Hexokinase II (HKII) is the predominant hexokinase isozyme expressed in insulin-responsive tissues. Since defects involving glucose transport and/or its phosphorylation to glucose-6-phosphate are present in muscle of insulin-resistant humans, HKII should be viewed as a candidate gene for inherited insulin resistance and susceptibility to non-insulin-dependent diabetes mellitus (NIDDM). To investigate the prevalence of potential mutations in the gene encoding HKII, we used the polymerase chain reaction (PCR) to amplify each of the 18 exons of the HKII gene from genomic DNA derived from 59 subjects: 25 insulin-resistant probands with clinical features of the type A syndrome and 34 NIDDM subjects enrolled in the United Kingdom Prospective Study of Therapies of NIDDM (UKPDS) who represented the highest percentile of fasting hyperinsulinemia in the UKPDS population of 5,098 subjects. PCR products corresponding to individual HKII exons derived from each subject were screened for the presence of nucleotide variation using a sensitive nonradioactive single-strand conformation polymorphism (SSCP) protocol. Variant SSCP patterns indicative of genetic variation were detected only in PCR amplimers containing exons 4-7, 10, 15, and 17. Direct sequencing of amplified DNA from individuals affected with variant SSCP patterns revealed the presence of the following silent polymorphisms: Asp251 (GAT/C) in exon 7 and Asn692 (AAT/C) in exon 15. SSCP variants detected in PCR products containing exons 5, 10, and 17 were due to single base substitutions in flanking intronic sequences. A polymorphic GGA repeat was identified within intron 5.(ABSTRACT TRUNCATED AT 250 WORDS)

Hexokinase (HK) II plays an important role in intracellular glucose metabolism by catalyzing the conversion of glucose to glucose-6-phosphate. HKII is considered to be a promising candidate gene for non-insulin-dependent diabetes mellitus (NIDDM) and insulin resistance. Therefore, we investigated the frequency of variants in the coding region of the HKII gene in patients with NIDDM. Initial screening included a population-based sample of 40 Finnish patients with typical NIDDM, and subsequent screening included an additional 72 patients with NIDDM. By applying single-strand conformation polymorphism analysis and direct sequencing, the following amino acid substitutions were found among the 112 NIDDM patients: Ala314Val in one patient (0.9%), Arg353Cys in three patients (2.7%), and Arg775Gln substitution in three patients (2.7%). We also screened 97 subjects with completely normal glucose tolerance and a negative family history of diabetes for these mutations. The Ala314Val and the Arg353Cys substitutions were not found in control subjects, but the Arg775Gln substitution was found in two (2.1%) control subjects. None of these mutations were located close to the glucose- and ATP-binding sites of HKII. We conclude that mutations of the HKII gene are not a major etiological factor for NIDDM in the Finnish population.

Insulin-dependent diabetes mellitus (IDDM) results from a T-cell-mediated destruction of the insulin-producing beta-cells. In this study, we designed a sensitive assay to detect and identify islet cell-reactive T-cells in patients with newly diagnosed IDDM. The relation between T-cell recognition of beta-cell antigens with IDDM and the pathogenesis of the disease (the beta-cell destruction process) was tested in a large group of IDDM patients and compared with T-cell responses in nondiabetic children with other chronic inflammations and in immunologically normal, age-matched control subjects. The results demonstrate that peripheral blood T-cells reacting with a beta-cell membrane preparation enriched for insulin-secretory granule antigen were detectable in the majority of newly diagnosed IDDM patients (27 of 40 [67%]; mean stimulation index [SI] 37.0). Such reactivity was reduced postonset in IDDM patients proportionally to the duration of the disease (11 of 30 [37%]; mean SI 8.7). Nondiabetic age-matched control subjects showed no responses or moderate responses to the granule preparation (4 of 48 [8%]; mean SI 3.4). The magnitude of the T-cell response was significantly greater in newly diagnosed IDDM patients than in IDDM patients tested at least 2 years postonset (P < 0.001). Two children in remission for insulin dependency (so-called honeymoon period) displayed exceptionally high proliferative responses to insulin-secretory granules (mean SI 86.7). These results imply that T-cell recognition of insulin-secretory granule antigens is associated with IDDM and in particular with the immune-mediated process of beta-cell destruction.

Recent studies suggest that insulin-dependent diabetes mellitus patients switched from animal to human insulin may have decreased awareness of hypoglycemic warning symptoms. The risk of severe or fatal hypoglycemia associated with the treatment of diabetes increases with age. We conducted these studies to determine if awareness of hypoglycemic warning symptoms was greater with animal than with human insulin in elderly patients with diabetes. Nonobese elderly patients with non-insulin-dependent diabetes mellitus (NIDDM) (n = 13; age, 74 +/- 1 years; body mass index, 26.6 +/- 0.7 kg/m2) underwent paired hyperinsulinemic glucose clamp studies (insulin infusion rate 60 mU.m-2.min) in random order. In one study, regular human insulin was infused, and in the other study, regular beef/pork insulin was infused. In all studies, plasma glucose was decreased from fasting levels to 5 mmol/l during the first 60 min and was then allowed to fall to 4.4, 3.8, 3.3, and 2.8 mmol/l in each subsequent hour. Subjects were blinded as to which study they were undergoing. In each study, a hypoglycemic symptom checklist was administered, and counterregulatory hormones were measured every 15 min. Neuropsychological tests were performed every hour. Counterregulatory hormone responses to the two insulin preparations were similar. Autonomic (P < 0.05) and neuroglycopenic (P < 0.01) symptom scores were significantly higher during the beef/pork insulin studies. The responses on the neuropsychological tests were not significantly different. We conclude that beef/pork insulin results in greater awareness of hypoglycemic warning symptoms than does human insulin in elderly patients with NIDDM.

In patients with non-insulin-dependent diabetes mellitus (NIDDM), a decreased effect of insulin in stimulating leg blood flow (LBF) has been reported. We reinvestigated the effect of insulin on LBF and validated our data by use of other measures. Eight healthy men (control group) and seven men with NIDDM were studied (age 59 +/- 1 and 58 +/- 3 years, weight 83 +/- 3 and 86 +/- 6 kg, fat-free mass 66 +/- 1 and 64 +/- 3 kg, respectively [mean +/- SE, all P > 0.05]; body mass index 26 +/- 1 and 29 +/- 1 kg/m2, fasting plasma insulin 72 +/- 7 and 187 +/- 22 pmol/l, fasting plasma glucose 5.8 +/- 0.2 and 10.2 +/- 1.7 mmol/l [all P < 0.05]). A three-step hyperinsulinemic glucose clamp (ambient glucose level) was performed, combined with catheterization of an artery and both femoral veins. Expiratory air was collected, LBF was measured by thermodilution, and blood was sampled and analyzed for oxygen content. Insulin concentration was increased to 416 +/- 22 and 509 +/- 43 (step I), 1,170 +/- 79 and 1,299 +/- 122 (step II), and 15,936 +/- 1,126 and 16,524 +/- 1,916 (step III) pmol/l in control and NIDDM subjects, respectively (P > 0.05). LBF increased similarly (P > 0.05) in the two groups (from 287 +/- 23 and 302 +/- 12 [basal] to 308 +/- 31 and 362 +/- 9 [I], 371 +/- 29 and 409 +/- 17 [II], and 434 +/- 32 and 472 +/- 29 [III] ml.min-1.leg-1 in control and NIDDM subjects, respectively).(ABSTRACT TRUNCATED AT 250 WORDS)

Bedtime insulin (BI)/daytime sulfonylurea (DSU) therapy was studied double-blind in 30 non-insulin-dependent diabetes mellitus subjects in whom sulfonylurea (SU) therapy had failed. Subjects were switched to glipizide for 2 months (phase I) to confirm failure (fasting plasma glucose [FPG] 12.0 +/- 0.4 mmol/l) and then randomly assigned into three groups: BI-DSU; BI-no DSU; and DSU-no BI. During phase II (3 months), the BI dose was fixed (20 U/1.73 m2, low-dose). In phase III (3 months), BI was titrated up (high-dose) to achieve good control or until hypoglycemic symptoms prevented further dose increases. In phase IV (6 months), 25 of the 30 original subjects received open-labeled, high-dose BI-DSU. Low-dose BI-DSU markedly reduced FPG (13.6 +/- 0.8 to 8.0 +/- 0.6 mmol/l, P < 0.001), mean 24-h glucose (P < 0.001), HbA1c (8.9 +/- 0.7 to 7.6 +/- 0.3%, P = 0.07), and basal hepatic glucose production (HGP) (P < 0.005). A positive correlation (r = 0.69, P < 0.05) between the declines in FPG and HGP was observed. Neither low-dose BI alone nor DSU alone reduced FPG, mean 24-h glucose, HbA1c, or basal HGP. High-dose (40 +/- 5 U/day) BI plus DSU further reduced the FPG (6.3 +/- 0.6 mmol/l), HbA1c (7.1 +/- 0.3%), mean 24-h plasma glucose, and basal HGP (all P < 0.05 vs. phase II).(ABSTRACT TRUNCATED AT 250 WORDS)

Until now, several endothelium-dependent hemostatic parameters have been proposed as markers of vascular endothelial dysfunction in diabetes. We studied tissue factor pathway inhibitor (TFPI) activity in insulin-dependent diabetes mellitus (IDDM) patients without macro-or microvascular complications, before and after intravenous administration of heparin, in comparison with age-matched control subjects. We also examined the effect of acute hyperglycemia on TFPI activity in healthy men. A clotting and a chromogenic assay were used for determining TFPI activity. In the clotting assay, the COOH-terminus of TFPI is essential, but in the chromogenic assay, it is of minor importance. When the chromogenic assay was used, TFPI activity before heparin injection was significantly higher in the IDDM patients (92 +/- 24 vs. 112 +/- 23%, P < 0.01). The postheparin increase in TFPI activity, measured with both assays, was significantly higher in the diabetic subjects (area under the curve: clotting assay 64 +/- 14 vs. 81 +/- 24, P < 0.05; chromogenic assay 82 +/- 26 vs. 121 +/- 35, P < 0.0001). A positive correlation between TFPI activity and glycated hemoglobin was demonstrated. Acute hyperglycemia did not alter TFPI activity. It can be concluded that TFPI activity, especially after stimulation with heparin, is affected by chronic hyperglycemia in diabetic subjects without vascular complications. Alterations in TFPI activity may therefore reflect early endothelial dysfunction.

Plasminogen activator inhibitor 1 (PAI-1) activity is increased in patients with non-insulin-dependent diabetes mellitus (NIDDM) and may contribute to their excess risk of cardiovascular disease. We examined the determinants of PAI-1 activity in 146 NIDDM subjects by using specific assays of insulin and intact and des-31,32-proinsulin and measures of insulin resistance, relating these measurements to serum lipids, hypoglycemic therapy, and a common 4G/5G polymorphism in the promoter region of the PAI-1 gene. Subjects were treated with insulin, sulfonylurea, sulfonylurea plus metformin, metformin, and diet alone. In the whole group, PAI-1 activity correlated significantly with serum triglycerides (r = 0.39, P < 0.001), specific insulin (r = 0.29, P < 0.001), intact proinsulin (r = 0.24, P = 0.004), and des-31,32-proinsulin (r = 0.30, P < 0.001) and in subjects not on insulin (n = 110), with insulin sensitivity (r = -0.42, P < 0.001). There was a significant difference in PAI-1 activity among the three genotypic groups (P = 0.016); subjects with the genotype 4G/4G had PAI-1 levels one-third higher than those with the 5G/5G genotype. In the 4G/4G group, PAI-1 activity correlated significantly with triglyceride levels (r = 0.65, P < 0.0001). There was no significant difference in PAI-1 activity in the different treatment groups despite a significant difference in concentrations of intact and des-31,32-proinsulin. In a multiple regression model, insulin sensitivity and the interaction between PAI-1 4G/5G genotype and triglyceride were the strongest determinants of PAI-1 activity.(ABSTRACT TRUNCATED AT 250 WORDS)

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)