Trends in Molecular Medicine
ReviewType 2 diabetes as a protein misfolding disease
Section snippets
Protein misfolding and disease
PMDs are diseases where at least one protein or peptide has been shown to misfold, aggregate, and accumulate in tissues where the disease-specific damage occurs. There are at least 30 different PMDs, including several neurodegenerative disorders such as AD, PD, Huntington disease (HD), transmissible spongiform encephalopathies (TSEs), and amyotrophic lateral sclerosis (ALS), as well as diverse systemic disorders such as familial amyloid polyneuropathy, T2D, secondary amyloidosis, and
The role of protein misfolding and aggregation in T2D
T2D is a complex metabolic disease characterized by chronic insulin resistance and progressive loss of β-cell function and β-cell mass [4], which leads to impaired insulin release and hyperglycemia. In a prediabetic context, compensatory increases in insulin secretion from β cells protects against hyperglycemia. However, genetic and environmental factors are believed to predispose some individuals (∼20% of the population) to β-cell failure under conditions of chronic insulin resistance [5].
The biological, biochemical, and aggregation properties of IAPP
To conceptualize the process of IAPP aggregation, we will describe the biological and biochemical features of IAPP, its sequence propensity to aggregate, and the pathways responsible for IAPP misfolding and aggregation. The IAPP amino acid sequence, especially at the amino and carboxyl termini, is highly conserved, suggesting an important physiological role [34]. The functions that have been proposed for IAPP include inhibition of insulin secretion, delay in gastric emptying, diminished
IAPP synthesis, processing, and clearance
IAPP is predominantly expressed by β cells as the 89-amino-acid pre-pro-IAPP. The 22-amino-acid signaling peptide is cleaved off in the endoplasmic reticulum (ER), producing pro-IAPP, which is further processed by the endoproteases prohormone convertase (PC) 2, PC1/3, and carboxypeptidase E in the late Golgi and secretory granules in a pH-dependent manner 56, 57, 58. These enzymes are also responsible for processing proinsulin. Post-translational modifications, including amidation of the COOH
Removing misfolded proteins
In long-lived cells such as neurons and β cells, it is crucial to have an efficient protein degradation machinery to avoid toxicity arising from sustained accumulation of damaged proteins. Cells mainly deploy three mechanisms to remove misfolded proteins: the ubiquitin proteasome system (UPS), autophagy, and aggresome formation. Defects in these mechanisms may result in the accumulation of misfolded and aggregated proteins. Table 1 summarizes current evidence implicating dysfunction of cellular
Mechanisms of IAPP-induced toxicity
Several mechanisms have been proposed for IAPP aggregate-mediated β-cell dysfunction and death in T2D. Membrane permeabilization, calpain hyperactivation, induction of ER stress, dysregulation of the clearance pathways, and induction of inflammation have all been reported (Figure 2). Interestingly, the same pattern of cellular defects has also been described in other PMDs, mostly those affecting the CNS [49]. Current evidence implicating protein aggregate-mediated cellular dysfunction in T2D
IAPP aggregates in non-pancreatic tissues
Severe and uncontrolled diabetes damages numerous non-pancreatic tissues, including kidney (diabetic nephropathy), sensory neurons (diabetic neuropathy), and heart (diabetic cardiomyopathy). IAPP deposits have been observed in several of these tissues in T2D patients. In a study conducted on biopsy-proven T2D nephropathy patients, 48.3% exhibited IAPP deposits in the kidneys [136]. The incidence of renal lesions such as glomerular nodular lesions and glomerulosclerosis was greater and tubular
Concluding remarks
The presence of misfolded IAPP aggregates of various sizes ranging from small soluble oligomers to large fibrillar aggregates deposited in the islets of Langerhans of patients affected by T2D is well established. The crucial question is whether these aggregates are inert bystanders that result as a consequence of the tissue damage during the disease or whether they play a crucial role in the pathogenesis. The diabetes field has mostly ignored the putative relevance of IAPP aggregates in T2D.
Acknowledgments
This study was supported in part by a grant from the National Institutes of Health (R01 GM100453) to C.S. and (R01 DK059579) to P.C.B.
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