Good insulin sensitivity is independently associated with a low risk for coronary heart disease, but it is unclear whether this risk factor differs between men and women. We compared insulin sensitivity of glucose uptake directly in muscle and heart tissues between healthy women (age 29 +/- 2 years, body mass index [BMI] 22 +/- 1 kg/m2, VO2max 39 +/- 4 ml.kg-1.min-1) and men matched for age (31 +/- 2 years), BMI (23 +/- 1 kg/m2), and VO2max (44 +/- 3 ml.kg-1.min-1) using [18F]fluoro-2-deoxy-D-glucose and positron emission tomography under hyperinsulinemic (insulin infusion rate 1 mU.kg-1.min-1) normoglycemic conditions. Whole body insulin sensitivity was 41% greater in women (52 +/- 6 mumol.kg body wt-1.min-1) than in men (37 +/- 3 mumol.kg body wt-1.min-1, P < 0.05). This difference was explained by a 47% greater rate of glucose uptake by femoral muscles (113 +/- 10 vs. 77 +/- 7 mumol.kg muscle-1.min-1, women vs. men, P < 0.01). Insulin-stimulated glucose uptake rates in the heart were similar in women (738 +/- 58) and men (749 +/- 62 mumol.kg muscle-1.min-1). Femoral muscle insulin sensitivity was closely correlated with whole body insulin sensitivity (r = 0.84, P < 0.001). Gender and VO2max together explained 68% of the variation in femoral muscle glucose uptake. We conclude that women are more sensitive to insulin than equally fit men because of enhanced muscle but not heart insulin sensitivity.

There is evidence that the renin-angiotensin system may be involved in the metabolic as well as the cardiovascular features of diabetes and that pressor doses of angiotensin II (ANG II) increase insulin sensitivity in parallel with blood pressure (BP) in healthy subjects, but the effects of ANG II on insulin sensitivity have not been previously reported in patients with non-insulin-dependent diabetes mellitus (NIDDM). In a randomized, double-blind, placebo-controlled, crossover study, 11 patients with NIDDM attended 3 study days to evaluate the effects of a 3-h infusion of subpressor and pressor doses of ANG II on whole body insulin sensitivity using the euglycemic hyperinsulinemic clamp. BP and heart rate were recorded, and blood samples were collected for serum insulin, C-peptide, potassium, catecholamines, plasma renin activity, and plasma ANG II concentrations. Plasma levels of ANG II (means +/- SD) were 9 +/- 4, 29 +/- 9, and 168 +/- 47 pmol/ml after placebo, low dose infusion, and high dose infusion, respectively. The higher dose of ANG II was associated with significant increases in BP (e.g., 18 mmHg systolic BP at 150 min) and plasma aldosterone. Whole body insulin sensitivity was 23.8 +/- 12.7 mumol glucose.kg-1.min-1 after placebo and 30.6 +/- 12.7 and 27.2 +/- 13.3 following low and high dose ANG II infusions, respectively (P < 0.05, analysis of variance). In summary, acute infusion of ANG II, with or without an increase in BP, increases insulin sensitivity in normotensive patients with NIDDM.(ABSTRACT TRUNCATED AT 250 WORDS)

This study investigated the neurobehavioral effects of mild and moderate hypoglycemia in adults with insulin-dependent diabetes mellitus (IDDM). On 2 consecutive days, 26 subjects were tested in a counterbalanced, randomized, single-blind, crossover design. On the experimental day, subjects performed tests at 6.4, 3.6, and 2.6 mmol/l and again after glycemic recovery to 6.3 mmol/l. On the control day, subjects performed tests four times at euglycemia. Three months after testing, 15 subjects repeated the experimental day protocol. Results demonstrated that both mild and moderate hypoglycemia significantly disrupted performance. However, performance deterioration varied substantially across individual subjects. Men exhibited significantly more deterioration than women at mild hypoglycemia, and subjects with a history of unconsciousness due to hypoglycemia exhibited more deterioration than subjects with no such history. Individual deterioration scores during repeat testing significantly correlated with performance during original testing. Recovery from hypoglycemia-related impairment varied across individuals and was correlated with degree of impairment during hypoglycemia. These results suggest that the glycemic threshold for onset and recovery from neurobehavioral deterioration with hypoglycemia, as well as degree of impairment experienced, varies across individuals. Furthermore, these individual differences are stable across time.

To determine the repeatability of insulin sensitivity measurements generated by the minimal model, we subjected 11 normal men to 3 frequently sampled intravenous glucose tolerance tests (FSIGTs) over the course of 12 days under conditions of fixed diet and limited physical activity. FSIGTs were analyzed by the minimal model using a full, 30-sample data set, as well as a reduced, 12-sample data set that has been proposed for population studies. Minimal model insulin sensitivity index (SI) calculated from the 30-sample data set averaged 0.8 +/- 0.083 x 10(-4) min-1.(pmol/l)-1 (range 0.10-1.64 x 10(-4) min-1.(pmol/l)-1 with an average interday coefficient of variation (CV) of 20.2 +/- 3.2% (range 6-44%). Glucose effectiveness (SG) was slightly less repeatable, with an average interday variability of 25.1 +/- 8.8%. The mean CVs for first-phase insulin secretion (20.1 +/- 3.5%) and total insulin secretion (21.4 +/- 3.2%) were similar to the CV for SI. Mean insulin sensitivity calculated from the 12-sample data set (0.82 +/- 0.08 x 10(-4) min-1.(pmol/l)-1 was not significantly different from the mean calculated from the full data set (P = 0.37, paired Student's t test). However, the mean CV of SI calculated from the reduced data set tended to be greater than that calculated from the full data set (27.7 +/- 5.4% vs. 20.2 +/- 3.2%).(ABSTRACT TRUNCATED AT 250 WORDS)

The brain usually depends almost exclusively on glucose for its energy requirements. During hypoglycemia associated with prolonged fasting or strenuous exercise, circulating ketone-body and lactate levels increase several-fold; in both situations, certain signs and symptoms of hypoglycemia are diminished. Therefore, to test the hypothesis that hyperketonemia or hyperlacticacidemia of the magnitude seen during certain clinical situations can substitute for glucose as an energy source for the brain and alter physiological responses to hypoglycemia, we assessed autonomic and neuroglycopenic symptoms, counterregulatory hormone responses, and cognitive function during standardized insulin-induced hypoglycemia in normal volunteers with and without infusion of beta-hydroxybutyrate (BOHB) or lactate designed to reproduce circulating levels of these substrates seen during prolonged fasting and strenuous exercise. Compared with paired control experiments, infusion of BOHB and lactate increased the glycemic threshold (required greater hypoglycemia for initiation) and reduced the magnitude of autonomic and neuroglycopenic symptoms, counterregulatory hormone responses, and cognitive dysfunction (all P < 0.05). The hypoglycemic threshold for autonomic symptoms increased from 3.8 +/- 0.1 to 3.1 +/- 0.2 mmol/l during BOHB infusion and from 3.7 +/- 0.1 to 2.8 +/- 0.1 mmol/l during lactate infusion, and the threshold for neuroglycopenic symptoms increased from 2.8 +/- 0.1 to 2.4 +/- 0.1 and 2.3 +/- 0.1 mmol/l, respectively. The magnitude for autonomic symptoms decreased from 12 +/- 2 and 11 +/- 1 to 6 +/- 2 and 4 +/- 1 during BOHB and lactate infusion, respectively. Neuroglycopenic synptoms decreased from 11 +/- 2 to 3 +/- 1 during both series of experiments.(ABSTRACT TRUNCATED AT 250 WORDS)

We have investigated whether glutamic acid decarboxylase (GAD) autoantibodies (GAD65 Ab) were affected by cyclosporin therapy and were related to subsequent non-insulin-requiring remission and loss of glucagon-stimulated C-peptide response in 132 recent-onset insulin-dependent diabetes mellitus (IDDM) patients treated with cyclosporin or placebo for 12 months. GAD65 Ab were detected in a quantitative radioligand assay using as tracer recombinant, in vitro translated, human islet [35S]methionine-labeled GAD65. GAD65 Ab were found at onset in 66% (87 of 132) of IDDM patients and in 1% (1 of 100) of healthy control subjects. The prevalence of GAD65 Ab and median GAD65 Ab levels did not change in serum samples taken 3, 6, 9, and 12 months after study entry in either the cyclosporin- or the placebo-treated groups. The presence or absence of GAD65 Ab at study entry did not predict non-insulin-requiring remission in either cyclosporin- or placebo-treated patients. However, the relative (compared with 0 months) glucagon-stimulated C-peptide response was more than 30% lower in GAD65 Ab+ patients receiving placebo at 9 and 12 months compared with the GAD65 Ab- placebo patients (P < 0.035). Islet cell cytoplasmic antibody (ICA) and GAD65 Ab+ placebo-treated patients showed no significant differences in stimulated C-peptide levels compared with those who were ICA- and GAD65 Ab+, suggesting that ICA was not independently associated with loss of beta-cell function.(ABSTRACT TRUNCATED AT 250 WORDS)

Apart from islet cell antibodies (ICAs), antibodies to glutamate decarboxylase (GAD), insulin autoantibodies (IAAs), and a novel islet antigen (37k antigen) are potential markers for insulin-dependent diabetes mellitus (IDDM). GAD is also an antigen in stiff-man syndrome (SMS), and both SMS and IDDM are associated with ICAs and autoimmunity to other endocrine organs. We investigated possible links between antibody responses to islet antigens with autoimmunity to other endocrine organs and determined which specific antibodies can identify individuals who progress to IDDM. Antibodies to GAD were detected in > or = 90% of both diabetic and nondiabetic patients with ICAs and other endocrine autoimmunity, in 59% of ICA-positive IDDM patients without endocrine autoimmunity, in all patients with SMS, but in only 1-3% of healthy (nondiabetic) and autoimmune disease control subjects. GAD antibody levels were increased in ICA-positive IDDM patients with polyendocrine autoimmunity compared with those without. In contrast, antibodies to 37k antigen were only detected in patients who developed acute-onset IDDM. IAAs were also associated with IDDM. Thus, certain factors enhance antibody responses to GAD in polyendocrine autoimmunity, but this does not necessarily lead to development of IDDM or SMS. Antibodies to 37k antigen are strongly associated with acute-onset IDDM and are useful serological markers for disease.

To describe the development in blood pressure (BP) in relation to urinary albumin excretion (UAE) more exactly, 44 initially normoalbuminuric type I diabetic patients and 21 healthy individuals were included in a 3.1-year follow-up study by using ambulatory BP (AMBP) monitoring. Six patients developed microalbuminuria according to accepted criteria (progressors; UAE at follow-up was > 20 micrograms/min). Initial UAE was higher in this group (9.0 x/divided by 1.4 micrograms/min) compared with both the nonprogressors (5.2 x/divided by 1.6 micrograms/min) and the control subjects (3.9 x/divided by 1.6 micrograms/min), P < 0.01. The values were almost identical for initial 24-h AMBP between the progressors and the two other groups. The transition to microalbuminuria (31.7 x/divided by 1.8 micrograms/min) was associated with an increase in 24-h systolic AMBP of 11.5 +/- 8.3 mmHg, which was significantly higher than the increase in the nonprogressors (3.1 +/- 7.7 mmHg) and the control subjects (2.2 +/- 6.1 mmHg, P = 0.02). Significant correlations were detected between development in UAE and development in systolic and diastolic 24-h AMBP (r = 0.39, r = 0.41, P < 0.01). In addition, an increase in UAE, even including increases within the normoalbuminuric range, was always associated with an increase in 24-h AMBP (P < 0.01). Ordinary clinical measurements did not reveal any of these differences or correlations. In conclusion, a close association between increases in UAE and 24-h AMBP emerges in this study. Initial BP was not increased in the progressors.(ABSTRACT TRUNCATED AT 250 WORDS)

In this study, we demonstrate that levels of glutamic acid decarboxylase (GAD) autoantibodies (GAAs) by radioassay differ between relatives with GAD-absorbable and GAD-nonabsorbable islet cell antibodies (ICAs). Extremely high levels of GAAs are often found in relatives with GAD-absorbable ICAs (> 1,800 cpm, > 9 SD above normal control subjects; mean = 1,991 cpm), and lower levels (mean = 1,078 cpm) of GAAs were present in relatives with nonabsorbable ICAs (P < 10(-5). The serum levels of GAAs were remarkably constant for relatives of both groups over time. The levels of GAAs were found to be inversely related to both the levels of insulin autoantibodies and the rate of loss of intravenous glucose-stimulated insulin secretion (P < 10(-5) and P < 0.01, respectively). Relatives with low positive levels of GAAs had more rapid loss of insulin secretion and were at high risk to become diabetic (50% diabetic at 4 years) compared with relatives with higher levels (1,800 cpm) of GAAs (10% diabetic at 4 years; P < 0.05). These data suggest that high levels of GAAs are associated with a decreased risk of progression to type I diabetes and extend the hypothesis that distinct subsets of ICAs and GAAs with differing prognostic significance can be identified.

To clarify the event that is involved in the pathogenesis of impaired glucose tolerance (IGT), we studied 15 individuals with IGT and 15 subjects with normal tolerance using the minimal model approach. Our IGT subjects were characterized by normal insulin secretory responses to oral glucose and mild impairments in insulin sensitivity (SI) and glucose effectiveness (SG) at basal and zero insulin. Next, we classified our IGT subjects into two subpopulations: one with normal insulin sensitivity (SI: 0.92 +/- 0.11 x 10(-4) min-1.pmol/l-1 and the other with insulin resistance (SI:0.31 +/- 0.06 x 10(-4)min-1.pmol/l-1, P < 0.05). The populations did not differ with respect to body mass index and fasting plasma glucose level. Basal plasma insulin level was higher in the insulin-resistant group (84.8 +/- 23.3 pmol/l) than in the insulin-sensitive group (48.7 +/- 6.8 pmol/l), but the difference was not statistically significant. The absolute insulin secretory responses to oral glucose were significantly higher in the resistant group (83,205 +/- 17,787 pmol/l x min) than in the sensitive group (24,727 +/- 3,591 pmol/l x min, P < 0.01), whose absolute responses were similar to those of normal control subjects (24,576 +/- 2,767 pmol/l x min). No significant difference was observed in SG between the resistant (0.016 +/- 0.002 min-1) and sensitive (0.013 +/- 0.002 min-1, P > 0.05) type of IGT, but SG was significantly type of IGT, but SG was significantly decreased in both groups compared with normal control subjects (0.023 +/- 0.002 min-1, P < 0.05-0.01).(ABSTRACT TRUNCATED AT 250 WORDS)

The hemodynamic hypothesis suggests that raised capillary pressure may play a role in the pathogenesis of diabetic microangiopathy. Although patients with non-insulin-dependent diabetes mellitus (NIDDM) and insulin-dependent diabetes NIDDM) develop a similar range of microvascular complications, differences in their expression and prevalence suggest that different pathogenic mechanisms may be operational. Capillary pressure is elevated in IDDM; the aim of this study was to assess whether capillary pressure was also elevated in NIDDM. Twenty-one patients with NIDDM (15 men) and 21 healthy control subjects matched for age, sex, and skin temperature were investigated supine with the hand at heart level. Finger nailfold capillary pressure was measured after direct cannulation at the summit of the capillary loops using glass micropipettes. The groups were matched for skin temperature (30.4 [24.2-33.8] degrees C, median [95% confidence interval], NIDDM patients vs. 30.0 [23.4-33.6] degrees C control subjects), age (62.0 [39.4-72.7] years NIDDM patients vs. 62.0 [39.4-72.0] years control subjects), and both systolic (sBP) and diastolic (dBP) blood pressures (133.0 [111.0-167.3]/78.0 [57.0-89.5] mmHg NIDDM patients vs. 133.0 [114.1-158.9]/80.0 [68.2-88.9] mmHg control subjects). Capillary pressure did not differ in the two groups (17.6 [13.1-21.2] mmHg NIDDM patients vs. 19.1 [14.1-23.6] mmHg control subjects [NS]). There was no correlation of capillary pressure with either HbA1c or glucose; however, there was a negative association between capillary pressure and diabetes duration (Rs = -0.50, P = 0.020).(ABSTRACT TRUNCATED AT 250 WORDS)

Diabetic nephropathy is characterized by hypertension and a relentless decline in kidney function. Angiotensin-converting enzyme inhibitors have been claimed to preserve kidney function better than an equal blood pressure (BP) reduction with conventional antihypertensive treatment (renoprotection). We compared the effect on kidney function of lisinopril (10-20 mg/day) and atenolol (50-100 mg/day) in hypertensive NIDDM patients (mean age 60 +/- 8 years) with diabetic nephropathy. Forty-three (21 lisinopril and 22 atenolol) patients were enrolled in a 1-year randomized double-blind parallel study. Eight patients dropped out, and the results for the remaining 35 patients (16 lisinopril and 19 atenolol) are presented. Diuretics were required in 10 of 16 lisinopril patients and 12 of 19 atenolol patients. The following variables were measured: 24-hour ambulatory BP (Takeda TM2420), albuminuria (enzyme-linked immunosorbent assay), fractional albumin clearance, and glomerular filtration rate (GFR) ([51Cr]EDTA technique). The average reduction in mean arterial BP during the 12 months was identical in the two groups 12 +/- 2 vs. 11 +/- 1 mmHg in the lisinopril and atenolol group, respectively. Albuminuria was on average reduced 45% in the lisinopril group vs. 12% in the atenolol group (P < 0.01), and fractional albumin clearance was on average reduced 49% in the lisinopril group vs. 1% in the atenolol group (P < 0.05). GFR declined identically in the two groups 11.7 +/- 2.3 vs. 11.6 +/- 2.3 ml.min-1.year-1 in the lisinopril and atenolol groups, respectively.(ABSTRACT TRUNCATED AT 250 WORDS)

To establish the antihyperglycemic mechanisms of metformin in non-insulin-dependent diabetes mellitus (NIDDM) independently of the long-term, aspecific effects of removal of glucotoxicity, 21 NIDDM subjects (14 obese, 7 nonobese) were studied on two separate occasions, with an isoglycemic (plasma glucose approximately 9 mM) hyperinsulinemic (two-step insulin infusion, 2 h each, at the rate of 4 and 40 mU.m-2.min-1) clamp combined with [3-3H]glucose infusion and indirect calorimetry, after administration of either metformin (500 mg per os, at -5 and -1 h before the clamp) or placebo. Compared with placebo, hepatic glucose production (HGP) decreased approximately 30% more after metformin (from 469 +/- 50 to 330 +/- 54 mumol/min), but glucose uptake did not increase. Metformin suppressed free fatty acids (FFAs) by approximately 17% (from 0.42 +/- 0.04 to 0.35 +/- 0.04 mM) and lipid oxidation by approximately 25% (from 4.5 +/- 0.4 to 3.4 +/- 0.4 mumol.kg-1.min-1) and increased glucose oxidation by approximately 16% (from 16.2 +/- 1.4 to 19.3 +/- 1.3 mumol.kg-1.min-1) compared with placebo (P < 0.05), but did not affect nonoxidative glucose metabolism, protein oxidation, or total energy expenditure. Suppression of FFA and lipid oxidation after metformin correlated with suppression of HGP (r = 0.70 and r = 0.51, P < 0.001). The effects of metformin in obese and nonobese subjects were no different. We conclude that the specific, antihyperglycemic effects of metformin in the clinical condition of hyperglycemia in NIDDM are primarily due to suppression of HGP, not stimulation of glucose uptake, and are mediated, at least in part, by suppression of FFA and lipid oxidation.

The effect of hyperglycemia on in vivo adipose tissue metabolism was studied with microdialysis in seven lean patients with insulin-dependent diabetes mellitus (IDDM) receiving a constant infusion of insulin (36 pmol.m-2.min-1). Glucose was infused in a randomized fashion to maintain either a lower glucose level (6.6 +/- 0.3 mM, mean +/- SE) or hyperglycemia (11.8 +/- 0.8 mM) for 3 h. For insulin concentrations of 84 +/- 12 and 96 +/- 12 pM, hyperglycemia (11.8 +/- 0.8 mM) did not alter the plasma glycerol or lactate levels significantly but resulted in a significant (P < 0.0001) increase in plasma free fatty acid levels (0.49 +/- 0.13 vs. 0.32 +/- 0.08 mM). Plasma catecholamine levels were unchanged during hyperglycemia. Interstitial glycerol concentrations, measured in abdominal subcutaneous adipose tissue as an index of lipolysis, were not significantly influenced by hyperglycemia when compared with concentrations at the lower glucose level (92 +/- 30 vs. 106 +/- 18 microM). Moreover, hyperglycemia did not change abdominal adipose interstitial lactate levels significantly (1,248 +/- 174 vs. 1,351 +/- 159 microM during euglycemia). It may be concluded that hyperglycemia has no independent antilipolytic effect in IDDM subjects. Furthermore, in these patients, hyperglycemia gives no further lactate production in the subcutaneous adipose tissue in the presence of low physiological insulin levels.

Systemic insulin passes the blood-brain barrier and insulin receptors have been detected in various brain regions. Yet, the biological significance of insulin acting on the brain remains rather unclear. Reports of different awareness of hypoglycemic symptoms during hypoglycemia induced by human insulin (HI) and porcine insulin (PI) suggest a modulatory influence of insulin on sensory processing. In a double-blind, within-subject, crossover comparison, we recorded visual-evoked potentials (VEP) in 30 healthy men during euglycemia and after 20 or 50 min of constant hypoglycemia of 2.66 mM (47.9 mg/dl) induced by HI and PI. Blood glucose and serum insulin levels were identical in both sessions. Hypoglycemia reduced amplitudes of the VEP components P1 and N2 and increased latencies of N1, P1, and N2. However, hypoglycemia-induced changes in VEP amplitudes and latencies were significantly stronger during PI and HI infusion: P1-N2 difference amplitude decreased from (mean +/- SE) 11.9 +/- 0.9 to 10.7 +/- 0.8 muV during HI and from 12.4 +/- 0.9 to 8.7 +/- 0.7 muV during PI infusion (P < 0.002). P1 latency increased from 112.0 +/- 3.2 to 118.8 +/- 3.2 ms during HI and from 114.0 +/- 3.3 to 126.3 +/- 4.6 ms during PI infusion (P < 0.05). Differences between the effects of the insulins were consistently apparent after 20 min of hypoglycemia, which indicates a short-term action of the hormone. The results add to those of a foregoing study demonstrating differential effects of HI- and PI-induced hypoglycemia on auditory evoked potentials.(ABSTRACT TRUNCATED AT 250 WORDS)

Altogether, 102 patients were randomized to intensified conventional treatment (ICT) (n = 48) or standard treatment (ST) (n = 54). After 7.5 years, 89 patients remained, and it was shown that microangiopathy was retarded by the lower blood glucose concentrations seen in the patients in the ICT group. HbA1c was reduced from (means +/- SE) 9.5 +/- 0.2% to 7.1 +/- 0.1% in the ICT group and from 9.4 +/- 0.2% to 8.5 +/- 0.1% in the ST group (P < 0.001). Of the patients, 4 in the ICT group and 3 in the ST group died. Mortality was predicted by albuminuria, the amplitude of the sural nerve action potential, and the test of arm blood flow during contraction of the contralateral hand (sympathetic nerve function) at baseline (P < 0.05). Weight increased by 4.4 +/- 1.1 kg in the ICT group and 1.8 +/- 0.7 kg in the ST group (P = 0.05). Atherosclerosis, measured with digital pulse plethysmography, was approximately the same in the groups at baseline and after five years. In each group, 3 patients had myocardial infarctions, and 2 from each group had ketoacidosis once. There was a mean of 1.1 episodes per patient and per year of serious hypoglycemia in the ICT group and 0.4 episodes per patient and per year in the ST group. No adverse incidents or accidents were observed in either group, and there were no differences between the groups with regard to cognitive function measured with a battery of tests.(ABSTRACT TRUNCATED AT 250 WORDS)

We determined whether overnight inhibition of lipolysis by a long-acting nicotinic acid derivative (acipimox) decreases gluconeogenesis from lactate in NIDDM patients. For this purpose, 250 mg of acipimox or placebo was administered in a double-blind crossover study at 2400, 0400, and 0800 to 8 NIDDM patients (54 +/- 4 yr of age, body mass index 29.5 +/- 1.3 kg/m2, fasting plasma glucose 11 +/- 1 mM). The next morning, total hepatic glucose production (glucose Ra) and gluconeogenesis from lactate were determined using primed, continuous infusions of [3-3H]glucose and [U-14C]acetate. Glucose and lipid oxidation rates were measured using indirect calorimetry. Mean overnight serum free fatty acid concentrations averaged 242 +/- 8 microM after acipimox and 721 +/- 30 microM after placebo (P < 0.001). Inhibition of lipolysis decreased lipid oxidation from 33 +/- 3 to 22 +/- 2 J.kg-1 x min-1 (P < 0.001) and increased carbohydrate oxidation from 15 +/- 3 to 23 +/- 2 mumol.kg-1.min-1 (P < 0.005). Gluconeogenesis from lactate decreased by approximately 40%, from 6.2 +/- 0.6 to 3.8 +/- 0.5 mumol.kg-1 x min-1 (P < 0.005); lactate oxidation increased from 5.6 +/- 0.8 to 7.9 +/- 1.1 mumol.kg-1 x min-1 (P < 0.005), with no change in plasma lactate concentrations or total lactate Rd. Fasting plasma glucose concentrations were comparable at 2400 (10.0 +/- 1.1 vs. 10.6 +/- 1.3 mM, acipimox vs. placebo) and between 0900 and 1000 (10.6 +/- 1.3 and 11.3 +/- 1.3 mM, respectively). Also, total glucose production rates remained unchanged (14.0 +/- 1.2 vs. 14.9 +/- 1.3 mol.kg-1 x min-1, respectively).(ABSTRACT TRUNCATED AT 250 WORDS)

Postoperative diabetes is a reported feature of the immunosuppressive agents cyclosporin A and FK 506. To date, however, no randomized comparative studies of the metabolic effects of these two drugs have been performed. In this study, extended (300 min) oral glucose tolerance tests (75 g) were performed a median of 8 mo (range 5-9 mo) postoperatively in 20 clinically stable liver transplant recipients randomly allocated to maintenance immunosuppression with either cyclosporin A (with or without azathioprine) or FK 506. None of the patients had clinically overt diabetes antedating transplantation. To avoid the confounding effects of corticosteroids, prednisolone was withdrawn at least 6 wk beforehand in each case. Ten healthy volunteers matched for age and body mass index served as control subjects. Overall blood glucose concentrations after the glucose challenge were significantly elevated in both groups of transplant recipients (P < 0.005 and P < 0.001 for cyclosporin A and FK 506 treatment groups, respectively) compared with the healthy control subjects. Venous whole-blood glucose concentration (mean +/- SE) 120 min after the ingestion of oral glucose was significantly higher in both the cyclosporin A (P < 0.05) and FK 506 (P < 0.01) treatment groups compared with the control subjects (6.6 +/- 0.5 vs. 8.8 +/- 0.9 vs. 5.2 +/- 0.2 mM, respectively). According to 1985 WHO criteria, 4 of 10 cyclosporin A-treated patients had impaired glucose tolerance, whereas 3 of 10 FK 506-treated patients had diabetes with 4 others having impaired glucose tolerance.(ABSTRACT TRUNCATED AT 250 WORDS)

To examine whether overnight suppression of free fatty acid levels reduces hepatic glucose production, 20 NIDDM patients were given a slow-release formulation of the antilipolytic agent acipimox, in a double-blind crossover manner at bedtime for 4 wk. During acipimox treatment, serum free fatty acid concentrations were suppressed between 2400 and 0600 by 64% (P < 0.001), but no reduction in hepatic glucose production was observed (2.16 +/- 0.16 vs. 2.23 +/- 0.16 mg.kg-1 x min-1, acipimox vs. placebo). In contrast, from 0800 to 2000 a sustained 50% rise occurred in serum free fatty acids (P < 0.001). As a consequence, the 24-h area under the free fatty acid curve was similar during both treatment periods. In the morning, the rise in free fatty acid concentration occurred despite identical serum acipimox concentrations as those measured at midnight, when free fatty acid levels were suppressed. Although energy expenditure was higher (P < 0.05) during periods of elevated free fatty acid levels, the sums of energy expenditure measured in the morning and in the evening were similar during the acipimox and placebo periods. To exclude that the free fatty acid rise was caused by administration of acipimox only once at bedtime, additional experiments were performed administering acipimox every 2 h for 4 days. Despite similar acipimox concentration on day 1 and day 4 of this frequent dosing regimen, the free fatty acid concentrations were significantly higher on day 4 compared with day 1 (P < 0.01).(ABSTRACT TRUNCATED AT 250 WORDS)

Diabetes mellitus has been associated with both elevated plasma concentrations of the natriuretic and vasorelaxant hormone atrial natriuretic factor and with a reduced natriuretic response to this hormone. We now hypothesize that the vasodilator response to atrial natriuretic factor is attenuated in IDDM. Forearm vasodilator responses to the infusion of six increasing dosages of atrial natriuretic factor into the brachial artery were registered by venous occlusion strain gauge plethysmography in 10 patients with uncomplicated IDDM and in 10 age-, sex-, and weight-matched control subjects. Baseline levels of blood pressure, forearm blood flow, and plasma concentrations of atrial natriuretic factor were not different between control subjects and patients with diabetes. In control subjects, atrial natriuretic factor induced a percentage fall in the forearm vascular resistance of -29 +/- 5% at the lowest to -72 +/- 4% at the highest infusion rate. In patients with diabetes this fall was significantly attenuated, measuring -2 +/- 7 and -45 +/- 4%, respectively, (P < 0.001 vs. control subjects). During infusion of atrial natriuretic factor into the brachial artery, the calculated regional production of cGMP (second messenger of atrial natriuretic factor) increased from 1.2 +/- 1.1 to 22.8 +/- 4.8 pmol.min-1 x 100 ml-1 in the control subjects, whereas hardly any change occurred in the patients with diabetes (from -2.1 +/- 1.2 to 2.9 +/- 4.7 pmol.min-1 x 100 ml-1). Furthermore, both control and diabetic subjects demonstrated an equal forearm vasodilator response to increasing infusion rates of the control vasodilator sodium nitroprusside. We conclude that uncomplicated IDDM is associated with a specific reduction in the vascular responsiveness to atrial natriuretic factor.(ABSTRACT TRUNCATED AT 250 WORDS)