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K N Conneely,
K Silander,
L J Scott,
K L Mohlke,
K N Lazaridis,
T T Valle,
J Tuomilehto,
R N Bergman, R M Watanabe,
T A Buchanan,
F S Collins,
M Boehnke
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ABSTRACT: Resistin is a peptide hormone produced by adipocytes that is present at high levels in sera of obese mice and may be involved in glucose homeostasis through regulation of insulin sensitivity. Several studies in humans have found associations between polymorphisms in the resistin gene and obesity, insulin sensitivity and blood pressure. An association between variation in the resistin gene and type 2 diabetes has been reported in some, but not all studies. The aim of this study was to analyse variants of the resistin gene for association with type 2 diabetes and related traits in a Finnish sample.
In 781 cases with type 2 diabetes, 187 spouse controls and 222 elderly controls of Finnish origin, we genotyped four previously identified non-coding single-nucleotide polymorphisms (SNPs): -420C>G from the promoter region, +156C>T and +298G>A from intron 2, and +1084G>A from the 3' untranslated region. We then tested whether these SNPs were associated with type 2 diabetes and related traits.
The SNPs were not significantly associated with type 2 diabetes. However, SNPs -420C>G, +156C>T and +298G>A and the common haplotype for these three markers were associated with increased values of weight-related traits and diastolic blood pressure in cases, lower weight in elderly control subjects, and lower insulin sensitivity and greater acute insulin response in spouses. Furthermore, the +1084G allele was associated with lower HDL cholesterol in both cases and controls, higher systolic blood pressure and waist circumference in cases, and greater acute insulin response in spouse controls.
Our results add to growing evidence that resistin is associated with variation in weight, fat distribution and insulin resistance.
Diabetologia 11/2004; 47(10):1782-8. · 6.81 Impact Factor
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ABSTRACT: As small increments in insulin concentration profoundly affect lipolysis, our goal was to describe the free fatty acid (FFA) profile during the frequently sampled intravenous glucose tolerance test (FSIGT) and determine if both endogenous and exogenous insulin influenced the FFA profile. Thirteen subjects had both a glucose-only (GO-FSIGT) and insulin-modified FSIGT (IM-FSIGT). Both protocols were of 6 hours duration. At baseline an intravenous glucose bolus (0.3 g/kg) was given. In the IM-FSIGT, insulin was infused from 20 to 25 minutes (4 mU/kg. min). Six additional subjects had both an IM-FSIGT and a normal saline study (NS-Study). For the NS-Study, normal saline solution was infused instead of glucose and insulin. Fasting glucose, insulin, FFA and epinephrine concentrations were similar for all tests. Endogenous insulin peaked at 4 +/- 1 minute in both FSIGTs. The mean calculated peak time of exogenous insulin in the IM-FSIGT was 26 +/- 1 minute. Glucose concentrations were lower and epinephrine concentrations higher in the IM-FSIGT versus GO-FSIGT. During the FSIGTs, the FFA time course revealed four distinct phases, which did not differ between protocols. In phase I (0 to 11 minutes), FFA levels remained near basal (491 +/- 183 micromol/L); in phase II (11 to 79 minutes), FFA levels declined achieving a nadir of 139 +/- 63 micromol/L; in phase III (79 to 188 minutes), FFA levels rose linearly and reattained basal levels; and in phase IV (188 to 360 minutes), FFA levels rose above basal and plateaued at 732 +/- 214 micromol/L (P <.001). In the NS-Study, FFA levels remained near baseline (388 +/- 118 mEq/L) until 180 minutes and then trended upward to 618 +/- 258 micromol/L at 360 minutes. FFA concentrations from 180 to 360 minutes did not differ in the IM-FSIGT versus NS-Study. As the 4 FFA phases did not differ between protocols, the insulin effect on FFA levels in the FSIGT can be attributed to endogenous insulin. But the similarity in FFA levels from 180 to 360 minutes in the IM-FSIGT and NS-Study suggests diurnal variation and not a dynamic related to insulin or the FSIGT protocol is responsible for the final suprabasal FFA plateau.
Metabolism 09/2004; 53(9):1202-7. · 2.66 Impact Factor
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K L Mohlke,
E M Lange,
T T Valle,
S Ghosh,
V L Magnuson,
K Silander, R M Watanabe,
P S Chines,
R N Bergman,
J Tuomilehto,
F S Collins,
M Boehnke
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ABSTRACT: Linkage disequilibrium (LD) is a proven tool for evaluating population structure and localizing genes for monogenic disorders. LD-based methods may also help localize genes for complex traits. We evaluated marker-marker LD using 43 microsatellite markers spanning chromosome 20 with an average density of 2.3 cM. We studied 837 individuals affected with type 2 diabetes and 386 mostly unaffected spouse controls. A test of homogeneity between the affected individuals and their spouses showed no difference, allowing the 1223 individuals to be analyzed together. Significant (P < 0.01) LD was observed using a likelihood ratio test in all (11/11) marker pairs within 1 cM, 78% (25/32) of pairs 1-3 cM apart, and 39% (7/18) of pairs 3-4 cM apart, but for only 12 of 842 pairs more than 4 cM apart. We used the human genome project working draft sequence to estimate kilobase (kb) intermarker distances, and observed highly significant LD (P < 10(-10)) for all six marker pairs up to 350 kb apart, although the correlation of LD with cM is slightly better than the correlation with megabases. These data suggest that microsatellites present at 1-cM density are sufficient to observe marker-marker LD in the Finnish population.
Genome Research 07/2001; 11(7):1221-6. · 13.61 Impact Factor
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J A Douglas,
M R Erdos, R M Watanabe,
A Braun,
C L Johnston,
P Oeth,
K L Mohlke,
T T Valle,
C Ehnholm,
T A Buchanan,
R N Bergman,
F S Collins,
M Boehnke,
J Tuomilehto
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ABSTRACT: Recent studies have identified a common proline-to-alanine substitution (Pro12Ala) in the peroxisome proliferator-activated receptor-gamma2 (PPAR-gamma2), a nuclear receptor that regulates adipocyte differentiation and possibly insulin sensitivity. The Pro12Ala variant has been associated in some studies with diabetes-related traits and/or protection against type 2 diabetes. We examined this variant in 935 Finnish subjects, including 522 subjects with type 2 diabetes, 193 nondiabetic spouses, and 220 elderly nondiabetic control subjects. The frequency of the Pro12Ala variant was significantly lower in diabetic subjects than in nondiabetic subjects (0.15 vs. 0.21; P = 0.001). We also compared diabetes-related traits between subjects with and without the Pro12Ala variant within subgroups. Among diabetic subjects, the variant was associated with greater weight gain after age 20 years (P = 0.023) and lower triglyceride levels (P = 0.033). Diastolic blood pressure was higher in grossly obese (BMI >40 kg/m2) diabetic subjects with the variant. In nondiabetic spouses, the variant was associated with higher fasting insulin (P = 0.033), systolic blood pressure (P = 0.021), and diastolic blood pressure (P = 0.045). These findings support a role for the PPAR-gamma2 Pro12Ala variant in the etiology of type 2 diabetes and the insulin resistance syndrome.
Diabetes 04/2001; 50(4):886-90. · 8.29 Impact Factor
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S Ghosh, R M Watanabe,
T T Valle,
E R Hauser,
V L Magnuson,
C D Langefeld,
D S Ally,
K L Mohlke,
K Silander,
K Kohtamäki, [......],
Z E Karanjawala,
J I Knapp,
K Kudelko,
C Martin,
A Morales-Mena,
A Musick,
T Musick,
C Pfahl,
R Porter,
J B Rayman
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ABSTRACT: We performed a genome scan at an average resolution of 8 cM in 719 Finnish sib pairs with type 2 diabetes. Our strongest results are for chromosome 20, where we observe a weighted maximum LOD score (MLS) of 2.15 at map position 69.5 cM from pter and secondary weighted LOD-score peaks of 2.04 at 56.5 cM and 1.99 at 17.5 cM. Our next largest MLS is for chromosome 11 (MLS = 1.75 at 84.0 cM), followed by chromosomes 2 (MLS = 0.87 at 5.5 cM), 10 (MLS = 0.77 at 75.0 cM), and 6 (MLS = 0.61 at 112.5 cM), all under an additive model. When we condition on chromosome 2 at 8.5 cM, the MLS for chromosome 20 increases to 5.50 at 69.0 cM (P=.0014). An ordered-subsets analysis based on families with high or low diabetes-related quantitative traits yielded results that support the possible existence of disease-predisposing genes on chromosomes 6 and 10. Genomewide linkage-disequilibrium analysis using microsatellite marker data revealed strong evidence of association for D22S423 (P=.00007). Further analyses are being carried out to confirm and to refine the location of these putative diabetes-predisposing genes.
The American Journal of Human Genetics 12/2000; 67(5):1174-85. · 10.60 Impact Factor
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R M Watanabe,
S Ghosh,
C D Langefeld,
T T Valle,
E R Hauser,
V L Magnuson,
K L Mohlke,
K Silander,
D S Ally,
P Chines, [......],
E M Lange,
C Li,
R C McEachin,
H M Stringham,
E Trager,
P P White,
J Balow Jr,
G Birznieks,
J Chang,
W Eldridge
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ABSTRACT: Type 2 diabetes mellitus is a complex disorder encompassing multiple metabolic defects. We report results from an autosomal genome scan for type 2 diabetes-related quantitative traits in 580 Finnish families ascertained for an affected sibling pair and analyzed by the variance components-based quantitative-trait locus (QTL) linkage approach. We analyzed diabetic and nondiabetic subjects separately, because of the possible impact of disease on the traits of interest. In diabetic individuals, our strongest results were observed on chromosomes 3 (fasting C-peptide/glucose: maximum LOD score [MLS] = 3.13 at 53.0 cM) and 13 (body-mass index: MLS = 3.28 at 5.0 cM). In nondiabetic individuals, the strongest results were observed on chromosomes 10 (acute insulin response: MLS = 3.11 at 21.0 cM), 13 (2-h insulin: MLS = 2.86 at 65.5 cM), and 17 (fasting insulin/glucose ratio: MLS = 3.20 at 9.0 cM). In several cases, there was evidence for overlapping signals between diabetic and nondiabetic individuals; therefore we performed joint analyses. In these joint analyses, we observed strong signals for chromosomes 3 (body-mass index: MLS = 3.43 at 59.5 cM), 17 (empirical insulin-resistance index: MLS = 3.61 at 0.0 cM), and 19 (empirical insulin-resistance index: MLS = 2.80 at 74.5 cM). Integrating genome-scan results from the companion article by Ghosh et al., we identify several regions that may harbor susceptibility genes for type 2 diabetes in the Finnish population.
The American Journal of Human Genetics 12/2000; 67(5):1186-200. · 10.60 Impact Factor
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ABSTRACT: The implication of beta-cell failure as an early defect in type 2 diabetes exacerbates the need for accurate but facile assessment of islet cell secretory rate, particularly in large group studies in which individual assessment of C-peptide kinetics is impractical. This study was designed to examine whether it is possible to obtain accurate secretory rates from the extended combined model, which provides insulin and C-peptide kinetics from plasma measurements of the two peptides. Equimolar intraportal infusions of insulin and C-peptide that are designed to simulate insulin secretion rates during both oral and intravenous glucose tolerance tests were used to generate plasma insulin and C-peptide data in conscious dogs that were examined under clamped glucose conditions. The plasma peptide kinetics were analyzed using the extended combined model to generate estimates of prehepatic insulin secretion that were then compared with the known intraportal infusion rates. The extended combined model was able to reproduce the known intraportal infusion profiles. The model-predicted rates were similar to those calculated with methods that require separate assessment of C-peptide kinetics. Simulation results supported lesser clearance of insulin during rapid changes of portal insulin (as measured by an intravenous glucose tolerance test) versus slow changes in portal insulin (as measured by an oral glucose tolerance test). The extended combined model accurately calculates prehepatic insulin appearance. It may be possible to apply this approach to large studies of beta-cell function designed to identify changes in islet function in subjects at risk for diabetes. Such an approach could strengthen epidemiological and genetic studies of the pathogenesis of diabetes.
Diabetes 04/2000; 49(3):373-82. · 8.29 Impact Factor
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R M Watanabe,
T Valle,
E R Hauser,
S Ghosh,
J Eriksson,
K Kohtamäki,
C Ehnholm,
J Tuomilehto,
F S Collins,
R N Bergman,
M Boehnke
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ABSTRACT: Type 2 diabetes mellitus (NIDDM) is a complex disorder encompassing multiple metabolic defects. There exists strong evidence for a genetic component to NIDDM; however, to date there have been few reports of linkage between genetic markers along the genome and NIDDM or NIDDM-related quantitative traits. We sought to determine whether individual quantitative traits which determine glucose tolerance exhibit familiality in Finnish families with at least one NIDDM-affected sibling pair. Tolbutamide-modified frequently sampled intravenous glucose tolerance tests (FSIGT) were performed on unaffected offspring (n = 431) and spouses (n = 154) of affected sibling pairs sampled for the Finland-United States Investigation of NIDDM Genetics (FUSION) study. FSIGT data were analyzed using the Minimal Model to obtain quantitative measures of insulin sensitivity (SI), glucose effectiveness (SG), and insulin secretion assessed as the acute insulin response to glucose (AIR). The disposition index (DI), a measure of insulin resistance-corrected beta-cell function, was also derived as the product of SI and AIR. Variance components analysis was used to determine for each trait, the heritability (h2), the proportion of the total trait variance accounted for by additive genes. After adjustment for age, gender, and body mass index, h2 estimates were: SG: 18 +/- 9%, SI: 28 +/- 8%, AIR: 35 +/- 8%, and DI: 23 +/- 8%. We conclude that there is strong evidence for modest heritability of Minimal-Model-derived NIDDM-related quantitative traits in unaffected spouses and offspring of Finnish affected sibling pairs.
Human Heredity 07/1999; 49(3):159-68. · 1.79 Impact Factor
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S Ghosh, R M Watanabe,
E R Hauser,
T Valle,
V L Magnuson,
M R Erdos,
C D Langefeld,
J Balow,
D S Ally,
K Kohtamaki, [......],
T Tenkula,
G Vidgren,
C Ehnholm,
E Tuomilehto-Wolf,
W Hagopian,
T A Buchanan,
J Tuomilehto,
R N Bergman,
F S Collins,
M Boehnke
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ABSTRACT: We are conducting a genome scan at an average resolution of 10 centimorgans (cM) for type 2 diabetes susceptibility genes in 716 affected sib pairs from 477 Finnish families. To date, our best evidence for linkage is on chromosome 20 with potentially separable peaks located on both the long and short arms. The unweighted multipoint maximum logarithm of odds score (MLS) was 3.08 on 20p (location, chi = 19.5 cM) under an additive model, whereas the weighted MLS was 2.06 on 20q (chi = 57 cM, recurrence risk,lambda(s) = 1. 25, P = 0.009). Weighted logarithm of odds scores of 2.00 (chi = 69.5 cM, P = 0.010) and 1.92 (chi = 18.5 cM, P = 0.013) were also observed. Ordered subset analyses based on sibships with extreme mean values of diabetes-related quantitative traits yielded sets of families who contributed disproportionately to the peaks. Two-hour glucose levels in offspring of diabetic individuals gave a MLS of 2. 12 (P = 0.0018) at 9.5 cM. Evidence from this and other studies suggests at least two diabetes-susceptibility genes on chromosome 20. We have also screened the gene for maturity-onset diabetes of the young 1, hepatic nuclear factor 4-a (HNF-4alpha) in 64 affected sibships with evidence for high chromosomal sharing at its location on chromosome 20q. We found no evidence that sequence changes in this gene accounted for the linkage results we observed.
Proceedings of the National Academy of Sciences 04/1999; 96(5):2198-203. · 9.68 Impact Factor
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S Ghosh,
C D Langefeld,
D Ally, R M Watanabe,
E R Hauser,
V L Magnuson,
S J Nylund,
T Valle,
J Eriksson,
R N Bergman,
J Tuomilehto,
F S Collins,
M Boehnke
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ABSTRACT: Recent studies have suggested an association between Type II (non-insulin-dependent) diabetes mellitus-related phenotypes and a cytosine-to-thymidine substitution that results in the replacement of tryptophan by arginine at codon 64 (Trp64Arg or W64R) of the beta3-adrenergic receptor gene. Here, we present the results of possibly the largest association study to date on the variant in a sample of 526 families with a total of 1725 subjects, 1053 of whom had Type II diabetes. Preliminary calculations suggested that we had excellent power to detect the moderate associations which were reported in previous studies. No associations were found between the W64R variant and the following phenotypes in our sample: Type II diabetes, age at diagnosis for Type II diabetes, measures of obesity, fasting glucose, fasting insulin, minimal model variables, and systolic and diastolic blood pressures. In the analysis of plasma lipids, we detected an association between the variant and HDL ratios (HDL cholesterol/total cholesterol) (p = 0.013), which remained significant even after adjusting for sex, affection status and age. Since W64R homozygotes (n = 11) had the highest HDL ratios, however, heterozygotes had the lowest and the wild-type subjects had intermediate values, we conclude that the W64R variant is unlikely to reduce HDL ratios in a dose-dependent, pathogenic manner.
Diabetologia 03/1999; 42(2):238-44. · 6.81 Impact Factor
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ABSTRACT: For complex diseases, underlying etiologic heterogeneity may reduce power to detect linkage. Thus, methods to identify more homogeneous subgroups within a given sample in a linkage study may improve detection of putative susceptibility loci. In this study we describe an ordered subsetting approach that utilizes disease-related quantitative trait data to complement traditional linkage analysis. This approach uses family-based lod scores derived from the initial genome screen and a family-based descriptor of the trait of interest. The goal of the approach is to identify more homogeneous subgroups of the data by ranking families based on their quantitative trait data. Permutation testing is used to assess statistical significance. This approach can be adapted to a variety of linkage methods and may provide a means to dissect some of the underlying heterogeneity in complex disease genetics.
Genetic Epidemiology 02/1999; 17 Suppl 1:S385-90. · 3.44 Impact Factor
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ABSTRACT: Error in phenotypic measurement can significantly compromise ability to detect linkage. We assessed the impact of introducing phenotypic measurement error on our ability to detect a quantitative trait locus in the Collaborative Study on the Genetics of Alcoholism (COGA) data. The impact of introducing three different types of errors was evaluated: 1) errors generated by sampling from a normal distribution; 2) errors generated by permuting phenotype values between subjects; and 3) errors generated by sampling from a uniform error distribution.
Genetic Epidemiology 02/1999; 17 Suppl 1:S61-6. · 3.44 Impact Factor
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ABSTRACT: Once linkage is detected to a quantitative trait locus (QTL), the next step towards localizing the gene involved may be to identify those families, or individuals, in whom the putative mutations are segregating. In this paper, we describe a jackknife procedure for identifying individuals (and families) who contribute disproportionately to the linkage. Following initial detection of linkage to a QTL, the strategy involves sequentially removing each individual (or each family) from the analysis and recomputing the lod score associated with the linked region using data from all remaining subjects (or families). This procedure can be used to determine if particular observations have substantial impact on evidence for linkage. Identification of such observations may provide insights for further efforts to localize the QTL.
Genetic Epidemiology 02/1999; 17 Suppl 1:S259-64. · 3.44 Impact Factor
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S Ghosh,
E R Hauser,
V L Magnuson,
T Valle,
D S Ally,
Z E Karanjawala,
J B Rayman,
J I Knapp,
A Musick,
J Tannenbaum, [......],
A So,
A Witt,
J B Harvan, R M Watanabe,
W Hagopian,
J Eriksson,
S J Nylund,
K Kohtamaki,
E Tuomilehto-Wolf,
M Boehnke
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ABSTRACT: In the first reported positive result from a genome scan for non-insulin-dependent diabetes mellitus (NIDDM), Hanis et al. found significant evidence of linkage for NIDDM on chromosome 2q37 and named the putative disease locus NIDDM1 (Hanis et al. 1996. Nat. Genet. 13:161-166). Their total sample was comprised of 440 Mexican-American affected sib-pairs from 246 sibships. The strongest evidence for linkage was at marker D2S125 and best estimates of lambdas (risk to siblings of probands/population prevalence) using this marker were 1.37 under an additive model and 1.36 under a multiplicative model. We examined this chromosomal region using linkage analysis in a Finnish sample comprised of 709 affected sib-pairs from 472 sibships. We excluded this region in our sample (multipoint logarithm of odds score </= -2) for lambdas >/= 1.37. We discuss possible reasons why linkage to 2q37 was not found and conclude that this region is unlikely to be playing a major role in NIDDM susceptibility in the Finnish Caucasian population.
Journal of Clinical Investigation 08/1998; 102(4):704-9. · 15.39 Impact Factor
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T Valle,
J Tuomilehto,
R N Bergman,
S Ghosh,
E R Hauser,
J Eriksson,
S J Nylund,
K Kohtamäki,
L Toivanen,
G Vidgren, [......],
J Blaschak,
C D Langefeld, R M Watanabe,
V Magnuson,
D S Ally,
W A Hagopian,
E Ross,
T A Buchanan,
F Collins,
M Boehnke
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ABSTRACT: To map and identify susceptibility genes for NIDDM and for the intermediate quantitative traits associated with NIDDM.
We describe the methodology and sample of the Finland-United States Investigation of NIDDM Genetics (FUSION) study. The whole genome search approach is being applied in studies of several different ethnic groups to locate susceptibility genes for NIDDM. Detailed description of the study materials and designs of such studies are important, particularly when comparing the findings in these studies and when combining different data sets.
Using a careful selection strategy, we have ascertained 495 families with confirmed NIDDM in at least two siblings and no history of IDDM among the first-degree relatives. These families were chosen from more than 22,000 NIDDM patients, representative of patients with NIDDM in the Finnish population. In a subset of families, a spouse and offspring were sampled, and they participated in a frequently sampled intravenous glucose tolerance test (FSIGT) analyzed with the Minimal Model. An FSIGT was completed successfully for at least two nondiabetic offspring in 156 families with a confirmed nondiabetic spouse and no history of IDDM in first-degree relatives.
Our work demonstrates the feasibility of collecting a large number of affected sib-pair families with NIDDM to provide data that will enable a whole genome search approach, including linkage analysis.
Diabetes Care 07/1998; 21(6):949-58. · 8.09 Impact Factor
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ABSTRACT: The combined model approach uses kinetic analysis of both plasma insulin and C-peptide dynamics to estimate prehepatic insulin secretion rates and parameters of insulin and C-peptide kinetics. The original model used single-compartment kinetics to describe both insulin and C-peptide despite knowledge that C-peptide follows two-compartment kinetics. The performance of the model under rapidly changing secretory conditions has come into question. Thus a more complex combined model is introduced, incorporating two-compartmental C-peptide disappearance. The addition of two-compartment C-peptide kinetics required a novel numerical approach to allow estimation of model parameters. This simulation study was undertaken to 1) compare the performance of the original combined model and 2) examine the numerical method used to identify parameters for the extended combined model with two-compartment C-peptide kinetics under simulated conditions of rapidly changing insulin and C-peptide. Monte Carlo simulation revealed that the original combined model does not provide accurate estimates of prehepatic insulin secretion under rapid kinetics. However, the extended combined model provides accurate reconstruction of prehepatic insulin secretory profile without separate quantification of C-peptide kinetics.
The American journal of physiology 02/1998; 274(1 Pt 1):E172-83.
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Diabetes Care 10/1996; 19(9):1018-30. · 8.09 Impact Factor
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ABSTRACT: To investigate the relationship between insulin level, insulin sensitivity and blood pressure in normoglycaemic men (n = 51) and women (n = 64) aged 53-61 years who were not receiving blood pressure medication and were participants in a previous population-based study.
Insulin sensitivity was estimated by the minimal model from a frequently sampled intravenous glucose tolerance test.
Systolic blood pressure (SBP) did not correlated significantly with fasting insulin level, 2 h insulin level or insulin sensitivity. Diastolic blood pressure (DBP) correlated positively with fasting insulin level but not with 2 h insulin level or insulin sensitivity. However, the positive association between fasting insulin level and DBP was not significant after adjustment for obesity and age. The relationship between high fasting insulin concentration and high DBP was stronger in lean than in obese subjects. The positive correlation between fasting insulin level and DBP was significant in lean but not in obese subjects.
The relationships between decreased insulin sensitivity and compensatory hyperinsulinaemia and blood pressure were rather weak. It is possible that different mechanisms may control blood pressure in lean and obese subjects, with a weaker association between insulin level and blood pressure in obese subjects. Alternatively, in obese subjects long-standing hyperinsulinaemia might increase blood pressure by mechanisms such as sympathetic activation and effects of vasculature, which may mask the underlying contribution of hyperinsulinaemia.
Journal of Hypertension 04/1996; 14(3):399-405. · 4.02 Impact Factor
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ABSTRACT: Mathematical modeling was used to explore the interaction between glucose, insulin, and lactate during the frequently sampled intravenous glucose tolerance test (FSIGTT). Insulin-modified FSIGTs were performed in 25 lean volunteers, and an additional 5 volunteers underwent FSIGTs with glucose injection alone to illustrate the effect of insulin on both glucose and lactate kinetics. The model chosen as the best representation of the system extended the minimal model of glucose kinetics (MM) by including a two-compartment model of lactate kinetics. The model accounted for both glucose and lactate kinetics, provided traditional MM parameters of insulin sensitivity and glucose effectiveness, and descriptive parameters of lactate kinetics. Modeling suggested that lactate production was limited by the rate of glucose disappearance, with no indication of direct effects of insulin on lactate. Inclusion of lactate kinetics had no adverse effect on MM parameters (SG: 0.023 +/- 0.009 vs. 0.023 +/- 0.010 min-1, SI: 1.01 +/- 0.70 vs. 1.03 +/- 0.71 x 10(4).min-1.pmol-1.1; P > 0.50, lactate model vs. MM), and indicated that approximately 1.2% min-1 of total glucose disappearance during the FSIGT is converted to lactate. An additional benefit of including lactate kinetics was the significant improvement in precision in MM parameter estimates as reflected by the fractional standard deviations (FSDs). This effect was most prominent for SG, in which a threefold improvement in parameter precision was observed (FSD: 13.5 +/- 3.1 vs. 42.5 +/- 48.5; means +/- SD).(ABSTRACT TRUNCATED AT 250 WORDS)
Diabetes 09/1995; 44(8):954-62. · 8.29 Impact Factor
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ABSTRACT: We performed oral glucose tolerance tests and frequently sampled iv glucose tolerance tests in a cross-sectional sample of women taking monophasic norgestrel containing oral contraceptives (OC). The goal of the study was to quantify the individual factors that determine glucose tolerance to assess responsibility for the reduced glucose tolerance associated with the use of OCs. Subjects were selected using stringent criteria to exclude confounding effects of ethnicity, adiposity, or conditions that may predispose subjects to metabolic disorders. Users of the low dose OC (Lo/Ovral and Nordette) and high dose OC (Ovral) were compared to controls, who were required to never have used OCs or to have discontinued OC use for at least 24 months. Oral glucose tolerance tests results confirmed the development of impaired glucose tolerance in both pill groups. Frequently sampled iv glucose tolerance test data were analyzed using the minimal model method to estimate parameters of insulin sensitivity, glucose effectiveness (SG), and beta-cell function. Lo/Ovral users had lower insulin sensitivity and SG compared to controls and inappropriately low beta-cell function in relation to the insulin resistance. Ovral users had metabolic parameters that were not different from controls. Based upon comparisons between normal and impaired glucose tolerant subjects combined with stepwise regression analysis, we conclude that Lo/Ovral use results in insulin and glucose resistance, which is not compensated by increased beta-cell function. The reduced glucose tolerance is due primarily to the defect in SG, and these OC users may place themselves at higher risk for the development of diabetes or cardiovascular disease. The reduced tolerance in Ovral users cannot be explained by the parameters measured in this study. We speculate that these latter subjects represent a special self-selected population in which tolerance is regulated by other factors. Ovral appears to be well tolerated by these women.
Journal of Clinical Endocrinology & Metabolism 12/1994; 79(5):1277-83. · 6.50 Impact Factor
