage at the gamma-secretase step . . .”

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