Islet Amyloid Polypeptide Amyloid Deposits & Diabetic Abnormalities
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Islet Amyloid Polypeptide Amyloid Deposits & Diabetic Abnormalities

By March 30, 2018 No Comments

Originally Posted on JEM | 1 August 2017

scientist studying Islet Amyloid Polypeptide Amyloid Deposits & Diabetic Abnormalities

Although a large proportion of patients with type 2 diabetes (T2D)F accumulate misfolded protein aggregates composed of the islet amyloid polypeptide (IAPP), its role in the disease is unknown. Here, we show that pancreatic IAPP aggregates can promote the misfolding and aggregation of endogenous IAPP in islet cultures obtained from transgenic mouse or healthy human pancreas.

Islet homogenates immunodepleted with anti-IAPP–specific antibodies were not able to induce IAPP aggregation. Importantly, intraperitoneal inoculation of pancreatic homogenates containing IAPP aggregates into transgenic mice expressing human IAPP dramatically accelerates IAPP amyloid deposits, which was accompanied by clinical abnormalities typical of T2D, including hyperglycemia, impaired glucose tolerance, and a substantial reduction on β cell number and mass.

Finally, induction of IAPP deposition and diabetic abnormalities were also induced in vivo by administration of IAPP aggregates prepared in vitro using pure, synthetic IAPP. Our findings suggest that some of the pathologic and clinical alterations of T2D might be transmissible through a similar mechanism by which prions propagate in prion diseases.

Type 2 diabetes (T2D) mellitus is characterized by hyperglycemia, insulin resistance, defective insulin secretion, loss of β cell function and mass, and accumulation of amyloid in the islets of Langerhans (Stumvoll et al., 2005). The cause of T2D is not completely understood but is suspected to be related to a combination of lifestyle and genetic factors. The disease is due to insufficient insulin production from β cells in the setting of insulin resistance. However, not all people with insulin resistance develop diabetes (Polonsky, 2000) because an impairment of insulin secretion from pancreatic β cell dysfunction is required (Kahn, 2003). Dysfunction and loss of β cells has been associated with glucolipotoxicity (Poitout and Robertson, 2002; El-Assaad et al., 2003), islet cholesterol accumulation (Brunham et al., 2010), and islet inflammation (Donath and Shoelson, 2011). However, compelling evidence suggests that accumulation of amyloid aggregates in the islets of Langerhans might significantly contribute to β cell dysfunction and disease (Hull et al., 2004; Haataja et al., 2008; Jurgens et al., 2011; Mukherjee et al., 2015).

Islet amyloid deposits, composed predominantly of a misfolded and aggregated form of the islet amyloid poly-peptide (IAPP), are observed in >90% of patients with T2D (Westermark, 1972; Clark et al., 1988; Betsholtz et al., 1989; Johnson et al., 1989). Autopsy studies in humans suggest that islet amyloid is associated with the loss of β cells mass (Clark et al., 1988). Mutations in the IAPP gene have been linked with an increased risk for T2D (Novials et al., 2001). Longitudinal studies in animals that spontaneously develop T2D (nonhuman primates and domestic cats) showed that detection of IAPP aggregates precedes β cell dysfunction and clinical signs of the disease (Howard, 1986; de Koning et al., 1993; Ma et al., 1998). Transgenic mice overexpressing human IAPP (hIAPP) develop islet amyloidosis and, associated to IAPP misfolding and oligomerization, the animals exhibit β cell loss, impaired insulin production, and fasting hypergly-cemia (Janson et al., 1996).

Overall, these results suggest an important role for IAPP misfolding and aggregation in islet pathology responsible for T2D. This finding does not contradict the widely accepted fact that insulin resistance is very important for T2D pathogenesis. Indeed, it is very likely that insulin resistance has a key role in IAPP aggregation because insulin resistance leads to an increase in IAPP production, Islet amyloid deposits, composed predominantly of a misfolded and aggregated form of the islet amyloid polypeptide (IAPP), are observed in >90% of patients with T2D (Westermark, 1972; Clark et al., 1988; Betsholtz et al., 1989; Johnson et al., 1989). Autopsy studies in humans suggest that islet amyloid is associated with the loss of β cells mass (Clark et al., 1988). Mutations in the IAPP gene have been linked with an increased risk for T2D (Novials et al., 2001). Longitudinal studies in animals that spontaneously develop T2D (nonhuman primates and domestic cats) showed that detection of IAPP aggregates precedes β cell dysfunction and clinical signs of the disease (Howard, 1986; de Koning et al., 1993; Ma et al., 1998).

Transgenic mice overexpressing human IAPP (hIAPP) develop islet amyloidosis and, associated to IAPP misfolding and oligomerization, the animals exhibit β cell loss, impaired insulin production, and fasting hyperglycemia (Janson et al., 1996). Overall, these results suggest an important role for IAPP misfolding and aggregation in islet pathology responsible for T2D. This finding does not contradict the widely accepted fact that insulin resistance is very important for T2D pathogenesis. Indeed, it is very likely that insulin resistance has a key role in IAPP aggregation because insulin resistance leads to an increase in IAPP production, aggregates were removed with antibodies specific to IAPP. Interestingly, associated to IAPP accumulation, animals developed some of the typical clinical abnormalities of T2D, including hyperglycemia, impaired glucose tolerance, and loss of β cells. Finally, islet pathology and associated clinical alterations were induced by administration of in vitro, prepared IAPP aggregates made from pure, synthetic hIAPP. Our findings suggest that misfolded IAPP can self-propagate in a manner reminiscent of infectious prions and that IAPP accumulation may have an important role in islet dysfunction in T2D.

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