Metformin vs. insulin in gestational diabetes. A randomized study characterizing metformin patients needing additional insulin.

AIMS: We compared metformin with insulin as treatment of gestational diabetes mellitus (GDM). Furthermore, we aimed to characterize metformin-treated patients needing additional insulin to achieve prespecified glucose targets. METHODS: We conducted a single centre randomized controlled study with non-inferiority design comparing metformin and insulin in the treatment of 217 GDM patients having birth weight as primary outcome variable. RESULTS: There were no significant differences in mean birth weight expressed in grams [+15 (90% confidence interval (CI): -121 to 89)] or SD units [+0.04 (90% CI: -0.27 to 0.18)] between the metformin and insulin groups. There were no significant differences in neonatal or maternal data between the groups. Only 23 (20.9%) of the 110 patients in the metformin group needed additional insulin. Compared with the patients on metformin only, those needing additional insulin were older (p = 0.04), their oral glucose tolerance test had been performed earlier and diabetes therapy started earlier in gestation (p = 0.01 and p = 0.004, respectively). The risk for additional insulin was 4.6-fold in women with baseline serum fructosamine concentration above median compared with those below median. CONCLUSIONS: Metformin is an effective alternative to insulin in the treatment of GDM patients. Serum fructosamine may help in predicting the adequacy of metformin treatment alone.

Proteinuria modifies the effect of systolic blood pressure on total and cardiovascular disease mortality in patients with type 2 diabetes.

OBJECTIVES: Hypertension and proteinuria are major risk factors for cardiovascular disease (CVD) mortality in patients with type 2 diabetes. Blood pressure (BP) targets have been progressively lowered in these patients to prevent or delay the progression of nephropathy. However, no long-term population-based studies have been reported on the interaction between BP and proteinuria with respect to total and CVD mortality in patients with type 2 diabetes. DESIGN: We prospectively followed 881 middle-aged type 2 diabetic patients, free of CVD events at baseline, for up to 18 years. Participants were categorized into four groups according to baseline systolic BP (<130, 130-139, 140-159 and ≥160 mmHg) and further stratified by proteinuria (≤150 or >150 mg L(-1)). Cox proportional hazards model was used to estimate the joint association between systolic BP and proteinuria and the risk of mortality. RESULTS: During follow-up, 607 patients died including 395 because of CVD. After adjustment for confounding factors, total and CVD mortality were significantly higher in patients with proteinuria and systolic BP <130 mmHg compared with those with systolic BP between 130 and 160 mmHg. The prognosis was similar in patients with systolic BP <130 mmHg or ≥160 mmHg. Among patients without proteinuria, systolic BP <130 mmHg was associated with a nonsignificant reduction in mortality. CONCLUSIONS: Type 2 diabetic patients with proteinuria and with systolic BP <130 mmHg may have an increased risk of CVD mortality. The presence of proteinuria should be taken into account when defining the target systolic BP level for the prevention of fatal CVD events in patients with type 2 diabetes.

Proteinuria modifies the effects of physical activity on total and cardiovascular disease mortality rates in patients with type 2 diabetes.

AIMS/HYPOTHESIS: Physical activity reduces cardiovascular disease (CVD) and total mortality rates in patients with type 2 diabetes. However, it is not known whether or not the effects of physical activity on mortality rates depend on the presence of proteinuria in type 2 diabetic patients. METHODS: We prospectively followed up 577 patients with type 2 diabetes who were aged 45 to 64 years and were free of CVD at baseline. Participants were stratified according to the presence of proteinuria (300 mg/l) and the degree of physical activity (0-4 metabolic equivalent tasks [MET] or >4 MET). The Cox proportional hazards model was used to estimate the association of physical activity and proteinuria with risk of mortality. RESULTS: During the 18-year follow-up, 356 patients died, of whom 217 died from CVD. Physically more active patients had significantly reduced total, CVD and CHD mortality rates if they did not have proteinuria. In contrast, physically active proteinuric patients had significantly increased total and CVD mortality rates (HR 1.83, 95% CI 1.00-3.36, p=0.049) in univariate analyses, with HR 2.43 (95% CI 1.09-5.40, p=0.030) in multivariate analyses. CONCLUSIONS/INTERPRETATION: Physical activity reduces total and CVD mortality rates in type 2 diabetic patients without proteinuria. However, in proteinuric patients, no protective effect was observed. Larger studies are needed to confirm the latter finding and to define which exercise intensity leads to possible harmful effects.

Follow-ups of the Cardiovascular Risk in Young Finns Study in 2001 and 2007: levels and 6-year changes in risk factors.

OBJECTIVES: To examine cardiovascular risk factor levels in 2007 and their 6-year changes between 2001 and 2007 using the data collected in the follow-ups of the Cardiovascular Risk in Young Finns Study. DESIGN: Population-based follow-up study. SUBJECTS: A total of 2204 healthy Finnish adults aged 30-45 years (1210 women; 994 men). MAIN OUTCOME MEASURES: Levels in 2007 and changes between 2001 and 2007 of lipids, insulin, glucose, blood pressure, smoking, body mass index, alcohol consumption, waist and hip circumferences. RESULTS: The mean serum total cholesterol, low density lipoprotein (LDL) cholesterol, high density lipoprotein (HDL) cholesterol and triglyceride concentrations in 30- to 45-year-old adults were 5.05, 3.09, 1.34 and 1.40 mmol L(-1), respectively. Significant changes (P < 0.05) between 2001 and 2007 in 30- to 39-year-old subjects included a decrease in total cholesterol (-6.6% in men, -5.8% in women), LDL-cholesterol (-10.2% and -11.6%) and an increase in diastolic blood pressure (3.5% and 3.9%). Waist circumference (1.8% and 5.5%) and systolic blood pressure increased in 36-39 year olds (2.3% and 2.3%). HDL-cholesterol increased in 30- to 33-year-old women (5.8%) Glucose levels increased in 30- to 39-year-old women (3.7%) and 36- to 39-year-old men (3.6%). Smoking prevalence decreased in 36- to 39-year-old men from 29.8% to 22.2%. CONCLUSIONS: The 6-year changes in total cholesterol, LDL-cholesterol and HDL-cholesterol in young Finns were favourable between 2001 and 2007. However, waist circumference, glucose and blood pressure levels increased. Therefore, continuous efforts are still needed in fighting against cardiovascular risk factors.

Dietary and lifestyle counselling reduces the clustering of overweight-related cardiometabolic risk factors in adolescents.

AIM: The aim of this study was to evaluate the impact of individualised dietary and lifestyle counselling, primarily aimed to decrease serum low-density lipoprotein cholesterol, on the clustering of overweight-related cardiometabolic risk factors in children. DESIGN AND PARTICIPANTS: The 7-month-old study children were randomized either to counselling (n = 540) or control group (n = 522). MAIN OUTCOME MEASURES: The 5- to 15-year-old participants who fulfilled the international criteria were classified as overweight. Being in the highest [lowest for high-density lipoprotein (HDL) cholesterol] age- and gender-specific quintile of body mass index (BMI), blood pressure, serum triglycerides, HDL cholesterol or glucose was considered a risk factor. A cluster was defined as having high BMI and > or = 2 other risk factors. RESULTS: The counselling did not reduce the prevalence of overweight in 5- to 15-year-old participants. From age 7 onwards, the proportion of children with > or = 2 risk factors was lower in the intervention than in the control group (p = 0.005). At the age of 15 years, 13.0% of girls and 10.8% of boys in the intervention group and 17.5% of girls and 18.8% of boys in the control group had the risk factor cluster (p = 0.046 for main effect of the study group). Having even one risk factor at the age of 5 years predicted the clustering of risk factors at the age of 15 years (OR: 3.8, p < 0.001). CONCLUSION: Repeated, individualized dietary and lifestyle counselling may reduce the clustering of overweight-related cardiometabolic risk factors in adolescents even though the counselling is not intense enough to prevent overweight.

Migration at early age from a high to a lower coronary heart disease risk country lowers the risk of subclinical atherosclerosis in middle-aged men.

BACKGROUND: Study of migrants offers a natural model to assess environmental risk of coronary heart disease (CHD) in countries differing in CHD occurrence. In Sweden, CHD risk has been markedly lower than in Finland from where a large migration occurred in the 1970s. OBJECTIVES: To study the structural and functional markers of subclinical atherosclerosis in twin pairs discordant for migration with the main focus on age at migration, length of residence and integration into Swedish society after migration from a high to a lower CHD risk country. METHODS: Carotid intima-media thickness (IMT) and brachial artery endothelial function (EF) were assessed with high-resolution ultrasound and a set of cardiovascular, socio-economic and psychosocial risk factors were estimated in 76 middle-aged male twin pairs discordant for migration from Finland to Sweden. RESULTS: Men who had migrated in adolescence had lower IMT values compared with their co-twins living in Finland (0.665 +/- 0.114 vs. 0.802 +/- 0.167 mm, P = 0.009). Also men who integrated well to Swedish society had lower (0.720 +/- 0.154 vs. 0.799 +/- 0.207 mm, P = 0.013) IMT values than their twin brothers living in Finland. Associations between IMT and migration age and between IMT and integration remained significant in multivariate analyses of several CHD risk factors. The intrapair difference in IMT was significantly associated with immigration age and integration (ANOVA, P = 0.0082), the difference being greatest among pairs where the brother living in Sweden had migrated at early age and integrated well to Swedish society. EF was better in men who had migrated to Sweden before the age of 21 years, but not later, compared with their co-twins in Finland (6.4 +/- 4.6% vs. 3.8 +/- 3.6%, P = 0.025). CONCLUSIONS: Migration at an early age and good integration are beneficial to vascular health associated with moving from a high to a lower CHD risk country, suggesting that an environment-sensitive period influences atherogenesis before adulthood.

Metabolic syndrome and short-term heart rate variability in young adults. The cardiovascular risk in young Finns study.

AIMS: Heart rate variability (HRV) can be used to estimate autonomic nervous control of the cardiovascular system. In middle-aged subjects, the metabolic syndrome (MetS) is associated with lower HRV. We hypothesized that alterations in autonomic balance are already present in young adults with the MetS, and analysed the association of short-term HRV with the MetS (using the National Cholesterol Education Program definition), in 1889 subjects aged 24-39 years. METHODS: Short-term (3 min) HRV analysis included high-frequency (HF), low-frequency (LF) and total (TP) spectral components of HRV and LF/HF ratio. RESULTS: The presence of the MetS was associated with lower HF, LF and TP in men and women, and with higher LF/HF ratio in women. In men, waist circumference was the strongest individual MetS component that associated with HRV. After adjustments for age and heart rate, MetS was associated with lower HF and higher LF/HF ratio in women, but only with a lower TP in men (all P < 0.05). CONCLUSIONS: MetS is associated with lower HRV in young adults. The individual components of MetS are differentially associated with HRV in men and in women. Our results are consistent with lower vagal activity and a possible increase in sympathetic predominance in women with the MetS. This sex difference in vagal activity and sympathovagal balance may partly explain the greater increase in cardiovascular risk associated with MetS in women than in men.

Intact insulin stimulation of skeletal muscle blood flow, its heterogeneity and redistribution, but not of glucose uptake in non-insulin-dependent diabetes mellitus.

We tested the hypothesis that defects in insulin stimulation of skeletal muscle blood flow, flow dispersion, and coupling between flow and glucose uptake contribute to insulin resistance of glucose uptake in non-insulin-dependent diabetes mellitus (NIDDM). We used positron emission tomography combined with [15O]H2O and [18F]-2-deoxy--glucose and a Bayesian iterative reconstruction algorithm to quantitate mean muscle blood flow, flow heterogeneity, and their relationship to glucose uptake under normoglycemic hyperinsulinemic conditions in 10 men with NIDDM (HbA1c 8.1+/-0.5%, age 43+/-2 yr, BMI 27.3+/-0.7 kg/m2) and in 7 matched normal men. In patients with NIDDM, rates of whole body (35+/-3 vs. 44+/-3 micromol/kg body weight.min, P < 0.05) and femoral muscle (71+/-6 vs. 96+/-7 micromol/kg muscle.min, P < 0.02) glucose uptake were significantly decreased. Insulin increased mean muscle blood flow similarly in both groups, from 1.9+/-0.3 to 2.8+/-0.4 ml/100 g muscle.min in the patients with NIDDM, P < 0.01, and from 2.3+/-0.3 to 3.0+/-0.3 ml/100 g muscle.min in the normal subjects, P < 0.02. Pixel-by-pixel analysis of flow images revealed marked spatial heterogeneity of blood flow. In both groups, insulin increased absolute but not relative dispersion of flow, and insulin-stimulated but not basal blood flow colocalized with glucose uptake. These data provide the first evidence for physiological flow heterogeneity in human skeletal muscle, and demonstrate that insulin increases absolute but not relative dispersion of flow. Furthermore, insulin redirects flow to areas where it stimulates glucose uptake. In patients with NIDDM, these novel actions of insulin are intact, implying that muscle insulin resistance can be attributed to impaired cellular glucose uptake.

Evaluation of serum zonulin for use as an early predictor for gestational diabetes.

Diet has an important role in regulating intestinal permeability and subsequently the risk for metabolic disorders. In this observational study, we examined whether serum intestinal permeability marker zonulin, could be used as a predictor for gestational diabetes mellitus (GDM). Serum zonulin concentration was measured in early pregnancy in overweight or obese pregnant women (n=88) at risk for developing GDM. Serum zonulin was associated with higher odds of GDM (adjusted OR for 1 ng ml-1 increase in zonulin: 1.08, 95% CI: 1.02-1.15; P=0.009), diagnosed by a 2-h 75-g oral glucose tolerance test at late pregnancy. The optimal cutoff value was 43.3 ng ml-1, with sensitivity of 88% (95% CI: 71-100%) and specificity of 47% (95% CI: 33-58%). The area under the ROC-curve was 0.67 (95% CI: 0.54-0.81). Our results show an association between increased early-pregnancy serum zonulin concentration and GDM, suggesting zonulin as a possible predictor for GDM.

Longitudinal trends in consumption of vegetables and fruit in Finnish children in an atherosclerosis prevention study (STRIP).

OBJECTIVE: To assess prospectively the consumption of fruit and vegetables and its' correlation to the parental consumption in boys and girls taking part in an atherosclerosis prevention study (Special Turku Coronary Risk Factor Intervention Project for Children (STRIP) study). HYPOTHESIS: Nutrition counselling focused on cardiovascular health effects vegetable and fruit consumption. DESIGN: A prospective, randomised, clinical trial. SUBJECTS: Children were recruited to the STRIP study between 1989 and 1992. At the age of 7 months, children were randomised to the intervention (n = 540) or the control group (n = 522) and were followed up until the age of 11 years. INTERVENTION: Families in the intervention group have, since randomisation, received biannual individualised dietary counselling aimed at reduction of cardiovascular risk factors, especially saturated fat intake. Food records were used to assess fruit and vegetable consumption of children and parents. RESULTS: The percentage of total energy intake provided by fruit and vegetables decreased when the children grew older (P for age <0.001). The 1- to 10-year-old intervention boys consumed more vegetables (mean difference 3.18 g/day; CI 1.48-4.86; P < 0.001) and fruit (mean difference 10.1 g/day; CI 5.28-14.94; P < 0.001) than did the control. Mother's consumption correlated with the consumption of their daughters and sons, whereas father's consumption correlated only with the consumption of their sons. CONCLUSIONS: Finnish children taking part in the atherosclerosis prevention study had a remarkably low fruit and vegetable consumption, which furthermore decreased with age. The children's consumption correlated with the parental consumption, except between boys and mothers. A slight intervention effect was present only among boys.

Prospective, randomized, infancy-onset trial of the effects of a low-saturated-fat, low-cholesterol diet on serum lipids and lipoproteins before school age: The Special Turku Coronary Risk Factor Intervention Project (STRIP).

BACKGROUND: We showed previously that repeated dietary counseling during the first 3 years of life reduces the concentration of serum nonfasting cholesterol. We have now extended the study to children 5 years of age and analyzed fasting blood samples, enabling LDL cholesterol calculations for the first time. METHODS AND RESULTS: Families of 7-month-old infants (n=1062) were randomized to a control group (n=522) or an intervention group (n=540) that received individualized dietary counseling with the aims of a fat intake of 30% to 35% of daily energy, a saturated/monounsaturated/polyunsaturated fatty acid ratio of 1:1:1, and a cholesterol intake of <200 mg/d. Nutrient intakes were studied biannually, nonfasting serum lipid values were studied annually, and fasting values were studied at 5 years of age. The intervention children always had lower intakes of saturated fat and cholesterol than the control children. The intervention boys had 0.39 mmol/L (P:<0.0001) lower mean serum cholesterol values than the control boys between 13 and 60 months of age, but among girls, the difference was of marginal significance (0.15 mmol/L, P:=0.052). Five-year-old intervention boys had 9% lower mean serum LDL cholesterol concentrations than the control boys (P:=0.0002; 95% CI, -0.39 to -0.12 mmol/L), whereas no difference was observed in girls. In both sexes, serum triglyceride concentrations were similar in the 2 groups. CONCLUSIONS: The restriction of saturated fat and cholesterol intake by repeated, individualized dietary counseling since infancy resulted in lower serum total and LDL cholesterol concentrations at 5 years of age. However, the effect was significant only in boys.

Increased aortic intima-media thickness: a marker of preclinical atherosclerosis in high-risk children.

BACKGROUND: Autopsy studies in children have shown that atherosclerotic lesions begin to develop first in the intima of the aorta. Recent developments in ultrasound techniques have made it possible to visualize the intima-medial thickness of the abdominal aorta directly (aIMT). Therefore, we examined the feasibility of measuring aIMT in children and studied its value in distinguishing high-risk children from healthy controls compared with a more established marker of subclinical atherosclerosis, the common carotid artery intima-medial thickness (cIMT). METHODS AND RESULTS: IMTs were measured using high-resolution (13 MHz) ultrasound in 88 children (aged 11+/-2 years); 16 had hypercholesterolemia (LDL cholesterol, 5.1+/-1.2 mmol/L), 44 had type 1 diabetes (mean duration, 4.4+/-3.1 years; LDL cholesterol, 2.3+/-0.7 mmol/L), and 28 were healthy (controls; LDL cholesterol, 2.5+/-0.8 mmol/L). High-risk children had significantly increased aIMTs and cIMTs (both P<0.001) compared with controls. In controls, aIMT was similar to cIMT (P=NS), but aIMT was higher than cIMT in the children with hypercholesterolemia and diabetes (both P<0.01). Both markers showed excellent and approximately equal between-observer (<4%) and between-subject variation (<5%). CONCLUSIONS: Children with hypercholesterolemia and diabetes show increased IMTs compared with healthy controls, with a relatively greater increase in the aIMT than in the cIMT. Because atherosclerosis begins first in the intima of the aorta, these data suggest that the aIMT might provide the best currently available noninvasive marker of preclinical atherosclerosis in children.

The relation of proinsulin, insulin, and proinsulin-to-insulin ratio to insulin sensitivity and acute insulin response in normoglycemic subjects.

Plasma levels of proinsulin and its conversion intermediates are elevated in NIDDM patients. Recent studies have suggested that proinsulin levels are also increased relative to insulin levels in subjects who subsequently develop NIDDM. This may be due to insulin resistance or a defect in proinsulin processing or insulin secretion. If insulin resistance is the trigger, the proinsulin-to-insulin ratio would be higher in insulin-resistant subjects than in insulin-sensitive subjects. We examined the association of fasting proinsulin, 32,33 split proinsulin, and the proinsulin-to-insulin ratio with insulin sensitivity (SI), estimated by a frequently sampled intravenous glucose tolerance test and the minimal model in 138 normoglycemic subjects ages 53-61 years. We also investigated the relation of proinsulins and the proinsulin-to-insulin ratio to acute insulin response (AIR). Fasting specific insulin (r = -0.64), intact proinsulin (r = -0.43), and 32,33 split proinsulin (r = -0.54) concentrations were inversely correlated and the proinsulin-to-insulin ratio positively (r = 0.31) correlated with SI (P < 0.001). Fasting specific insulin (r = 0.64), intact proinsulin (r = 0.35), and 32,33 split proinsulin (r = 0.45) concentrations were positively correlated and proinsulin-to-insulin ratio (r = -0.40) inversely correlated with AIR (P < 0.001). The proinsulin-to-insulin ratio increased by increasing levels of SI (quartiles of SI from low to high: 0.048, 0.078, 0.078, 0.068; P = 0.012) and decreased by increasing AIR (quartiles of AIR from low to high: 0.088, 0.068, 0.058, 0.058; P = 0.005). These associations were independent of age, sex, BMI, and waist-to-hip ratio. Furthermore, the relation between the proinsulin-to-insulin ratio and AIR was independent of SI. In conclusion, in normoglycemic subjects, insulin resistance (low SI) was associated with a low rather than a high proinsulin-to-insulin ratio. Subjects who maintained normoglycemia with a low AIR had an increased proinsulin-to-insulin ratio compared with those who needed high AIR to maintain normoglycemia. These results suggest that, in subjects with normal glucose tolerance, insulin resistance does not induce increased proinsulin relative to insulin secretion, but rather is associated with enhanced processing of proinsulin.

Dyslipidemia and hyperglycemia predict coronary heart disease events in middle-aged patients with NIDDM.

Patients with NIDDM are at increased risk for coronary heart disease (CHD). However, information on the predictive value of cardiovascular risk factors and the degree of hyperglycemia with respect to the risk for CHD in diabetic patients is still limited. Therefore, we carried out a prospective study on risk factors for CHD, including a large number of NIDDM patients. At baseline, risk factor levels of CHD were determined in 1,059 NIDDM patients (581 men and 478 women), aged from 45 to 64 years. These patients were followed up to 7 years with respect to CHD events. Altogether, 158 NIDDM patients (97 men [16.7%] and 61 women [12.8%]) died of CHD and 256 NIDDM patients (156 men [26.8%] and 100 women [20.9%]) had a serious CHD event (death from CHD or nonfatal myocardial infarction). A previous history of myocardial infarction, low HDL cholesterol level (<1.0 mmol/l), high non-HDL cholesterol (> or =5.2 mmol/l), high total triglyceride level (>2.3 mmol/l), and high fasting plasma glucose (>13.4 mmol/l) were associated with a twofold increase in the risk of CHD mortality or morbidity, independently of other cardiovascular risk factors. High calculated LDL cholesterol level (> or =4.1 mmol/l) was significantly associated with all CHD events. The simultaneous presence of high fasting glucose (>13.4 mmol/l) with low HDL cholesterol, low HDL-to-total cholesterol ratio, or high total triglycerides further increased the risk for CHD events up to threefold. Our 7-year follow-up study provides evidence that dyslipidemia and poor glycemic control predict CHD mortality and morbidity in patients with NIDDM.

Resistance to exercise-induced increase in glucose uptake during hyperinsulinemia in insulin-resistant skeletal muscle of patients with type 1 diabetes.

Insulin and exercise have been shown to activate glucose transport at least in part via different signaling pathways. However, it is unknown whether insulin resistance is associated with a defect in the ability of an acute bout of exercise to enhance muscle glucose uptake in vivo. We compared the abilities of insulin and isometric exercise to stimulate muscle blood flow and glucose uptake in 12 men with type 1 diabetes (age 24 +/- 1 years, BMI 23.0 +/- 0.4 kg/m(2)) and in 11 age- and weight-matched nondiabetic men (age 25 +/- 1 years, BMI 22.3 +/- 0.6 kg/m(2)) during euglycemic hyperinsulinemia (1 mU. kg(-1). min(-1) insulin infusion for 150 min). One-legged exercise was performed at an intensity of 10% of maximal isometric force for 105 min (range 45-150). Rates of muscle blood flow, oxygen consumption, and glucose uptake were quantitated simultaneously in both legs using [(15)O]water, [(15)O]oxygen, [(18)F]-2-fluoro-2-deoxy-D-glucose, and positron emission tomography. Resting rates of oxygen consumption were similar during hyperinsulinemia between the groups (2.4 +/- 0.3 vs. 2.0 +/- 0.5 ml. kg(-1) muscle. min(-1); normal subjects versus patients with type 1 diabetes, NS), and exercise increased oxygen consumption similarly in both groups (25.3 +/- 4.3 vs. 20.1 +/- 3.0 ml. kg(-1) muscle. min(-1), respectively, NS). Rates of insulin-stimulated muscle blood flow and the increments in muscle blood flow induced by exercise were also similar in normal subjects (129 +/- 14 ml. kg(-1). min(-1)) and in patients with type 1 diabetes (115 +/- 12 ml. kg(-1). min(-1)). The patients with type 1 diabetes exhibited resistance to both insulin stimulation of glucose uptake (34 +/- 6 vs. 76 +/- 9 micromol. kg(-1) muscle. min(-1), P < 0.001) and also to the exercise-induced increment in glucose uptake (82 +/- 15 vs. 162 +/- 29 micromol. kg(-1) muscle. min(-1), P < 0.05). We conclude that the ability of exercise to increase insulin-stimulated glucose uptake in vivo is blunted in patients with insulin-resistant type 1 diabetes compared with normal subjects. This could be caused by either separate or common defects in exercise- and insulin-stimulated pathways.

Coronary flow reserve is reduced in young men with IDDM.

Disturbances of coronary circulation have been reported in diabetic patients with microvascular complications but without obstructive coronary atherosclerosis. The aim of the present study was to investigate coronary flow reserve in young adult patients with IDDM but without microalbuminuria and diabetic autonomic neuropathy. Coronary flow reserve was determined in 12 nonsmoking male patients with IDDM (age 30.0 +/- 6.6 years) and 12 healthy matched volunteers. Groups were similar with respect to blood pressure and serum lipid concentrations, and no subject had a positive family history of coronary heart disease. The patients with IDDM had normal exercise echocardiography and autonomic nervous function tests. Five patients had minimal background retinopathy, and none had microalbuminuria. Positron emission tomography and [15O]H2O were used to measure myocardial blood flow at rest and after dipyridamole administration. The studies were performed during euglycemic hyperinsulinemia (serum insulin approximately 70 mU/l). The baseline myocardial blood flow was similar in patients with IDDM and in control subjects (0.84 +/- 0.18 vs. 0.88 +/- 0.25 ml x g(-1) x min(-1), NS). The myocardial blood flow during hyperemia was 29% lower in patients with IDDM (3.17 +/- 1.57) compared with the control subjects (4.45 +/- 1.37 ml x g(-1) x min(-1), P < 0.05). Consequently, coronary flow reserve (the ratio of flow during hyperemia and at rest) was lower in diabetic patients than in control subjects (3.76 +/- 1.69 vs. 5.31 +/- 1.86, P < 0.05) and the total coronary resistance during hyperemia was higher in diabetic patients (53.7 +/- 31.5) compared with the control subjects (31.4 +/- 11.6 mmHg x min x g x ml(-1), P < 0.05). The coronary flow reserve was similar in diabetic patients with and without mild background retinopathy. No association was found between the coronary flow reserve and serum lipid or HbA1c values in either group. Coronary flow reserve is impaired in young adult males with IDDM and no or minimal microvascular complications and without any evidence of coronary heart disease. This abnormality cannot be explained by standard coronary heart disease risk factors. The results imply early impairment of coronary vascular reactivity in IDDM patients, which may represent an early precursor of future coronary heart disease or may contribute to the pathogenesis of diabetic cardiomyopathy.

Coronary flow reserve is impaired in young men with familial hypercholesterolemia.

OBJECTIVES: We sought to investigate whether functional abnormalities in coronary vasomotion exist in young adults by studying 15 men (age 31 +/- 8 years [mean +/- SD]) with familial hypercholesterolemia (FH) and a matched group of 20 healthy control subjects. BACKGROUND: Precursors of morphologic coronary artery disease are known to be present in adolescents and young adults with a high risk factor profile. METHODS: Myocardial blood flow was measured at the basal state and during dipyridamole-induced hyperemia using positron emission tomography and oxygen-15-labeled water. RESULTS: Serum total and low density lipoprotein cholesterol concentrations were higher in the patients than in the control subjects (mean +/- SD): 7.7 +/- 1.9 versus 5.3 +/- 1.5 mmol/liter (298 +/- 73 vs. 205 +/- 58 mg/dl) and 6.1 +/- 1.8 versus 3.5 +/- 1.4 mmol/liter (236 +/- 70 vs. 135 +/- 54 mg/dl), respectively (both p < 0.001). The baseline myocardial blood flow was similar in the patients and control subjects: 0.92 +/- 0.24 versus 0.83 +/- 0.13 ml/g per min, respectively (p = 0.21). A significant increase in flow was observed in both groups after dipyridamole infusion, but the flow at maximal vasodilation was 29% lower in the patients: 3.19 +/- 1.59 versus 4.49 +/- 1.27 ml/g per min (p = 0.011). Consequently, coronary flow reserve (the ratio of hyperemia flow to basal flow) was 35% lower in the patients than in the control subjects: 3.5 +/- 1.6 versus 5.4 +/- 1.5 (p = 0.0008). Total coronary resistance during hyperemia was higher in the patients than in the control subjects: 36 +/- 25 versus 21 +/- 10 mm Hg/min per g per ml (p = 0.045). Coronary flow reserve was inversely associated with serum total cholesterol concentration: r = -0.43 (p = 0.009). CONCLUSIONS: Coronary flow reserve is reduced in young men with FH, and, consequently, coronary resistance during hyperemia is increased. The results demonstrate very early impairment of coronary vasomotion in hypercholesterolemic patients.

Population-based twin study of the effects of migration from Finland to Sweden on endothelial function and intima-media thickness.

Finnish men have higher coronary heart disease (CHD) mortality than Swedish men do. To assess the impact of migration to a country with lower CHD mortality on subclinical atherosclerosis, we measured early functional and structural atherosclerotic vascular changes in twins discordant for migration from Finland to Sweden. Conventional CHD risk factors, flow-mediated dilatation (FMD) of the brachial artery, carotid intima-media thickness, and carotid artery compliance were measured in 74 male twin pairs (20 monozygous, 54 dizygous), aged 42 to 69 years, in which co-one twin had migrated more than 20 years ago permanently to Sweden. There were no significant differences in CHD risk factors except for diastolic blood pressure and body fat percentage, which were higher in Sweden. In all subjects, mean FMD was non-significantly higher in Sweden (5.7+/-4.3% vs 4.9+/-4.2%, P=0.22), but in monozygous twins the difference in FMD was highly significant (7.2+/-4.4 vs 3.7+/-2.9%, P=0.003). There was no significant difference in intima-media thickness or carotid artery compliance between Sweden and Finland. We conclude that in Finnish monozygous twins the endothelial function is better among the twins that have migrated to a country with lower CHD prevalence.

Prevalence of isthmic lumbar spondylolisthesis in nondiabetic subjects and NIDDM patients.

OBJECTIVE: To compare the prevalence of lumbar spondylolytic spondylolisthesis (LSS) in nondiabetic and diabetic subjects. RESEARCH DESIGN AND METHODS: A cross-sectional study of 1,147 randomly selected nondiabetic subjects and 892 non-insulin-dependent diabetes mellitus (NIDDM) patients, 45-64 years of age. LSS was diagnosed radiographically using a lateral view of the lumbosacral spine. RESULTS: No significant difference was seen in the prevalence of LSS between nondiabetic (6.0%) and diabetic (5.7%) subjects. LSS was more frequent in nondiabetic men (7.7%) than in nondiabetic women (4.6%; P = 0.026), whereas diabetic patients showed no significant sex difference in the prevalence of LSS (men 5.6% and women 5.9%). CONCLUSIONS: NIDDM does not predispose one to lumbar spondylolisthesis. However, diabetes seems to abolish the sex difference in the prevalence of LSS observed in nondiabetic populations.

Combined effect of exercise and ambient temperature on insulin absorption and postprandial glycemia in type I patients.

We studied the combined effect of cool (10 degrees C) and warm (30 degrees C) ambient temperatures and physical exercise on insulin absorption and postprandial glycemia. Nine type I (insulin-dependent) diabetic patients were injected subcutaneously with their usual morning dose of short- and intermediate-acting human insulin and were given breakfast. Warm temperature was associated with 3- to 5-fold higher insulin absorption (P less than .01) and significantly lower blood glucose concentration (P less than .001) than cool temperature regardless of exercise. Exercise was associated with 28% (P less than .01) and 22% (P less than .05) increases in plasma insulin and maximally 5.7 mM (P less than .025) and 7.1 mM (P less than .01) lower blood glucose at cool and warm temperatures, respectively. Warm temperature and exercise had an additive effect in stimulating insulin absorption and in lowering blood glucose concentrations. However, there was no evidence of synergism between higher temperature and exercise in increasing free-insulin concentrations or decreasing blood glucose concentrations. To avoid postprandial hyperglycemia at cool temperature or hypoglycemia after exercise at warm temperature, appropriate adjustments in diet and insulin dose, or both, should be made.