The EGIR-RISC STUDY (The European group for the study of insulin resistance: relationship between insulin sensitivity and cardiovascular disease risk): I. Methodology and Objectives

Hills, S. A.; Balkau, Beverley; Sw, Coppack; Dekker, J.M.; Mari, Andrea; Natali, Andrea; Walker, Mark; Ferrannini, Eleuterio

doi:10.1007/s00125-004-1335-5

Cited by 170 publications

(204 citation statements)

References 24 publications

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“…The study population is part of the prospective Relationship between Insulin Sensitivity and Cardiovascular risk (RISC) study cohort [12]. From 2002 to 2004, individuals were recruited in 19 centres in 14 European countries [12].…”

Section: Methodsmentioning

confidence: 99%

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Beta cell (dys)function in non-diabetic offspring of diabetic patients

et al. 2009

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Aims/hypothesis The first-degree offspring of patients with type 2 diabetes are prone to develop type 2 diabetes, and have both insulin resistance and beta cell impairment. However, it is still unclear whether both pathophysiological features are inseparably combined and which is the outstanding determinant in the offspring. Methods Glucose metabolism, insulin sensitivity (calculated as M value divided by insulin [M/I]) and beta cell function were studied in the offspring of individuals with type 2 diabetes (n=187; 57% females; age 43.8±8.1 years; BMI 26.8±4.5 kg/m 2 ) and in individuals without a family history of type 2 diabetes (controls, n=519, 55% females; age 43.4± 8.2 years; BMI 26.4± 3.7 kg/m 2 , no significant differences between the groups for any characteristic) by performance of 75 g OGTT and 2 h hyperinsulinaemic (40 mU min −1 m −2 )-isoglycaemic clamp tests. Beta cell function was evaluated by calculating insulinogenic index (IGI) from C-peptide AUC:glucose AUC ratios from the first hour of OGTT (IGI[60 min]) and from the total OGTT (IGI[120 min]). Results During the OGTT, the offspring of individuals with type 2 diabetes showed 4-14% higher plasma glucose from 30 to 120 min (p<0.05) and 20-29% higher serum insulin from 90 to 120 min, but decreased IGI(60 min) and IGI (120 min) (p<0.05). M/I was 11% lower in the offspring of affected individuals than in controls (p<0.01). To study the offspring of patients with type 2 diabetes with insulin sensitivity similar to that of the control group, the offspring of affected patients were divided into M/I quartiles. Those in the third M/I quartile showed M/I values and major anthropometric characteristics similar to those of the controls, but insulin AUC and C-peptide AUC values were lower in the first hour and the total OGTT (p<0.05). The third M/I quartile had lower IGI values at 60 min and 120 min: 11% and 14% lower, respectively (p<0.02). Conclusions/interpretation The first-degree offspring of type 2 diabetic patients show insulin resistance and beta cell dysfunction in response to oral glucose challenge. Beta cell impairment exists in insulin-sensitive offspring of patients with type 2 diabetes, suggesting beta cell dysfunction to be a major defect determining diabetes development in diabetic offspring.

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Section: Methodsmentioning

confidence: 99%

“…From 2002 to 2004, individuals were recruited in 19 centres in 14 European countries [12]. They were screened initially to confirm excellent health and the absence of any regular drug intake that may affect insulin sensitivity, blood pressure, circulating lipids or glucose.…”

Section: Methodsmentioning

confidence: 99%

Beta cell (dys)function in non-diabetic offspring of diabetic patients

et al. 2009

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“…We next included these loci and those of the other four genes reported to alter beta cell function, CDKN2A/B (rs10811661), IGF2BP2 (rs4402960), SLC30A8 (rs13266634) and KCNJ11 (rs5219), in our model to test the effects of all seven variants. To do this we used the RISC cohort that comprises non-diabetic men and women of European ancestry from 19 centres across 13 different countries [14]. Volunteers were recruited as part of a long-term study of insulin sensitivity and cardiovascular disease and those with diabetes, hypertension or dyslipidaemia were excluded.…”

Section: Methodsmentioning

confidence: 99%

“…Many of the confirmed type 2 diabetes variants have since been shown in population cohorts to alter beta cell function [7][8][9][10][11][12][13]. These studies include the RISC (Relationship between Insulin Sensitivity and Cardiovascular Disease) study [14], where we previously showed that CDKAL1 (rs10946398) and HHEX/IDE (rs1111875) loci were associated with altered beta cell function as measured by the 30 min insulin response and pancreatic beta cell glucose sensitivity derived from an OGTT [10]. The aim of this study was to test the cumulative effects of variants shown individually to alter beta cell function.…”

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confidence: 99%

Beta cell glucose sensitivity is decreased by 39% in non-diabetic individuals carrying multiple diabetes-risk alleles compared with those with no risk alleles

et al. 2008

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Aims/hypothesis Novel type 2 diabetes-susceptibility loci have been identified with evidence that individually they mediate the increased diabetes risk through altered pancreatic beta cell function. The aim of this study was to test the cumulative effects of diabetes-risk alleles on measures of beta cell function in non-diabetic individuals. Methods A total of 1,211 non-diabetic individuals underwent metabolic assessment including an OGTT, from which measures of beta cell function were derived. Individuals were genotyped at each of the risk loci and then classified according to the total number of risk alleles that they carried. Initial analysis focused on CDKAL1, HHEX/IDE and TCF7L2 loci, which were individually associated with a decrease in beta cell function in our cohort. Risk alleles for CDKN2A/B, SLC30A8, IGF2BP2 and KCNJ11 loci were subsequently included into the analysis. Results The diabetes-risk alleles for CDKAL1, HHEX/IDE and TCF7L2 showed an additive model of association with measures of beta cell function. Beta cell glucose sensitivity was decreased by 39% in those individuals with five or more risk alleles compared with those individuals with no risk alleles (geometric mean [SEM]: 84 [1.07] vs 137 [1.11] pmol min −1 m −2 (mmol/l) −1 , p=1.51×10 −6 ). The same was seen for the 30 min insulin response (p=4.17×10 −7 ). The relationship remained after adding in the other four susceptibility loci (30 min insulin response and beta cell glucose sensitivity, p<0.001 and p=0.003, respectively).Conclusions/interpretation This study shows how individual type 2 diabetes-risk alleles combine in an additive manner to impact upon pancreatic beta cell function in nondiabetic individuals.

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“…The Relationship Between Insulin Sensitivity and Cardiovascular Disease Risk (RISC) study is a prospective, observational cohort study whose rationale and methodology have been published [14]. In brief, participants were recruited from the local population at 19 centres in 14 countries in Europe, according to the following inclusion criteria: men and women, age between 30-60 years and clinically healthy.…”

Section: Study Participantsmentioning

confidence: 99%

Association of fasting glucagon and proinsulin concentrations with insulin resistance

et al. 2007

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Aims/hypothesis Hyperproinsulinaemia and relative hyperglucagonaemia are features of type 2 diabetes. We hypothesised that raised fasting glucagon and proinsulin concentrations may be associated with insulin resistance (IR) IR was related to fasting proinsulin or pancreatic glucagon concentrations in univariate and multivariate analyses. Given its known relationship to IR, serum adiponectin was used as a positive control. Results In either sex, both glucagon and proinsulin were directly related to IR, while adiponectin was negatively associated with it (all p<0.0001). In multivariate models, controlling for known determinants of insulin sensitivity (i.e. sex, age, BMI and glucose tolerance) as well as factors potentially affecting glucagon and proinsulin (i.e. fasting plasma glucose and C-peptide concentrations), glucagon and proinsulin were still positively associated, and adiponectin was negatively associated, with IR. Finally, when these associations were tested as the probability that individuals in the top IR quartile would have hormone levels in the top quartile of their distribution independently of covariates, the odds ratio was ∼2 for both glucagon (p=0.05) and proinsulin (p=0.02) and 0.36 for adiponectin (p<0.0001). Conclusions/interpretation Whole-body IR is independently associated with raised fasting plasma glucagon and proinsulin concentrations, possibly as a result of IR at the level of alpha cells and beta cells in pancreatic islets.

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The EGIR-RISC STUDY (The European group for the study of insulin resistance: relationship between insulin sensitivity and cardiovascular disease risk): I. Methodology and Objectives

Abstract: This study will evaluate the importance of insulin resistance in the development of CVD and diabetes, and has implications for the development of prevention and treatment strategies.

Cited by 170 publications

References 24 publications

Beta cell (dys)function in non-diabetic offspring of diabetic patients

Beta cell (dys)function in non-diabetic offspring of diabetic patients

Beta cell glucose sensitivity is decreased by 39% in non-diabetic individuals carrying multiple diabetes-risk alleles compared with those with no risk alleles

Association of fasting glucagon and proinsulin concentrations with insulin resistance

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