Islet amyloid and type 2 diabetes: overproduction or inadequate clearance and detoxification?

Abstract

C o m m e n t a r y 3 2 9 2 jci.org Volume 124 Number 8 August 2014Islet amyloid and type 2 diabetes: overproduction or inadequate clearance and detoxification?Dhananjay Gupta and Jack L. LeahyDivision of Endocrinology, Diabetes and Metabolism and Department of Medicine, University of Vermont, Burlington, Vermont, USA. Type 2 diabetes mellitus and the pancreatic islet β cellType 2 diabetes mellitus is a complex metabolic disorder that is comprised of defective insulin action in the periphery as well as within the liver and adipose tissue. Numerous cross-sectional and prospective studies have shown that what determines whether a person develops diabetes resides within their pancreatic β cells (1, 2). Insulin resistance is common in our modern society due to extenuating factors, including obesity, poor dietary and lifestyle habits, disordered sleep, and emotional stress. However, β cell compensation, the normal biological counter response of hyperinsulinemia, prevents most individuals from becoming diabetic. In turn, a defining feature of those at risk for type 2 diabetes is a defective β cell compensation response, with subtle β cell dysfunction evident even when blood glucose is still in the normal glucose tolerance range (1-3). As metabolic demands exceed an individual's capacity for β cell compensation, glucose levels rise along with the onset of a multidimensional pathogenic response in β cells that is likely driven by glucotoxicity, lipotoxicity, ER and oxidative stress, inflammation, and dedifferentiation. Once the pathogenic cascade is initiated, there is a progressive loss of β cell mass and function that results in worsening hyperglycemia and a waning response to therapy, which are both typical of this disease.Research into the mechanisms that promote β cell dysfunction has been performed mostly in isolated cells, cell lines, or animal models, given the inability to perform pancreas biopsies on healthy subjects for clinical research purposes. While these models are useful to probe the biology of the β cell pathogenic processes, it remains unclear which β cell dysfunction-promoting mechanism is most active for induction of the inadequate β cell compensation in human type 2 diabetes. Studies performed with isolated islets from brain-dead pancreas donors and pathological pancreas specimens -from nondiabetic and type 2 diabetic subjects -have provided evidence that supports multiple pathways for β cell dysfunction. Unfortunately, these studies lack the ability to identify the initial steps in this process that occur before the onset of diabetes and directly cause the β cell dysfunction. It is clear that both reduced β cell mass and lowered insulin secretory function are elements of the β cell pathophysiology of type 2 diabetes. Furthermore, a defective β cell compensation system, which predisposes patients to type 2 diabetes, is operative well before the diagnosis of abnormal blood glucose values by current criteria (1, 2). As such, the hunt continues for mechanisms for β cell dysfunction that are independen...

The receptor for advanced glycation endproducts is a mediator of toxicity by IAPP and other proteotoxic aggregates: Establishing and exploiting common ground for novel amyloidosis therapies

“…There are likely to be multiple mechanisms of toxicity and a variety have been reported; their relative contributions could depend upon cellular conditions. Defects in autophagy, increased production of pro‐inflammatory cytokines, endoplasmic reticulum (ER) stress, permeabilization of cell membranes, mitochondrial membrane damage, activation of Calpain‐2, receptor‐mediated mechanisms including Fas and RAGE activation linked to induction of cell stress and apoptotic signaling pathways, have all been proposed to contribute to IAPP‐induced β‐cell cytotoxicity …”

“…The resulting accumulation of amyloidogenic aggregates can lead to autophagy‐mediated lysosomal cell death or dysfunction. Along these lines, the overexpression of hIAPP in β‐cells has been reported to lead to impairment in autophagy . Stimulation of autophagy has been shown to protect against IAPP toxicity, while inhibition of autophagy‐lysosomal degradation has been shown to enhance hIAPP‐induced β‐cell apoptosis .…”

“…Defects in autophagy, increased production of pro-inflammatory cytokines, endoplasmic reticulum (ER) stress, permeabilization of cell membranes, mitochondrial membrane damage, activation of Calpain-2, receptor-mediated mechanisms including Fas and RAGE activation linked to induction of cell stress and apoptotic signaling pathways, have all been proposed to contribute to IAPP-induced b-cell cytotoxicity. 2,[7][8][9]111,[116][117][118][119][120][121][122][123][124][125][126][127][128][129][130][131][132] Impairment of autophagy, and ER stress in hIAPP-induced b-cell proteotoxicity. Defects in autophagy play a role in the toxicity of a range of amyloidogenic proteins.…”

“…Along these lines, the overexpression of hIAPP in b-cells has been reported to lead to impairment in autophagy. 125,129,130 Stimulation of autophagy has been shown to protect against IAPP toxicity, while inhibition of autophagy-lysosomal degradation has been shown to enhance hIAPP-induced b-cell apoptosis. 125,130,[133][134][135] ER stress, defects in the unfolded protein response (UPR) and in ER-associated protein degradation have all been proposed to contribute to hIAPP-induced b-cell death in T2D.…”

“…125,129,130 Stimulation of autophagy has been shown to protect against IAPP toxicity, while inhibition of autophagy-lysosomal degradation has been shown to enhance hIAPP-induced b-cell apoptosis. 125,130,[133][134][135] ER stress, defects in the unfolded protein response (UPR) and in ER-associated protein degradation have all been proposed to contribute to hIAPP-induced b-cell death in T2D. ProIAPP and partially processed proIAPP could contribute to toxicity in cases where toxicity arises from intracellular aggregates since proIAPP mis-processing occurs in T2D, and processing is completed in the Golgi and insulin secretory granules.…”