Y.A. Kesaniemi

Concordance for Type 1 (insulin-dependent) and Type 2 (non-insulin-dependent) diabetes mellitus in a population-based cohort of twins in Finland

SummaryWe studied the cumulative incidence, concordance rate and heritability for diabetes mellitus in a nationwide cohort of 13,888 Finnish twin pairs of the same sex. The twins were born before 1958 and both co-twins were alive in 1967. Data on diabetes were derived through computerized record linkage from death certificates, the National Hospital Discharge Register and the National Drug Register. Records were reviewed in order to assign a diagnostic category to the 738 diabetic patients identified. Of these patients 109 had Type 1 (insulin-dependent) diabetes, 505 Type 2 (non-insulin-dependent) diabetes, 46 gestational diabetes, 24 secondary diabetes, 38 impaired glucose tolerance and 16 remained unclassified. The cumulative incidence of diabetes was 1.4 % in men and 1.3 % in women aged 28–59 years and 9.3 % and 7.0 % in men and women aged 60 years and over, respectively. The cumulative incidence did not differ between monozygotic and dizygotic twins. The concordance rate for Type 1 diabetes was higher among monozygotic (23 % probandwise and 13 % pairwise) than dizygotic twins (5 % probandwise and 3 % pairwise). The probandwise and pairwise concordance rates for Type 2 diabetes were 34% and 20% among monozygotic tiwns and 16% and 9 % in dizygotic twins, respectively. Heritability for Type 1 diabetes was greater than that for Type 2 where both genetic and environmental effects seemed to play a significant role.

Ghrelin Arg51Gln mutation is a risk factor for Type 2 diabetes and hypertension in a random sample of middle-aged subjects

Aims/hypothesisExperimental studies have suggested that ghrelin, a novel gastrointestinal peptide hormone, could play a role in glucose homeostasis. In addition, ghrelin has been associated with beneficial haemodynamic effects in experimental settings. Since the Arg51Gln mutation changes the carboxyterminal amino acid of the mature hormone and is associated with low ghrelin concentrations, we assessed the hypothesis that Arg51Gln mutation is a risk factor for Type 2 diabetes, impaired glucose tolerance, and hypertension.MethodsBlood pressure recordings and oral glucose tolerance test were carried out in the hypertensive (n=519) and control cohorts (n=526) of our well-defined OPERA study. The genotypes and plasma IGF-I and IGFBP-1 concentrations of 1031 subjects were analysed.ResultsThe ghrelin 51Gln allele was a risk factor for Type 2 diabetes, and the effect remained significant after adjustment for age, BMI, and study group (OR=2.53, CI: 1.11–5.75, p=0.027). In addition, the 51Gln allele was a risk factor for hypertension (OR=2.63, CI: 1.37–5.08, p=0.003). 51Gln carriers had lower concentrations of IGF-I and higher concentrations of IGFBP-1 compared to non-carriers.Conclusion/interpretationThe ghrelin 51Gln allele could increase the risk for Type 2 diabetes and hypertension. The low IGF-I concentrations in 51Gln carriers suggest that the mechanism might be associated with low GH concentrations.

The need for a large-scale trial of fibrate therapy in diabetes : the rationale and design of the Fenofibrate Intervention and Event Lowering in Diabetes (FIELD) study

BackgroundFibrates correct the typical lipid abnormalities of type 2 diabetes mellitus, yet no study, to date, has specifically set out to evaluate the role of fibrate therapy in preventing cardiovascular events in this setting.MethodsSubjects with type 2 diabetes, aged 50–75 years, were screened for eligibility to participate in a long-term trial of comicronized fenofibrate 200 mg daily compared with matching placebo to assess benefits of treatment on the occurrence of coronary and other vascular events. People with total cholesterol levels 3.0–6.5 mmol/L plus either a total-to-HDLc ratio >4.0 or triglyceride level >1.0 mmol/L with no clear indication for lipid-modifying therapy were eligible.ResultsA total of 9795 people were randomized into the Fenofibrate Intervention and Event Lowering in Diabetes (FIELD) trial. All received dietary advice, followed by a 6-week single-blind placebo run-in, then a 6-week active run-in period before randomization. Participants are being followed up every 6 months for outcome events and safety assessments. The study is designed to yield at least 500 coronary events (primary endpoint: first nonfatal myocardial infarction or coronary death) over 5 years, to have 80% power to identify as statistically significant at 2P = 0.05 a 22% reduction in such events, using intention-to-treat methods.ConclusionsType 2 diabetes is the most common endocrine disorder worldwide, and its prevalence is increasing. The current evidence about use of fibrates in type 2 diabetes, from around 2000 people treated, will increase with FIELD to evidence from around 12000. FIELD will establish the role of fenofibrate treatment in reducing cardiovascular risk in people with type 2 diabetes. The main results are expected to be available in late 2005.Background Fibrates correct the typical lipid abnormalities of type 2 diabetes mellitus, yet no study, to date, has specifically set out to evaluate the role of fibrate therapy in preventing cardiovascular events in this setting. Methods Subjects with type 2 diabetes, aged 50–75 years, were screened for eligibility to participate in a long-term trial of comicronized fenofibrate 200 mg daily compared with matching placebo to assess benefits of treatment on the occurrence of coronary and other vascular events. People with total cholesterol levels 3.0–6.5 mmol/L plus either a total-to-HDLc ratio >4.0 or triglyceride level >1.0 mmol/L with no clear indication for lipid-modifying therapy were eligible. Results A total of 9795 people were randomized into the Fenofibrate Intervention and Event Lowering in Diabetes (FIELD) trial. All received dietary advice, followed by a 6-week single-blind placebo run-in, then a 6-week active run-in period before randomization. Participants are being followed up every 6 months for outcome events and safety assessments. The study is designed to yield at least 500 coronary events (primary endpoint: first nonfatal myocardial infarction or coronary death) over 5 years, to have 80% power to identify as statistically significant at 2P = 0.05 a 22% reduction in such events, using intention-to-treat methods. Conclusions Type 2 diabetes is the most common endocrine disorder worldwide, and its prevalence is increasing. The current evidence about use of fibrates in type 2 diabetes, from around 2000 people treated, will increase with FIELD to evidence from around 12000. FIELD will establish the role of fenofibrate treatment in reducing cardiovascular risk in people with type 2 diabetes. The main results are expected to be available in late 2005.

Association between angiotensin converting enzyme gene polymorphism and carotid atherosclerosis.

Objective Variations in the angiotensin converting enzyme (ACE) gene have been implicated in cardiovascular pathology. Therefore, the association between the intima–media thickness (IMT) of the carotid artery and the insertion/deletion (I/D) polymorphism of the ACE gene was investigated. Subjects Three hundred men and 300 women were selected randomly from the middle-aged population living in the town Oulu, Finland, of whom 515 subjects (85.8%) participated. Methods The IMT of the carotid arteries was determined by bilateral B-mode ultrasonography. IMT values were adjusted for gender, age, height, plasma low-density lipoprotein cholesterol level, smoking and systolic blood pressure. The I/D polymorphism of the ACE gene was determined by polymerase chain reaction. Results Among non-smokers, the subjects with the DD genotype had significantly higher carotid IMT than did those with II or ID. The association was found also in combined IMT plaque values. In the total population the association was weaker and it was absent in current smokers. Genotype could explain 1.3–2.7% of the variance of carotid IMT in non-smokers. No association between the amount or size of carotid plaques and genotype was observed. Conclusions Variations at the ACE gene locus contribute to the degree of the early changes in carotid atherosclerosis in the population. The gene effect is, however, masked by stronger effects of environmental factors such as smoking. The lack of association between atherosclerotic plaques and genotypes may reflect different mechanisms being involved in plaque development and early arterial wall thickening.

Plasma ghrelin concentrations are positively associated with carotid artery atherosclerosis in males

Background.  Ghrelin, a peptide hormone from stomach, stimulates food intake and decreases fat utilization. Ghrelin binds to growth hormone secretagogue receptor (GHSR). GHSR density has been shown to be upregulated in atherosclerotic lesions, but the relationship between ghrelin concentration and atherosclerosis has not yet been studied. We, therefore, characterized the association between ghrelin concentration and carotid artery intima‐media thickness (IMT) in a population‐based cohort of 1024 middle‐aged (40–60 years) men and women.

The negative association between plasma ghrelin and IGF-I is modified by obesity, insulin resistance and type 2 diabetes

Aims/hypothesisGhrelin is a natural growth hormone-releasing peptide thought to be involved in the regulation of energy metabolism. The recent studies concerning the association between ghrelin and insulin-like growth factor-I (IGF-I) concentrations have shown either negative correlation or no correlation at all. The aims of this study were to clarify the association between ghrelin and IGF-I concentrations in a large cohort and to characterize whether obesity, insulin resistance and type 2 diabetes affect this association.MethodsWe analysed fasting plasma ghrelin and IGF-I concentrations of 1,004 middle-aged subjects of the population-based OPERA study. Insulin resistance was estimated using QUICKI.ResultsIGF-I concentrations were negatively associated with ghrelin concentrations in the analysis of all subjects before (β=−0.32, p<0.001) and after adjustments for BMI, insulin levels, sex and age (β=−0.40, p<0.001). The association was particularly strong in males and in the higher BMI tertiles. The degree of association varied in relation to the glycaemic status: no insulin resistance: r2=6.5% (p<0.001), insulin resistance without type 2 diabetes: r2=21.0% (p<0.001), type 2 diabetes: r2=25.4 (p<0.001). IGF-I levels explained larger proportion (r2=9.8%) of the variation in ghrelin concentrations compared to fasting insulin concentration (r2=3.0%) and BMI (r2=1.5%).Conclusions/interpretationThere is a negative and independent association between ghrelin and IGF-I concentrations in middle-aged subjects. The interaction between IGF-I and ghrelin is modified by obesity, IR and type 2 diabetes. Further studies are warranted to elucidate the role of ghrelin in the development of these states.

Hyperinsulinemia and Carotid Atherosclerosis in Hypertensive and Control Subjects

OBJECTIVE To analyze the relationships between carotid atherosclerosis measured as intima-media thickness (IMT) and different measures of insulin in a population-based casecontrol study of men and women. RESEARCH DESIGN AND METHODS Carotid ultrasonographic measurements and 2-h oral glucose tolerance tests were performed in a random sample of 513 hypertensive subjects, aged 40–59 years, and in 518 age- and sex-matched control subjects. The associations between IMT and the different measures of insulin were analyzed through multiple regression and by insulin quintiles. The independent effect of insulin was estimated after concurrent adjustment for age, obesity, LDL cholesterol, and systolic blood pressure. RESULTS The most powerful correlates with IMT were LDL cholesterol, age, systolic blood pressure, pack-years of smoking, and of the different insulin parameters, 2-h post-load insulin. In stepwise regression analysis, the independent predictors of the mean IMT were LDL cholesterol, systolic blood pressure, pack-years of smoking, and age (P < 0.0001) after adjustment for the independent predictors. In analysis of variance, no positive association of insulin parameters with IMT was found between the 2-h insulin quintiles after adjustment for the independent variables. The exclusion of diabetic subjects did not change the results. CONCLUSIONS The present study of a population-based sample of men and women found inconsistent associations between different insulin measures and IMT after adjustment for the independent variables.

Glycemic Control Over 5 Years in 4,900 People With Type 2 Diabetes: Real-world diabetes therapy in a clinical trial cohort

OBJECTIVE Glycemic control in type 2 diabetes generally worsens over time, requiring intensification of therapy. The Fenofibrate Intervention and Event Lowering in Diabetes (FIELD) trial provided the opportunity to observe glycemic control in a real-world setting. We assessed the adequacy of metformin, sulfonylureas, and insulin to maintain glycemic control and their effects on weight. RESEARCH DESIGN AND METHODS Diabetes control was measured at baseline and yearly for a median of 5 years in the 4,900 patients from the nonintervention arm of this study allocated to placebo. RESULTS Median HbA1c was 6.9% at baseline and increased by an average of 0.22% over 5 years (P < 0.001). Median weight was 86.3 kg at baseline and decreased by 0.4 kg over 5 years (P = 0.002). Baseline therapy was lifestyle measures only in 27%, oral agents without insulin in 59%, and insulin in 14% (7% also taking oral agents). Over 5 years, insulin use increased to 32% (21% also taking oral agents). Use of oral agents remained similar at 56%. Only 2% of patients at baseline and 4% after 5 years were taking oral agents other than metformin or sulfonylureas. Initiation of insulin therapy in 855 patients produced a sustained reduction of HbA1c from a median of 8.2 to 7.7%, with a weight gain of 4.6 kg over 5 years. CONCLUSIONS With intensification of traditional therapies, glycemic control deteriorated very little over 5 years in a large cohort of type 2 diabetes. However, the requirement for insulin therapy doubled, at the expense of significant weight gain and risk of hypoglycemia.

High ambulatory blood pressure values associated with non-alcoholic fatty liver in middle-aged adults.

Objective: Nonalcoholic fatty liver and hypertension are associated with metabolic syndrome. Both conditions increase the risk for cardiovascular morbidity. The objective of this study was to analyze whether 24-h blood pressure (BP) levels and nondipping phenomenon associate with hepatic steatosis defined as liver brightness. Methods: Twenty-four hour ambulatory BP measurement (ABPM) and liver brightness were investigated in a population-based cohort of 890 hypertensive (n = 433) and normotensive (n = 457) individuals aged 40–60 years. ABPM was recorded using the fully automatic SpaceLabs90207 oscillometric unit. Results: Fatty liver was associated with male sex, increased alcohol consumption, high BMI, large waist (P < 0.001 for all) and increased prevalence of smoking (P < 0.03). Values of alanine aminotransferase (ALT), gamma-glutamyltransferase (GGT), triglycerides and high-sensitivity CRP (hsCRP) were higher and high-density lipoprotein cholesterol lower (P < 0.001 for all) in individuals with fatty liver. After adjustments for BMI, sex and age, fatty liver was associated with 24-h (P < 0.005), daytime (P < 0.02) and night-time (P < 0.005) SBP measurements and DBP at daytime (P < 0.03). The association with nondipping showed only a trend (P = 0.057). Conclusion: Significantly higher ambulatory daytime and night-time SBP levels were seen in individuals with fatty liver. Nondipping does not seem to associate with liver fat. The coexistence of liver fat accumulation and high BP are likely to potentiate the risk for cardiovascular disease.

Early atherosclerosis and IgG2 to bacteria are associated with FcγRIIa genotype in non‐smokers

Background  Involvement of low density lipoprotein (LDL) immune complexes (ICs) in atherogenesis has been proposed. Human FcγRIIa receptor (CD32) plays a crucial role in the phagocytosis of IgG2 ICs and a functional point mutation 131His/Arg diminishes IgG2 binding to the receptor.