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O Pedersen

Publications and source records attributed to O Pedersen.

At least 145 records · Page 8Linked to original sources
PubMed1997

White coat hypertension in NIDDM patients with and without incipient and overt diabetic nephropathy.

OBJECTIVE: Early data have suggested a high prevalence of white coat hypertension (approximately 50%) in NIDDM patients. To study this phenomenon further, we determined the prevalence of white coat hypertension in NIDDM patients with normo- or microalbuminuria or with diabetic nephropathy. RESEARCH DESIGN AND METHODS: Three groups of hypertensive NIDDM patients (repeated clinic blood pressure > 140/90 mmHg or antihypertensive treatment) attending the Steno Diabetes Center were investigated in a cross-sectional study. Group 1 had normoalbuminuria (a urinary albumin excretion [UAE] rate < 30 mg/24 h, n = 30, age 61 +/- 7 [mean +/- SD] years, 20 men), group 2 had microalbuminuria (UAE rate 30-300 mg/24 h, n = 51, age 55 +/- 7 years, 35 men), and group 3 had diabetic nephropathy (UAE rate > 300 mg/24 h, n = 47, 62 +/- 7 years, 36 men). If given, all previous antihypertensive medication was withdrawn at least 2 weeks before the study (48%). The prevalence of white coat hypertension (clinic hypertension with normal blood pressure values at home) was determined by comparison of clinic blood pressure (Hawksley Random sphygmomanometer) and the ambulatory daytime (7:00 A.M. to 11:00 P.M.) blood pressure (A&D TM2420). By applying established criteria, white coat hypertension was confirmed if daytime blood pressure was < 135/85 mmHg. RESULTS: The clinic blood pressure was 155/86 (SE 3/2) mmHg, 156/89 (2/1) mmHg, and 171/90 (3/2) mmHg in group 1, 2, and 3, respectively (P < 0.05 comparing group 3 with groups 1 and 2). The prevalence of white coat hypertension was significantly higher in group 1 as compared with groups 2 and 3, 23% (95% CI 10-42) vs. 8% (2-19) and 9% (2-20) (P < 0.05), with no difference between the latter two groups. CONCLUSIONS: The prevalence of white coat hypertension in normoalbuminuric NIDDM patients resembles that observed in nondiabetic subjects with essential hypertension, whereas the prevalence is significantly lower in NIDDM patients with incipient or overt diabetic nephropathy, suggesting a difference between primary and secondary hypertension.

Albuminuria↗
PubMed1997

Intake of a diet high in trans monounsaturated fatty acids or saturated fatty acids. Effects on postprandial insulinemia and glycemia in obese patients with NIDDM.

OBJECTIVE: High intake of trans fatty acids and saturated fatty acids (SFAs) is known to increase the risk of coronary heart disease. We studied the effects of diets enriched in various fatty acids on postprandial insulinemia and fasting serum levels of lipids and lipoproteins in obese patients with NIDDM. RESEARCH DESIGN AND METHODS: Sixteen obese NIDDM patients were studied in a free-living outpatient regimen. After a run-in period, the patients received three different isocaloric diets for 6 weeks using a randomized crossover design. The patients were instructed to keep the energy intake from carbohydrate and protein constant at 50 and 20 E% (percent of energy intake), respectively, on all three diets. The fat composition of the diets differed: saturated fat (SAT) diet (20 E% SFAs, 5 E% polyunsaturated fatty acids [PUFAs], and 5 E% monounsaturated fatty acids [MUFAs]) versus cis monounsaturated fatty acid (CMUFA) diet (20 E% cis-MUFAs, 5 E% PUFAs, and 5 E% SFAs) versus trans monounsaturated fatty acid (TMUFA) diet (20 E% trans-MUFAs, 5 E% PUFAs, and 5 E% SFAs). Fasting serum levels of lipids and lipoproteins were measured at baseline and in the fasting state before meal tolerance tests at the end of each study period. Insulin secretion was assessed from incremental serum insulin and C-peptide responses during the meal tests. RESULTS: BMI, waist-to-hip ratio, and glycemic control remained stable throughout the study. After meal stimulation, postprandial glycemic responses were similar on all diets; however, serum insulin and C-peptide responses were greater following the TMUFA and SAT diets than following the baseline or CMUFA diets (P < 0.05). No statistical difference was found in fasting levels of serum lipids (total cholesterol, triglyceride, phospholipid, and nonesterified fatty acids) or lipoproteins of HDL cholesterol, VLDL cholesterol, LDL cholesterol, and apolipoprotein B between diets. CONCLUSIONS: In the presence of unchanged glycemia, both dietary trans fatty acids and SFAs induce an increase in postprandial insulinemia in obese patients with NIDDM.

Blood Glucose↗
PubMed1996

Mutations in the hepatocyte nuclear factor-1alpha gene in maturity-onset diabetes of the young (MODY3)

The disease non-insulin-dependent (type 2) diabetes mellitus (NIDDM) is characterized by abnormally high blood glucose resulting from a relative deficiency of insulin. It affects about 2% of the world's population and treatment of diabetes and its complications are an increasing health-care burden. Genetic factors are important in the aetiology of NIDDM, and linkage studies are starting to localize some of the genes that influence the development of this disorder. Maturity-onset diabetes of the young (MODY), a single-gene disorder responsible for 2-5% of NIDDM, is characterized by autosomal dominant inheritance and an age of onset of 25 years or younger. MODY genes have been localized to chromosomes 7, 12 and 20 (refs 5, 7, 8) and clinical studies indicate that mutations in these genes are associated with abnormal patterns of glucose-stimulated insulin secretion. The gene on chromosome 7 (MODY2) encodes the glycolytic enzyme glucokinases which plays a key role in generating the metabolic signal for insulin secretion and in integrating hepatic glucose uptake. Here we show that subjects with the MODY3-form of NIDDM have mutations in the gene encoding hepatocyte nuclear factor-1alpha (HNF-1alpha, which is encoded by the gene TCF1). HNF-1alpha is a transcription factor that helps in the tissue-specific regulation of the expression of several liver genes and also functions as a weak transactivator of the rat insulin-I gene.

Animals↗
PubMed1996

Insulin sensitivity index, acute insulin response, and glucose effectiveness in a population-based sample of 380 young healthy Caucasians. Analysis of the impact of gender, body fat, physical fitness, and life-style factors.

BACKGROUND: Insulin sensitivity and insulin secretion are traits that are both genetically and environmentally determined. AIM: The aim of this study was to describe the distribution of the insulin sensitivity index (Si), the acute insulin response, and glucose effectiveness (Sg) in young healthy Caucasians and to estimate the relative impact of anthropometric and environmental determinants on these variables. METHODS: The material included 380 unrelated Caucasian subjects (18-32 yr) with measurement of Si, Sg and insulin secretion during a combined intravenous glucose (0.3 grams/kg body weight) and tolbutamide (3 mg/kg body weight) tolerance test. RESULTS: The distributions of Si and acute insulin response were skewed to the right, whereas the distribution of Sg was Gaussian distributed. Sg was 15% higher in women compared with men (P < 0.001). Waist circumference, body mass index, maximal aerobic capacity, and women's use of oral contraceptives were the most important determinants of Si. Approximately one-third of the variation of Si could be explained by these factors. Compared with individuals in the upper four-fifths of the distribution of Si, subjects with Si in the lowest fifth had higher waist circumference, higher blood pressure, lower VO2max, and lower glucose tolerance and fasting dyslipidemia and dysfibrinolysis. Only 10% of the variation in acute insulin response could be explained by measured determinants. CONCLUSION: Estimates of body fat, maximal aerobic capacity, and women's use of oral contraceptives explain about one-third of the variation in Si in a population-based sample of young healthy Caucasians.

Adolescent↗
PubMed1996

A common amino acid polymorphism in insulin receptor substrate-1 causes impaired insulin signaling. Evidence from transfection studies.

Insulin receptor substrates-1 (IRS-1) is the major cytoplasmic substrate of the insulin and IGF-1 receptors. Recent studies have identified multiple sequence variants of IRS-1, especially in patients with non-insulin-dependent diabetes mellitus. In the present study, we have examined insulin-stimulated processes in 32D(IR) cells, a myeloid progenitor cell stably overexpressing the insulin receptor, transfected with wild-type human-IRS-1 or the most common human variant of IRS-1 in which glycine 972 is replaced by arginine. As compared to wild-type IRS-1, insulin stimulation of cells transfected with mutant IRS-1 exhibited a 32% decrease in incorporation of [3H]thymidine into DNA (P = 0.002), a 36% decrease in IRS-1 associated phosphatidylinositol (PI) 3-kinase activity (P = 0.004) and a 25% decrease in binding of the p85 regulatory subunit of PI 3-kinase to IRS-1 (P = 0.002). There was also a tendency for a decrease in Grb2 binding to IRS-1 and insulin-stimulated mitogen-activated protein kinase activity, however, these were not statistically significant. The changes occurred with no change in insulin receptor or IRS-1 tyrosine phosphorylation. These data indicate that the mutation in codon 972 in IRS-1 impairs insulin-stimulated signaling, especially along the PI 3-kinase pathway, and may contribute to insulin resistance in normal and diabetic populations.

Arginine↗
PubMed1996

Association of the glycogen synthase locus on 19q13 with NIDDM in Pima Indians.

Skeletal muscle glycogen synthase (encoded by GYS1 on chromosome 19q13.3) is the rate-limiting enzyme in insulin-mediated non-oxidative glucose disposal. Our previous studies have demonstrated an impairment of insulin-stimulated GYS1 activities in insulin-resistant Pima Indians, and associations of non-insulin-dependent diabetes mellitus (NIDDM) with the GYS1 locus were reported recently in Finnish and Japanese populations. We have performed linkage and association analyses of GYS1 and seven additional DNA markers on 19q with NIDDM, and with parameters of insulin action in the Pima Indians. We have found a significant association of NIDDM with GYS1 genotypes (p = 0.009), and with common GYS1 alleles (p = 0.022) in the Pima Indians. We have performed a detailed comparative analysis of the GYS1 gene, mRNA, and protein product in insulin-sensitive and insulin-resistant Pima Indians. No mutations in GYS1 coding sequences were detected; nor did we find alterations of GYS1 mRNA expression or of its basal enzymatic activity in insulin-resistant Pima Indians. These results contrasted with a 25% reduction of immunoreactive protein in insulin-resistant subjects as detected by Western blotting with an antibody specific for the C-terminal end of GYS1 (t-test p = 0.024; Wilcoxon's rank-sum test, p = 0.04). Because no mutations were detected in the DNA encoding this epitope, the difference in immunoreactivity may reflect post-translational modification(s) of the protein rather than a difference in the gene itself, or it could have occurred by chance. We conclude that our data do not indicate alterations in the GYS1 gene as the cause for the observed association, and that a different locus near GYS1 may be the contributing genetic element.

Adult↗
PubMed1996

Lens autofluorescence is increased in newly diagnosed patients with NIDDM.

Lens and cornea autofluorescence has been shown to be increased in patients with insulin-dependent diabetes mellitus and to be positively correlated to glycaemic control and duration of diabetes. We have studied lens and cornea autofluorescence at the clinical onset of non-insulin-dependent diabetes mellitus (NIDDM), in comparison with age-matched subjects with normal glucose tolerance. Fourteen subjects with NIDDM diagnosed less than 6 months prior to the examination were characterised by ocular fluorometry, glycosylated hemoglobin A1c, plasma lipid status, arterial blood pressure, and an oral glucose tolerance test (OGTT). Eleven age- and gender-matched healthy subjects without a family history of diabetes and with a normal glucose tolerance underwent the same examinations. In 11 of the 14 diabetic patients lens autofluorescence was increased to levels higher than the age-related mean + 2SD of healthy subjects. For the entire study population, control and diabetic subjects, lens fluorescence was positively correlated with HbA1c (p < 0.0001, r = 0.73), fasting plasma glucose (p = 0.002, r = 0.60) and the plasma glucose level 2 h after an OGTT (p = 0.004, r = 0.55). Cornea autofluorescence was also significantly increased in the group of newly diagnosed NIDDM patients, but only 9 patients had values above the mean + 2SD of the healthy subjects. NIDDM could be detected by ocular fluorometry with a sensitivity of 79% and a specificity of 100%. We conclude that lens and cornea autofluorescence is abnormally increased in the majority of patients with newly diagnosed NIDDM. The sensitivity and specificity of the method indicate that lens fluorometry may potentially be useful for screening for undiagnosed NIDDM in the general population. Additionally, we propose that the method may be a clinically useful indicator of cumulative glycaemia and risk of development of secondary complications in patients with diabetes.

Adult↗
PubMed1996

Impaired insulin-stimulated nonoxidative glucose metabolism in glucose-tolerant women with previous gestational diabetes.

OBJECTIVE: Our purpose was to investigate insulin sensitivity and insulin secretion in women with previous gestational diabetes. STUDY DESIGN: Twelve women with previous gestational diabetes and 11 controls were examined by oral and intravenous glucose tolerance tests and a hyperinsulinemic euglycemic clamp including indirect calorimetry. All women were lean and had normal oral glucose tolerance test results. Activities of glycogen synthase, phosphofructokinase, and hexokinase were measured in vastus lateralis muscle biopsy specimens obtained in the basal state and after insulin stimulation. RESULTS: Women with previous gestational diabetes had a decreased glucose disposal rate (p<0.01) because of a reduced insulin-stimulated nonoxidative glucose metabolism (6.63 +/- 0.47 vs 9.04 +/- 0.57 mg/kg fat-free mass per minute, p<0.01). The muscle activities of glycogen synthase, phosphofructokinase, and hexokinase were similar in the two groups. The first-phase insulin response to the intravenous glucose tolerance test was, in absolute terms, comparable in the two groups. However, when the decreased insulin sensitivity was taken into account, women with previous gestational diabetes had a relative insulin secretion deficiency. CONCLUSION: Women with previous gestational diabetes have a decreased insulin sensitivity and a relative impairment of insulin secretion.

Adult↗
PubMed1996

Studies of insulin resistance in congenital generalized lipodystrophy.

Two well-characterized patients with congenital, generalized lipodystrophy have been studied by the euglycaemic hyperinsulinaemic clamp technique in combination with indirect calorimetry. Furthermore, glycogen synthase in muscle biopsies was studied in one patient with regard to enzyme activity, immunoreactive protein and mRNA levels. The patients had fasting hyperinsulinaemia, and the rate of total glucose disposal was severely impaired, primarily due to a decreased non-oxidative glucose metabolism. In the patient studied with muscle biopsy, the expected activation of glycogen synthase by insulin did not occur. In both patients there was severely increased hepatic glucose output in the basal state, suggesting a failure of insulin to suppress hepatic gluconeogenesis. During insulin infusion a substantially elevated rate of lipid oxidation remained in the patients, in contrast to the almost completely suppressed lipid oxidation in the controls. It is concluded that patients with congenital generalized lipodystrophy may present severe insulin resistance with regard to hepatic glucose production as well as muscle glycogen synthesis and lipid oxidation. The results suggest a postreceptor defect in the action of insulin in congenital generalized lipodystrophy. The further localization of such a defect is hampered by the still incomplete understanding of the pathways that link insulin-stimulated tyrosine phosphorylation to the ultimate action of insulin upon target cells.

Calorimetry, Indirect↗
PubMed1996

Pancreatic endocrine function in recipients of segmental and whole pancreas transplantation.

To determine potential abnormalities in beta-cell function after pancreas transplantation, the secretory capacity of the pancreatic grafts was assessed by measuring the glucose-potentiating effect on arginine-induced insulin secretion in recipients of cadaveric segmental (SPx; n = 8) and whole organ pancreas grafts (WPx; n = 6) and compared to that in nondiabetic kidney transplant recipients (Kx; n = 6) and normal controls (Ns; n = 7). alpha-Cell adaptation to increasing hyperglycemia and the glucagon response to arginine stimulation were also studied. The secretory capacity of the beta-cell to arginine-induced (5 g L-arginine) insulin secretion was measured at fasting plasma glucose and 15 and 30 mmol/L glucose. Insulin secretion was evaluated by the calculation of insulin secretion rates. Insulin sensitivity was markedly reduced in all three transplanted groups compared to that in normal subjects (P < 0.05). The prestimulation insulin secretion rate and maximal insulin secretion rate in response to hyperglycemia and arginine were significantly lower in SPx than in WPx, Kx, or Ns (P < 0.05). The incremental amount of insulin secreted in response to arginine was reduced by 40-70% in SPx depending on glycemia compared to that in all other groups (P < 0.05), among which there were no statistical differences. Both SPx and WPx demonstrated suppression of glucagon release in response to graded hyperglycemia, but failure to adequately suppress arginine-induced glucagon release. In conclusion, recipients of cadaveric segmental pancreas grafts display a markedly reduced maximal insulin secretory reserve capacity. This impairment was primarily due to an insufficient beta-cell mass. Taking the concomitant insulin resistance into account, recipients of a cadaver whole organ pancreas graft had an impaired insulin secretory reserve capacity as well.

Adult↗
PubMed1996

Insulin sensitivity and body weight changes in young white carriers of the codon 64 amino acid polymorphism of the beta 3-adrenergic receptor gene.

Recently, a missense mutation replacing tryptophan with arginine at codon 64 of the beta 3-adrenergic receptor gene was shown to be associated with insulin resistance in nondiabetic subjects and to an earlier onset of NIDDM in Pima Indians. We studied whether the codon 64 amino acid polymorphism of the beta 3-adrenergic receptor gene in a cohort of young healthy Danes was associated with high birth weight, accelerated weight gain during childhood and adolescence, present obesity, or impaired insulin sensitivity. The protocol included 380 unrelated white subjects in whom insulin sensitivity and secretion were measured during a combined intravenous glucose and tolbutamide tolerance test. A number of biochemical and anthropometric characteristics were determined for each subject. The subjects were genotyped for the codon 64 polymorphism by applying polymerase chain reaction restriction fragment-length polymorphism screening with the use of endonuclease BstN1. The allelic frequency of the mutated allele was 7% (95% CI: 5-10%), and it was similar in obese and nonobese subjects. The beta 3-adrenergic receptor gene variant was not related to birth weight or weight gain during childhood or adolescence. In its heterozygous form, the gene variant was not associated with an altered insulin sensitivity index (SI) or other features of the insulin resistance syndrome (BMI, blood pressure, fasting serum lipid levels, or fasting serum fibrinolytic variables). Three homozygous carriers of the polymorphism were identified, and each had a significantly higher BMI (27.4 +/- 1.3 vs. 23.5 +/- 3.7 kg/m2 [mean +/- SD]; P = 0.032), lower SI [4.9 +/- 2.9 vs. 15.4 +/- 9.0 10(-5) x (min x pmol/l)-1; P = 0.013], and higher fasting serum C-peptide (730 +/- 155 vs. 471 +/- 158 pmol/l; P = 0.016) than the wild-type carriers. The homozygous carriers also had significantly higher levels of fasting serum triglyceride (P = 0.042) and serum LDL cholesterol (P = 0.013). When adjustments were made for age, sex, BMI, and VO2max in a multiple regression analysis, a significantly negative association was found between homozygosity for the codon 64 variant and the SI (P = 0.009). We conclude that in young healthy Danes, the homozygous form but not the heterozygous form of the codon 64 amino acid polymorphism of the beta 3-adrenergic receptor may be associated with obesity and, independent of BMI, with a low SI. Since only three homozygous carriers were identified among 380 subjects, the results must be interpreted with caution, and studies of larger population samples are needed.

Adult↗
PubMed1996

Impaired insulin-stimulated nonoxidative glucose metabolism in pancreas-kidney transplant recipients. Dose-response effects of insulin on glucose turnover.

Insulin resistance is a characteristic feature in recipients of a pancreas transplant, but the relative contribution of the liver and peripheral tissues to this abnormality within a spanning range of insulin concentrations is unknown. To assess the impact of insulin action on glucose metabolism after pancreas transplantation, a euglycemic-hyperinsulinemic clamp with sequential insulin infusions (5, 40, and 200 mU.m-2.min-1 for 120 min each), combined with isotopic determinations of the rates of hepatic glucose production and extrahepatic glucose uptake, indirect calorimetry, and measurements of glycogen synthase and hexokinase activities in vastus lateralis muscle, were performed in six pancreas-kidney transplant recipients (Px group) and compared with those performed in six nondiabetic kidney transplant recipients with similar immunosuppression (Kx group) and six nondiabetic control subjects. The overall effects of insulin on whole-body glucose metabolism, determined as the glucose infusion rates versus the corresponding steady-state serum insulin concentrations, demonstrated a rightward shift in the dose-response curves of the transplanted groups compared with those of normal subjects. The dose-response curve for glucose disposal rates (Rd) was shifted to the right in the Px and Kx groups, and the maximal glucose disposal rate was reduced by 40% in the Px group (11.7 +/- 1.1 mg.kg-1 fat-free mass.min-1) and 30% in the Kx group (13.9 +/- 1.2 mg.kg-1 fat-free mass.min-1) compared with that in control subjects (19.1 +/- 2.2 mg.kg-1 fat-free mass.min-1) (P < 0.05). The dose-response curve for suppression of hepatic glucose output rates was similar at increasing hepatic sinusoidal insulin concentrations. Glucose oxidation rates were similar in all groups, whereas nonoxidative glucose rates were reduced by 50% in the Px group and by 30% in the Kx group compared with those in the control group (P < 0.05). In the Px group, an impaired activation of the fractional velocity and absent decrease in the half-maximal stimulation of muscle glycogen synthase occurred during the insulin infusion. However, this finding could only explain in part the degree of impairment in nonoxidative glucose metabolism. No differences were found in total hexokinase activity in muscle between normal subjects and the transplant groups at basal insulinemia or after insulin stimulation. During hyperinsulinemia, glucagon and nonesterified fatty acids were not suppressed as much in the transplanted groups as they were in normal control subjects (P < 0.05). In conclusion, pancreas transplantation causes impaired peripheral action of insulin as compared with that in normal subjects and kidney transplant recipients. The main course of insulin resistance in the two transplant groups is explained by the immunosuppressive treatment, but the augmented insulin resistance in pancreas transplant recipients could partly be explained by the chronic peripheral hyperinsulinemia. The principal site of insulin resistance was a reduced insulin-stimulated nonoxidative glucose metabolism of peripheral tissues, which resulted in decreased capacity to store glucose as glycogen. The impaired peripheral insulin action could only partly be explained by a reduced activation of the glycogen synthase enzyme in skeletal muscle.

Adult↗
PubMed1995

Contraction stimulates translocation of glucose transporter GLUT4 in skeletal muscle through a mechanism distinct from that of insulin.

The acute effects of contraction and insulin on the glucose transport and GLUT4 glucose transporter translocation were investigated in rat soleus muscles by using a 3-O-methylglucose transport assay and the sensitive exofacial labeling technique with the impermeant photoaffinity reagent 2-N-4-(1-azi-2,2,2-trifluoroethyl)benzoyl-1,3-bis(D-mannose-4-y loxy)-2- propylamine (ATB-BMPA), respectively. Addition of wortmannin, which inhibits phosphatidylinositol 3-kinase, reduced insulin-stimulated glucose transport (8.8 +/- 0.5 mumol per ml per h vs. 1.4 +/- 0.1 mumol per ml per h) and GLUT4 translocation [2.79 +/- 0.20 pmol/g (wet muscle weight) vs. 0.49 +/- 0.05 pmol/g (wet muscle weight)]. In contrast, even at a high concentration (1 microM), wortmannin had no effect on contraction-mediated glucose uptake (4.4 +/- 0.1 mumol per ml per h vs. 4.1 +/- 0.2 mumol per ml per h) and GLUT4 cell surface content [1.75 +/- 0.16 pmol/g (wet muscle weight) vs. 1.52 +/- 0.16 pmol/g (wet muscle weight)]. Contraction-mediated translocation of the GLUT4 transporters to the cell surface was closely correlated with the glucose transport activity and could account fully for the increment in glucose uptake after contraction. The combined effects of contraction and maximal insulin stimulation were greater than either stimulation alone on glucose transport activity (11.5 +/- 0.4 mumol per ml per h vs. 5.6 +/- 0.2 mumol per ml per h and 9.0 +/- 0.2 mumol per ml per h) and on GLUT4 translocation [4.10 +/- 0.20 pmol/g (wet muscle weight) vs. 1.75 +/- 0.25 pmol/g (wet muscle weight) and 3.15 +/- 0.18 pmol/g (wet muscle weight)]. The results provide evidence that contraction stimulates translocation of GLUT4 in skeletal muscle through a mechanism distinct from that of insulin.

3-O-Methylglucose↗
PubMed1995

Insulin receptor substrate-1 gene mutations in NIDDM; implications for the study of polygenic disease.

Variations in the coding regions of the insulin receptor substrate-1 (IRS-1) gene have recently been suggested to contribute to the susceptibility of non-insulin-dependent diabetes mellitus (NIDDM). The purpose of this study was to examine the role of the IRS-1 missense mutations at codons 972 (glycine to arginine) and 513 (alanine to proline) in two diverse populations from South India and Finland at high risk for NIDDM. DNA was amplified and digested with restriction enzymes BstN1 to detect the codon 972 mutation and Dra III to detect the codon 513 mutation. The codon 513 mutation was not found in the study subjects. The codon 972 mutation was present in 10.3% of 126 middle-aged NIDDM subjects and 5.3% of 95 matched control subjects in the South Indians (p = 0.17). In elderly Finnish subjects the frequency of the mutation was 7.5% in 40 NIDDM subjects and 7% in 42 matched control subjects. The frequency of codon 972 mutation in the South Indian NIDDM subjects was very similar to the two previously published studies in Danish and French subjects although each study individually fails to reach conventional levels of significance. The data from all four ethnic groups were analysed together after ascertaining that significant heterogeneity did not exist between the studies. Overall, the frequency of the codon 972 mutation is found in 10.7% NIDDM subjects and 5.8% control subjects (p = 0.02). These studies suggest that the codon 972 mutation of the IRS-1 gene might act as a susceptibility gene predisposing to NIDDM in certain ethnic groups.

Adult↗
PubMed1995

Unchanged gene expression of glycogen synthase in muscle from patients with NIDDM following sulphonylurea-induced improvement of glycaemic control.

We have previously shown that the mRNA expression of muscle glycogen synthase is decreased in non-insulin-dependent diabetic (NIDDM) patients; the objective of the present protocol was to examine whether the gene expression of muscle glycogen synthase in NIDDM is affected by chronic sulphonylurea treatment. Ten obese patients with NIDDM were studied before and after 8 weeks of treatment with a weight-maintaining diet in combination with the sulphonylurea gliclazide. Gliclazide treatment was associated with significant reductions in HbA1C (p=0.001) and fasting plasma glucose (p=0.005) as well as enhanced beta-cell responses to an oral glucose load. During euglycaemic, hyperinsulinaemic clamp (2 mU x kg-1 x min-1) in combination with indirect calorimetry, a 35% (p=0.005) increase in whole-body insulin-stimulated glucose disposal rate, predominantly due to an increased non-oxidative glucose metabolism (p=0.02) was demonstrated in teh gliclazide-treated patients when compared to pre-treatment values. In biopsies obtained from vastus lateralis muscle during insulin infusion, the half-maximal activation of glycogen synthase was achieved at a significantly lower concentration of the allosteric activator glucose 6-phosphate (p=0.01). However, despite significant increases in both insulin-stimulated non-oxidative glucose metabolism and muscle glycogen synthase activation in gliclazide-treated patients no changes were found in levels of glycogen synthase mRNA or immunoreactive protein in muscle. In conclusion, improved blood glucose control in gliclazide-treated obese NIDDM patients has no impact on the gene expression of muscle glycogen synthase.

Adult↗
PubMed1995

Insulin-resistant glucose metabolism in patients with microvascular angina--syndrome X.

Studies in patients with microvascular angina (MA) or the cardiologic syndrome X have shown a hyperinsulinemic response to an oral glucose challenge, suggesting insulin resistance and a role for increased serum insulin in coronary microvascular dysfunction. The aim of the present study was to examine whether patients with MA are insulin-resistant. Nine patients with MA and seven control subjects were studied. All were sedentary and glucose-tolerant. Coronary arteriography was normal in all participants, and exercise-induced coronary ischemia was demonstrated in all MA patients. A euglycemic, hyperinsulinemic clamp was performed in combination with indirect calorimetry. Biopsy of vastus lateralis muscle was taken in the basal state and after 4 hours of euglycemia and hyperinsulinemia (2 mU.kg-1.min-1). The fasting level of "true" serum insulin was significantly higher (43 +/- 6 v 22 +/- 3 pmol/L, P < .02) and the rate of insulin-stimulated glucose disposal to peripheral tissues was lower in patients with MA (13.4 +/- 1.0 v 18.2 +/- 1.4 mg.kg fat-free mass [FFM]-1.min-1, P < .02) due to a decrease in nonoxidative glucose metabolism (8.4 +/- 0.9 v 12.5 +/- 1.3 mg.kg FFM-1.min-1, P < .02). No difference was found in glucose or lipid oxidation rates between the two groups.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMed1995

Lewis phenotypes and the insulin resistance syndrome in young healthy white men and women.

An increased risk of ischemic heart disease in men with the Lewis blood group phenotype Le(a-b-) has been reported. It has been suggested that the Le(a-b-) phenotype is a genetic marker of the insulin resistance syndrome. To examine whether Le(a-b-) confers the insulin resistance syndrome, we studied a random sample of unrelated healthy young white men and women living in Copenhagen (n = 380, 18 to 32 years). All individuals had their insulin sensitivity estimated using Bergman's minimal model (intravenous glucose in combination with tolbutamide) and systolic blood pressure (SBP) was measured with a London School of Hygiene Sphygmomanometer. A number of anthropometric measurements including body mass index (BMI, kilograms/meters squared) and biochemical characteristics were performed. The Lewis blood group typing was carried out on erythrocytes. Twenty-one men had the Le(a-b-) phenotype. Compared to all other men (N = 165), the Le(a-b-) men had a significantly higher SBP (6 mm Hg, P = .0024). They also had higher values of BMI (8%, P = .016), total body fat mass (25%, P = .015), fasting values of serum insulin (32%, P = .006), serum C-peptide (20%, P = .029), and plasma glucose (8%, P = .003). The fasting values of serum lipids, plasminogen activator inhibitor (PAI-1) activity, tissue plasminogen activator (t-PA) antigen, and insulin sensitivity did not differ between Le(a-b-) men and men with other Lewis phenotypes. Altogether 194 women participated in the study of which 21 women had the Le(a-b-) phenotype. Except for a lower PAI-1 activity (45%, P = .044), no values differed between Le(a-b-) women and women with other Lewis phenotypes. The women were also stratified according to use of oral contraceptives. Le(a-b-) women using oral contraceptives (N = 8) had a significantly lower plasma level of fasting PAI-1 activity (P = .029) and t-PA antigen (P = .004) compared to women using oral contraceptives without the Le(a-b-) phenotype (N = 42). Our data support the hypothesis that Le(a-b-) men exhibit features of the insulin resistance syndrome, including higher levels of BMI, SBP, and fasting levels of serum insulin and plasma glucose. In young women no signs of the insulin resistance syndrome were found in subjects with the Le(a-b-) phenotype.

Adolescent↗