Missense mutation of amylin gene (S20G) in Japanese NIDDM patients

Sakagashira, Setsuya; Sanke, Tokio; Hanabusa, T.; Shimomura, H.; Ohagi, S.; Kumagaye, K. Y.; Nakajima, K.; Nanjo, K

doi:10.2337/diabetes.45.9.1279

Cited by 53 publications

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“…A missense heterozygous substitution in hIAPP at position 20 of a serine residue for a glycine has been identified in Japanese and Chinese studies [63]. However the prevalence of the mutation in T2DM is low, although significant, in both Japanese (2.6% in T2DM vs 0.8% in non-diabetic group, p<0.0007) [64] and Chinese cohorts (2.0-2.8% in T2DM; 0-0.5% in controls, p<0.05) [65] but not found in large cohorts of Caucasians [66]. The S20G mutation is associated with only moderate alterations in insulin secretion in the small number of patients examined so far and, therefore, its role in T2DM is unclear [67].…”

Section: Genetically Determined Structural Changesmutations In the Iamentioning

confidence: 99%

Islet amyloid: a complication of islet dysfunction or an aetiological factor in Type 2 diabetes?

2004

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The role of islet amyloidosis in the onset and progression of Type 2 diabetes remains obscure. Islet amyloid polypeptide is a 37 amino-acid, beta-cell peptide which is co-stored and co-released with insulin. Human islet amyloid polypeptide refolds to a β-conformation and oligomerises to form insoluble fibrils; proline substitutions in rodent islet amyloid polypeptide prevent this molecular transition. Pro-islet amyloid polypeptide (67 amino acids in man) is processed in secretory granules. Refolding of islet amyloid polypeptide may be prevented by intragranular heterodimer formation with insulin (but not proinsulin). Diabetes-associated abnormal proinsulin processing could contribute to de-stabilisation of granular islet amyloid polypeptide. Increased pro-islet amyloid polypeptide secretion as a consequence of islet dysfunction could promote fibrillogenesis; the propeptide forms fibrils and binds to basement membrane glycosamino-glycans. Islet amyloid polypeptide gene polymorphisms are not universally associated with Type 2 diabetes. Transgenic mice expressing human islet amyloid polypeptide gene have increased islet amyloid polypeptide concentrations but develop islet amyloid only against a background of obesity and/or high fat diet. In transgenic mice, obese monkeys and cats, initially small perivascular deposits progressively increase to occupy 80% islet mass; the severity of amyloidosis in animal models is related to the onset of hyperglycaemia, suggesting that islet amyloid and the associated destruction of islet cells cause diabetes. In human diabetes, islet amyloid can affect less than 1% or up to 80% of islets indicating that islet amyloidosis largely results from diabetes-related pathologies and is not an aetiological factor for hyperglycaemia. However, the associated progressive betacell destruction leads to severe islet dysfunction and insulin requirement. [Diabetologia (2004) 47:157-169]

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Section: Genetically Determined Structural Changesmutations In the Iamentioning

confidence: 99%

Islet amyloid: a complication of islet dysfunction or an aetiological factor in Type 2 diabetes?

2004

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“…The substitution of serine at position 20 by glycine leads to early onset T2D. 9 (B) Curcumin, a biphenol found in the Indian spice turmeric, exists in solution as a keto−enol tautomer. 22 is simple: fluorescence is enhanced in the presence of β-sheetcontaining fibrils.…”

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confidence: 99%

Kinetic Profile of Amyloid Formation in the Presence of an Aromatic Inhibitor by Nuclear Magnetic Resonance

Liu

Gaines

Robbins

et al. 2012

ACS Med. Chem. Lett.

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The self-assembly of amyloid proteins into β-sheet rich assemblies is associated with human amyloidoses including Alzheimer's disease, Parkinson's disease, and type 2 diabetes. An attractive therapeutic strategy therefore is to develop small molecules that would inhibit protein self-assembly. Natural polyphenols are potential inhibitors of β-sheet formation. How these compounds affect the kinetics of self-assembly studied by thioflavin T (ThT) fluorescence is not understood primarily because their presence interferes with ThT fluorescence. Here, we show that by plotting peak intensities from nuclear magnetic resonance (NMR) against incubation time, kinetic profiles in the presence of the polyphenol can be obtained from which kinetic parameters of self-assembly can be easily determined. In applying this technique to the selfassembly of the islet amyloid polypeptide in the presence of curcumin, a biphenolic compound found in turmeric, we show that the kinetic profile is atypical in that it shows a prenucleation period during which there is no observable decrease in NMR peak intensities. KEYWORDS: amyloid, ThT fluorescence, curcumin, NMR A total of 27 proteins have been identified to form the extracellular β-sheet containing amyloid fibrils associated with human amyloidoses. 1 These include the amyloid-β protein (Aβ) in Alzheimer's disease, α-synuclein in Parkinson's disease, and the islet amyloid polypeptide (IAPP) in type 2 diabetes (T2D). In spite of the large differences in the primary structure of the precursor proteins, the mature fibrils possess common characteristics including unbranched, 10 nm wide morphology as determined by electron microscopy, the ability to bind Congo red and exhibit green birefringence, and X-ray diffraction patterns consistent with cross-β-sheet. 1 Mechanistic studies of fibril formation in hydro have shown that Aβ, α-synuclein, and IAPP undergo a random coil to β-sheet conformational transition. 2 IAPP is a 37-residue polypeptide ( Figure 1A) that is cosecreted with insulin by β-cells of the islets of Langerhans in the pancreas. Molecular biological, biophysical, and genetic evidence support a central role for IAPP in β-cell death and dysfunction associated with T2D. 3,4 The progressive formation of islet amyloid leads to a decrease in β-cell mass. 5 The toxicity of fibrillar IAPP was first demonstrated in the early 1990s, 6 but more recent studies suggest that oligomeric assemblies could be the proximate cytotoxic species in T2D. 3,7 A number of mechanisms behind the toxicity of IAPP oligomers have been proposed, 8 but recent biophysical studies have focused on the ability of IAPP to disrupt model membranes, as reviewed recently. 3 A missense mutation involving the substitution of serine at position 20 with glycine ( Figure 1A) has been linked to an early onset, more severe form of T2D. 9 The mutant polypeptide aggregates faster 10,11 and is more toxic than wildtype IAPP. 10 Together, these findings suggest that molecules that significantly delay or completely inhibit IAP...

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“…The amylin gene coding region mutation, S20G, reported in Japanese and Chinese populations [9,10], was not observed in Maori patients or control subjects and is therefore not likely to be a major contributing factor for Type 2 diabetes in Maori people despite evidence for a common genetic origin for these populations [7,8].…”

Section: Resultsmentioning

confidence: 99%

“…A missense mutation in the amylin gene, S20G, has been shown to predispose Japanese and Chinese [9,10], but not Caucasian populations [11,12] to Type 2 diabetes. This mutation was prevalent in 0.4% of Chinese and 4.1% of Japanese patients with late-onset Type 2 diabetes.…”

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confidence: 99%

Amylin gene promoter mutations predispose to Type 2 diabetes in New Zealand Maori

2003

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Aims/hypothesis. Amylin gene mutations are known to predispose Chinese and Japanese subjects, but not Caucasian subjects, to Type 2 diabetes. New Zealand Maori, who have a high prevalence of Type 2 diabetes, have genetic origins in South East Asia. Amylin gene mutations could therefore predispose New Zealand Maori to Type 2 diabetes. Methods. The amylin gene was screened for mutations in the proximal promoter region, exons 1 and 2, intron 1, and coding region of exon 3 by polymerase chain reaction amplification and direct sequencing of 131 Type 2 diabetic Maori patients and 258 non-diabetic Maori control subjects. Results. We identified three new amylin gene mutations: two mutations in the promoter region (-215T>G and −132G>A) and a missense mutation in exon 3 (Q10R). The −215T>G mutation was observed in 5.4% of Type 2 Maori diabetic patients and predisposed the carrier to diabetes with a relative risk of 7.23. The −215T>G mutation was inherited with a previously described amylin promoter polymorphism (−230A>C) in 3% of the Maori with Type 2 diabetes, which suggests linkage disequilibrium exists between these two mutations. The −230A>C polymorphism on its own, however, was not associated with Type 2 diabetes in Maori subjects. The −132G>A and Q10R mutations were both observed in 0.76% of Type 2 diabetic patients and were absent in non-diabetic subjects. Conclusion/Interpretation. The amylin gene mutations identified in this study are associated with Type 2 diabetes in 7% of Maori. Amylin is likely to be an important susceptibility gene for Type 2 diabetes in Maori people. [Diabetologia (2003) 46:574-578]

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Missense mutation of amylin gene (S20G) in Japanese NIDDM patients

Cited by 53 publications

References 0 publications

Islet amyloid: a complication of islet dysfunction or an aetiological factor in Type 2 diabetes?

Islet amyloid: a complication of islet dysfunction or an aetiological factor in Type 2 diabetes?

Kinetic Profile of Amyloid Formation in the Presence of an Aromatic Inhibitor by Nuclear Magnetic Resonance

Amylin gene promoter mutations predispose to Type 2 diabetes in New Zealand Maori

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