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Leif Groop

Publications and source records attributed to Leif Groop.

At least 37 records · Page 2Linked to original sources
PubMed2005

Calpain 10 and type 2 diabetes: are we getting closer to an explanation?

PURPOSE OF REVIEW: A variation in the gene encoding the cysteine protease calpain 10 (CAPN10) was recently linked and associated with type 2 diabetes by positional cloning. This positional cloning was a follow-up investigation to the identification of a diabetes-linked region on human chromosome 2 identified by genome-wide scanning a few years earlier. In this paper we give a general background on the genetic studies performed on CAPN10 to date, and review the most recent studies on the functional role of calpain 10. RECENT FINDING: A haplotype or haplotype combination comprising three intronic single nucleotide polymorphisms (UCSNP-43, 19, and 63) were associated with a threefold increased risk of type 2 diabetes in the population in which linkage was first found. Another polymorphism, UCSNP-44, which is in linkage disequilibrium with a coding single-nucleotide polymorphism (Thr504Ala), has subsequently been associated with type 2 diabetes in extensive meta-analyses. Meanwhile, initial studies probing the possible role of calpain-10, completely unknown at the time, are now being pursued, both in isolated cells and humans. SUMMARY: The positional cloning of CAPN10 as a candidate gene for type 2 diabetes has been particularly fruitful. Not only has it identified an important and surprising piece of the puzzle underlying the development of diabetes, but it has also modelled and paved the way for investigations concerning complex genetic diseases other than type 2 diabetes.

Calpain↗
PubMed2005

Predictors of and longitudinal changes in insulin sensitivity and secretion preceding onset of type 2 diabetes.

Identification of individuals at high risk of developing type 2 diabetes is a prerequisite for prevention of the disease. We therefore studied risk factors predicting type 2 diabetes in the Botnia Study in Western Finland. A total of 2,115 nondiabetic individuals were prospectively followed with repeated oral glucose tolerance tests. After a median follow-up of 6 years, 127 (6%) subjects developed diabetes. A family history of diabetes (hazard ratio [HR] 2.2, P = 0.008), BMI (HR for comparison of values below or above the median 2.1, P < 0.001), waist-to-height index (2.3, P < 0.001), insulin resistance (2.1, P = 0.0004), and beta-cell function adjusted for insulin resistance (2.7, P < 0.0001) predicted diabetes. Marked deterioration in beta-cell function with modest changes in insulin sensitivity was observed during the transition to diabetes. The combination of FPG > or =5.6 mmol/l, BMI > or =30 kg/m(2), and family history of diabetes was a strong predictor of diabetes (3.7, P < 0.0001). Of note, using FPG > or =6.1 mmol/l or 2-h glucose > or =7.8 mmol/l did not significantly improve prediction of type 2 diabetes. In conclusion, a marked deterioration in beta-cell function precedes the onset of type 2 diabetes. These individuals can be identified early by knowledge of FPG, BMI, and family history of diabetes.

Adult↗
PubMed2005

Genetic and nongenetic regulation of CAPN10 mRNA expression in skeletal muscle.

The gene encoding calpain-10 (CAPN10) has been identified as a candidate gene for type 2 diabetes. Our aim was to study the impact of genetic (heritability and polymorphisms) and nongenetic (insulin, free fatty acids, and age) factors on CAPN10 mRNA expression in skeletal muscle using two different study designs. Muscle biopsies were obtained before and after hyperinsulinemic-euglycemic clamps from 166 young and elderly monozygotic and dizygotic twins as well as from 15 subjects with normal (NGT) or impaired glucose tolerance (IGT) exposed to an Intralipid infusion. We found hereditary effects on both basal and insulin-exposed CAPN10 mRNA expression. Carriers of the type 2 diabetes-associated single nucleotide polymorphism (SNP)-43 G/G genotype had reduced CAPN10 mRNA levels compared with subjects carrying the SNP-43 A-allele. Age had no significant influence on CAPN10 mRNA levels. Insulin had no significant effect on CAPN10 mRNA levels, neither in the twins nor in the basal state of the Intralipid study. However, after a 24-h infusion of Intralipid, we noted a significant increase in CAPN10 mRNA in response to insulin in subjects with NGT but not in subjects with IGT. In conclusion, we provide evidence that mRNA expression of CAPN10 in skeletal muscle is under genetic control. Glucose-tolerant but not glucose-intolerant individuals upregulate their CAPN10 mRNA levels in response to prolonged exposure to fat.

Adult↗
PubMed2005

Association testing of variants in the hepatocyte nuclear factor 4alpha gene with risk of type 2 diabetes in 7,883 people.

Two recent publications reported association of common polymorphisms in the P2 promoter of hepatocyte nuclear factor 4alpha (HNF4alpha) (the MODY1 gene) with risk for type 2 diabetes. We attempted to reproduce this putative association by genotyping 11 single nucleotide polymorphism (SNPs) spanning the HNF4alpha coding region and the P2 promoter in >3,400 patients and control subjects from Sweden, Finland, and Canada. One SNP that was consistently associated in the two previous reports (rs1884613, in the P2 promoter region) also trended in the same direction in our sample, albeit with a lower estimated odds ratio (OR) of 1.11 (P = 0.05, one-tailed). We genotyped this SNP (rs1884613) in an additional 4,400 subjects from North America and Poland. In this sample, the association was not confirmed and trended in the opposite direction (OR 0.88). Meta-analysis of our combined sample of 7,883 people (three times larger than the two initial reports combined) yielded an OR of 0.97 (P = 0.27). Finally, we provide an updated analysis of haplotype structure in the region to guide any further investigation of common variation in HNF4alpha. Although our combined results fail to replicate the previously reported association of common variants in HNF4alpha with risk for type 2 diabetes, we cannot exclude an effect smaller than that originally proposed, heterogeneity among samples, variation in as-yet-unmeasured genotypic or environmental modifiers, or true association secondary to linkage disequilibrium (LD) with as-yet-undiscovered variant(s) in the region.

Adult↗
PubMed2005

Association testing of the protein tyrosine phosphatase 1B gene (PTPN1) with type 2 diabetes in 7,883 people.

Protein tyrosine phosphatase (PTP)-1B, encoded by the PTPN1 gene, inactivates the insulin signal transduction cascade by dephosphorylating phosphotyrosine residues in insulin signaling molecules. Due to its chromosomal location under a chromosome 20 linkage peak and the metabolic effects of its absence in knockout mice, it is a candidate gene for type 2 diabetes. Recent studies have associated common sequence variants in PTPN1 with type 2 diabetes and diabetes-related phenotypes. We sought to replicate the association of common single nucleotide polymorphisms (SNPs) and haplotypes in PTPN1 with type 2 diabetes, fasting plasma glucose, and insulin sensitivity in a large collection of subjects. We assessed linkage disequilibrium, selected tag SNPs, and typed these markers in 3,347 cases of type 2 diabetes and 3,347 control subjects as well as 1,189 siblings discordant for type 2 diabetes. Despite power estimated at >95% to replicate the previously reported associations, no statistically significant evidence of association was observed between PTPN1 SNPs or common haplotypes with type 2 diabetes or with diabetic phenotypes.

Base Sequence↗
PubMed2005

Association of common variation in the HNF1alpha gene region with risk of type 2 diabetes.

It is currently unclear how often genes that are mutated to cause rare, early-onset monogenic forms of disease also harbor common variants that contribute to the more typical polygenic form of each disease. The gene for MODY3 diabetes, HNF1alpha, lies in a region that has shown linkage to late-onset type 2 diabetes (12q24, NIDDM2), and previous association studies have suggested a weak trend toward association for common missense variants in HNF1alpha with glucose-related traits. Based on genotyping of 79 common SNPs in the 118 kb spanning HNF1alpha, we selected 21 haplotype tag single nucleotide polymorphisms (SNPs) and genotyped them in >4,000 diabetic patients and control subjects from Sweden, Finland, and Canada. Several SNPs from the coding region and 5' of the gene demonstrated nominal association with type 2 diabetes, with the most significant marker (rs1920792) having an odds ratio of 1.17 and a P value of 0.002. We then genotyped three SNPs with the strongest evidence for association to type 2 diabetes (rs1920792, I27L, and A98V) in an additional 4,400 type 2 diabetic and control subjects from North America and Poland and compared our results with those of the original sample and of Weedon et al. None of the results were consistently observed across all samples, with the possible exception of a modest association of the rare (3-5%) A98V variant. These results indicate that common variants in HNF1alpha either play no role in type 2 diabetes, a very small role, or a role that cannot be consistently observed without consideration of as yet unmeasured genetic or environmental modifiers.

Case-Control Studies↗
PubMed2005

Relationship between testosterone levels, insulin sensitivity, and mitochondrial function in men.

OBJECTIVE: The goal of this study was to examine the relationship between serum testosterone levels and insulin sensitivity and mitochondrial function in men. RESEARCH DESIGN AND METHODS: A total of 60 men (mean age 60.5 +/- 1.2 years) had a detailed hormonal and metabolic evaluation. Insulin sensitivity was measured using a hyperinsulinemic-euglycemic clamp. Mitochondrial function was assessed by measuring maximal aerobic capacity (V(O2max)) and expression of oxidative phosphorylation genes in skeletal muscle. RESULTS: A total of 45% of subjects had normal glucose tolerance, 20% had impaired glucose tolerance, and 35% had type 2 diabetes. Testosterone levels were positively correlated with insulin sensitivity (r = 0.4, P < 0.005). Subjects with hypogonadal testosterone levels (n = 10) had a BMI >25 kg/m(2) and a threefold higher prevalence of the metabolic syndrome than their eugonadal counterparts (n = 50); this relationship held true after adjusting for age and sex hormone-binding globulin but not BMI. Testosterone levels also correlated with V(O2max) (r = 0.43, P < 0.05) and oxidative phosphorylation gene expression (r = 0.57, P < 0.0001). CONCLUSIONS: These data indicate that low serum testosterone levels are associated with an adverse metabolic profile and suggest a novel unifying mechanism for the previously independent observations that low testosterone levels and impaired mitochondrial function promote insulin resistance in men.

Adult↗
PubMed2004

The FOXC2 C-512T polymorphism is associated with obesity and dyslipidemia.

The transcription factor FOXC2 has been implicated in resistance to diet-induced obesity and insulin resistance. To investigate the possible role for FOXC2 in obesity and related phenotypes, we performed two association studies for obesity using unrelated case-control materials by genotyping the FOXC2 C-512T polymorphism. In the first study (127 obese and 127 normal-weight nondiabetic subjects matched for age and sex), the C-allele showed association with obesity, odds ratio 1.74 (1.12 to 2.73; p < 0.01) for the C- vs. T-allele and 1.81 (1.04 to 3.25; p < 0.05) for the C/C and C/T vs. T/T genotype. BMI was higher in carriers of the C/C and C/T genotype in normal weight [adjusted p value (p(adj)) = 0.02] but not in obese subjects (p(adj) = 0.1). In the replication study (223 obese and 231 nonobese subjects), subjects with the C/C genotype exhibited an increased risk for obesity, odds ratio 2.01 (1.15 to 3.52; p = 0.01). Obese carriers of the C-allele had lower high-density lipoprotein-cholesterol [1.1 (0.9 to 1.3) vs. 1.2 (1.0 to 1.4) mM, p(adj) = 0.006] and increased triglyceride levels (1.95 [1.30 to 2.68] vs. 1.60 [1.10 to 2.40] mM, p(adj) = 0.02) compared with obese carriers of the T/T genotype. Our data suggest that FOXC2 is a weak but consistent candidate gene for obesity and dyslipidemia.

Abdomen↗
PubMed2004

Association between a polymorphism in the carboxyl ester lipase gene and serum cholesterol profile.

Carboxyl ester lipase (CEL) is involved in the hydrolysis and absorption of dietary lipids, but it is largely unknown to what extent CEL could be involved in determining the serum lipid levels. The C-terminal part of CEL consists of a unique structure with proline-rich O-glycosylated repeats of 11 amino-acid residues each. The common variant of the human CEL gene contains 16 proline-rich repeats, but there is a high degree of polymorphism in the repeated region. While the biological function of the polymorphic repeat region is unknown, it has been suggested that it may be important for protein stability and/or secretion of the enzyme. Given that the polymorphism in the repeated region may affect the functionality of the protein, this study aimed to investigate whether the number of repeated units is correlated to serum lipid phenotype. Comparison of CEL repeat genotype and serum lipid phenotype revealed an association between the number of repeats and serum cholesterol profile. Individuals carrying at least one allele with fewer than the common 16 repeats had significantly lower total and low-density lipoprotein (LDL) cholesterol levels compared to individuals carrying two common alleles. This gives support to the notion that CEL may be involved in determining the plasma lipid composition.

Cholesterol↗
PubMed2004

Heritability of ambulatory and office blood pressure phenotypes in Swedish families.

OBJECTIVE: The aim of this study was to estimate the heritability of 24-h ambulatory blood pressure and office blood pressure phenotypes in Swedish families. METHODS: We measured ambulatory and office blood pressure in 260 siblings without antihypertensive treatment from 118 families. Blood pressure heritability was estimated using standard quantitative genetic variance component analysis implemented in the 'SOLAR' software package after adjustment for significant covariates. RESULTS: Heritability values were significant for night-time systolic (37%), diastolic (32%) and mean (32%) ambulatory blood pressure (P < 0.05 for all). During daytime, systolic ambulatory blood pressure was significantly heritable (33%, P < 0.05). Twenty-four-hour systolic (30%) and diastolic (29%) ambulatory blood pressure also had significant values of heritability (P < 0.05). Pulse pressure ambulatory blood pressure was significantly heritable over 24 h (63%, P < 0.01), during daytime (53%, P < 0.01) and at night (34%, P < 0.05). None of the office blood pressure phenotypes had a significant heritability. CONCLUSIONS: We conclude that ambulatory blood pressure, in particular at night, seems better than office blood pressure to capture the heritable part of blood pressure, suggesting that ambulatory blood pressure may be a more exact estimate of an individual's true blood pressure. Genetic studies using ambulatory blood pressure as the phenotype are likely to be more powerful than those using office blood pressure. The high heritability of pulse pressure ambulatory blood pressure indicates that variation in arterial stiffness in subjects free from antihypertensive medication is strongly affected by genetic factors.

Adult↗
PubMed2004

Multiple environmental and genetic factors influence skeletal muscle PGC-1alpha and PGC-1beta gene expression in twins.

Genetic and environmental factors contribute to age-dependent susceptibility to type 2 diabetes. Recent studies have reported reduced expression of PPARgamma coactivator 1alpha (PGC-1alpha) and PGC-1beta genes in skeletal muscle from type 2 diabetic patients, but it is not known whether this is an inherited or acquired defect. To address this question we studied expression of these genes in muscle biopsies obtained from young and elderly dizygotic and monozygotic twins without known diabetes before and after insulin stimulation and related the expression to a Gly482Ser variant in the PGC-1alpha gene. Insulin increased and aging reduced skeletal muscle PGC-1alpha and PGC-1beta mRNA levels. This age-dependent decrease in muscle gene expression was partially heritable and influenced by the PGC-1alpha Gly482Ser polymorphism. In addition, sex, birth weight, and aerobic capacity influenced expression of PGC-1alpha in a complex fashion. Whereas expression of PGC-1alpha in muscle was positively related to insulin-stimulated glucose uptake and oxidation, PGC-1beta expression was positively related to fat oxidation and nonoxidative glucose metabolism. We conclude that skeletal muscle PGC-1alpha and PGC-1beta expression are stimulated by insulin and reduced by aging. The data also suggest different regulatory functions for PGC-1alpha and PGC-1beta on glucose and fat oxidation in muscle cells. The finding that the age-dependent decrease in the expression of these key genes regulating oxidative phosphorylation is under genetic control could provide an explanation by which an environmental trigger (age) modifies genetic susceptibility to type 2 diabetes.

Adult↗
PubMed2004

Variation in the calpain-10 gene is associated with elevated triglyceride levels and reduced adipose tissue messenger ribonucleic acid expression in obese Swedish subjects.

Our aim was to investigate the possible role of the type 2 diabetes susceptibility gene CAPN10 in obesity. A case control study consisting of 235 obese Swedish subjects [body mass index, 40 (35-45) kg/m(2)] and 235 controls matched for age and gender [body mass index, 22 (21-24) kg/m(2)], and a transmission disequilibrium test consisting of 116 parents-offspring trios, where the offspring was abdominally obese [waist, 100 (95-110) cm], were performed. CAPN10 mRNA expression was studied in adipose tissue biopsies from 33 of the obese subjects participating in the case control study. The CAPN10 single-nucleotide polymorphism (SNP)-43 was genotyped using PCR followed by NdeI digestion or by allelic discrimination. CAPN10 mRNA levels were quantified using real-time RT-PCR with Cyclophilin A as an internal standard. No significant associations between CAPN10 SNP-43 and obesity were seen, neither in the case control study nor in the transmission disequilibrium test, but obese subjects homozygous for the SNP-43 G allele had significantly elevated triglyceride levels compared with subjects carrying the A allele [1.7 (1.1-2.4) vs. 1.4 (1.0-2.0); P = 0.03]. The CAPN10 mRNA expression in sc fat was significantly reduced in subjects with the SNP-43 G/G genotype compared with carriers of SNP-43 G/A (G/G, 0.33 +/- 0.02, vs. G/A, 0.51 +/- 0.09; P = 0.048), and a similar trend was observed in visceral fat (G/G, 0.52 +/- 0.06, vs. G/A, 0.65 +/- 0.10; P = 0.22). Our data suggest that reduced CAPN10 expression may be a risk factor for features associated with the metabolic syndrome in obese subjects, although variation in the gene does not seem to contribute to the risk for developing obesity per se.

Adipose Tissue↗
PubMed2004

Association testing in 9,000 people fails to confirm the association of the insulin receptor substrate-1 G972R polymorphism with type 2 diabetes.

The insulin receptor substrate (IRS)-1 is an important component of the insulin signal transduction cascade. Several reports suggest that a Gly-->Arg change in codon 972 is associated with type 2 diabetes and related traits, and a recent meta-analysis reported a modest but nominally significant association with type 2 diabetes (odds ratio [OR] 1.25 in favor of carriers of the Arg allele [95% CI 1.05-1.48). To test the reproducibility of the model in a recent meta-analysis, we examined genotype-phenotype correlation in three large Caucasian samples (not previously reported for this variant) totaling 9,000 individuals (estimated to have >95% power to obtain a P < 0.05 for the OR of 1.25 estimated in the meta-analysis). In our combined sample, comprising 4,279 case and 3,532 control subjects, as well as 1,189 siblings discordant for type 2 diabetes, G972R was not associated with type 2 diabetes (OR 0.96 [0.84-1.10], P = 0.60). Genotype at G972R had no significant effect on various measures of insulin secretion or insulin resistance in a set of Scandinavian samples in whom we had detailed phenotypic data. In contrast, the well-documented associations of peroxisome proliferator-activated receptor gamma P12A and Kir6.2 E23K with type 2 diabetes are both robustly observed in these 9,000 subjects, including an additional (previously unpublished) confirmation of Kir6.2 E23K and type 2 diabetes in the Polish and North American samples (combined OR 1.15 [1.05-1.26], P = 0.001). Despite genotyping 9,000 people and >95% power to reproduce the estimated OR from the recent meta-analysis, we were unable to replicate the association of the IRS-1 G972R polymorphism with type 2 diabetes.

Amino Acid Substitution↗
PubMed2004

Haplotype structure and genotype-phenotype correlations of the sulfonylurea receptor and the islet ATP-sensitive potassium channel gene region.

The genes for the sulfonylurea receptor (SUR1; encoded by ABCC8) and its associated islet ATP-sensitive potassium channel (Kir6.2; encoded by KCNJ11) are adjacent to one another on human chromosome 11. Multiple studies have reported association of the E23K variant of Kir6.2 with risk of type 2 diabetes. Whether and how E23K itself-or other variant(s) in either of these two closely linked genes-influences type 2 diabetes remains to be fully determined. To better understand genotype-phenotype correlation at this important candidate gene locus, we 1) characterized haplotype structures across the gene region by typing 77 working, high-frequency markers spanning 207 kb and both genes; 2) performed association studies of E23K and nearby markers in >3,400 patients (type 2 diabetes and control) not previously reported in the literature; and 3) analyzed the resulting data for measures of insulin secretion. These data independently replicate the association of E23K with type 2 diabetes with an odds ratio (OR) in the new data of 1.17 (P = 0.003) as compared with an OR of 1.14 provided by meta-analysis of previously published, nonoverlapping data (P = 0.0002). We find that the E23K variant in Kir6.2 demonstrates very strong allelic association with a coding variant (A1369S) in the neighboring SUR1 gene (r(2) > 0.9) across a range of population samples, making it difficult to distinguish which gene and polymorphism in this region are most likely responsible for the reported association. We show that E23K is also associated with decreased insulin secretion in glucose-tolerant control subjects, supporting a mechanism whereby beta-cell dysfunction contributes to the common form of type 2 diabetes. Like peroxisome proliferator-activated receptor gamma, the SUR1/Kir6.2 gene region both contributes to the inherited risk of type 2 diabetes and encodes proteins that are targets for hypoglycemic medications, providing an intriguing link between the underlying mechanism of disease and validated targets for pharmacological treatment.

ATP-Binding Cassette Transporters↗
PubMed2004

Cosegregation of MIDD and MODY in a pedigree: functional and clinical consequences.

The aim of this study was characterization of a family carrying two mutations known to cause monogenic forms of diabetes, the M626K mutation in the HNF1alpha gene (MODY3) and the A3243G in mtDNA. Beta-cell function and insulin sensitivity were assessed with the Botnia clamp. Heteroplasmy of the A3243G mutation and variants in type 2 diabetes susceptibility genes were determined, and transcriptional activity, DNA binding, and subcellular localization of mutated HNF1alpha were studied. Thirteen family members carried the mutation in mtDNA; 6 of them also had the M626K mutation, whereas none had only the M626K mutation. The protective Ala12 allele in peroxisome proliferator-activated receptor (PPAR)gamma was present in two nondiabetic individuals. Carriers of both mtDNA and HNF1alpha mutations showed an earlier age at onset of diabetes than carriers of only the mtDNA mutation (median 22 vs. 45 years) but no clear difference in beta-cell function or insulin sensitivity. In vitro, the M626K mutation caused a 53% decrease in transcriptional activity in HeLa cells. The mutated protein showed normal nuclear targeting but increased DNA binding. These data demonstrate that several genetic factors might contribute to diabetes risk, even in families with mtDNA and HNF1alpha mutations.

Adolescent↗
PubMed2004

Elevated plasma levels of Nt-proBNP in patients with type 2 diabetes without overt cardiovascular disease.

OBJECTIVE: The NH(2)-terminal portion of the precursor of brain natriuretic peptide (Nt-proBNP) has been reported to be elevated in left ventricular dysfunction. This peptide is a split product from the proBNP molecule, and its level in the circulation is not, as the mature BNP peptide, dependent on the peripheral number of BNP receptors. We aimed to test the hypothesis that asymptomatic left ventricular dysfunction (ALVD), as estimated by Nt-proBNP, would be more prevalent in patients with type 2 diabetes without overt cardiovascular disease in comparison with matched control subjects. RESEARCH DESIGN AND METHODS: The study population consisted of 253 patients with type 2 diabetes and 230 matched control subjects aged 40-70 years without any overt heart disease from primary care centers in Western Finland and Southern Sweden. Nt-proBNP was measured in plasma by competitive enzyme immunosorbent assay. RESULTS: Patients with type 2 diabetes were shown to have higher Nt-proBNP values (360.9 pmol/l [262.6-467.9]) than control subjects (302.7 pmol/l [215.4-419.2]) (P < 0.001). Nt-proBNP levels were independently related to diabetes after adjustment for age, sex, systolic and diastolic blood pressure, BMI, heart rate, drug treatment, serum creatinine, and cystatin C. CONCLUSIONS: Our data suggest that the secretion of Nt-proBNP is increased in type 2 diabetic patients with no overt heart disease, suggesting that type 2 diabetes is associated with a higher prevalence of ALVD than hitherto thought. Nt-proBNP may thus serve as a screening instrument to select patients with type 2 diabetes who could benefit from an echocardiographical examination.

Adult↗
PubMed2004

Contribution of insulin-stimulated glucose uptake and basal hepatic insulin sensitivity to surrogate measures of insulin sensitivity.

OBJECTIVE: The goal of this study was to evaluate the performance of surrogate measures of insulin sensitivity and insulin secretion. RESEARCH DESIGN AND METHODS: The homeostasis model assessment (HOMA) of insulin resistance (IR) and the insulin sensitivity index (S(i)) from oral glucose tolerance test (OGTT) were compared with the M value from a hyperinsulinemic-euglycemic clamp in 467 subjects with various degrees of glucose tolerance. Endogenous glucose production (EGP) and hepatic insulin sensitivity were determined in a subset (n = 143). Insulin secretion was estimated as the HOMA beta-cell index and as the insulinogenic index from the first 30 min of the OGTT (I/G30) and compared with the first-phase insulin response (FPIR) to an intravenous glucose tolerance test (n = 218). RESULTS: The M value correlated with the HOMA-IR (r = -0.591, P < 0.0001) and the S(i) (r = 0.533, P < 0.0001) indexes in the total study group. HOMA-IR correlated with basal EGP in the total study group (r = 0.378, P < 0.0005) and in subjects with diabetes (r = 0.330, P = 0.01). However, neither HOMA-IR nor S(i) correlated significantly with the M value in subjects with impaired fasting glucose (IFG) (r = -0.108, P = 0.5; r = 0.01, P = 0.9) or IFG/impaired glucose tolerance (IGT) (r = -0.167, P = 0.4; r = 0.09, P = 0.6). The HOMA-IR correlated with hepatic insulin sensitivity in the whole study group (r = -0.395, P < 0.005) as well as in the IFG/IGT subgroup (r = -0.634, P = 0.002) and in the diabetic subgroup (r = -0.348, P = 0.008). In subjects with IFG/IGT, hepatic insulin sensitivity was the most important determinant of HOMA-IR, explaining 40% of its variation. The HOMA beta-cell index showed a weak correlation with FPIR in the whole study group (r = 0.294, P = 0.001) but not in the subgroups. In contrast, the I/G30 correlated with FPIR in the whole study group (r = 0.472, P < 0.0005) and in the IFG/IGT subgroup (r = 0.493, P < 0.005). CONCLUSIONS: HOMA-IR is dependent upon both peripheral and hepatic insulin sensitivity, the contribution of which differs between subjects with normal and elevated fasting glucose concentrations. These discrepancies develop as a consequence of a nonparallel deterioration of the variables included in the equations with worsening of glucose tolerance.

Blood Glucose↗