Hyperglycaemia is associated with changes in the regional concentrations of glucose and myo-inositol within the brain.

AIMS/HYPOTHESIS: The aim of the study was to assess the effect of hyperglycaemia on regional concentrations of glucose and other substrates within the brain in non-diabetic individuals and in patients with type 1 diabetes. METHODS: The brain metabolites of 17 men with type 1 diabetes and 12 age-matched non-diabetic men (22-43 years old) were studied after an overnight fast (plasma glucose 9.2 +/- 3.0 vs 4.8 +/- 0.5 mmol/l, respectively). N-Acetylaspartate (NAA), creatine, choline, myo-inositol (mI) and glucose in the frontal cortex, frontal white matter and thalamus were quantified with proton magnetic resonance spectroscopy. RESULTS: In the non-diabetic participants, the glucose level was 47% higher (p < 0.01) in the frontal cortex than in the frontal white matter. In contrast, this regional variation was not observed in the diabetic participants, in whom the glucose level in the frontal white matter was 64% higher (p < 0.001) and in the frontal cortex 25% higher (p = 0.033) than that of the non-diabetic participants. In the diabetic participants, the glucose level in each of the three regions studied correlated with fasting plasma glucose (r = 0.88-0.67, p < 0.01). In addition, in the diabetic participants, mI was 20% higher (p < 0.001) and NAA 6% lower (p = 0.037) in the frontal white matter, and mI was 8% higher (p = 0.042) in the frontal cortex, than in the non-diabetic participants. CONCLUSIONS/INTERPRETATION: In type 1 diabetes, hyperglycaemia is associated with accumulation of glucose and mI in the cortex and in the white matter.

Family histories of Type II diabetes and hypertension predict intima-media thickness in patients with Type I diabetes.

AIMS/HYPOTHESIS: Hyperglycaemia predicts microvascular complications but data on macrovascular disease are limited. We searched for predictors of carotid artery intima-media thickness in young adults with Type I (insulin-dependent) diabetes mellitus. METHODS: A total of 71 children (F/M = 34/37) were followed after their diagnosis until they reached 32 +/- 1 years of age, when duration of diabetes averaged 22 +/- 1 years. Cardiovascular risk markers [lipids, blood pressure, smoking, urinary albumin excretion rate, lifetime glycaemic exposure (A(1c) months), exercise habits, alcohol consumption, family history] were evaluated at age 21 +/- 1 for the baseline examination and at age 32 +/- 1 years for the follow-up examination years. During follow-up, intima-media thickness of common and internal carotid arteries and the carotid bulb were quantitated using a high-resolution B-mode ultrasound. RESULTS: In univariate analysis, age, BMI, blood pressure, lifetime glycaemic exposure, a positive family history of Type II (non-insulin-dependent) diabetes mellitus, hypertension and cardiovascular disease were predictors of carotid intima-media thickness. In multivariate analysis, a positive family history of Type II diabetes predicted maximal ( p< 0.05) and common ( p< 0.005) carotid artery intima-media thickness, family history of hypertension predicted increases in maximal ( p< 0.04), and far wall ( p< 0.006) carotid artery intima-media thickness, and lifetime glycaemic exposure was an independent predictor of increased carotid bulb thickness ( p< 0.03). CONCLUSION/INTERPRETATION: Positive family histories of Type II diabetes and hypertension are independent predictors of carotid intima-media thickness in patients with Type I diabetes, and could therefore predispose these patients to atherosclerosis

In vivo glucose-stimulated amylin secretion is increased in nondiabetic patients with pancreatic cancer.

The incidence of diabetes is increased in patients with pancreatic cancer, but the mechanisms underlying this association are not clear. Alterations in beta-cell function, such as formation of amyloid from excessive production of amylin and reduced expression of GLUT2, have been suggested to be possible mechanisms. We compared in vivo secretory responses of amylin and insulin (n = 37) and expression of GLUT2 in pancreata (n = 10) obtained at surgery between diabetic and nondiabetic patients with and without pancreatic tumors. Fourteen had pancreatic adenocarcinoma, 7 had diabetes (duration 6 +/- 3 years) and a pancreatic tumor, 8 had type 2 diabetes (duration 6 +/- 2 years), and 8 were normal subjects. First (0 to 10 minutes) and second (10 to 120 minutes) phase insulin and amylin secretion were characterized using the hyperglycemic clamp technique. Both amylin and insulin concentrations followed a biphasic pattern in nondiabetic subjects. In nondiabetic patients with pancreatic cancer, total, as well as nonglycosylated amylin concentrations, were increased compared with nondiabetic subjects without pancreatic cancer. Both first- and second-phase plasma amylin and serum immunoreactive insulin concentrations were low in all patients with diabetes, ie, both in type 2 diabetes and in those patients with diabetes and pancreatic tumors. At surgery, specimens were obtained for characterization of GLUT2 expression in beta cells, which was unaltered in nondiabetic (n = 7) and diabetic (n = 3) patients. Amyloid staining was similarly negative in diabetic and nondiabetic pancreata independent of pancreatic carcinoma. In conclusion, plasma amylin, but not insulin concentrations, are increased in nondiabetic patients with pancreatic cancer, but low in all patients with diabetes. These data support the potential of using an increase in the ratio of circulating amylin to insulin as a marker for pancreatic cancer in nondiabetic patients.

Predictors of abnormal cardiovascular autonomic function measured by frequence domain analysis of heart rate variability and conventional tests in patients with type 1 diabetes.

OBJECTIVE: Frequency domain analysis of heart rate variability (HRV) is used to assess cardiovascular autonomic function. There are no prospective data on the sensitivity of its various components to glycemia or other diabetes-related risk factors compared with conventional tests and with other complications of diabetes. RESEARCH DESIGN AND METHODS: In 1985, possible risk factors of future complications were determined in 115 children with type 1 diabetes. In 1996, the presence of complications (HRV analysis, conventional tests of autonomic function, urinary albumin excretion rate [UAER], and retinopathy) were assessed in 83 of these patients (age 32 +/- 1 years, duration of diabetes 22 +/- 1 years). RESULTS: Poor glycemic control (measured as lifetime glycemic exposure or HbA1c in 1985) was the most important independent predictor of decreases in all measures of absolute power of HRV (total power [TP] and very low frequency, low frequency [LF], and high frequency [HF] power) and square root of the mean square of R-R interval differences but not of changes of normalized measures or ratios (normalized HF and LF LF/HF). Other significant independent predictors of autonomic dysfunction were late age of onset of diabetes, female sex, and high BMI. To examine the sensitivity of the various tests to glycemia, the patients were divided into tertiles based on lifetime glycemic exposure (A1c months). Glycemic exposure in the tertiles averaged 194 +/- 25 A1c months (20 years of HbA1c 0.8% above normal), 556 +/- 19 A1c months(20 years of HbA1c 2.3% above normal), and 963 +/- 30 A1c months (20 years of HbA1c 4% above normal). Tests of complications that were significantly abnormal in patients already in the lowest tertile and were correlated with glycemia were TP and severity of retinopathy. Of conventional tests, only the ratio of length of R-R intervals during expiration to inspiration (E/I ratio) was significantly related to glycemic exposure, but it required high glycemic exposure (20 years of HbA1c 4% above normal) to be abnormal. UAER was significantly increased only in the highest tertile of glycemic exposure. CONCLUSIONS: TP and retinopathy score were much more sensitive to antecedent glycemia than conventional tests of autonomic function or UAER and were significantly abnormal in patients exposed to approximately 20 years' duration of an HbA1c 0.8% above normal.

Deficiency of total and nonglycosylated amylin in plasma characterizes subjects with impaired glucose tolerance and type 2 diabetes.

This study was undertaken to characterize first and second phase secretory profiles of total and nonglycosylated amylin and insulin and to determine whether excessive glycosylation of amylin or hyperamylinemia is a feature of abnormal glucose tolerance in humans. Plasma concentrations of total and nonglycosylated amylin and serum immunoreactive insulin were measured under identical hyperglycemic conditions using the hyperglycemic clamp technique in subjects with type 2 diabetes, impaired and normal glucose tolerance. Both amylin and insulin concentrations followed a biphasic pattern in subjects with normal and impaired glucose tolerance. In the subjects with normal and impaired glucose tolerance, the second phase amylin concentrations markedly exceeded those of the first phase, whereas the reverse was true for insulin. The first phase concentrations of both peptides were significantly lower in impaired than the normal glucose tolerance subjects. In patients with type 2 diabetes no first phase peak for either amylin or insulin could be identified, and the second phases of both amylin and insulin were significantly lower compared to subjects with normal or impaired glucose tolerance. Nonglycosylated amylin concentrations accounted for 25-45% of total amylin, regardless of glucose tolerance, and mimicked the pattern of total amylin concentrations. In summary: 1) glucose-induced increases in the magnitude of the first and second phase amylin plasma concentrations differed from those of insulin; 2) subjects with impaired glucose tolerance and more strikingly those with type 2 diabetes have impaired amylin responses; and 3) the ratio of nonglycosylated to total amylin is normal irrespective of glucose tolerance. These data imply, in view of many reports describing accumulation of amyloid in the pancreas, that circulating levels of amylin decrease as amyloid deposits accumulate and beta-cell function deteriorates and that the amount of glycosylated amylin in plasma is not increased in patients with type 2 diabetes.

Endothelial dysfunction in men with small LDL particles.

BACKGROUND: It is unknown whether LDL particle size is, independent of other lipids and lipoproteins, associated with endothelial dysfunction in vivo. METHODS AND RESULTS: We determined in vivo endothelial function in 34 healthy men by measuring forearm blood flow responses to intrabrachial artery infusions of acetylcholine (ACh, an endothelium-dependent vasodilator) and sodium nitroprusside (an endothelium-independent vasodilator). LDL peak particle size was measured with gradient gel electrophoresis. Men with small LDL particles (LDL diameter 25. 5 nm, n=24, blood flow 6.9+/-3.6 versus 11.4+/-5.1 mL/dL. min, P=0. 006). The groups had comparable LDL cholesterol concentrations (3. 9+/-0.6 versus 3.7+/-1.0 mmol/L, men with small versus large LDL particles), blood pressure, glucose concentrations, and body mass indexes. LDL size (r=0.45, P=0.01) but not HDL cholesterol (r=0.31, P=0.09) or triglycerides (r=-0.19, P=0.30) was significantly correlated with endothelium-dependent vasodilation. Serum triglyceride concentrations and LDL size were inversely correlated (r=-0.44, P=0.01). In multivariate regression analysis, LDL size was the only significant determinant of the ACh-induced increase in blood flow. Sodium nitroprusside-stimulated endothelium-independent vasodilation was similar in both groups. CONCLUSIONS: Small LDL particles are associated with impaired in vivo endothelial function independent of HDL and LDL cholesterol and triglyceride concentrations. LDL size may therefore mediate adverse effects of hypertriglyceridemia on vascular function.

Direct measurement of the lumped constant for 2-deoxy-[1-(14)C]glucose in vivo in human skeletal muscle.

The lumped constant (LC) is used to convert the clearance rate of 2-deoxy-D-glucose (2-DG(CR)) to that of glucose (Glc(CR)). There are currently no data to validate the widely used assumption of an LC of 1.0 for human skeletal muscle. We determined the LC for 2-deoxy-[1-(14)C]glucose (2-DG) in 18 normal male subjects (age, 29+/- 2 yr; body mass index, 24.8+/-0.8 kg/m(2)) after an overnight fast and during physiological (1 mU x kg(-1) x min(-1) insulin infusion for 180 min) and supraphysiological (5 mU x kg(-1) x min(-1) insulin infusion for 180 min) hyperinsulinemic conditions. Normoglycemia was maintained with the euglycemic clamp technique. The LC was measured directly with the use of a novel triple tracer-based method. [3-(3)H]glucose, 2-[1-(14)C]DG, and [(12)C]mannitol (Man) were injected as a bolus into the brachial artery. The concentrations of [3-(3)H]glucose and 2-[1-(14)C]DG (dpm/ml plasma) and of Man (micromol/l) were determined in 50 blood samples withdrawn from the ipsilateral deep forearm vein over 15 min after the bolus injection. The LC was calculated by a formula involving blood flow calculated from Man and the Glc(CR) and 2-DG(CR). The LC averaged 1.26+/-0.08 (range 1.06-1.43), 1.15+/-0.05 (0.99-1.39), and 1.18+/-0.05 (0.97-1.37) under fasting conditions and during the 1 and 5 mU x kg(-1). min(-1) insulin infusions (not significant between the different insulin concentrations, mean LC = 1.2, P<0.01 vs. 1.0). We conclude that, in normal subjects, the LC for 2-DG in human skeletal muscle is constant over a wide range of insulin concentrations and averages 1. 2.

Insulin-induced decrease in large artery stiffness is impaired in uncomplicated type 1 diabetes mellitus.

Normal insulin action in vivo involves a decrease in stiffness of large arteries (a decrease in aortic pressure augmentation). We determined whether the ability of insulin to decrease arterial stiffness is altered in uncomplicated type 1 diabetes. Nine type 1 diabetic men (age 28+/-2 years, body mass index 24+/-1 kg/m(2)) and 9 matched normal men were studied under normoglycemic hyperinsulinemic (sequential 2-hour insulin infusions of 1 [step 1] and 2 [step 2] mU x kg(-1) x min(-1)) conditions. Central aortic pressure waveforms were synthesized from those recorded in periphery with applanation tonometry on the radial artery and a validated reverse transfer function to construct the central aortic pressure wave every 30 minutes. This allowed the determination of aortic augmentation (the pressure difference between the first and the second systolic peaks) and the augmentation index (augmentation divided by pulse pressure), as the measure of stiffness of large arteries. Whole-body glucose uptake was 44% (step 1) and 37% (step 2) lower (P<0.001) in the diabetic patients than in the normal subjects. At baseline, before the insulin infusion, augmentation averaged 0+/-1 and 2+/-1 mm Hg (NS) and the augmentation index was -1.5+/-4.5% and 4.0+/-3.7% (NS) in the normal and diabetic subjects, respectively. After 1 hour of hyperinsulinemia, the augmentation index had decreased significantly (P<0.01) to -9.5+/-4.8% in the normal subjects but remained at 4.4+/-4.2% in the diabetic patients. A significant decrease was not observed in the diabetic patients until 150 minutes (-1.2+/-4.1%, P<0.05 versus baseline). Whole-body glucose uptake was significantly inversely correlated with the change in the augmentation index during step 1 (r=-0.61, P<0.01). Insulin resistance in type 1 diabetes involves a defect in the ability of insulin to decrease central aortic pressure. This defect could predispose these patients to premature stiffening of large arteries.

Insulin therapy improves endothelial function in type 2 diabetes.

A total of 75 in vivo endothelial function tests (intrabrachial artery infusions of endothelium-dependent [acetylcholine] and -independent [sodium nitroprusside] vasoactive agents) were performed in 18 type 2 diabetic patients (aged 58+/-2 years, body mass index 28.5+/-0.6 kg/m(2), and fasting plasma glucose 229+/-11 mg/dL) and 27 matched normal subjects. These tests were performed before and 6 months after combination therapy with insulin and metformin and before and 6 months after metformin therapy only. Before insulin therapy, blood flow responses to acetylcholine (15 microg/min) were significantly blunted in type 2 diabetic patients (7.5+/-0.7 mL x dL(-1) x min(-1)) compared with normal subjects (11.6+/-0.9 mL x dL(-1) x min(-1), P<0.01). During insulin therapy, the acetylcholine response increased by 44% to 10.8+/-1.6 mL x dL(-1) x min(-1) (P<0.05). Insulin therapy also significantly increased the blood flow responses to both low and high doses of sodium nitroprusside. We conclude that insulin therapy improves endothelium-dependent and -independent vasodilatation. These data support the idea that insulin therapy has beneficial rather than harmful effects on vascular function.

Autoantibodies against oxidized LDL and endothelium-dependent vasodilation in insulin-dependent diabetes mellitus.

We determined whether autoantibodies against oxidized LDL are increased in patients with IDDM, and if so, whether they are associated with endothelial dysfunction in vivo. Autoantibodies against oxidized LDL (ratio of antibodies against oxidized vs. native LDL, oxLDLab) were determined in 38 patients with IDDM (HbA(1c) 8.4+/-0.2%), who were clinically free of macrovascular disease, and 33 healthy normolipidemic subjects (HbA(1c) 5.1+/-0.1%, P<0.001 vs. IDDM). The groups had comparable serum total-, LDL- (2. 9+/-0.1 vs. 2.8+/-0.1 mmol/l, IDDM vs. controls), and HDL-cholesterol concentrations. OxLDLab were 1.5-fold higher in the IDDM patients (1.8+/-0.1) than in the normal subjects (1.2+/-0.1, P<0.001). OxLDLab were correlated with age in normal subjects, but not with age, duration of disease, LDL-cholesterol, HbA(1c) or degree of microvascular complications in patients with IDDM. To determine whether oxLDLab are associated with endothelial dysfunction in vivo, blood flow responses to intrabrachial infusions of acetylcholine, sodium nitroprusside and L-NMMA were determined in 23 of the patients with IDDM (age 33+/-1 years, body mass index 24. 3+/-0.6 kg/m(2), HbA(1c) 8.5+/-0.3%) and in the 33 matched normal males. OxLDLab were 41% increased in IDDM (1.7+/-0.2 vs. 1.2+/-0.1, P<0.01). Within the group of IDDM patients, HbA(1c) but not oxLDLab or LDL-cholesterol, was inversely correlated with the forearm blood flow response to acetylcholine (r=-0.51, P<0.02), an endothelium-dependent vasodilator, but not to sodium nitroprusside (r=0.06, NS). These data demonstrate that oxLDLab concentrations are increased in patients with IDDM, but show that chronic hyperglycemia rather than oxLDLab, is associated with impaired endothelium-dependent vasodilation in these patients.

Intense physical training decreases circulating antioxidants and endothelium-dependent vasodilatation in vivo.

Physical training increases free radical production and consumes antioxidants. It has previously been shown that acute exercise markedly increases the susceptibility of LDL to oxidation but whether such changes are observed during physical training is unknown. We measured circulating antioxidants, lipids and lipoproteins, and blood flow responses to intrabrachial infusions of endothelium-dependent (acetylcholine, ACh, L-N-monomethyl-arginine, L-NMMA) and -independent (sodium nitroprusside, SNP) vasoactive agents, before and after 3 months of running in 9 fit male subjects. Maximal aerobic power increased from 53 +/- 1 to 58 +/- 2 ml/kg min (P < 0.02). All circulating antioxidants (uric acid, SH-groups, alpha-tocopherol, beta-carotene, retinol) except ascorbate decreased significantly during training. Endothelium-dependent vasodilatation in forearm vessels decreased by 32-35% (P < 0.05), as determined from blood flow responses to both a low (10.8 +/- 2.1 vs. 7.3 +/- 1.5 ml/dl min, 0 vs. 3 months) and a high (14.8 +/- 2.6 vs. 9.6 +/- 1.8) ACh dose. The % endothelium-dependent blood flow (% decrease in basal flow by L-NMMA), decreased through training from 37 +/- 3 to 22 +/- 7% (P < 0.05). Blood flow responses to SNP remained unchanged. The decrease in uric acid was significantly correlated with the change in the % decrease in blood flow by L-NMMA (r = 0.74, P < 0.05). The lag time for the susceptibility of plasma LDL to oxidation in vitro, LDL size and the concentration of LDL cholestetol remained unchanged. We conclude that relatively intense aerobic training decreases circulating antioxidant concentrations and impairs endothelial function in forearm vessels.

Effect of weight loss and regional fat distribution on plasma leptin concentration in obese women.

OBJECTIVES: To investigate how circulating leptin concentrations are related to regional fat distribution and whether moderate weight loss alters these relationships. DESIGN: A 6 month, clinical weight reduction trial with measurements before and after weight loss. SUBJECTS: 38 healthy, obese women (age: 44.3+/-9.9 y, BMI: 34.0+/-4.0 kg/m2). MEASUREMENTS: The following measurements were made. 1. indices of obesity and fat distribution: weight, body mass index (BMI), hip circumference (peripheral fat), waist circumference, total body fat (bioelectrical impedance), abdominal fat distribution: visceral fat and abdominal subcutaneous fat (ultrasonography); and 2. Biochemical measurements: plasma leptin and serum insulin. RESULTS: Baseline plasma leptin concentrations were three-fold higher in obese women than in normal weight controls. After weight loss averaging 8.4 kg (9.0%), plasma leptin decreased by a mean of 22.3% (P < 0.001), corresponding to body fat decrease of 16.6% (P < 0.001), abdominal subcutaneous fat decrease of 17.4% (P < 0.001) and visceral fat decrease of 18.7% (P < 0.001). The total amount of body fat correlated with plasma (serum) leptin before (r = 0.64, P < 0.001) and after (r = 0.75, P < 0.001) weight loss. Plasma leptin concentrations expressed per kg of body fat did not change significantly during weight loss. After controlling for body fat, baseline leptin concentrations were significantly associated with hip circumference (r = 0.57, P < 0.001) but not with any indices of abdominal fat distribution. After weight loss the associations became significant for hip and waist circumference as well as for visceral and abdominal subcutaneous fat. Changes in leptin correlated with changes in all indices of obesity except visceral fat. CONCLUSIONS: Plasma leptin concentrations reflect not only total fat mass but also adipose tissue distribution, especially peripheral fat. Plasma leptin values per kilogram of fat mass do not change significantly with modest weight loss.

A marathon run increases the susceptibility of LDL to oxidation in vitro and modifies plasma antioxidants.

Physical activity increases the production of oxygen free radicals, which may consume antioxidants and oxidize low-density lipoprotein (LDL). To determine whether this occurs during strenuous aerobic exercise, we studied 11 well-trained runners who participated in the Helsinki City Marathon. Blood samples were collected before, immediately after, and 4 days after the race to determine its effect on circulating antioxidants and LDL oxidizability in vitro. LDL oxidizability was increased as determined from a reduction in the lag time for formation of conjugated dienes both immediately after (180 +/- 7 vs. 152 +/- 4 min, P < 0.001) and 4 days after (155 +/- 7 min, P < 0.001) the race. No significant changes in lipid-soluble antioxidants in LDL or in the peak LDL particle size were observed after the race. Total peroxyl radical trapping antioxidant capacity of plasma (TRAP) and uric acid concentrations were increased after the race, but, except for TRAP, these changes disappeared within 4 days. Plasma thiol concentrations were reduced after the race. No significant changes were observed in plasma ascorbic acid, alpha-tocopherol, beta-carotene, and retinol concentrations after the marathon race. We conclude that strenuous aerobic exercise increases the susceptibility of LDL to oxidation in vitro for up to 4 days. Although the increase in the concentration of plasma TRAP reflects an increase of plasma antioxidant capacity, it seems insufficient to prevent the increased susceptibility of LDL to oxidation in vitro, which was still observed 4 days after the race.

Impaired endothelium-dependent vasodilation in type 2 diabetes. Relation to LDL size, oxidized LDL, and antioxidants.

OBJECTIVE: To search for determinants of endothelial dysfunction in type 2 diabetes. RESEARCH DESIGN AND METHODS: We performed a comprehensive analysis of cardiovascular risk markers and measured blood flow responses to endothelium-dependent (acetylcholine [ACh] and NG-monomethyl-L-arginine) and -independent (sodium nitroprusside [SNP]) vasoactive agents in 30 nonsmoking men with type 2 diabetes (age 51 +/- 1 years, BMI 27.8 +/- 0.4 kg/m2, HbA1c 7.4 +/- 0.3%) and 12 matched normal control men. RESULTS: ACh-induced vasodilation was 37% lower in type 2 diabetic (6.1 +/- 0.5) than in normal subjects (9.7 +/- 1.5 ml.dl-1.min-1, P < 0.01), while flows during SNP were similar (9.1 +/- 0.6 vs. 9.9 +/- 1.3 ml.dl-1.min-1, NS). The ratio of endothelium-dependent vs. -independent flow (ACh:SNP ratio) was 31% lower in type 2 diabetic (0.70 +/- 0.05) than in normal subjects (1.10 +/- 0.18, P < 0.01). Total (2.2 +/- 0.4 vs. 1.3 +/- 0.2 mmol/l, P < 0.05), VLDL, and intermediate-density lipoprotein triglycerides were significantly higher, and the mean LDL particle diameter was significantly smaller in type 2 diabetic than in normal subjects. The lag times for LDL oxidation by Cu2+ in vitro were similar in patients with type 2 diabetes (183 +/- 7) and in normal subjects (183 +/- 9 min, NS). Measured and calculated (sum of concentration of individual antioxidants in serum) total peroxyl radical-trapping capacities (TRAPs) were comparable between the groups. In the patients with type 2 diabetes, LDL size was significantly correlated with endothelium-dependent vasodilation (r = 0.43, P < 0.05), serum triglycerides (r = -0.75, P < 0.001), and the lag time for LDL oxidation in vitro (r = 0.38, P < 0.05). HbA1c was inversely correlated with the lag time for LDL oxidation in vitro (r = -0.41, P < 0.05) and TRAP. CONCLUSIONS: In summary, patients with type 2 diabetes exhibited impaired endothelium-dependent vasodilation in vivo, elevated serum triglycerides, decreased LDL size, and normal antioxidant capacity. Of these parameters, LDL size was significantly correlated with endothelial function.

Causes of weight gain during insulin therapy with and without metformin in patients with Type II diabetes mellitus.

AIMS/HYPOTHESIS: To determine causes of weight gain during insulin therapy with and without metformin in Type II (non-insulin-dependent) diabetes mellitus. METHODS: Twenty-six patients with Type II diabetes (body mass index 28+/-1 kg/m2) were treated with insulin alone (n = 13) or insulin and with metformin (n = 13). Components of energy balance (basal metabolic rate, energy intake, glucosuria) were measured at 0 and 12 months. RESULTS: Glycaemic control improved similarly in patients using (HbA1c 10.5+/-0.3 vs 7.6+/-0.2%, p<0.001) and not using (10.2+/-0.3 vs 7.8+/-0.3%, p < 0.001) metformin. The metformin group required 47 % less insulin than the group not using metformin (p < 0.001). Body weight increased by 3.8+/-0.8 and 7.5+/-1.6 kg (p < 0.05), respectively. Basal metabolic rate and glucosuria were similar at 0 and 12 months in both groups but the metformin group decreased energy intake by 1.12+/-0.46 MJ/day, whereas it remained unchanged in the other group (0.15+/-0.42 MJ/day). Changes in body weight and glycaemia were statistically significant independent determinants of basal metabolic rate. Their change in opposite directions explained why basal metabolic rate remained unchanged. CONCLUSION/INTERPRETATION: Improved glycaemia promotes weight gain by decreasing both basal metabolic rate and glucosuria. Use of metformin decreases weight gain by reducing energy intake and is therefore a useful adjunct to insulin therapy in patients with Type II diabetes.

Serum total renin, an independent marker of the activity and severity of retinopathy in patients with IDDM.

BACKGROUND/AIMS: Recent studies have demonstrated marked renin and prorenin concentration gradients between ocular tissues and blood, and local expression of the renin-angiotensin system (RAS) in the eye. The authors determined whether serum total renin, which mostly consists of prorenin, is a marker of the activity and severity of diabetic retinopathy independent of other microvascular complications. METHODS: Total renin concentrations (TRC) were measured with a time resolved immunofluorometric assay in 38 patients with IDDM (age 34 (SD 7) years, duration of disease 22 (7) years, serum creatinine 95 (15) mumol/l, urinary albumin excretion rate (UAER) 207 (829) micrograms/min, HbA1c 8.5% (1.2%)), and in 13 matched normal subjects. All subjects were carefully characterised with respect to the presence and severity of retinopathy (RP score), nephropathy, and neuropathy using seven different tests of autonomic neuropathy. RESULTS: Serum TRC was on average twofold higher in IDDM (396 (SE 211) ng/l) than in normal subjects (201 (88) ng/l, p < 0.001). It was nearly twofold higher in patients with preproliferative or active proliferative retinopathy requiring careful follow up or therapy (TRC 596 (268) ng/l, n = 11) compared with those with quiescent proliferative retinopathy after laser treatment (TRC 338 (183) ng/l, p < 0.01, n = 5); moderately severe non-proliferative retinopathy (337 (106) ng/l, p < 0.01, n = 13), no retinopathy, or only minimal non-proliferative retinopathy (270 (43) ng/l, p < 0.001, n = 9). In multiple linear regression analysis, RP score (p < 0.01), but not the UAER or any index of autonomic neuropathy, was an independent determinant of serum TRC, and explained 32% of its variation (R = 0.57, p < 0.005). CONCLUSIONS: Serum TRC in patients with diabetic retinopathy is increased independent of renal function and autonomic neuropathy especially in those with severe active changes requiring careful follow up or treatment. These findings support the idea that diabetic retinopathy is the most important determinant of serum TRC in patients with IDDM, and that TRC is produced when retinopathy is active.

Mechanisms of altered hemodynamic and metabolic responses to insulin in patients with insulin-dependent diabetes mellitus and autonomic dysfunction.

Patients with autonomic neuropathy are more susceptible to insulin-induced hypotension than normal subjects, but the mechanisms are unclear. We quantitated the hemodynamic and metabolic effects of two doses of i.v. insulin (1 and 5 mU/kg.min, 120 min each) and several aspects of autonomic function in 28 patients with insulin-dependent diabetes mellitus (IDDM) and in 7 matched normal subjects under standardized normoglycemic conditions. The autonomic function tests included those predominantly assessing the integrity of vagal heart rate control (the expiration inspiration ratio during deep breathing and high frequency power of heart rate variability) and tests measuring sympathetic nervous function (reflex vasoconstriction to cold and blood pressure responses to standing and handgrip). During hyperinsulinemia, heart rate increased less (2 +/- 1 vs. 6 +/- 2 beats/min; P < 0.04) and diastolic blood pressure fell more (-3.1 +/- 1.2 vs. 0.9 +/- 2.1; P = NS) in the patients with IDDM than in the normal subjects. Forearm vascular resistance decreased significantly in the patients with IDDM [by -7.1 +/- 1.4 mm Hg/(mL/dL.min); P < 0.001 for high vs. low dose insulin], but not in the normal subjects (-0.1 +/- 2.5 mm Hg/(mL/dL.min; P = NS). Reflex vasoconstriction to cold was inversely correlated with the decreases in diastolic (r = -0.51; P < 0.005) and systolic (r = -0.59; P < 0.001) blood pressure and forearm vascular resistance (r = -0.53; P < 0.005), but not with the change in heart rate. The expiration inspiration ratio was, however, directly correlated with the insulin-induced change in heart rate (r = 0.63; P < 0.001), but not with diastolic or systolic blood pressure or forearm vascular resistance. Whole body (48 +/- 2 vs. 67 +/- 5 mumol/kg.min; P < 0.005) and forearm (44 +/- 4 vs. 67 +/- 8 mumol/kg.min; P < 0.05) glucose uptake were significantly lower in the IDDM patients than in the normal subjects. The latter could be attributed to a defect in the forearm glucose arterio-venous difference (1.5 +/- 0.1 vs. 2.2 +/- 0.2 mmol/L, respectively; P < 0.01), but not in blood flow. We conclude that both impaired vagal heart rate control and sympathetic nervous dysfunction exaggerate the hemodynamic effects of insulin in patients with IDDM and could contribute to insulin-induced hypotension.