Islet amyloid accumulates in non-insulin-dependent diabetes mellitus (NIDDM). This amyloid is comprised of islet amyloid polypeptide (IAPP), a normal secretory product of the beta-cell. Transgenic mice expressing the human IAPP (hIAPP) gene and producing the human peptide have been developed to study the mechanism of amyloid formation. The applicant has observed the development of islet amyloid in 81% of the male mice in his colony of hIAPP transgenic mice, often associated with hyperglycemia. This observation was made when the mice were receiving a diet containing an increased proportion of fat (9%). These amyloid deposits contain not only human IAPP, but also apolipoprotein E (apoE) and perlecan, a heparan sulfate proteoglycan. These two constituents are commonly found in other amyloidoses. Based on these observations, he hypothesizes that besides the presence of an amyloidogenic IAPP sequence as occurs with the human form of IAPP, factors such as a high fat diet, hyperglycemia, and apoE are also important for IAPP to deposit as islet amyloid. To address this hypothesis, hIAPP transgenic mice will be studied under conditions of varying dietary fat content controlling for the effect of obesity (6.7% and 24.4%) for periods of 3, 6, and 12 months; hyperglycemia by a) transplantation of islets from hIAPP transgenic mice into hyperglycemic mice and b) crossing hIAPP transgenic mice with heterozygous beta-cell glucokinase knockout mice that develop glucose intolerance; and apoE deficiency by crossing hIAPP transgenic mice with homozygous apoE knockout mice. Islet amyloid accumulation and its constituents will be determined by light and electron microscopy and related to glycemia, plasma lipids, pancreatic mRNA and peptide/protein content. To determine whether beta-cell secretory function and/or IAPP processing from its larger precursor prolAPP is altered in mice studied under the different experimental paradigms associated with islet amyloid formation, pancreas perfusion studies and pulse-chase experiments using isolated islets will be performed. Finally, to examine whether apoE and perlecan are synthesized in islets and what regulates their production, mRNA levels will be measured in isolated islets and pulse-chase experiments will be used to assess protein synthesis in response to fatty acids and glucose.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
1R01DK050703-01A2
Application #
2406428
Study Section
Metabolism Study Section (MET)
Program Officer
Laughlin, Maren R
Project Start
1997-09-15
Project End
2001-07-31
Budget Start
1997-09-15
Budget End
1998-07-31
Support Year
1
Fiscal Year
1997
Total Cost
Indirect Cost
Name
University of Washington
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
135646524
City
Seattle
State
WA
Country
United States
Zip Code
98195
Fujimoto, Wilfred Y (2016) 2015 Yutaka Seino Distinguished Leadership Award Lecture: The Japanese American Community Diabetes Study and the 'canary in the coal mine'. J Diabetes Investig 7:664-73
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Hull, Rebecca L; Watts, Melissah R; Kodama, Keiichi et al. (2005) Genetic background determines the extent of islet amyloid formation in human islet amyloid polypeptide transgenic mice. Am J Physiol Endocrinol Metab 289:E703-9
Andrikopoulos, Sofianos; Hull, Rebecca L; Verchere, C Bruce et al. (2004) Extended life span is associated with insulin resistance in a transgenic mouse model of insulinoma secreting human islet amyloid polypeptide. Am J Physiol Endocrinol Metab 286:E418-24
Hull, Rebecca L; Westermark, Gunilla T; Westermark, Per et al. (2004) Islet amyloid: a critical entity in the pathogenesis of type 2 diabetes. J Clin Endocrinol Metab 89:3629-43
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Kahn, S E (2003) The relative contributions of insulin resistance and beta-cell dysfunction to the pathophysiology of Type 2 diabetes. Diabetologia 46:3-19
Potter-Perigo, Susan; Hull, Rebecca L; Tsoi, Christina et al. (2003) Proteoglycans synthesized and secreted by pancreatic islet beta-cells bind amylin. Arch Biochem Biophys 413:182-90
Hull, Rebecca L; Andrikopoulos, Sofianos; Verchere, C Bruce et al. (2003) Increased dietary fat promotes islet amyloid formation and beta-cell secretory dysfunction in a transgenic mouse model of islet amyloid. Diabetes 52:372-9

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