Matrix Metalloproteinase-9 Reduces Islet Amyloid Formation by Degrading Islet Amyloid Polypeptide

VA Puget Sound Health Care System and University of Washington, United States
Journal of Biological Chemistry (Impact Factor: 4.57). 12/2012; 288(5). DOI: 10.1074/jbc.M112.438457
Source: PubMed


Deposition of islet amyloid polypeptide (IAPP) as amyloid is a pathological hallmark of the islet in type 2 diabetes, which is toxic to β cells. We previously showed that the enzyme neprilysin reduces islet amyloid deposition, and thereby reduces β-cell apoptosis, by inhibiting fibril formation. Two other enzymes, matrix metalloproteinase (MMP)-2 and MMP-9, are extracellular gelatinases capable of degrading another amyloidogenic peptide, Aβ, the constituent of amyloid deposits in Alzheimers disease. We therefore investigated whether MMP-2 and MMP-9 play a role in reducing islet amyloid deposition. MMP-2 and MMP-9 mRNA were present in mouse islets but only MMP-9 activity was detectable. In an islet culture model where human IAPP (hIAPP) transgenic mouse islets develop amyloid but non-transgenic islets do not, a broad-spectrum MMP inhibitor (GM6001) and an MMP-2/9 inhibitor increased amyloid formation and the resultant β-cell apoptosis. In contrast, a specific MMP-2 inhibitor had no effect on either amyloid deposition or β-cell apoptosis. Mass spectrometry demonstrated that MMP-9 degraded amyloidogenic hIAPP but not non-amyloidogenic mouse IAPP. Thus, MMP-9 constitutes an endogenous islet protease that limits islet amyloid deposition and its toxic effects via degradation of hIAPP. As islet MMP-9 mRNA levels are decreased in type 2 diabetic subjects, islet MMP-9 activity may also be decreased in human type 2 diabetes, thereby contributing to increased islet amyloid deposition and β-cell loss. Approaches to increase islet MMP-9 activity could reduce or prevent amyloid deposition and its toxic effects in type 2 diabetes.

1 Follower
8 Reads
  • Source
    • "Similarly, increasing islet numbers decreased the SD and led to smaller sample sizes. Based on these determinations , it would appear that 4 to 8 separate studies using 30 islets will provide sufficient power to detect treatment effects that are frequently observed with interventions that change amyloid deposition, β-cell area and/ or β-cell apoptosis (Zraika et al. 2009; Zraika et al. 2010; Aston-Mourney et al. 2011; Subramanian et al. 2012; Aston-Mourney et al. 2013). "
    [Show abstract] [Hide abstract]
    ABSTRACT: Culture of isolated rodent islets is widely used in diabetes research to assess different endpoints, including outcomes requiring histochemical staining. As islet yields during isolation are limited, we determined the number of islets required to obtain reliable data by histology. We found that mean values for insulin-positive β-cell area/islet area, thioflavin S-positive amyloid area/islet area and β-cell apoptosis do not vary markedly when more than 30 islets are examined. Measurement variability declines as more islets are quantified, so that the variability of the coefficient of variation (CV) in human islet amyloid polypeptide (hIAPP) transgenic islets for β-cell area/islet area, amyloid area/islet area and β-cell apoptosis are 13.20% ± 1.52%, 10.03% ± 1.76% and 6.78% ± 1.53%, respectively (non-transgenic: 7.65% ± 1.17% β-cell area/islet area and 8.93% ± 1.56% β-cell apoptosis). Increasing the number of islets beyond 30 had marginal effects on the CV. Using 30 islets, 6 hIAPP-transgenic preparations are required to detect treatment effects of 14% for β-cell area/islet area, 30% for amyloid area/islet area and 23% for β-cell apoptosis (non-transgenic: 9% for β-cell area/islet area and 45% for β-cell apoptosis). This information will be of value in the design of studies using isolated islets to examine β cells and islet amyloid. © The Author(s) 2015.
    Journal of Histochemistry and Cytochemistry 08/2015; 63(8):663-73. DOI:10.1369/0022155415585995 · 1.96 Impact Factor
    • "[24] Moreover, it was found that metal ion-induced aggregation of IAPP depends also on the origin of the peptide, i.e. if it is hu- man [18] [22] or murine (m-IAPP), [25] and mass spectrometry (MS) has also been applied to elucidate the structure of copper(II)–IAPP complexes and the putative binding sites. [26] On the other hand, IAPP homeostasis seems to be regulated also by the action of some metalloproteases which have been found to be able to degrade [27] [28] [29] this hormone and/or to impede its aggre- gation. [30] In particular, more than 10 years ago, insulin-degrading enzyme (IDE) was suggested to have an important role in the regulation of IAPP homeostasis and aggregation. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Amylin or islet amyloid polypeptide (IAPP) is a 37-residue peptide hormone secreted from the pancreatic islets into the blood circulation and is cleared by peptidases in the kidney. IAPP aggregates are strongly associated with β-cell degeneration in type 2 diabetes, as demonstrated by the fact that more than 95% of patients exhibit IAPP amyloid upon autopsy. Recently, it has been reported that metal ions such as copper(II) and zinc(II) are implicated in the aggregation of IAPP as well as able to modulate the proteolytic activity of IAPP degrading enzymes. For this reason, in this work, the role of the latter metal ions in the degradation of IAPP by insulin-degrading enzyme (IDE) has been investigated by a chromatographic and mass spectrometric combined method. The latter experimental approach allowed not only to assess the overall metal ion inhibition of the human and murine IAPP degradation by IDE but also to have information on copper- and zinc-induced changes in IAPP aggregation. In addition, IDE cleavage site preferences in the presence of metal ions are rationalized as metal ion-induced changes in substrate accessibility. Copyright © 2014 John Wiley & Sons, Ltd.
    Journal of Mass Spectrometry 04/2014; 49(4). DOI:10.1002/jms.3338 · 2.38 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: The DPP-4 inhibitor sitagliptin is an attractive therapy for diabetes as it increases insulin release and may preserve beta-cell mass. However, sitagliptin also increases beta-cell release of human islet amyloid polypeptide (hIAPP), the peptide component of islet amyloid, which is co-secreted with insulin. Thus, sitagliptin treatment may promote islet amyloid formation and its associated beta-cell toxicity. Conversely, metformin treatment decreases islet amyloid formation by decreasing beta-cell secretory demand, and could therefore offset sitagliptin's potential pro-amyloidogenic effects. Sitagliptin treatment has also been reported to be detrimental to the exocrine pancreas. We investigated whether long-term sitagliptin treatment, alone or with metformin, increased islet amyloid deposition and beta-cell toxicity, and induced pancreatic ductal proliferation, pancreatitis and/or pancreatic metaplasia/neoplasia. hIAPP transgenic and non-transgenic littermates were followed for one year on no treatment, sitagliptin, metformin, or the combination. Islet amyloid deposition, beta-cell mass, insulin release and measures of exocrine pancreas pathology were determined. Relative to untreated mice, sitagliptin treatment did not increase amyloid deposition, despite increasing hIAPP release, and prevented amyloid-induced beta-cell loss. Metformin treatment alone or with sitagliptin decreased islet amyloid deposition to a similar extent vs untreated mice. Ductal proliferation was not altered among treatment groups and no evidence of pancreatitis, ductal metaplasia or neoplasia, were observed. Therefore, long-term sitagliptin treatment stimulates beta-cell secretion without increasing amyloid formation and protects against amyloid-induced beta-cell loss. This suggests a novel effect of sitagliptin to protect the beta cell in type 2 diabetes which appears to occur without adverse effects on the exocrine pancreas.
    AJP Endocrinology and Metabolism 06/2013; 305(4). DOI:10.1152/ajpendo.00025.2013 · 3.79 Impact Factor
Show more