Genetic background determines the extent of islet amyloid formation in human islet amyloid polypeptide transgenic mice

2005 ◽  
Vol 289 (4) ◽  
pp. E703-E709 ◽  
Author(s):  
Rebecca L. Hull ◽  
Melissah R. Watts ◽  
Keiichi Kodama ◽  
Zhen-ping Shen ◽  
Kristina M. Utzschneider ◽  
...  
Keyword(s):  
Transgenic Mice ◽  
Genetic Background ◽  
Cell Mass ◽  
Islet Amyloid Polypeptide ◽  
Amyloid Deposition ◽  
Human Islet ◽  
Amyloid Formation ◽  
Β Cell ◽  
Islet Amyloid ◽  
Background Strain

Genetic background is important in determining susceptibility to metabolic abnormalities such as insulin resistance and β-cell dysfunction. Islet amyloid is associated with reduced β-cell mass and function and develops in the majority of our C57BL/6J × DBA/2J (F1) male human islet amyloid polypeptide (hIAPP) transgenic mice after 1 yr of increased fat feeding. To determine the relative contribution of each parental strain, C57BL/6J (BL6) and DBA/2J (DBA2), to islet amyloid formation, we studied male hIAPP mice on each background strain (BL6, n = 13; and DBA2 n = 11) and C57BL/6J × DBA/2J F1mice ( n = 17) on a 9% (wt/wt) fat diet for 1 yr. At the end of 12 mo, islet amyloid deposition was quantified from thioflavin S-stained pancreas sections. The majority of mice in all groups developed islet amyloid (BL6: 91%, F1: 76%, DBA2: 100%). However, the prevalence (%amyloid-positive islets; BL6: 14 ± 3%, F1: 44 ± 8%, DBA2: 49 ± 9%, P < 0.05) and severity (%islet area occupied by amyloid; BL6: 0.03 ± 0.01%, F1: 9.2 ± 2.9%, DBA2: 5.7 ± 2.3%, p ≤ 0.01) were significantly lower in BL6 than F1and DBA2 mice. Increased islet amyloid severity was negatively correlated with insulin-positive area per islet, in F1( r2= 0.75, P < 0.001) and DBA2 ( r2= 0.87, P < 0.001) mice but not BL6 mice ( r2= 0.07). In summary, the extent of islet amyloid formation in hIAPP transgenic mice is determined by background strain, with mice expressing DBA/2J genes (F1and DBA2 mice) being more susceptible to amyloid deposition that replaces β-cell mass. These findings underscore the importance of genetic and environmental factors in studying metabolic disease.

scholarly journals Amyloid Formation in Response to β Cell Stress Occurs In Vitro, but Not In Vivo, in Islets of Transgenic Mice Expressing Human Islet Amyloid Polypeptide

1995 ◽  
Vol 1 (5) ◽  
pp. 542-553 ◽  
Author(s):  
Gunilla Westermark ◽  
Michelle Benig Arora ◽  
Niles Fox ◽  
Raymond Carroll ◽  
Shu Jin Chan ◽  
...  
Keyword(s):  
Transgenic Mice ◽  
Islet Amyloid Polypeptide ◽  
Human Islet ◽  
Cell Stress ◽  
Amyloid Formation ◽  
Β Cell ◽  
Islet Amyloid ◽  
Human Islet Amyloid Polypeptide

scholarly journals Loss of perlecan heparan sulfate glycosaminoglycans lowers body weight and decreases islet amyloid deposition in human islet amyloid polypeptide transgenic mice

2019 ◽  
Vol 32 (2) ◽  
pp. 95-102
Author(s):  
Andrew T Templin ◽  
Mahnaz Mellati ◽  
Raija Soininen ◽  
Meghan F Hogan ◽  
Nathalie Esser ◽  
...  
Keyword(s):  
Body Weight ◽  
Transgenic Mice ◽  
Heparan Sulfate ◽  
Islet Amyloid Polypeptide ◽  
Amyloid Deposition ◽  
Secretory Product ◽  
Cell Area ◽  
Β Cell ◽  
Islet Amyloid

Abstract Islet amyloid is a pathologic feature of type 2 diabetes (T2D) that is associated with β-cell loss and dysfunction. These amyloid deposits form via aggregation of the β-cell secretory product islet amyloid polypeptide (IAPP) and contain other molecules including the heparan sulfate proteoglycan perlecan. Perlecan has been shown to bind amyloidogenic human IAPP (hIAPP) via its heparan sulfate glycosaminoglycan (HS GAG) chains and to enhance hIAPP aggregation in vitro. We postulated that reducing the HS GAG content of perlecan would also decrease islet amyloid deposition in vivo. hIAPP transgenic mice were crossed with Hspg2Δ3/Δ3 mice harboring a perlecan mutation that prevents HS GAG attachment (hIAPP;Hspg2Δ3/Δ3), and male offspring from this cross were fed a high fat diet for 12 months to induce islet amyloid deposition. At the end of the study body weight, islet amyloid area, β-cell area, glucose tolerance and insulin secretion were analyzed. hIAPP;Hspg2Δ3/Δ3 mice exhibited significantly less islet amyloid deposition and greater β-cell area compared to hIAPP mice expressing wild type perlecan. hIAPP;Hspg2Δ3/Δ3 mice also gained significantly less weight than other genotypes. When adjusted for differences in body weight using multiple linear regression modeling, we found no differences in islet amyloid deposition or β-cell area between hIAPP transgenic and hIAPP;Hspg2Δ3/Δ3 mice. We conclude that loss of perlecan exon 3 reduces islet amyloid deposition in vivo through indirect effects on body weight and possibly also through direct effects on hIAPP aggregation. Both of these mechanisms may promote maintenance of glucose homeostasis in the setting of T2D.

Differences in amyloid deposition in islets of transgenic mice expressing human islet amyloid polypeptide versus human islets implanted into nude mice

Metabolism ◽  
1999 ◽  
Vol 48 (4) ◽  
pp. 448-454 ◽  
Author(s):  
Gunilla Westermark ◽  
Per Westermark ◽  
Decio L. Eizirik ◽  
Claes Hellerström ◽  
Niles Fox ◽  
...  
Keyword(s):  
Transgenic Mice ◽  
Nude Mice ◽  
Islet Amyloid Polypeptide ◽  
Human Islets ◽  
Amyloid Deposition ◽  
Human Islet ◽  
Islet Amyloid ◽  
Human Islet Amyloid Polypeptide

Oophorectomy promotes islet amyloid formation in human islet amyloid polypeptide transgenic mice

Diabetes ◽  
2001 ◽  
Vol 50 (Supplement 1) ◽  
pp. S184-S185 ◽  
Author(s):  
R. L. Hull ◽  
B. Verchere ◽  
S. Andrikopoulos ◽  
F. Wang ◽  
J. Vidal ◽  
...  
Keyword(s):  
Transgenic Mice ◽  
Islet Amyloid Polypeptide ◽  
Human Islet ◽  
Amyloid Formation ◽  
Islet Amyloid ◽  
Human Islet Amyloid Polypeptide

scholarly journals One year of sitagliptin treatment protects against islet amyloid-associated β-cell loss and does not induce pancreatitis or pancreatic neoplasia in mice

2013 ◽  
Vol 305 (4) ◽  
pp. E475-E484 ◽  
Author(s):  
Kathryn Aston-Mourney ◽  
Shoba L. Subramanian ◽  
Sakeneh Zraika ◽  
Thanya Samarasekera ◽  
Daniel T. Meier ◽  
...  
Keyword(s):  
Exocrine Pancreas ◽  
Cell Mass ◽  
Cell Loss ◽  
Amyloid Deposition ◽  
Amyloid Formation ◽  
Metformin Treatment ◽  
Cell Toxicity ◽  
Β Cell ◽  
Islet Amyloid

The dipeptidyl peptidase-4 (DPP-4) inhibitor sitagliptin is an attractive therapy for diabetes, as it increases insulin release and may preserve β-cell mass. However, sitagliptin also increases β-cell release of human islet amyloid polypeptide (hIAPP), the peptide component of islet amyloid, which is cosecreted with insulin. Thus, sitagliptin treatment may promote islet amyloid formation and its associated β-cell toxicity. Conversely, metformin treatment decreases islet amyloid formation by decreasing β-cell secretory demand and could therefore offset sitagliptin's potential proamyloidogenic 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 β-cell toxicity and induced pancreatic ductal proliferation, pancreatitis, and/or pancreatic metaplasia/neoplasia. hIAPP transgenic and nontransgenic littermates were followed for 1 yr on no treatment, sitagliptin, metformin, or the combination. Islet amyloid deposition, β-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 β-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 β-cell secretion without increasing amyloid formation and protects against amyloid-induced β-cell loss. This suggests a novel effect of sitagliptin to protect the β-cell in type 2 diabetes that appears to occur without adverse effects on the exocrine pancreas.

scholarly journals A novel assay in vitro of human islet amyloid polypeptide amyloidogenesis and effects of insulin secretory vesicle peptides on amyloid formation

1998 ◽  
Vol 331 (3) ◽  
pp. 809-813 ◽  
Author(s):  
Yogish C. KUDVA ◽  
Cheryl MUESKE ◽  
Peter C. BUTLER ◽  
Norman L. EBERHARDT
Keyword(s):  
Diabetes Mellitus ◽  
Islet Amyloid Polypeptide ◽  
Insulin Dependent Diabetes Mellitus ◽  
Human Islet ◽  
Dependent Diabetes Mellitus ◽  
Amyloid Formation ◽  
Β Cell ◽  
Islet Amyloid ◽  
C Peptide ◽  
Insulin Dependent

Human islet amyloid polypeptide (IAPP) is a 37-residue peptide that is co-secreted with insulin by the β-cell and might be involved in the pathogenesis of non-insulin-dependent diabetes mellitus. We developed an improved assay in vitrobased on the fluorescence of bound thioflavin T to study factors affecting amyloidogenesis. Monomeric IAPP formed amyloid fibrils, as detected by increased fluorescence and by electron microscopy. Fluorimetric analysis revealed that the initial rate of amyloid formation was: (1) proportional to the peptide monomer concentration, (2) maximal at pH 9.5, (3) maximal at 200 mM KCl, and (4) proportional to temperature from 4 to 37 °C. We found that 5-fold and 10-fold molar excesses of proinsulin inhibited fibril formation by 39% and 59% respectively. Insulin was somewhat more potent with 5-fold and 10-fold molar excesses inhibiting fibril formation by 69% and 73% respectively, whereas C-peptide had no effect at these concentrations. Thus at physiological ratios of IAPP to insulin, insulin and proinsulin, but not C-peptide, can retard amyloidogenesis. Because insulin resistance or hyperglycaemia increase the IAPP-to-insulin ratio, increased intracellular IAPP compared with insulin expression in genetically predisposed individuals might contribute to intracellular amyloid formation, β-cell death and the genesis of non-insulin-dependent diabetes mellitus.

scholarly journals The effect of apolipoprotein E deficiency on islet amyloid deposition in human islet amyloid polypeptide transgenic mice

Diabetologia ◽  
2003 ◽  
Vol 46 (1) ◽  
pp. 71-79 ◽  
Author(s):  
J. Vidal ◽  
C. Bruce Verchere ◽  
S. Andrikopoulos ◽  
F. Wang ◽  
R. Hull ◽  
...  
Keyword(s):  
Transgenic Mice ◽  
Apolipoprotein E ◽  
Islet Amyloid Polypeptide ◽  
Amyloid Deposition ◽  
Human Islet ◽  
Islet Amyloid ◽  
Human Islet Amyloid Polypeptide

Induction of endoplasmic reticulum stress-induced β-cell apoptosis and accumulation of polyubiquitinated proteins by human islet amyloid polypeptide

2007 ◽  
Vol 293 (6) ◽  
pp. E1656-E1662 ◽  
Author(s):  
Chang-jiang Huang ◽  
Leena Haataja ◽  
Tatyana Gurlo ◽  
Alexandra E. Butler ◽  
Xiuju Wu ◽  
...  
Keyword(s):  
Endoplasmic Reticulum ◽  
Mouse Model ◽  
Transgenic Mice ◽  
Er Stress ◽  
Cell Apoptosis ◽  
Cell Mass ◽  
Islet Amyloid Polypeptide ◽  
Protein Overexpression ◽  
Β Cell ◽  
Islet Amyloid

The islet in type 2 diabetes is characterized by an ∼60% β-cell deficit, increased β-cell apoptosis, and islet amyloid derived from islet amyloid polypeptide (IAPP). Human IAPP (hIAPP) but not rodent IAPP (rIAPP) forms toxic oligomers and amyloid fibrils in an aqueous environment. We previously reported that overexpression of hIAPP in transgenic rats triggered endoplasmic reticulum (ER) stress-induced apoptosis in β-cells. In the present study, we sought to establish whether the cytotoxic effects of hIAPP depend on its propensity to oligomerize, rather than as a consequence of protein overexpression. To accomplish this, we established a novel homozygous mouse model overexpressing rIAPP at a comparable expression rate and, on the same background, as a homozygous transgenic hIAPP mouse model previously reported to develop diabetes associated with β-cell loss. We report that by 10 wk of age hIAPP mice develop diabetes with a deficit in β-cell mass due to increased β-cell apoptosis. The rIAPP transgenic mice counterparts do not develop diabetes or have decreased β-cell mass. Both rIAPP and hIAPP transgenic mice have increased expression of BiP, but only hIAPP transgenic mice have elevated ER stress markers (X-box-binding protein-1, nuclear localized CCAAT/enhancer binding-protein homologous protein, active caspase-12, and accumulation of ubiquitinated proteins). These findings indicate that the β-cell toxic effects of hIAPP depend on the propensity of IAPP to aggregate, but not on the consequence of protein overexpression.

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