A family history of diabetes is associated with reduced physical fitness in the Prevalence, Prediction and Prevention of Diabetes (PPP)-Botnia study.

AIMS/HYPOTHESIS: We studied the impact of a family history of type 2 diabetes on physical fitness, lifestyle factors and diabetes-related metabolic factors. METHODS: The Prevalence, Prediction and Prevention of Diabetes (PPP)-Botnia study is a population-based study in Western Finland, which includes a random sample of 5,208 individuals aged 18 to 75 years identified through the national Finnish Population Registry. Physical activity, dietary habits and family history of type 2 diabetes were assessed by questionnaires and physical fitness by a validated 2 km walking test. Insulin secretion and action were assessed based upon OGTT measurements of insulin and glucose. RESULTS: A family history of type 2 diabetes was associated with a 2.4-fold risk of diabetes and lower physical fitness (maximal aerobic capacity 29.2 +/- 7.2 vs 32.1 +/- 7.0, p = 0.01) despite having similar reported physical activity to that of individuals with no family history. The same individuals also had reduced insulin secretion adjusted for insulin resistance, i.e. disposition index (p < 0.001) despite having higher BMI (27.4 +/- 4.6 vs 26.0 +/- 4.3 kg/m(2), p < 0.001). CONCLUSIONS/INTERPRETATION: Individuals with a family history of type 2 diabetes are characterised by lower physical fitness, which cannot solely be explained by lower physical activity. They also have an impaired capacity of beta cells to compensate for an increase in insulin resistance imposed by an increase in BMI. These defects should be important targets for interventions aiming at preventing type 2 diabetes in individuals with inherited susceptibility to the disease.

Metabolic effects of metformin in patients with impaired glucose tolerance.

AIMS: To assess the effect of metformin on insulin sensitivity, glucose tolerance and components of the metabolic syndrome in patients with impaired glucose tolerance (IGT). METHODS: Forty first-degree relatives of patients with Type 2 diabetes fulfilling WHO criteria for IGT and participating in the Botnia study in Finland were randomized to treatment with either metformin 500 mg b.i.d. or placebo for 6 months. An oral glucose tolerance test (OGTT) and a euglycaemic hyperinsulinaemic clamp in combination with indirect calorimetry was performed at 0 and 6 months. The patients were followed after stopping treatment for another 6 months in an open trial and a repeat OGTT was performed at 12 months. RESULTS: Metformin treatment resulted in a 20% improvement in insulin-stimulated glucose metabolism (from 28.7 +/- 13 to 34.4 +/- 10.7 micromol/kg fat-free mass (FFM)/min) compared with placebo (P = 0.01), which was primarily due to an increase in glucose oxidation (from 16.6 +/- 3.6 to 19.1 +/- 4.4 micromol/kg FFM; P = 0.03) These changes were associated with a minimal improvement in glucose tolerance, which was maintained after 12 months. CONCLUSIONS: Metformin improves insulin sensitivity in subjects with IGT primarily by reversal of the glucose fatty acid cycle. Obviously large multicentre studies are needed to establish whether these effects are sufficient to prevent progression to manifest Type 2 diabetes and associated cardiovascular morbidity and mortality. Diabet. Med. 18, 578-583 (2001)

Cardiovascular morbidity and mortality associated with the metabolic syndrome.

OBJECTIVE: To estimate the prevalence of and the cardiovascular risk associated with the metabolic syndrome using the new definition proposed by the World Health Organization RESEARCH DESIGN AND METHODS: A total of 4,483 subjects aged 35-70 years participating in a large family study of type 2 diabetes in Finland and Sweden (the Botnia study) were included in the analysis of cardiovascular risk associated with the metabolic syndrome. In subjects who had type 2 diabetes (n = 1,697), impaired fasting glucose (IFG)/impaired glucose tolerance (IGT) (n = 798) or insulin-resistance with normal glucose tolerance (NGT) (n = 1,988), the metabolic syndrome was defined as presence of at least two of the following risk factors: obesity, hypertension, dyslipidemia, or microalbuminuria. Cardiovascular mortality was assessed in 3,606 subjects with a median follow-up of 6.9 years. RESULTS: In women and men, respectively, the metabolic syndrome was seen in 10 and 15% of subjects with NGT, 42 and 64% of those with IFG/IGT, and 78 and 84% of those with type 2 diabetes. The risk for coronary heart disease and stroke was increased threefold in subjects with the syndrome (P < 0.001). Cardiovascular mortality was markedly increased in subjects with the metabolic syndrome (12.0 vs. 2.2%, P < 0.001). Of the individual components of the metabolic syndrome, microalbuminuria conferred the strongest risk of cardiovascular death (RR 2.80; P = 0.002). CONCLUSIONS: The WHO definition of the metabolic syndrome identifies subjects with increased cardiovascular morbidity and mortality and offers a tool for comparison of results from diferent studies.

Antihypertensive treatment in elderly patients aged 75 years or over: a 24-week study of the tolerability of candesartan cilexetil in relation to hydrochlorothiazide.

OBJECTIVE: To assess the safety and tolerability of the AT1-receptor blocker candesartan cilexetil in relation to the diuretic hydrochlorothiazide (HCTZ) in elderly patients. DESIGN AND SETTING: A multicentre, double-blind, randomised, parallel group study. 32 general practice centres and 3 hospital centres in Denmark and Finland participated in this study. PATIENTS: 185 patients aged > or =75 years with mean sitting diastolic blood pressure (DBP) of 95 to 114mm Hg. INTERVENTIONS: After a placebo run-in period of 4 to 8 weeks, patients were randomised to once daily treatment with candesartan cilexetil 8mg or HCTZ 12.5mg for 24 weeks. In both treatment groups the dosage could be doubled after > or =2 weeks [according to blood pressure (BP) response] and, if necessary, subsequently decreased if the higher dosage was poorly tolerated. MAIN OUTCOME MEASURES: Proportion of patients with at least 1 adverse event; changes in laboratory values, electrocardiogram and BP during the double-blind treatment period. RESULTS: Once daily candesartan cilexetil 8 to 16mg was very well tolerated. The most common adverse events in both treatment groups were dizziness or vertigo and headache. Although the profile of adverse events was generally similar in the 2 treatment groups, it was notable that hypokalaemia and hyperuricaemia were not found in patients treated with candesartan cilexetil but occurred in 8.1 and 6.5%, respectively, of patients treated with HCTZ. At week 24, the adjusted mean changes in sitting DBP (24 hours postdose) from baseline were -12.0mm Hg [95% confidence interval (CI) -1 0.4 to -13.6] in patients treated with candesartan cilexetil and -11.4mm Hg (95% CI -9.3 to -13.6) in patients treated with HCTZ. The difference between treatments in favour of candesartan cilexetil was not statistically significant. CONCLUSIONS: This study shows that antihypertensive treatment with candesartan cilexetil in elderly patients (aged > or =75 years) is well tolerated with a good safety profile and avoids the metabolic adverse effects of diuretic therapy.

Clinical and genetic characteristics of type 2 diabetes with and without GAD antibodies.

The aim of the study was 1) to establish the prevalence of GAD antibodies (GADab) in a population-based study of type 2 diabetes in western Finland, 2) to genetically and phenotypically characterize this subgroup, and 3) to provide a definition for latent autoimmune diabetes in adults (LADA). The prevalence of GADab was 9.3% among 1,122 type 2 diabetic patients, 3.6% among 558 impaired glucose tolerance (IGT) subjects, and 4.4% among 383 nondiabetic control subjects. Islet antigen 2 antibodies (IA2ab) or islet cell antibodies were detected in only 0.5% of the GADab- patients. The GADab+ patients had lower fasting C-peptide concentrations (median [interquartile range]: 0.46 [0.45] vs. 0.62 [0.44] nmol/l, P = 0.0002) and lower insulin response to oral glucose compared with GADab- patients. With respect to features of the metabolic syndrome, the GADab+ patients had lower systolic (140 [29.1] vs. 148 [26.0] mmHg, P = 0.009) and diastolic (79.2 [17.6] vs. 81.0 [13.1] mmHg, P = 0.030) blood pressure values, as well as lower triglyceride concentrations (1.40 [1.18] vs. 1.75 [1.25] mmol/l, P = 0.003). GADab+ men had a lower waist-to-hip ratio compared with GADab- patients. Compared with GADab- patients and control subjects, the GADab+ patients had an increased frequency HLA-DQB1*0201/0302 (13 vs. 4%; P = 0.002) and other genotypes containing the *0302 allele (22 vs. 12%; P = 0.010). However, the frequency of these high-risk genotypes was significantly lower in GADab+ type 2 patients than in type 1 diabetes of young or adult onset (0201/0302 or 0302/X: 36 vs. 66 vs. 64%, P < 0.001). The GADab+ type 2 group did not differ from control subjects with respect to genotypes containing the protective DQB1-alleles *0602 or *0603, nor with respect to the type 1 high-risk genotype in the IDDM1 (Hph1 +/+). We conclude that GADab+ patients differ from both GADab- type 2 diabetic patients and type 1 diabetic patients with respect to beta-cell function, features of the metabolic syndrome, and type 1 diabetes susceptibility genes. Further, we propose that LADA be defined as GADab positivity (>5 relative units) in patients older than 35 years at onset of type 2 diabetes.

Metabolic consequences of a family history of NIDDM (the Botnia study): evidence for sex-specific parental effects.

Although a strong genetic susceptibility has been established for NIDDM and a maternal transmission of the disease predominates in some populations, a relationship between parental diabetes status and metabolic abnormalities in nondiabetic offspring has not been shown in humans. To address this question, we studied 2,152 first-degree relatives of patients with NIDDM (FH+) and 528 age- and weight-matched spouses without a family history of NIDDM (FH-) in Western Finland (the Botnia study). A subset of the subjects underwent a euglycemic insulin clamp combined with indirect calorimetry to measure insulin sensitivity and energy expenditure. Despite similar amounts of total body fat, persons with a family history of NIDDM had a greater waist-to-hip ratio (WHR) than spouses without a family history of diabetes (P < 0.003). They also had a decreased resting metabolic rate (P = 0.005), but this difference disappeared when adjusted for the difference in WHR. Insulin-stimulated glucose metabolism (P = 0.002), particularly nonoxidative glucose metabolism (P = 0.009), was reduced in FH+ compared with FH- subjects, and this difference remained after adjustment for WHR. A parental history of NIDDM influenced the insulin response to the oral glucose load, with male offspring of diabetic mothers showing the lowest insulin values (P = 0.011). Moreover, a parental effect was also observed on HDL and HDL2 cholesterol concentrations with female offspring of diabetic mothers showing lower values than female offspring of diabetic fathers (both P < 0.002). We conclude that abdominal obesity, insulin resistance, and decreased resting metabolic rate are characteristic features of first-degree relatives of patients with NIDDM and that the decrease in resting metabolic rate is partially related to the degree of abdominal obesity. A sex-specific paternal effect was observed on insulin and HDL cholesterol concentrations. Therefore, one has to consider the possibility of unprecedented maternal or paternal inheritance of different NIDDM phenotypes.

Clinical and metabolic characteristics of type 1 and type 2 diabetes: an epidemiological study from the Närpes community in western Finland.

Clinical and metabolic characteristics of all known Type 1 and Type 2 diabetic patients in a well-defined area in Western Finland are described. Retrospective data from the time of diagnosis and follow-up data were examined. Overall prevalence of diabetes was 25.4 cases per 1000 population. Patients were defined as having Type 1 or Type 2 diabetes based upon early insulin requirement and C-peptide levels. Applying these criteria 84% of the patients had Type 2 diabetes. Onset before the age of 40 years was observed in only 3% of Type 2 diabetic patients. This age limit therefore had a sensitivity of 97% and a specificity of 90% in correctly predicting Type 2 diabetes. At diagnosis, hypertension was observed in 2% of Type 1 and in 75% of Type 2 diabetic patients; the corresponding numbers at follow-up were 6 and 63%. At investigation, 27% of Type 1 and 22% of Type 2 diabetic patients had microalbuminuria. Retinopathy was observed in only 12% of Type 2 compared with 54% of Type 1 diabetic patients. The presence of retinopathy was associated with longer diabetes duration both among Type 1 and Type 2 diabetic patients. A significant decrease in C-peptide concentration was observed in Type 2 diabetic patients with increasing diabetes duration. The data therefore suggest that Type 2 diabetes is associated with a deterioration of beta-cell function with time.

Comparative study of hydrochlorothiazide and a fixed combination of metoprolol and hydrochlorothiazide essential hypertension.

In a double-blind study comprising 31 patients with essential hypertension not satisfactorily controlled on hydrochlorothiazide 25 mg o.m., a fixed-ratio combination of metoprolol 100 mg and hydrochlorothiazide 12.5 mg, given as 2 tablets o.m. has been compared with hydrochlorothiazide 50 mg o.m. monotherapy. With the combination regimen a significant reduction of blood pressure was achieved while doubling of the thiazide dose did not adequately control the blood pressure. In 7 patients in the thiazide-group the therapy was changed to the combination during a follow-up period and their blood pressure was normalised. During the follow-up period, 22 patients were thus treated with the fixed combination; 50% of them were controlled on one tablet o.m. The tolerability was good in both groups and no changes were observed regarding laboratory variables except for an increase in serum uric acid in the thiazide-group. The study indicates that a fixed-ratio combination of hydrochlorothiazide 12.5 mg and metoprolol 100 mg in a dose of one or two tablets once daily is a well tolerated and more effective therapy than hydrochlorothiazide 50 mg once daily monotherapy.