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The metabolic syndrome influences the risk of chronic complications in patients with Type II diabetes

Abstract.Aims/hypothesis: We examined features of the metabolic syndrome to see if they modified the risk of chronic diabetic complications in patients with Type II (non-insulin-dependent) diabetes mellitus. Methods: A total of 85 randomly selected patients with the metabolic syndrome (WHO definition) were compared with 85 Type II diabetic patients matched for age, sex, duration of diabetes, glycaemic control and without the syndrome to assess the microvascular and macrovascular complications. Results: The patients with the metabolic syndrome had a higher prevalence of cardiovascular disease (52 vs 21 %, p < 0.001), microalbuminuria or macroalbuminuria (23 vs 7 %, p = 0.003) and distal neuropathy (16 vs 6 %, p = 0.048) than patients without the syndrome. The patients with the metabolic syndrome had smaller LDL particle size (25.4 ± 1.4 vs 26.4 ± 1.1 nm; p < 0.001), which correlated with the ratio of serum triglycerides to HDL cholesterol (r = –0.64, p < 0.001). In a multiple logistic regression analysis the metabolic syndrome was associated with coronary heart disease (RR 3.84, p < 0.001) and microalbuminuria (RR 3.99, p = 0.01). Small LDL particle size was independently associated with neuropathy (RR 0.58; p = 0.04), whereas a high HbA1 c was related to neuropathy (RR 1.69, p = 0.04), retinopathy (RR 1.53, p = 0.002) and microalbuminuria (RR 1.54, p = 0.01). Conclusion/interpretation: Although chronic hyperglycaemia is the main predictor of microvascular complications in patients with Type II diabetes, this risk is modified by some of the components of the metabolic syndrome. [Diabetologia (2001) 44: 1148–1154]

Characterization of the MODY3 phenotype. Early-onset diabetes caused by an insulin secretion defect.

Maturity-onset diabetes of the young (MODY) type 3 is a dominantly inherited form of diabetes, which is often misdiagnosed as non-insulin-dependent diabetes mellitus (NIDDM) or insulin-dependent diabetes mellitus (IDDM). Phenotypic analysis of members from four large Finnish MODY3 kindreds (linked to chromosome 12q with a maximum lod score of 15) revealed a severe impairment in insulin secretion, which was present also in those normoglycemic family members who had inherited the MODY3 gene. In contrast to patients with NIDDM, MODY3 patients did not show any features of the insulin resistance syndrome. They could be discriminated from patients with IDDM by lack of glutamic acid decarboxylase antibodies (GAD-Ab). Taken together with our recent findings of linkage between this region on chromosome 12 and an insulin-deficient form of NIDDM (NIDDM2), the data suggest that mutations at the MODY3/NIDDM2 gene(s) result in a reduced insulin secretory response, that subsequently progresses to diabetes and underlines the importance of subphenotypic classification in studies of diabetes.

Age influences DNA methylation and gene expression of COX7A1 in human skeletal muscle

Aims/hypothesisReduced oxidative capacity of the mitochondria in skeletal muscle has been suggested to contribute to insulin resistance and type 2 diabetes. Moreover, a set of genes influencing oxidative phosphorylation (OXPHOS) is downregulated in diabetic muscle. Here we studied whether genetic, epigenetic and non-genetic factors influence a component of the respiratory chain, COX7A1, previously shown to be downregulated in skeletal muscle from patients with type 2 diabetes. The specific aims were to: (1) evaluate the impact of genetic (single nucleotide polymorphisms [SNPs]), epigenetic (DNA methylation) and non-genetic (age) factors on the expression of COX7A1 in human skeletal muscle; and (2) investigate whether common variants in the COX7A1 gene are associated with increased risk of type 2 diabetes.MethodsCOX7A1 mRNA expression was analysed in muscle biopsies from young (n = 110) and elderly (n = 86) non-diabetic twins and related to measures of in vivo metabolism. Genetic variants (three SNPs) from the COX7A1 locus were genotyped in the twins and in two independent type 2 diabetes case–control cohorts (n = 1466 and 6380, respectively). DNA methylation of the COX7A1 promoter was analysed in a subset of twins (ten young, ten elderly) using bisulphite sequencing.ResultsWhile DNA methylation of the COX7A1 promoter was increased in muscle from elderly compared with young twins (19.9 ± 8.3% vs 1.8 ± 2.7%; p = 0.035), the opposite was found for COX7A1 mRNA expression (elderly 1.00 ± 0.05 vs young 1.68 ± 0.06; p = 0.0005). The heritability of COX7A1 expression was estimated to be 50% in young and 72% in elderly twins. One of the polymorphisms investigated, rs753420, influenced basal COX7A1 expression in muscle of young (p = 0.0001) but not of elderly twins. The transcript level of COX7A1 was associated with increased in vivo glucose uptake and

Stressful Life Events and the Metabolic Syndrome - The Prevalence, Prediction and Prevention of Diabetes (PPP)-Botnia Study

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A common variant upstream of the PAX6 gene influences islet function in man

(p = 0.009 and p = 0.001, respectively). We did not observe any genetic association between COX7A1 polymorphisms and type 2 diabetes after correcting for multiple testing.Conclusions/interpretationOur results provide further evidence for age as a factor influencing DNA methylation and expression of OXPHOS genes, and thereby in vivo metabolism.

Genetic Variation in ATP5O Is Associated with Skeletal Muscle ATP50 mRNA Expression and Glucose Uptake in Young Twins

Summary MODY3 diabetes, which is caused by a mutation in the hepatocyte nuclear factor-1α gene (HNF-1α) on chromosome 12, represents a relatively common monogenic form of diabetes in Finland. Age at onset of the disease can vary from 10 to 60 years, but little is known about the natural course of the disease, particularly the development of diabetes-related chronic complications. The availability of genetic markers now allows description of the clinical course of the disease. In order to examine the prevalence of chronic diabetic complications in MODY3, we examined 57 carriers with HNF-1α mutations for the presence of micro- and macrovascular complications. Thirty-four percent of the MODY patients had mild and 13 % had severe non-proliferative or proliferative retinopathy; this figure did not differ from the figures in insulin-dependent diabetes mellitus (IDDM) and non-insulin-dependent diabetes mellitus (NIDDM) patients matched for duration and glycaemic control but not for age. Neither did the prevalence of microalbuminuria differ between MODY3 and IDDM or NIDDM patients (19 vs 24 and 23 %). Neuropathy was observed with the same frequency as previously reported in IDDM. Hypertension was less frequent in MODY3 and IDDM than in NIDDM (24.5 and 19 vs 53.7 %; p < 0.001). Coronary heart disease was more common in MODY3 than in IDDM (16 vs 4.5 %; p < 0.02) but less common than in the older NIDDM patients (33.3 %; p < 0.02). In a multiple logistic regression analysis, poor glycaemic control was an independent risk factor for retinopathy (p = 0.03), microalbuminuria (p < 0.04) and neuropathy (p = 0.03). In conclusion, microangiopathic complications are observed with the same frequency in patients with MODY3 diabetes as in IDDM and NIDDM and are strongly related to poor glycaemic control. [Diabetologia (1998) 41: 467–473]

Genetic testing for maturity onset diabetes of the young: uptake, attitudes and comparison with hereditary non-polyposis colorectal cancer

OBJECTIVE Stress may play a role in the pathogenesis of the metabolic syndrome. However, the scant evidence available is not population-based, restricting the external validity of the findings. Our aim was to test associations between stressful life events, their accumulation, and the metabolic syndrome in a large population-based cohort. We also tested associations between stress and the individual components related to the metabolic syndrome. RESEARCH DESIGN AND METHODS This was a population-based, random sample of 3,407 women and men aged 18–78 years residing in Western Finland. Metabolic syndrome was defined according to the National Cholesterol Education Program Adult Treatment Panel III and International Diabetes Federation criteria. The severity of 15 stressful life events pertaining to finance, work, social relationships, health, and housing was self-rated. RESULTS In comparison with subjects not reporting any extremely stressful life events, those reporting work- or finance-related events had an increased odds for having the metabolic syndrome. The risk was further increased according to accumulation of stressful finance-related events and to having at least three stressful life events in any of the life domains assessed. Accumulation of stressful life events was associated with insulin resistance, obesity, and triglycerides. The associations were not confounded by sex, age, lifestyle, or family history of diabetes. CONCLUSIONS Life events perceived as stressful, particularly those related to finance and work, may be a signal for poor metabolic health.

Lower Incidence of Hypertension among Swedish Speakers as Compared to Finnish Speakers in the Helsinki Birth Cohort from Finland – An Example of Early Programming of Disease?

Aims/hypothesis. To evaluate insulin sensitivity and insulin secretion in prediabetic and diabetic subjects with mutations in MODY1 (HNF-4α) and MODY3 (HNF-1α) genes, in subjects with GAD antibodies, latent autoimmune diabetes in adults and in subjects with the common form of Type II (non-insulin-dependent) diabetes mellitus. Methods. Insulin secretion was measured as the incremental 30-min insulin (I30) and insulin glucose ratio (I:G30) during OGTT whereas insulin sensitivity was measured as the insulin sensitivity index during OGTT in 131 carriers of MODY mutations [NGT = 38, IFG/IGT = 21, diabetes mellitus (DM) = 72], in 293 subjects with GADA (NGT = 47, IFG/IGT = 29, DM = 217) and in 2961 subjects with a family history of the common form of Type II diabetes but without MODY mutations or GADA (NGT = 1360, IFG/IGT = 857, DM = 744). A subgroup of the subjects underwent a euglycaemic clamp (n = 210) and intravenous glucose tolerance test (n = 337) for the estimation of insulin sensitivity and first-phase insulin secretion. Results. Non-diabetic subjects with MODY mutations had pronounced impaired insulin secretion (I30, I:G30) compared with the two other groups (p = 0.005). Normal or non-diabetic glucose tolerance was maintained by enhanced insulin sensitivity compared with the other two groups (p < 0.05 and p < 0.005). In contrast to patients with Type II diabetes and with adult latent autoimmune diabetes, MODY patients showed only a modest deterioration in insulin sensitivity at onset of diabetes. The 2-h glucose values inversely correlated with insulin sensitivity in subjects with GADA (r = –0.447, p < 0.001) and subjects from Type II diabetic families (r = –0.426, p < 0.001), whereas no such relation was observed in subjects with MODY mutations (r = 0.151, p = NS). There were no statistically significant differences in insulin secretion or insulin sensitivity between subjects with GADA or subjects with a family history of Type II diabetes, either at the NGT or the IFG/IGT stage. Conclusion/interpretation. Glucose-tolerant carriers of MODY mutations are characterised by a severe impairment in insulin secretion. Enhanced insulin sensitivity is the most likely explanation for the normal glucose tolerance. Whereas subjects with positive GADA or Type II diabetes have impaired insulin sensitivity with increasing glucose concentrations, MODY mutation carriers seem to be protected from the effect of glucose toxicity. [Diabetologia (2000) 43: 1476–1483]