The Gly972→Arg IRS-1 Variant Is Associated With Type 1 Diabetes in Continental Italy

Federici, Massimo; Petrone, Antonio; Porzio, Ottavia; Bizzarri, Carla; Lauro, Davide; D’Alfonso, Rossella; Patera, Ippolita Patrizia; Cappa, Marco; Nisticò, Lorenza; Baroni, Marco Giorgio; Sesti, Giorgio; Mario, U. Di; Lauro, Renato; Buzzetti, Raffaella

doi:10.2337/diabetes.52.3.887

Cited by 36 publications

(24 citation statements)

References 25 publications

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“…It has been reported that patients with apparent secondary failure to sulfonylurea are positive for anti-GAD antibody, and they tend to develop insulin deficiency requiring insulin treatment in a short period (4,32). Interestingly, we have recently reported that the frequency of the Arg 972 IRS-1 variant is significantly increased in patients with type 1 diabetes compared with nondiabetic individuals, conferring an OR of 2.5 (22). However, the possibility that patients with type 1 diabetes or latent autoimmune diabetes in adults might account for the increased prevalence of the Arg 972 IRS-1 variant among patients with secondary failure to sulfonylurea was excluded a priori by recruiting exclusively anti-GAD Ϫ patients.…”

Section: Discussionmentioning

confidence: 98%

“…The Gly972Arg of the human IRS-1 sequence was detected by digestion of PCR products with restriction enzyme BstNI as previously described (14,20,22). The Pro12Ala polymorphism in exon B of the peroxisome proliferator-activated receptor (PPAR)-␥ gene was detected by digestion of PCR products with restriction enzyme BstUI as previously described (23).…”

Section: Dna Analysismentioning

confidence: 99%

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The Arg972 Variant in Insulin Receptor Substrate-1 Is Associated With an Increased Risk of Secondary Failure to Sulfonylurea in Patients With Type 2 Diabetes

et al. 2004

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OBJECTIVE -The aim of this study was to investigate whether diabetic patients carrying the Arg 972 insulin receptor substrate-1 (IRS-1) variant are at increased risk for secondary failure to sulfonylurea. RESEARCH DESIGN AND METHODS -A total of 477 unrelatedCaucasian type 2 diabetic patients were recruited according to the following criteria: onset of diabetes after age 35 years, absence of ketonuria at diagnosis, and anti-GAD Ϫ antibody. Type 2 diabetes was diagnosed according to the American Diabetes Association criteria. Patients with secondary sulfonylurea failure were defined as those requiring insulin due to uncontrolled hyperglycemia (fasting plasma glucose Ͼ300 mg/dl) despite sulfonylurea-metformin combined therapy, appropriate diet, and absence of any conditions causing hyperglycemia.RESULTS -Of the total patients, 53 (11.1%) were heterozygous for the Arg 972 IRS-1 variant, 1 (0.2%) was homozygous, and the remainder (88.7%) were homozygous for the wild-type allele. The genotype frequency of the Arg 972 IRS-1 variant was 8.7% among diabetic patients well controlled with oral therapy and 16.7% among patients with secondary failure to sulfonylurea (odds ratio 2.1 [95% CI 1.18 -3.70], P ϭ 0.01). Adjustment for age, sex, BMI, metabolic control, age at diagnosis, duration of diabetes, and Pro12Ala polymorphism of peroxisome proliferatoractivated receptor-␥2 gene in a logistic regression analysis with secondary failure to sulfonylurea as a dependent variable did not change this association (2.0 [1.38 -3.86], P ϭ 0.038).CONCLUSIONS -These data demonstrate that the Arg 972 IRS-1 variant is associated with increased risk for secondary failure to sulfonylurea, thus representing a potential example of pharmacogenetics in type 2 diabetes. Diabetes Care 27:1394 -1398, 2004T ype 2 diabetes is a progressive disorder, and maintenance of good metabolic control has been demonstrated to reduce the risk of its associated long-term vascular complications and a delay in their onset (1). It has been estimated that each year 5-7% of diabetic patients treated with sulfonylurea convert to insulin treatment progressively as sulfonylurea fails (2,3). This clinical phenomenon has been termed secondary failure to sulfonylurea. Secondary failure to sulfonylurea has been variably attributed to change in body weight, lack of adequate diet regimen, young age at diagnosis, deterioration of insulin sensitivity or presence of anti-islet cell and anti-GAD antibodies (3,4). However, the U.K. Prospective Diabetes Study has demonstrated that the progressive deterioration of glycemic control in type 2 diabetic patients was associated with declining of pancreatic ␤-cell function despite either conventional treatment with dietary modification or intensive monotherapy treatment (1,3). A progressive deterioration of insulin secretion has been confirmed in smaller studies, and ␤-cell homeostatic model assessment has been demonstrated to be a better predictor of the insulinrequiring stage in type 2 diabetes than clinical indexes such as duration of di...

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Section: Discussionmentioning

confidence: 98%

Section: Dna Analysismentioning

confidence: 99%

The Arg972 Variant in Insulin Receptor Substrate-1 Is Associated With an Increased Risk of Secondary Failure to Sulfonylurea in Patients With Type 2 Diabetes

et al. 2004

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“…glucotoxicity due to uncontrolled diabetes and cytotoxicity by islet amyloid polypeptide (IAPP) [21,22] [23]. Mechanistically, it has also been discussed whether chronic hyperglycemia and different genetic variants of the insulin receptor may affect the clinical course of diabetes [24][25][26].…”

Section: Discussionmentioning

confidence: 99%

No signs of progressive beta cell damage during 20 years of prospective follow-up of autoantibody-negative diabetes

et al. 2011

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Aims Both type 1 (T1D) and type 2 (T2D) diabetes are considered to be associated with different degrees of progressive beta cell damage. However, few long term studies have been made. Our aim was to study the clinical course of 20 years of diabetes disease, including diabetes progression, co-morbidity and mortality in a prospectively studied cohort of consecutively diagnosed diabetic patients.Methods Among all 233 patients diagnosed with diabetes during 1985-1987 in Malmö, Sweden, 50 of 118 surviving patients were followed-up after 20 years. The age at diagnose was 42.323.1 and 57.513.6 yrs for antibody positive and antibody negative patients, respectively. HbA1c and plasma lipids were analysed with regard to metabolic control.Results Islet antibody negative patients at diagnosis had highly preserved C-peptide levels after 20 years in contrast to antibody positive patients (antibody-negative: C-peptide 0yrs 0.780.47 and 20yrs 0.700.46 (nmol/l), p=0.51 and antibody-positive: C-peptide 0yrs 0.330.35 and 20yrs 0.100.18; p<0.001. Islet antibodies but not age, BMI or C-peptide at diagnosis were predictors of C-peptide levels at 20 years when analysed by logistic regression (p<0.05). HbA1c did not differ between the groups after 20 years. The 20-year mortality was higher among antibody-negative patients, dependent on the higher age at diagnosis in this group (number of deaths: antibody-positive: 18 of 56 vs. antibody-negative: 109 of 188, p<0.001). Of the deceased, 79 % had died from diseases or complications that may be associated to diabetes. ConclusionWe found no progressive beta cell damage in autoantibody negative diabetes at a 20 year follow-up of the clinical course of diabetes.

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“…Polymorphisms in the IRS1 (rs1801278; p.Gly972Arg) and IRS2 (rs1805097; p.Gly1057Asp) genes were genotyped by PCR-restriction fragment length polymorphism analysis, following modification and optimization of previously described methods [11,12]. The rs1801278 and rs1805097 polymorphisms were detected by restriction digestion with BstNI and HaeII, respectively.…”

Section: Genetic Analysismentioning

confidence: 99%

Effect of Interaction between Polymorphisms in Insulin Receptor Substrate Genes in Type 2 Diabetes Mellitus Patients with Severe/Acute Hyperglycemia

Huri¹,

Makmor‐Bakry²,

Hashim³

et al. 2014

Trop. J. Pharm Res

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The Gly972→Arg IRS-1 Variant Is Associated With Type 1 Diabetes in Continental Italy

Cited by 36 publications

References 25 publications

The Arg972 Variant in Insulin Receptor Substrate-1 Is Associated With an Increased Risk of Secondary Failure to Sulfonylurea in Patients With Type 2 Diabetes

The Arg972 Variant in Insulin Receptor Substrate-1 Is Associated With an Increased Risk of Secondary Failure to Sulfonylurea in Patients With Type 2 Diabetes

No signs of progressive beta cell damage during 20 years of prospective follow-up of autoantibody-negative diabetes

Effect of Interaction between Polymorphisms in Insulin Receptor Substrate Genes in Type 2 Diabetes Mellitus Patients with Severe/Acute Hyperglycemia

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