Variants Within the Calpain-10 Gene on Chromosome 2q37 (<i>NIDDM1</i>) and Relationships to Type 2 Diabetes, Insulin Resistance, and Impaired Acute Insulin Secretion Among Scandinavian Caucasians

Rasmussen, Søren K.; Urhammer, Søren A.; Berglund, Lars; Jensen, Jan; Hansen, Lars; Echwald, Søren M.; Borch‐Johnsen, Knut; Horikawa, Yukio; Mashima, Hirosato; Lithell, Hans; Cox, Nancy J.; Hansen, Torben; Bell, Graeme I.; Pedersen, Oluf

doi:10.2337/diabetes.51.12.3561

Cited by 70 publications

(52 citation statements)

References 33 publications

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“…This sexrelated difference could be due to the higher prevalence of central obesity in men. No association of SNP-43 and waist-to-hip ratio was observed in our study, in agreement with a study of 70-year-old Swedish men [37]. An interaction of SNP-43 with sex ( Fig.…”

Section: Subjects Insupporting

confidence: 93%

Common polymorphisms of calpain-10 are associated with abdominal obesity in subjects at high risk of type 2 diabetes

et al. 2006

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Aims/hypothesis: The mechanisms by which the calpain-10 gene (CAPN10) affects the risk of type 2 diabetes are unclear. Therefore, we investigated the effects of four polymorphisms in CAPN10 (single nucleotide polymorphism [SNP]-43, SNP-44, Insertion/Deletion [Indel]-19 and SNP-63) on insulin secretion, insulin action and abdominal fat distribution in offspring of patients with type 2 diabetes. Subjects and methods: Insulin secretion was determined by an IVGTT, insulin action by the hyperinsulinaemic-euglycaemic clamp and abdominal fat distribution by computed tomography in 158 non-diabetic offspring (age 34.9±6.3 years [mean±SD], BMI 26.2± 4.9 kg/m 2 ) of type 2 diabetic patients. Results: SNP-43 (p=0.009 over the three genotypes, adjusted for age, sex, BMI and family relationship) and haplotypes carrying the A allele of SNP-43 were associated with intra-abdominal fat area. The A allele of SNP-43 was associated with intraabdominal fat area in men (p=0.014) but not in women. were not associated with intra-abdominal fat area or insulin action. Furthermore, we demonstrated in a separate sample of middle-aged men (n=234) who had a history of type 2 diabetes in firstdegree relatives that the A allele of SNP-43 was associated with a large waist circumference, and high insulin levels in an OGTT.Conclusions/interpretation: SNP-43 of CAPN10 may contribute to the risk of diabetes by regulating abdominal obesity in subjects with high risk of type 2 diabetes.

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Section: Subjects Insupporting

confidence: 93%

Common polymorphisms of calpain-10 are associated with abdominal obesity in subjects at high risk of type 2 diabetes

et al. 2006

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“…Our results differ from those of two recent studies, one from Scandinavia and the other from Japan. Both these studies were unable to demonstrate any association between risk haplotype combinations of SNP-43, -19, -63 and insulin resistance [53,54]. However, neither of them compared the genotype combinations of SNP-43 and -44.…”

Section: Beta Cell Functionmentioning

confidence: 90%

Parallel manifestation of insulin resistance and beta cell decompensation is compatible with a common defect in Type 2 diabetes

et al. 2004

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Aims/hypothesis. The aim of the study was to evaluate the relationship between insulin sensitivity, beta cell function and glucose tolerance, and its dependence on variants in the newly identified Type 2 diabetes susceptibility gene, calpain-10 (CAPN10). Methods. We studied 203 men of the same age but with varying degrees of glucose tolerance. These men participated in (i) an oral glucose tolerance test, (ii) a euglycaemic clamp combined with indirect calorimetry and infusion of [3-3 H]-glucose and (iii) a stepwise assessment of acute insulin response to arginine (AIR) at three different glucose concentrations (fasting, 14 and 28 mmol/l).Results. There was a linear increase in NEFA levels (p<0.0005) and WHR (p<0.0005) and decrease in glucose uptake due to a reduction in glucose storage over the entire range of glucose tolerance (r=−0.404; p<0.005). No increase in endogenous glucose production (EGP) was seen until patients had manifest diabetes. However, when EGP was expressed relative to fasting insulin concentrations, there was a linear deterioration of basal hepatic insulin sensitivity (r= −0.514; p<0.005). The AIR followed a bell-shaped curve with an initial rise and subsequent decrease. However, AIR adjusted for insulin sensitivity (disposition index) showed a linear decrease with increasing glucose concentrations (r=−0.563; p<0.001) starting already in subjects with normal glucose tolerance. There was an inverse correlation between increase in WHR and NEFA and peripheral as well as hepatic insulin sensitivity. Subjects with the genotype combination of CAPN10 consisting of SNP44 TT and SNP43 GG genotypes had significantly lower insulin-stimulated glucose uptake than carriers of the other genotype combinations (5.3±0.4 vs 7.2±0.4 mg·ffm kg −1 min −1 ·mU·l −1 ; p<0.005). Conclusions/interpretation. We conclude that the prediabetic state is characterised by a similar linear deterioration of peripheral and hepatic insulin sensitivity as beta cell function and that variants in the CAPN10 gene modify this relationship. These findings are compatible with a common defect in muscle, liver and beta cells in the pathogenesis of Type 2 diabetes.

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“…117,118 Originally, the G allele of a non-coding single nucleotide polymorphism (UCSNP-43) was reported to be associated with type 2 diabetes, while specific haplotype combinations of several single nucleotide polymorphisms (UCSNP-19, 43, 63) seemed to increase the risk of diabetes in selected populations. 116 In later studies, this finding could not be replicated 119,120 but another single nucleotide polymorphism (UCSNP-44) was found to be associated with type 2 diabetes. [121][122][123][124] Genetic variants in calpain-10 might affect insulin sensitivity, 125 or insulin secretion, 126 or the relation between the two (table 4).…”

Section: Calpain-10mentioning

confidence: 95%

Type 2 diabetes: principles of pathogenesis and therapy

Stümvoll¹,

Goldstein²,

Haeften³

2005

The Lancet

2,175

1,507

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Type 2 diabetes mellitus has become an epidemic, and virtually no physician is without patients who have the disease. Whereas insulin insensitivity is an early phenomenon partly related to obesity, pancreas ␤-cell function declines gradually over time already before the onset of clinical hyperglycaemia. Several mechanisms have been proposed, including increased non-esterified fatty acids, inflammatory cytokines, adipokines, and mitochondrial dysfunction for insulin resistance, and glucotoxicity, lipotoxicity, and amyloid formation for ␤-cell dysfunction. Moreover, the disease has a strong genetic component, but only a handful of genes have been identified so far: genes for calpain 10, potassium inward-rectifier 6·2, peroxisome proliferator-activated receptor ␥, insulin receptor substrate-1, and others. Management includes not only diet and exercise, but also combinations of antihyperglycaemic drug treatment with lipid-lowering, antihypertensive, and anti platelet therapy. Glucose concentration in venous plasma (mmol/L) Diabetes mellitusFasting у7·0 or 2-h post-glucose load у11·1 Impaired glucose tolerance Fasting (if measured) Ͻ7·0 and 2-h post-glucose load у7·8 and Ͻ11·1 Impaired fasting glucose Fasting у6·1 and Ͻ7·0 and 2 h post-glucose load (if measured) Ͻ7·8Glucose load=75 g glucose orally. 10

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Variants Within the Calpain-10 Gene on Chromosome 2q37 (NIDDM1) and Relationships to Type 2 Diabetes, Insulin Resistance, and Impaired Acute Insulin Secretion Among Scandinavian Caucasians

Cited by 70 publications

References 33 publications

Common polymorphisms of calpain-10 are associated with abdominal obesity in subjects at high risk of type 2 diabetes

Common polymorphisms of calpain-10 are associated with abdominal obesity in subjects at high risk of type 2 diabetes

Parallel manifestation of insulin resistance and beta cell decompensation is compatible with a common defect in Type 2 diabetes

Type 2 diabetes: principles of pathogenesis and therapy

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