Biomedical subjects

Oluf Pedersen

Publications and source records attributed to Oluf Pedersen.

At least 55 records · Page 3Linked to original sources

PubMed2004

Maturity-onset diabetes of the young with end-stage nephropathy: a new indication for simultaneous pancreas and kidney transplantation?

UNLABELLED: BACKGROUND AND CASE: Simultaneous pancreas and kidney transplantation (SPK) is applied almost exclusively in C-peptide-negative type 1 diabetic patients, although some data on SPK in type 2 diabetes have been published as well. Nothing is known about SPK in the autosomal diabetes form, maturity-onset diabetes of the young (MODY). SPK was performed in a 47-year old man who has MODY3 because of a Arg272His mutation in the hepatocyte nuclear factor-1alphagene. He developed overt diabetes mellitus at 19 years and end-stage diabetic nephropathy 26 years thereafter. Before SPK, the patient had measurable fasting serum C-peptide levels, but lacked beta-cell response to intravenous glucose and glucagon. He was treated with 34 IU of insulin per day. At 2 years post-transplantation, the patient remains normoglycemic and insulin independent. A hyperglycemic clamp test showed a normal beta-cell function. CONCLUSION: Identification of MODY3 among all C-peptide-positive patients with advanced diabetic nephropathy might help to select a specific group profiting from SPK.

C-Peptide↗

PubMed2004

Mutation analysis of NR0B2 among 1545 Danish men identifies a novel c.278G>A (p.G93D) variant with reduced functional activity.

Variations of the small heterodimer partner (SHP, NR0B2) gene, an atypical nuclear receptor that inhibits transactivation by hepatocyte nuclear factor (HNF)-4alpha, are associated with obesity among Japanese. The purpose of the study was to evaluate the prevalence of SHP variants among obese Danish men. Using combined SSCP and heteroduplex analysis, we analyzed the entire coding region of SHP for variants in a cohort of 750 Danish men with early-onset obesity and genotyped a cohort of 795 nonobese control subjects using PCR-RFLP. Functional analyses of the identified coding region variants were performed in both MIN6-m9 and HepG2 cell lines. A total of five novel variants, including three missense variants (c.100C>G [p.R34G], c.278G>A [p.G93D], and c.415C>A [p.P139H]) and two silent variants (c.65C>T [p.Y22Y] and c.339G>A [p.P113P]) were identified. Moreover, the previously reported c.512G>C [p.G171A] polymorphism was identified. The 171A allele was not associated with obesity (p = 0.07). The 34G, 93D, and 139H-alleles were rare variants, which were found only among obese subjects. Among the four coding region variants, the 93D-allele showed a reduced in vitro inhibition of the HNF-4alpha transactivation of the HNF-1alpha promoter expression when expressed in MIN6-m9 and HepG2 cell lines (p<0.01). In contrast to reported findings among obese Japanese, functional variants are rare among Danish men. A functional 93D variant of SHP was identified in 1 out of 750 obese and in none of 795 nonobese control subjects. Further large-scale population studies are necessary to assess the clinical impact of this rare variant on obesity risk among European subjects.

Adolescent↗

PubMed2004

Grey-box modelling of pharmacokinetic/pharmacodynamic systems.

Grey-box pharmacokinetic/pharmacodynamic (PK/PD) modelling is presented as a promising way of modelling PK/PD systems. The concept behind grey-box modelling is based on combining physiological knowledge along with information from data in the estimation of model parameters. Grey-box modelling consists of using stochastic differential equations (SDEs) where the stochastic term in the differential equations represents unknown or incorrectly modelled dynamics of the system. The methodology behind the grey-box PK/PD modelling framework for systematic model improvement is illustrated using simulated data and furthermore applied to Bergman's minimal model of glucose kinetics using clinical data from an intravenous glucose tolerance test (IVGTT). The grey-box estimates of the stochastic system noise parameters indicate that the glucose minimal model is too simple and should preferably be revised in order to describe the complicated in vivo system of insulin and glucose following an IVGTT.

Blood Glucose↗

PubMed2004

A common polymorphism in the promoter of the IGF-I gene associates with increased fasting serum triglyceride levels in glucose-tolerant subjects.

OBJECTIVE: The aim of the present study was to examine if absence of a common allele in a microsatellite polymorphism in the insulin-like growth factor I (IGF-I) promoter was associated with type 2 diabetes and alterations in quantitative traits in glucose-tolerant subjects. METHODS: The IGF-I promoter polymorphism was investigated in a case-control study comprising 694 type 2 diabetic patients and 218 glucose-tolerant control subjects, and in two genotype-quantitative trait studies involving 208 glucose-tolerant first-degree offspring of type 2 diabetic patients and 218 unrelated middle-aged subjects with normal glucose tolerance. RESULTS: No associations were found between the lack of the common promoter allele and type 2 diabetes (P = 0.25) or estimates of glucose metabolism in glucose-tolerant subjects. Presence of the wild-type allele was associated with an increase in fasting serum triglyceride levels in the group of 208 glucose-tolerant first-degree offspring of type 2 diabetic patients (P = 0.002). This finding was replicated in an independent sample of 218 unrelated middle-aged subjects with normal glucose tolerance (P = 0.007). CONCLUSION: The present study provides evidence that the common wild-type allele of the IGF-I promoter polymorphism is associated with increased levels of fasting serum triglyceride in glucose-tolerant whites.

Aged↗

PubMed2004

Target intervention against multiple-risk markers to reduce cardiovascular disease in patients with type 2 diabetes.

The risk of cardiovascular disease is markedly increased in patients with type 2 diabetes with a prevalence twice as high compared to the background population. With the recognition of multiple concomitant risk factors for both microvascular as well as cardiovascular disease in type 2 diabetic patients, treatment strategies have changed during recent years. This review focuses on the many recent drug trials that have set the course for an effective multifactorial treatment of the disease. Thus, the Steno-2 Study has shown that an intensified multifactorial intervention targeting several risk factors for cardiovascular disease is capable of reducing the risk for a combined endpoint of cardiovascular mortality, non-fatal myocardial infarction, non-fatal stroke, coronary interventions, revascularisation to legs, and amputations by 50%.

Albuminuria↗

PubMed2004

Variation in NCB5OR: studies of relationships to type 2 diabetes, maturity-onset diabetes of the young, and gestational diabetes mellitus.

Recent data show that homozygous Ncb5or(-/-) knock-out mice present with an early-onset nonautoimmune diabetes phenotype. Furthermore, genome-wide scans have reported linkage to the chromosome 6q14.2 region close to the human NCB5OR. We therefore considered NCB5OR to be a biological and positional candidate gene and examined the coding region of NCB5OR in 120 type 2 diabetic patients and 63 patients with maturity-onset diabetes of the young using denaturing high-performance liquid chromatography. We identified a total of 22 novel nucleotide variants. Three variants [IVS5+7del(CT), Gln187Arg, and His223Arg] were genotyped in a case-control design comprising 1,246 subjects (717 type 2 diabetic patients and 529 subjects with normal glucose tolerance). In addition, four rare variants were investigated for cosegregation with diabetes in multiplex type 2 diabetic families. The IVS5+7del(CT) variant was associated with common late-onset type 2 diabetes; however, we failed to relate this variant to any diabetes-related quantitative traits among the 529 control subjects. Thus, variation in the coding region of NCB5OR is not a major contributor in the pathogenesis of nonautoimmune diabetes.

Animals↗

PubMed2004

Variation in the interleukin-6 receptor gene associates with type 2 diabetes in Danish whites.

Interleukin-6 (IL-6) is a pleiotropic cytokine involved in the pathophysiology of various human diseases such as type 2 diabetes and obesity. IL-6 signals via a heterodimeric receptor complex consisting of a soluble IL-6 alpha-subunit (IL-6 receptor [IL6R]) and a signal transducing subunit (gp130). The IL6R gene maps to an important candidate locus for type 2 diabetes on chromosome 1q21. An Asp358Ala polymorphism of the IL6R has been reported to associate with obesity in Pima Indians. We investigated the Asp358Ala polymorphism in relation to type 2 diabetes, obesity, and other pre-diabetic quantitative traits among Danish whites. By applying a recessive genetic model in a case-control study of 1,349 type 2 diabetic patients and 4,596 glucose-tolerant control subjects, we found a significant difference in genotype distribution (P = 0.008) and in allele frequency (Ala-allele 38.3% [95% CI 36.5-40.1] in diabetic subjects vs. 41.2% [40.2-42.2] in control subjects; P = 0.007). The odds ratio for the Asp/Asp carriers versus Ala/Ala carriers was 1.38 (1.09-1.71). Among 4,251 middle-aged glucose-tolerant subjects, the Asp358Ala polymorphism was not associated with estimates of obesity, post-oral glucose tolerance test serum insulin release, or the homeostasis model assessment of insulin resistance index. In conclusion, the Asp358Ala polymorphism of the IL6R associates with type 2 diabetes in Danish whites.

Amino Acid Substitution↗

PubMed2004

A novel syndrome of autosomal-dominant hyperinsulinemic hypoglycemia linked to a mutation in the human insulin receptor gene.

Recently, various subtypes of familial hyperinsulinemic hypoglycemia with an autosomal-dominant inheritance have been etiologically characterized. In the present study, we have delineated the genetics and metabolic phenotype of a novel form of hypoglycemia in a large pedigree with an apparent autosomal-dominant transmission. After initial investigations of the proband, her mother, and a sister, the study was extended to 19 family members in three generations. Glucose tolerance was assessed by a 5-h oral glucose tolerance test (OGTT) and insulin sensitivity by euglycemic-hyperinsulinemic clamp in six affected family members and six control subjects. To identify the genetic cause of hypoglycemia, linkage analysis and mutation analysis of genomic DNA from all family members were performed. All affected family members were characterized by postprandial hypoglycemia, fasting hyperinsulinemia, and an elevated serum insulin-to-C-peptide ratio. The 5-h OGTT demonstrated hyperinsulinemic hypoglycemia, and the clamp studies showed reduced insulin sensitivity and clearance of serum insulin in affected family members compared with control subjects. Linkage analysis and subsequent mutation screening revealed a missense mutation (Arg1174Gln) in the tyrosine kinase domain of the insulin receptor gene that cosegregated with the disease phenotype (logarithm of odds [LOD] score 3.21). In conclusion, we report a novel syndrome of autosomal-dominant hyperinsulinemic hypoglycemia. The findings demonstrate the coexistence of severe postprandial hypoglycemia, insulin resistance, and impaired insulin clearance and suggest that hypoglycemia should be considered as a phenotype linked to heterozygote mutations in the insulin receptor gene.

Adolescent↗

PubMed2004

Intensive integrated therapy of type 2 diabetes: implications for long-term prognosis.

The macro- and microvascular burden of type 2 diabetes is well established. A number of recent single risk factor intervention trials targeting hyperglycemia, dyslipidemia, hypertension, procoagulation, microalbumuria, and existing cardiovascular disorders have, however, shown major beneficial effects on long-term outcome. The results from these studies are anticipated to change the future management of type 2 diabetes, and most of the updated national guidelines for the treatment of type 2 diabetes recommend a multipronged approach driven by ambitious treatment targets. The outcome of this intensive integrated therapy has, however, only been investigated in a few studies of patients with type 2 diabetes. One of these trials, the Steno-2 Study, showed that intensive intervention for an average of 7.8 years cuts cardiovascular events as well as nephropathy, retinopathy, and autonomic neuropathy by about half when compared with a conventional multifactorial treatment. The challenge for now is to ensure that the trial experiences are widely adopted in daily clinical practice.

Algorithms↗

PubMed2004

Increasing incidence of diabetes after gestational diabetes: a long-term follow-up in a Danish population.

OBJECTIVE: To study the incidence of diabetes among women with previous diet-treated gestational diabetes mellitus (GDM) in the light of the general increasing incidence of overweight and diabetes and to identify risk factors for the development of diabetes. RESEARCH DESIGN AND METHODS: Women with diet-treated GDM during 1978-1985 (old cohort, n = 241, also followed up around 1990) or 1987-1996 (new cohort, n = 512) were examined in 2000-2002. Women were classified by a 2-h, 75-g oral glucose tolerance test according to the World Health Organization criteria or an intravenous glucagon test supplemented by measurement of GAD antibodies. Historical data from index-pregnancy and anthropometrical measurements were collected. RESULTS: A total of 481 (63.9%) women were examined (median 9.8 years [interquartile range 6.4-17.2]) after index pregnancy. Diabetes and impaired glucose tolerance (IGT)/impaired fasting glucose were present in 40.0 and 27.0% of women, respectively. In the new cohort, 40.9% had diabetes compared with 18.3% in the old cohort at the 1990 follow-up (P < 0.0005). Prepregnancy BMI was significantly higher in the new compared with the old cohort (26.0 [22.5-30.8] vs. 22.9 kg/m2 [20.2-28.0], P < 0.0005). Among others, new-cohort membership, prepregnancy overweight (BMI > or = 25 kg/m2), and IGT postpartum were identified as independent predictors of diabetes by multiple logistic regression analyses. CONCLUSIONS: The incidence of diabetes among Danish women with previous diet-treated GDM was very high and had more than doubled over a 10-year period. This seems to be due to a substantial increase in BMI in women with GDM.

Adult↗

PubMed2003

Multifactorial intervention and cardiovascular disease in patients with type 2 diabetes.

BACKGROUND: Cardiovascular morbidity is a major burden in patients with type 2 diabetes. In the Steno-2 Study, we compared the effect of a targeted, intensified, multifactorial intervention with that of conventional treatment on modifiable risk factors for cardiovascular disease in patients with type 2 diabetes and microalbuminuria. METHODS: The primary end point of this open, parallel trial was a composite of death from cardiovascular causes, nonfatal myocardial infarction, nonfatal stroke, revascularization, and amputation. Eighty patients were randomly assigned to receive conventional treatment in accordance with national guidelines and 80 to receive intensive treatment, with a stepwise implementation of behavior modification and pharmacologic therapy that targeted hyperglycemia, hypertension, dyslipidemia, and microalbuminuria, along with secondary prevention of cardiovascular disease with aspirin. RESULTS: The mean age of the patients was 55.1 years, and the mean follow-up was 7.8 years. The decline in glycosylated hemoglobin values, systolic and diastolic blood pressure, serum cholesterol and triglyceride levels measured after an overnight fast, and urinary albumin excretion rate were all significantly greater in the intensive-therapy group than in the conventional-therapy group. Patients receiving intensive therapy also had a significantly lower risk of cardiovascular disease (hazard ratio, 0.47; 95 percent confidence interval, 0.24 to 0.73), nephropathy (hazard ratio, 0.39; 95 percent confidence interval, 0.17 to 0.87), retinopathy (hazard ratio, 0.42; 95 percent confidence interval, 0.21 to 0.86), and autonomic neuropathy (hazard ratio, 0.37; 95 percent confidence interval, 0.18 to 0.79). CONCLUSIONS: A target-driven, long-term, intensified intervention aimed at multiple risk factors in patients with type 2 diabetes and microalbuminuria reduces the risk of cardiovascular and microvascular events by about 50 percent.

Amputation, Surgical↗

PubMed2003

Insulin resistance and maximal oxygen uptake.

BACKGROUND: Type 2 diabetes, coronary atherosclerosis, and physical fitness all correlate with insulin resistance, but the relative importance of each component is unknown. HYPOTHESIS: This study was undertaken to determine the relationship between insulin resistance, maximal oxygen uptake, and the presence of either diabetes or ischemic heart disease. METHODS: The study population comprised 33 patients with and without diabetes and ischemic heart disease. Insulin resistance was measured by a hyperinsulinemic euglycemic clamp; maximal oxygen uptake was measured during a bicycle exercise test. RESULTS: There was a strong correlation between maximal oxygen uptake and insulin-stimulated glucose uptake (r = 0.7, p = 0.001), and maximal oxygen uptake was the only factor of importance for determining insulin sensitivity in a model, which also included the presence of diabetes and ischemic heart disease. CONCLUSION: Maximal oxygen uptake may be a more important determinant for insulin sensitivity than ischemic heart disease and type 2 diabetes.

Diabetes Mellitus, Type 2↗

PubMed2003

Intensified multifactorial intervention and cardiovascular outcome in type 2 diabetes: the Steno-2 study.

We recently published the results of the Steno-2 study, which evaluated the benefits of intensified integrated behavior modification and targeted polypharmacy. The results provide abundant evidence that an ambitious treatment strategy is superior to a conventional one. The study involved 160 high-risk type 2 diabetic patients with microalbuminuria-a strong risk factor of both macrovascular and microvascular complications-aged 55.1 years, who were randomly assigned to a conventional or an intensive, multifactorial intervention for a period of 7.8 years. In the intensive group, a stepwise treatment plan was adopted involving both continuous lifestyle education and motivation and an ambitious goal-oriented pharmacological treatment of known modifiable risk factors. The conventional group was treated in accordance with national guidelines for type 2 diabetes with less stringent goals. The specific significant group differences in the degree of change in key clinical and biochemical variables at the end of the study were (in the intensive group): lower systolic and diastolic blood pressures, hemoglobin A(1c) (HbA(1c)), fasting serum total and low-density lipoprotein (LDL) cholesterol, fasting serum triglycerides, and 24-hour urine albumin excretion, as well as increased carbohydrate and decreased fat intake as percentage of total energy. There was no difference in weight gain between groups during follow-up and no other major side effects were reported. The primary end point was a macrovascular outcome: a composite of death from cardiovascular causes, nonfatal myocardial infarction, coronary artery bypass grafting, percutaneous coronary intervention, nonfatal stroke, amputation for ischemia, or vascular surgery for peripheral arterial atherosclerosis. The differences between groups in surrogate end points translated into the following significant group differences in final clinical end points: 44% of patients in the conventional group had a cardiovascular event compared with 24% in the intensive group, ie, a relative risk reduction of about 50%. Also, the relative risk of nephropathy, retinopathy, and autonomic neuropathy (secondary end points) was diminished by about 60% in the intensively treated group. In conclusion, an intensified and goal-oriented multipronged approach to the treatment of type 2 diabetes reduces cardiovascular events, as well as nephropathy, retinopathy, and autonomic neuropathy, by about half. The challenge is to ensure that this experience is widely adopted in daily practice.

Behavior Therapy↗

PubMed2003

Mutational analysis of the UCP2 core promoter and relationships of variants with obesity.

OBJECTIVE: To identify polymorphisms in the human uncoupling protein 2 gene (UCP2) promoter and to investigate whether these were associated with obesity or weight gain. RESEARCH METHODS AND PROCEDURES: The human UCP2 promoter was characterized by reporter gene analysis in cell lines derived from skeletal muscle, white adipose tissue, and embryonic tissue. We analyzed the core promoter for polymorphisms in 60 obese subjects. A prevalent polymorphism, the -866 G/A variant, was investigated for association with obesity in 749 men obese as young adults and 816 men of the same age representing the background population. Genotype-phenotype interaction studies were performed in two other population-based samples: one group of middle-aged-to-elderly Danish subjects (mean age, 53 years; range, 30 to 88 years) and one group of 60-year-old Danish subjects. RESULTS: The region up to -1202 bp relative to the UCP2 transcription initiation site gave rise to the highest promoter activity. Eight mutations in this region were identified comprising -866 G/A, -850 G/A, -337 G/C, -41 G/T, -28 insertion T, -5 insertion (cactgcgaagccc), +45 C/T, and +53 G/C, but none of these was associated with consistent alterations in BMI, body fat content, weight gain, or fasting levels of plasma glucose and serum insulin. DISCUSSION: Variation of the UCP2 promoter including the single common variant (-866 A/G) is not associated with obesity or obesity-related intermediary phenotypes in Danish subjects.

Adipose Tissue↗

PubMed2003

Impact of low-dose acetylsalicylic acid on kidney function in type 2 diabetic patients with elevated urinary albumin excretion rate.

BACKGROUND: Low-dose treatment with acetylsalicylic acid (ASA) is widely recommended to type 2 diabetic patients as primary prevention against cardiovascular disease. High-dose treatment with cyclooxygenase inhibitors reduces urinary albumin excretion rate (AER) in type 1 diabetic patients with micro- or macroalbuminuria. Whether a similar effect on AER exists during low-dose ASA treatment, which may confound the diagnosis and monitoring of micro- and macroalbuminuria in type 2 diabetic patients, remains to be elucidated. METHODS: In a randomized, double-blind, crossover trial, 31 type 2 diabetic patients with elevated levels of AER (>30 mg/24 h) were, in random order, given ASA (150 mg/day) for 4 weeks followed by placebo for 4 weeks with a 2 week washout period or vice versa. At the end of each treatment period AER, glomerular filtration rate (GFR), blood pressure (BP), transcapillary escape rate (TER(alb)) of albumin and haemoglobin A(1c) (HbA(1c)) were measured. RESULTS: The following variables remained unchanged (mean (95% CI) unless otherwise noted) (ASA vs placebo, paired Student's t-test): AER (201 (119-341) vs 205 (124-340) mg/24 h (geometric mean, 95% CI); P=0.78), GFR (103 (94-111) vs 102 (93-110) ml/min; P=0.58), systolic BP (151 (146-158) vs 152 (146-158) mmHg; P=0.68), diastolic BP (87 (83-91) vs 87 (82-91) mmHg; P=0.88), TER(alb) (6.3 (5.7-6.9) vs 5.9 (5.1-6.7); P=0.45) and HbA(1c) (8.6 (8.1-9.0) vs 8.5 (8.1-9.0) %; P=0.60). CONCLUSIONS: Low-dose treatment with 150 mg ASA daily does not have any impact on AER or GFR in type 2 diabetic patients with micro- or macroalbuminuria. Consequently, the widely recommended prescription of low-dose ASA as a primary and secondary prevention strategy against cardiovascular disease in these patients does not confound the diagnosis or monitoring of micro- or macroalbuminuria.

Adult↗

PubMed2003

Evidence for an association between the Leu162Val polymorphism of the PPARalpha gene and decreased fasting serum triglyceride levels in glucose tolerant subjects.

The aim of the study was to investigate whether genetic variation in the peroxisome proliferator-activated receptor-alpha (PPARalpha) is associated with type 2 diabetes and altered lipid or carbohydrate metabolism in glucose tolerant subjects. Mutation analyses of PPARalpha were performed in 56 type 2 diabetic patients. Six variants were identified: IVS3 + 76T>C, IVS3-19C>T, IVS4 + 35C>T, Leu162Val, Arg178Gly and Ala268Val. In a case-control study comprising 738 type 2 diabetic patients and 524 glucose tolerant subjects, the three exon variants did not show any significant differences in allele frequencies between type 2 diabetic patients and control subjects. The functional Leu162Val polymorphism was further investigated in genotype-phenotype studies involving 340 young, healthy subjects and 502 middle-aged glucose tolerant subjects. The young, healthy subjects who were heterozygous for the Leu162Val variant had, on average, a 20% decrease in fasting serum triglyceride levels (P=0.014). This finding was replicated in middle-aged subjects (P=0.023). The Leu162Val polymorphism was not related to alterations in insulin sensitivity, insulin release or level of glycaemia. In conclusion, the Leu162Val polymorphism of PPARalpha is associated with a decreased level of fasting serum triglyceride in glucose tolerant white subjects.

Adult↗

PubMed2003

Leptin and bone mineral density: a cross-sectional study in obese and nonobese men.

Leptin has been suggested to decrease bone mineral density (BMD). This observational analysis explored the relationship between serum leptin and BMD in 327 nonobese men (controls) (body mass index 26.1 +/- 3.7 kg/m(2), age 49.9 +/- 6.0 yr) and 285 juvenile obese men (body mass index 35.9 +/- 5.9 kg/m(2), age 47.5 +/- 5.1 yr). Whole-body dual-energy x-ray absorptiometry scan measured BMD, fat mass, and lean mass. Fasting serum leptin (nanograms per milliliter) was strongly associated with fat mass (kilograms) in both controls (r = 0.876; P < 0.01) and juvenile obese (r = 0.838; P < 0.001). An inverse relation between BMD adjusted for body weight and serum leptin emerged in both the control group (r = -0.186; P < 0.01) and the juvenile obese group (r = -0.135; P < 0.05). In a multiple linear regression, fat mass, lean body mass, and occupational physical activity were positively associated with BMD in the control group, whereas in the juvenile obese, only lean body mass was positively associated with BMD and smoking negatively associated with BMD. Our study supports that leptin is inversely associated with BMD and may play a direct role in the bone metabolism in nonobese and obese Danish males, but it also stresses the fact that the strong covariation between the examined variables is a shortcoming of the cross-sectional design.

Adult↗

PubMed2003

Impact of two common polymorphisms in the PPARgamma gene on glucose tolerance and plasma insulin profiles in monozygotic and dizygotic twins: thrifty genotype, thrifty phenotype, or both?

The Pro12Ala polymorphism in the PPARgamma2 gene has been associated with reduced risk of type 2 diabetes and insulin resistance. Recently, an association between dizygotic twinning and PPARgamma gene polymorphisms has been proposed. We investigated the phenotypic appearance of the two polymorphisms (Pro12Ala and exon 6 C-->T) in PPARgamma among elderly twins (207 monozygotic [MZ] and 342 dizygotic [DZ]) and evaluated whether they could explain previously reported differences in plasma glucose and insulin profiles among MZ and DZ twins. We demonstrated a significant impact of the Pro12Ala polymorphism on glucose tolerance, diabetic status, homeostasis model assessment for insulin resistance, and plasma insulin profiles in twins. No impact of the silent exon 6 polymorphism on glucose homeostasis or plasma insulin profiles was found. Independent of the polymorphisms, we observed a significant impact of zygosity status per se on the plasma insulin profile after oral glucose ingestion, with the MZ twins being more hyperinsulinemic, indicating insulin resistance, than the DZ twins. Nonsignificantly higher glucose concentrations were observed among MZ compared with DZ twins. We demonstrated an association between the Ala allele and reduced risk of diabetes and insulin resistance in twins. However, the differences in metabolic profiles among MZ and DZ twins were not explained by differences in frequencies of the genetic variants and may be due to intrauterine environmental factors operating in twins independent of genotype. Accordingly, our study simultaneously supports a role for both the intrauterine environment (thrifty phenotype) and for genetics (thrifty genotype) in the etiology of insulin resistance and perhaps glucose intolerance in twins.

Aged↗