Missense Mutation of Amylin Gene (S20G) in Japanese NIDDM Patients

Sakagashira, Setsuya; Sanke, Tokio; Hanabusa, Tadashi; Shimomura, Hiroko; Ohagi, Shinya; Kumagaye, Kumiko Yoshizawa; Nakajima, Kiichiro; Nanjo, Kishio

doi:10.2337/diab.45.9.1279

Cited by 122 publications

(87 citation statements)

References 11 publications

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“…The naturally occurring mutation Ser20Gly (S20G) found in a small number of Asian diabetic patients (Sakagashira et al 1996, Lee et al 2001 has been shown to enhance amyloidosis and cytotoxicity in hIAPP S20G transgenic mice compared to hIAPP-native sequence transgenic mice (Meier et al 2016) and to accelerate fibril formation in vitro (Sakagashira et al 2000, Ma et al 2001, Figure 2 Structural models of the hIAPP protofibril. (A) A β-bend in regions 18-27 results in a horseshoe shaped structure with the N-and C-termini (N-term, C-term) on the same face.…”

Section: The Structure Of Iapp and Fibril Assemblymentioning

confidence: 99%

The β-cell assassin: IAPP cytotoxicity

Raleigh

Zhang

Hastoy

et al. 2017

Journal of Molecular Endocrinology

110

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Islet amyloid polypeptide (IAPP) forms cytotoxic oligomers and amyloid fibrils in islets in type 2 diabetes (T2DM). The causal factors for amyloid formation are largely unknown. Mechanisms of molecular folding and assembly of human IAPP (hIAPP) into β-sheets, oligomers and fibrils have been assessed by detailed biophysical studies of hIAPP and non-fibrillogenic, rodent IAPP (rIAPP); cytotoxicity is associated with the early phases (oligomers/multimers) of fibrillogenesis. Interaction with synthetic membranes promotes β-sheet assembly possibly via a transient α-helical molecular conformation. Cellular hIAPP cytotoxicity can be activated from intracellular or extracellular sites. In transgenic rodents overexpressing hIAPP, intracellular pro-apoptotic signals can be generated at different points in β-cell protein synthesis. Increased cellular trafficking of proIAPP, failure of the unfolded protein response (UPR) or excess trafficking of misfolded peptide via the degradation pathways can induce apoptosis; these data indicate that defects in intracellular handling of hIAPP can induce cytotoxicity. However, there is no evidence for IAPP overexpression in T2DM. Extracellular amyloidosis is directly related to the degree of β-cell apoptosis in islets in T2DM. IAPP fragments, fibrils and multimers interact with membranes causing disruption in vivo and in vitro. These findings support a role for extracellular IAPP in β-sheet conformation in cytotoxicity. Inhibitors of fibrillogenesis are useful tools to determine the aberrant mechanisms that result in hIAPP molecular refolding and islet amyloidosis. However, currently, their role as therapeutic agents remains uncertain.

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Section: The Structure Of Iapp and Fibril Assemblymentioning

confidence: 99%

The β-cell assassin: IAPP cytotoxicity

Raleigh

Zhang

Hastoy

et al. 2017

Journal of Molecular Endocrinology

110

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“…Amyloid fibrils were observed within WW and GW founders on both control and high fat diet as shown in the supplemental data (Appendix S2). It is important to note that the penetrance of the S20G mutation with premature onset type 2 diabetes is low and appears to be restricted to a genetic background predisposing to normal onset type 2 diabetes, 10 although it is unknown whether these genetic differences affect amyloidogenesis in these patients.…”

Section: Discussionmentioning

confidence: 99%

“…Asians with premature onset type 2 diabetes harbor a mutation in the h IAPP gene (S20G), providing a causal link between this gene and disease 10 . The mutation is rare affecting 1.9–2.6% of type 2 diabetics 11,12 and 0.8% of non‐diabetic control subjects 11 .…”

Section: Introductionmentioning

confidence: 99%

Expression of wild‐type and mutant S20G hIAPP in physiologic knock‐in mouse models fails to induce islet amyloid formation, but induces mild glucose intolerance

Hiddinga¹,

Sakagashira²,

Ishigame³

et al. 2011

J of Diabetes Invest

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Aims/Introduction: Human islet polypeptide S20G mutation (hIAPPS20G) is associated with earlier onset type 2 diabetes and increased amyloidogenicity and cytotoxicity in vitro vs wild‐type hIAPP (hIAPPWT), suggesting that amyloidogenesis may be pathogenic for type 2 diabetes. We compared the contributions of hIAPPS20G and hIAPPWT toward intra islet amyloid formation and development of type 2 diabetes in a unique physiologic knock‐in mouse model.Materials and Methods: We replaced the mouse IAPP gene (M allele) with hIAPPWT (W allele) and hIAPPS20G (G allele) via homologous recombination and backbred transgenic mice against C57Bl/6 strain 5 generations to minimize genetic variation. Mice (3 month old) were maintained on control (CD) or high fat diet (HFD) for 15 months and studied at 3 month intervals by oral glucose tolerance testing (OGTT) and pancreas histology to assess glucose homeostastis, amyloidogeneisis, islet mass, β cell replication, and apoptosis.Results: IAPP blood levels were indistinguishable in all mice. WW and GW mice maintained on both diets lacked intraislet amyloid at all ages. On both diets relative to MM controls WW and GW mice exhibit glucose intolerance (P < 0.008) with no differences in insulin secretion. However, GW mice secreted significantly more insulin (P < 0.03 that WW mice on both diets throughout the study. By 12 months on the high fat diet all mice increased their β cell mass about 3‐fold and were indistinguishable.Conclusions: Physiologic expression of hIAPPWT and hIAPPS20G in C57Bl/6 mice produces mild glucose intolerance with inappropriately normal insulin secretion that is independent of intraislet amyloid formation. (J Diabetes Invest, doi: 10.1111/j.2040‐1124.2011.00166.x, 2011)

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“…Near relatives (especially first degree) suffering from type II increases risks of developing diabetes substantially in individuals. In addition, there is also a mutation to the Islet Amyloid Polypeptide gene that results in an earlier onset, more severe form, of diabetes (Wild et al, 1996;Cho, 2003). Exercise and life style modification plays significant role in the prevention of type II diabetes as well as in minimizing its complications (Bennion, 1979;Manson et al, 1991;Yamoka et al, 2005;Lindstrom et al, 2006); Li et al, 2008).…”

Section: Journal Of Biology and Life Sciencementioning

confidence: 99%

The Hepatoprotective Effect of Olive Leaf Extract on Diabetic Pregnant Mice and Their Fetuses

Ahmad

Dawran

Uddin

et al. 2017

JBLS

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This study aimed to see the role of diet and exercise in the control of disease or in minimizing the complications associated with diabetes. This was hospital based study conducted on four hundred and twenty (420) human subjects, divided in to six (06) main groups of seventy (70) subjects each. Exercise and diet protocol was set according to the international standards. Blood and urinary glucose level of subjects from each group was estimated before the start and at different intervals during the study to compare the effect of diet and exercise in minimizing the disease associated complications. Blood and urinary glucose level of various groups of diet (252.66 ± 6.5/203.00 ± 5.1, 252.66 ± 6.5/159.90 ± 3.3 and 252.66 ± 6.5/158.24 ± 2.70) and diet as well as exercise (252.66 ± 6.5/201.90 ±4.7, 252.66 ± 6.5/164.30 ± 3.7 and 252.66 ± 6.5/157.80 ± 2.70) were compared with that of the control group. The data was recorded and analyzed on SPSS version 16. The role of diet and exercise was observed significant (P ≤ 0.05) in the control of diabetes mellitus type II. Comparison of the blood and urinary glucose levels of individual of various groups under study was made. Significance improvement on the health of individuals in the diet and exercise was observed with P-values of exercise, diet and diet + exercise groups less than 0.05 each. It is concluded that a low calorie intake with regular exercise not only reduces the economic burden of the diabetics but also minimize the associated long term fatal pathologies. The disease is a growing health concern which needs lifelong treatment. Life style modification with changes in dietary habits and exercise therapy would reduce the economic burden on poor and needy diabetics, both in term of chemotherapeutic cost in the early stage of the disease, as well as minimizing the devastating complications of the disease. Type II diabetes and its prevention and treatment is a challenge for the future. The use of drugs therapy should be restricted only where dietary restrictions and exercise fail to achieve the desired goal. Even, in patients where drug therapy is the ultimate choice, life style modifications and dietary control are extremely fruitful and minimize the associated complications.

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Missense Mutation of Amylin Gene (S20G) in Japanese NIDDM Patients

Cited by 122 publications

References 11 publications

The β-cell assassin: IAPP cytotoxicity

The β-cell assassin: IAPP cytotoxicity

Expression of wild‐type and mutant S20G hIAPP in physiologic knock‐in mouse models fails to induce islet amyloid formation, but induces mild glucose intolerance

The Hepatoprotective Effect of Olive Leaf Extract on Diabetic Pregnant Mice and Their Fetuses

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