Study of the rate of early glucose disappearance following insulin injection: insulin sensitivity index

The euglycaemic hyperinsulinaemic glucose clamp is usually considered as the reference technique to evaluate insulin sensitivity. As it is an-expensive and time-consuming tool, we therefore tried to validate a simple insulin tolerance test (ITT) (IV bolus of 0.1 IU/kg of regular insulin, with glucose sampling at −5, 0, 3, 5, 7, 10 and 15 min) and to demonstrate its usefulness. Insulin sensitivity was measured by DG/G0 ratio (G0 = initial glycaemia, DG is the variation between G0 and the glycaemia obtained at 15 min by the calculation of the regression plot). We confirmed the existence of a correlation between the glucose uptake (mg/kg per min) evaluated by glucose clamp and the DG/G0 index (r = 0.9, P < 0.01). There was no stimulation of hormonal counter regulation during the test. The ITT was significantly correlated both with fasting insulin (r = −0.43, P < 0.01), and post-glucose load insulin concentration (r = −0.67, P < 0.01); each measurement expressing insulin sensitivity. Four groups of patients with different insulin sensitivity; controls, NIDDM, gynoid and android obese subjects, were clearly separated by ITT. We showed that fasting glycaemia and DG/G0 were correlated (y = 2.63/x − 0.093; r = 0.82, P < 0.01). These results suggest that ITT could be an easy, quick and low cost method to evaluate insulin resistance in clinical practice and epidemiological studies.     

Adrenoceptor antagonists, but not guanethidine, reduce glucopenia-induced glucagon secretion from perfused rat pancreas

This study was designed to investigate (1) whether norepinephrine is released in response to glucopenia in vitro, thereby stimulating glucagon secretion and, (2) the modulating effects of norepinephrine on insulin and glucagon secretion, using isolated perfused rat pancreas preparations. Simultaneous addition of the adrenergic receptor antagonists yohimbine, prazosin and propranolol, each at a concentration of 10⁻⁵ mol/l, significantly potentiated glucose-stimulated insulin secretion (6.23 ± 0.76 vs. 2.11 ± 0.72 (control) nmol/min, P < 0.01), and suppressed glucopenia-induced glucagon secretion (0.59 ± 0.10 vs. 1.34 ± 0.18 (control) ng/min, P < 0.05). Also, 10⁻⁵ mol/l yohimbine alone significantly potentiated glucose-stimulated insulin secretion (4.86 ± 0.50 nmol/min, P < 0.05). The norepinephrine release inhibitor, guanethidine, significantly inhibited tyramine-induced secretion of both norepinephrine (7.86 ± 0.77 vs. 49.7 ± 2.3 nmol/min, P < 0.01) and glucagon (0.31 ± 0.08 vs. 1.21 ± 0.15 ng/min, P < 0.01), but exerted no effects on glucopenia-induced secretion of either norepinephrine or glucagon. We conclude that these results further support the concept that the neurotransmitter norepinephrine is released in response to glucopenia in vitro, and modulates insulin and glucagon secretion. Our data do not, however, provide evidence indicating that glucopenia-induced glucagon secretion is mainly mediated by activation of sympathetic nerve terminals around the -cells in the isolated perfused rat pancreas.     

Circulating erythropoietin in microalbuminuric type 2 diabetic patients with normal renal function: a pilot study

To verify the hypothesis of an early impairment of erythropoietin (Epo) production and to assess the adequacy of its circulating levels in diabetic nephropathy, we investigated Epo values in 18 microalbuminuric type 2 diabetic patients with normal renal function (7 anaemic and 11 nonanaemic), 24 subjects with uncomplicated iron-deficiency anaemia, and 15 healthy controls comparable for sex and age. Mean±S.D. plasma Epo level was 56.4±12.7 mU/mL in iron-deficient patients and 9.3±2.6 mU/mL in controls. In diabetic groups, mean±S.D. Epo level was 11.38±3.65 mU/mL in nonanaemic and 49.12±6.44 mU/mL in anaemic subjects. No significant difference (P>.05) in Epo values was found between controls and nonanaemic diabetic patients. Anaemic diabetics and iron-deficient subjects had significantly higher values than the nonanaemic groups (P>.001). An inverse significant relation between Epo levels and Hb concentration resulted in both anaemic diabetics (r=−.44, P>.05) and iron-deficient patients (r=−.61, P=.001). Analysis of covariance (P>.05) and comparison of the two regression lines (t=0.4, df=29, P>.05) did not show any significant difference between diabetic patients with anaemia and iron-deficient patients. These results suggest that normochromic anaemia observed in microalbuminuric diabetic patients with normal renal function is not due to Epo deficiency, and circulating levels of this hormone are suitably increased with regard to Hb concentration.     

In vivo and in vitro studies of GAD-antibody positive subjects with Type 2 diabetes: A distinct sub-phenotype

The purpose of this study was to determine if immune mechanisms in GAD positive patients’ contribute to the pathogenesis of a specific sub-type of Type 2 diabetes. GAD positive (n = 8) and GAD negative (n = 8) subjects diagnosed with Type 2 diabetes were matched for age, gender, body mass index, duration of diabetes and glycaemic control. All subjects underwent an insulin-modified frequently sampled intravenous glucose tolerance test to measure insulin sensitivity and insulin secretory function with minimal model analysis. In addition, BRIN-BD11 clonal β-cells were supplemented with patients’ sera to determine basal and alanine-stimulated insulin secretion and terminal complement complex (TCC) formation. Both groups were severely insulin resistant (0.56 ± 0.17 vs. 0.99 ± 0.33 10⁻⁴ min⁻¹/(μU ml⁻¹) for GADneg and GADpos, respectively) but the GAD negative subjects had a higher basal (87 ± 11 vs. 58 ± 14 pmol l⁻¹, p < 0.05) and glucose-stimulated insulin secretion (ΔAUCins 0.96 ± 0.12 vs. 0.60 ± 0.12 pmol/(l⁻¹ min), p < 0.05). In vivo measures of insulin secretion were negatively correlated with TCC formation, independent of antibody status. In conclusion, GAD positive subjects initially diagnosed with Type 2 diabetes are unable to compensate for insulin resistance due to more pronounced β-cell impairment. TCC formation may be partly responsible for the insulin secretory dysfunction associated with this specific sub-type of Type 2 diabetes.     

Reduction of urinary albumin excretion by thromboxane synthetase inhibitor, OKY-046, through modulating renal prostaglandins in patients with diabetic nephropathy

We evaluated the effects of thromboxane synthetase inhibitor, OKY-046, on urinary albumin and prostaglandin (PG) excretion in 14 patients with non-insulin-dependent diabetes mellitus (NIDDM).

Urinary excretion of 6-keto-PGF₁ (a stable metabolite of PGI₂), TXB₂ (a stable metabolite of TXA₂) and PGE₂ in NIDDM patients was comparable with that in control subjects. However, the urinary 6-keto-PGF₁/TXB₂ ratio in NIDDM patients with both micro- and macroalbuminuria was significantly (P < 0.001) lower than that in the controls.

By a single administration of OKY-046 (40 mg, i.v.) to the diabetic patients, urinary TXB₂ excretion significantly (P < 0.05) decreased from 169.7 ± 23.9 to 140.2 ± 17.9 ng/gCr, but urinary 6-keto-PGF₁ and PGE₂ excretion did not change significantly. The urinary 6-keto-PGF₁/TXB₂ ratio thus significantly (P < 0.01) increased from 1.02 ± 0.13 to 1.73 ± 0.41 as associated with significant increments in urine volume (P < 0.05), urinary sodium excretion (P < 0.01) and creatinine clearance (P < 0.05).

Of 14 diabetic patients, 7 with macroalbuminuria (albumin index exceeding 100 mg/gCr) were orally given OKY-046 (600 mg/day) for 8 weeks. After this period, the urinary albumin index significantly (P < 0.05) decreased from 524.9 ± 149.6 to 317.6 ± 90.6 mg/gCr. Urinary PG excretion did not change significantly, although the urinary 6-keto-PGF₁/TXB₂ ratio significantly (P < 0.01) increased from 1.33 ± 0.16 to 2.42 ± 0.65 and decreased to 1.09 ± 0.15 (P < 0.01) following termination of this drug. Similarly, creatinine clearance significantly (P < 0.01) increased, from 56.3 ± 14.1 to 69.4 ± 15.1 ml/min. During the period of 8 weeks, no significant alteration occurred in systemic blood pressure or glycemic control.

In conclusion, OKY-046 has a beneficial effect on albuminuria in diabetic nephropathy by modulating altered renal PGs synthesis, which leads to a change in renal hemodynamics.     

Reactive oxygen species in essential hypertension and non–insulin-dependent diabetes mellitus

To evaluate whether increased levels of reactive oxygen species (ROS) are involved in the pathogenesis of essential hypertension (EH) and non–insulin-dependent diabetes mellitus (NIDDM), both resting and stimulated levels of intracellular ROS were measured in lymphocytes from patients with EH (n = 10), NIDDM (n = 16) and age-matched healthy individuals (control subjects, n = 19). ROS was monitored with the dye, dihydrorhodamine-123 (DHR; 1 μmol/L) in the presence or absence of superoxide dismutase (superoxide scavenger), sodium azide (singlet oxygen/hydrogen peroxide scavenger), genistein (tyrosine kinase inhibitor), or bisindolylmaleimide (protein kinase C inhibitor). Simultaneous monitoring of cytosolic [Ca²⁺]_i was done with fura-2. Resting ROS levels were significantly higher in NIDDM (4.71 ± 0.25 nmol/10⁶ cells; mean ± SEM, P < .05) compared with EH (4.03 ± 0.22 nmol/10⁶ cells) or controls (4.05 ± 0.15 nmol/10⁶ cells). The formyl-Met-Leu-Phenylalanine-(fMLP)–induced ROS generation was significantly higher in NIDDM (21.92 ± 2.23 nmol/10⁶ cells; P < .05) compared with EH (14.58 ± 1.90 nmol/10⁶ cells) or control (16.06 ± 1.22 nmol/10⁶ cells). The fMLP-induced ROS increase was significantly reduced in the presence of sodium azide in all groups (P < .01) but was largely unaffected in the presence of SOD. Genistein and bisindolylmaleimide significantly inhibited the fMLP-induced ROS in all groups. The fMLP-induced [Ca²⁺]_i increase was significantly higher in NIDDM (71 ± 12 nmol/L, P < .01) compared with EH (42 ± 4 nmol/L) and control subjects (35 ± 3 nmol/L). Phytohemagglutinin was more effective in increasing [Ca²⁺]_i than ROS. It is concluded that ROS may play a role in the metabolic syndrome of NIDDM but not in EH.     

Postprandial cholesteryl ester transfer and high density lipoprotein composition in normotriglyceridemic non-insulin-dependent diabetic patients

Altered postprandial HDL metabolism is a possible cause of defective reverse cholesterol transport and increased cardiovascular risk in diabetic patients with a normal fasting lipoprotein profile. Ten normolipidemic, normoponderal non-insulin dependent diabetes mellitus (NIDDM) patients and seven controls received a 980 kcal meal containing 78 g lipids with 100000 IU vitamin A. Chylomicron clearance was not different, but area under the curve (AUC) for retinyl palmitate in chylimicron-free serum (remnant clearance) was greater in patients (P < 0.02). LCAT activity increased postprandially to the same extent in both groups. In control subjects, cholesteryl ester transfer protein (CETP) activity (CETA) also increased by 20% (P < 0.01 at 6 h) in parallel with a 20% decrease in HDL₂-CE (r= −0.55, P = 0.009). In NIDDM patients, on the contrary, CETA which was 35% higher in the fasting state (P < 0.005), decreased postprandially yet HDL₂-CE remained unchanged. Postprandial HDL₃ of controls were enriched with phospholipid (PL) (30.3 ± 2.6% at 6 h) with respect to fasting (25.6 ± 2.5%, P < 0.01) and to NIDDM-HDL₃ (25.8 ± 1.7% at 6 h, P < 0.01). These results show that variation in plasma CETA has little impact on HDL₂-CE in NIDDH subjects. They support the concept that, in controls, the combined enrichment of HDL₃ with PL, increased LCAT and CETA create the conditions for stimulation of cell cholesterol efflux and CE transfer to apo B lipoproteins. In NIDDM, because of the lesser HDL₃ enrichment with PL and of the inverse trend of CETA, these conditions fail to occur, depriving the patients of a potentially efficient mechanism of unesterified cholesterol (UC) clearance, despite their strictly normal preprandial profile.     

Elevated plasma activator inhibitor 1 is not related to insulin resistance and to gene polymorphism in healthy centenarians

Previous studies demonstrated a relationship between the degree of insulin resistance and plasma plasminogen activator inhibitor type-1 (PAI-1) levels. We aim at investigating the relationship between the degree of insulin resistance and plasma PAI-1 levels in aged subjects (n=83) and in healthy centenarians (n=42). In all subjects the degree of insulin resistance was assessed by HOMA method. Our data demonstrated that healthy centenarians have higher plasma PAI-1 levels (73.1±13.9 vs 23.7±14.7 ng/ml, P<0.001) and lower degree of insulin resistance (1.4±0.5 vs 3.3±1.3, P<0.001) than aged subjects. In aged subjects plasma PAI-1 levels correlated with the degree of insulin resistance (r=0.61, P<0.001), fasting plasma triglycerides (r=0.74, P<0.001) and age (r=0.33, P<0.001). All such associations were lost in centenarians. Plasma PAI-1 Ag levels were also similar in aged subjects and centenarians even after categorization for PAI gene polymorphism. In multivariate analysis, a model made by age, sex, body mass index, fasting plasma triglycerides, HOMA and PAI-1 gene explained 65 and 50% of plasma PAI-1 level variations in aged subjects and centenarians, respectively. Nevertheless, HOMA (P<0.001) was significantly and independently associated with plasma PAI-1 levels only in aged subjects. In conclusion, our data demonstrates that in healthy centenarians, plasma PAI-1 were not associated with the degree of insulin resistance as in aged subjects. Frequency of PAI-1 genotype does not provide an explanation for such differences between aged subjects and centenarians.     

Five fold increase of insulin concentration delays the absorption of subcutaneously injected human insulin suspensions in pigs

Human NPH U100 (100 IU/ml), given once daily, is often absorbed too fast to cover the basal insulin demand throughout 24 h. The aim of the present study was to examine whether the absorption of human insulin suspensions would be delayed by increasing the insulin concentration from U100 to U500. In each experiment 10 IU of corresponding human Ul00 and U500 preparations, labelled with ¹²⁵I-insulin, were injected subcutaneously and contralaterally in the neck of a pig followed by monitoring residual radioactivity over the injection sites. The time until 75, 50 and 25% residual radioactivity (T_75%, T_50% and T_25%) using NPH U500 was compared with NPH U100 in 14 experiments: T_75%: 5.0±0.5 (mean±SEM) vs 3.8±0.3 h (P=0.007, paired t-test), T_50%: 12.2±0.9 vs 9.0±0.6 h (P=0.003) and T_25%. 24.2±1.2 vs 17.9±1.2 h (P=0.001). The corresponding values for semilente U500 compared with semilente U100 in eight experiments were: T_75%: 2.8±0.4 vs 1.6±0.2 h (P=0.02), T_50%: 5.6±0.6 vs 3.4±0.3 h (P=0.01) and T_25%: 10.9±1.1 vs 7.2±0.7 h (P=0.009). Thus, the absorption of a given dose of human NPH or human semilente insulin in pigs is substantially delayed by changing the insulin concentration from Ul00 to U500. Human NPH U500 appears to be more appropriate than human NPH U100 for injection once daily in basal insulin therapy.     

Pulse waveform analysis of arterial compliance: relation to other techniques, age, and metabolic variables

T o assess the physiologic and clinical relevance of newer noninvasive measures of vascular compliance, computerized arterial pulse waveform analysis (CAPWA) of the radial pulse was used to calculate two components of compliance, C1 (capacitive) and C2 (oscillatory or reflective), in 87 normotensive (NlBP, n = 20), untreated hypertensive (HiBP, n = 21), and treated hypertensive (HiBP-Rx, n = 46) subjects. These values were compared with two other indices of compliance, the ratio of stroke volume to pulse pressure (SV/PP) and magnetic resonance imaging (MRI)–based aortic distensibility; and were also correlated with demographic and biochemical values.

The HiBP subjects displayed lower C1 (1.34 ± 0.09 v 1.70 ± 0.11 mL/mm Hg, significance [sig] = .05) and C2 (0.031 ± 0.003 v 0.073 ± 0.02 mL/mm Hg, sig = .005) than NlBP subjects. This was not true for C1 (1.64 ± 0.08 mL/mm Hg) and C2 (0.052 ± 0.005 mL/mm Hg) values in HiBP-Rx subjects. The C1 (r = 0.917, P < .0001) and C2 (r = 0.677, P < .0001) were both closely related to SV/PP, whereas C1 (r = 0.748, P = .002), but not C2, was significantly related to MRI-determined aortic distensibility.

Among other factors measured, age exerted a strong negative influence on both C1 (r = −0.696, P < .0001) and C2 (r = −0.611, P < .0001) compliance components. Positive correlations were observed between C1 (r = 0.863, P = .006), aortic distensibility (r = 0.597, P = .19) and 24-h urinary sodium excretion, and between C1- and MR spectroscopy-determined in situ skeletal muscle intracellular free magnesium (r = 0.827, P = .006), whereas C2 was inversely related to MRI-determined abdominal visceral fat area (r = −0.512, P = .042) and fasting blood glucose (r = −0.846, P = .001).

Altogether, the close correspondence between CAPWA, other compliance techniques, and known cardiovascular risk factors suggests the clinical relevance of CAPWA in the assessment of altered vascular function in hypertension.     

Effects of the angiotensin II antagonist losartan on endothelin-1 and norepinephrine plasma levels during cold pressor test in patients with chronic heart failure

We evaluate the acute hemodynamic and neurohormonal effects of losartan in 15 patients with symptomatic chronic heart failure (CHF), mean age 72 ± 8 years, which were classified in two subgroups: (A) Patients with left ventricular ejection fraction (LVEF) ≤0.35 (n = 7); (B) subjects with LVEF >0.35 (n = 8). Sympathetic reactivity (blood pressure, heart rate and plasma norepinephrine) and plasma endothelin-1 (ET-1) were evaluated by a cold pressor test (CPT). Single doses of losartan (50 mg p.o.) lowered delta DBP in both subgroups (A, 8 ± 9 to 0 ± 5 mmHg, P < 0.05; B, 10 ± 6 to 3 ± 4 mmHg, P < 0.05) and attenuated the rise of HR in patients with mild (4 ± 6 to −1 ± 2 bpm, P < 0.05) but not with severe (4 ± 5 to 2 ± 5 bpm, n.s.) impairment of left ventricular function. Losartan blunted the response (delta) of PNE during CPT (A, 142 ± 131 to 10 ± 74 pg/ml, P < 0.05; B, 129 ± 72 to 1 ± 144 pg/ml, P < 0.01). A significant rise in plasma ET-1 was observed during CPT in patients from subgroup B (0.64 ± 0.40 to 0.81 ± 0.40 fmol/ml, P < 0.05) but not in patients with LVEF ≤0.35 (1.79 ± 0.44 to 1.51 ± 0.66 fmol/ml, n.s.). Losartan attenuated the rise in ET-1 during CPT in patients with LVEF >0.35 (delta ET-1 0.17 ± 0.86 to 0.03 ± 0.11 fmol/ml, P < 0.05), with no significant changes in subgroup A. Acute effects of losartan were characterized by a more favorable hemodynamic and neurohumoral response in patients with chronic heart failure and preserved systolic ventricular function related to subjects with lower ejection fractions.     

Proinsulin-like molecules and plasminogen activator inhibitor type 1 (PAI-1) activity in diabetic and non-diabetic subjects with and without myocardial infarction

Elevated plasminogen activator inhibitor type 1 (PAI-1) activity has been shown to correlate with plasma insulin, proinsulin-like molecules, serum triglycerides and insulin sensitivity in both non-insulin dependent diabetic (NIDDM) subjects and subjects with coronary heart disease. We examined the relative roles of these variables in determining PAI-1 activity in four groups of male caucasian subjects: non-diabetic subjects with (n=38) and without (n=38) previous myocardial infarction (MI) and NIDDM subjects with (n=26) and without (n=30) previous MI. Insulin and proinsulin-like molecules were measured using specific two-site immunometric assays and insulin sensitivity estimated using the Homeostasis Model Assessment (HOMA) model. Subjects were comparable in age and body mass index. In univariate analysis, there were significant correlations of PAI-1 activity with intact and des-31,32-proinsulin and serum triglycerides in non-diabetic subjects with (r=0.52, P=0.001; r=0.58, P<0.001; r=0.41, P=0.010) and without (r=0.31, P=0.056; r=0.46, P=0.006; r=0.41, P=0.011) MI, but not with plasma insulin or insulin sensitivity. In NIDDM subjects, PAI-1 activity correlated significantly with intact and des-31,32-proinsulin and serum triglyceride (r=0.47, P=0.015; r=0.58, P=0.002; r=0.44, P=0.026) only in subjects with MI. In multiple regression analysis, MI was the most important determinant of PAI-1 activity levels (r²=0.31, F=55.6, P<0.001). In conclusion, concentrations of proinsulin-like molecules and serum triglycerides appear to be stronger determinants of PAI-1 activity than plasma insulin or insulin sensitivity in both NIDDM subjects and non-diabetic subjects with and without MI. However, the relationship of MI with PAI-1 activity is independent of these variables.     

Population-based study of the relationship among muscle morphology, insulin action, and hypertension

To examine whether changes in muscle morphology are linked to the metabolic abnormalities associated with the insulin resistance syndrome, muscle morphology and the metabolic profile were examined in 52 individuals with untreated hypertension (mean arterial pressure [MAP] = 117 ± 7 mm Hg) and 38 carefully matched controls (MAP = 89 ± 5 mm Hg). Oral glucose tolerance tests and hyperglycemic clamps were performed for measurements of insulin action on glucose disposal and suppression of nonesterified fatty acids (NEFA). Fully automated, computer-aided techniques were used for morphometric measurements of muscle biopsies from m. vastus lateralis. The hypertensive and normotensive groups did not differ in insulin sensitivity to glucose disposal (0.18 ± 0.16 v 0.19 ± 0.13 μmol/kg/min/pmol/L; P = .20) and NEFA suppression (87.5 ± 7.3 v 87.2 ± 9.4%, P > 0.30) during a hyperglycemic clamp. The groups were similar in the proportion of types 1, 2a, and 2b muscle fibers, fiber size, and capillary density. Fiber roundness (ratio of fiber perimeter squared to fiber area) differed in the hypertensive (1.51 ± 0.07) and normotensive (1.58 ± 0.12, P = .004) groups, showing that the muscle fibers in the hypertensive group were more rounded in shape, a nonspecific change often seen after minimal ischemic lesions. The quotient expressing fiber roundness was associated with systolic (r = −0.29, P = .01) and diastolic (r = −0.32, P = .005) blood pressure.

We conclude that persons with mild and moderate hypertension do not have abnormalities in muscle morphology that could explain the impairment of insulin action often observed in this condition. However, hypertensive individuals have increased muscle fiber roundness. It is wondered whether hypertension may be a condition with defects in the regulation of the transmembranous ion transport, leading to raised intracellular sodium concentration, swelling of the cytoplasma, and roundening of the fibers.     

The role of obesity and cardiovascular fitness in the impaired glucose tolerance of aging

The prevalence of impaired glucose tolerance (IGT) increases with aging. Although some data suggest that age is independently associated with IGT, other studies suggest that age-associated changes in body composition and reduced cardiovascular fitness are responsible for the development of IGT. We, therefore, examined the relationship of age, total and regional adiposity, and level of fitness (VO₂max) to the presence of IGT in 155 healthy, nondiabetic, nonsmoking, older community dwelling men. Sixty-two of 155 men (40%) had IGT, while 93 men (60%) had normal glucose tolerance (WHO criteria). The subjects with IGT were of similar age (61.0 ± 1.0 vs. 59.0 ± 0.7 years, p = 0.49) and had the same maximal aerobic capacity, (VO₂max) (42 0 ± 1.0 vs. 44.0 ± 0.8 mL/kg ffm/min, p = 0.42), but had a higher waist to hip ratio (WHR) (0.98 ± 0.01) vs. 0.96 ± 0.01, p = 0.005) and percent body fat (30.0 ± 0.4 vs. 26.0 ± 0.6, p = 0.004) than the men with normal glucose tolerance. In univariate analysis, the 2-h glucose level correlated positively with percent body fat (r = 0.30, P = 0.0002), WHR (0.24, p = 0.002), and age (r = 0.17, P = 0.03) and negatively with VO₂max (r = −0.23, P = 0.005). In both multiple logistic and linear regression analyses, percent body fat was the only independent predictor of IGT (p = 0.002). These results suggest that the age-associated increase in total adiposity is a major contributor to the development of IGT in middle-aged and older men. Thus, lifestyle modifications that reduce body fat should reduce the risk for IGT and the development of noninsulin-dependent diabetes mellitus in the elderly.     

The relationship between first-phase insulin secretion and glucose metabolism.

A possible pathogenetic link between absence of first-phase insulin secretion and development of impaired glucose metabolism has been suggested by the results of several cross-sectional studies. First-phase insulin secretion measured during a +7 mmol/l hyperglycemic glucose clamp correlated with total glucose disposal during the clamp (r = 0.65, p < 0.001, N = 59). To examine whether restoration of first-phase insulin secretion improves peripheral glucose uptake in subjects with impaired glucose utilization, seven insulin-resistant subjects (age 54 (38-62) years: BMI 29.3 (21.7-35.8); fasting plasma glucose 5.5 (4.8-7.2) mmol/l; fasting insulin 57 (37-105) pmol/l with impaired first-phase (148 (29-587) vs controls 485 (326-1086) pmol/l x 10 min; p < 0.05) and normal second-phase (1604 (777-4480) vs controls (1799 (763-2771) pmol/l x 110 min) insulin secretion were restudied. The impaired first-phase insulin secretion was restored by an iv insulin bolus at the start of the hyperglycemic clamp. Substrate oxidation rates and hepatic glucose production were determined by indirect calorimetry and [3-3H]glucose infusion. Total glucose uptake was impaired in the insulin-resistant subjects with impaired first-phase insulin secretion compared to controls (18.8 (13.2-22.2) vs 34.8 (24.3-62.1) mumol.kg-1 x min-1; p < 0.01). Restoration of first-phase insulin secretion (1467 (746-2440) pmol/l x 10 min) did not affect glucose uptake (20.2 (9.9-23.8) mumol.kg-1.min-1), with no difference in oxidative and non-oxidative glucose metabolism between the experiments. Second-phase insulin secretion was similar during both experiments.(ABSTRACT TRUNCATED AT 250 WORDS)     

Influence of endogenous hyperinsulinism on high density lipoprotein2 level in type 2 (non-insulin-dependent) diabetes mellitus and impaired glucose tolerance

We determined the insulin response to an oral glucose ingestion and levels of serum lipoproteins in 25 untreated patients with type 2 diabetes mellitus, in 26 subjects with impaired glucose tolerance (IGT), and in 35 non-diabetic control subjects. The three groups had similar compositions with respect to age and sex distribution. The levels of VLDL triglycende in the subjects with type 2 diabetes or IGT were higher than those in controls. Serum HDL- and HDL₂ cholesterol were significantly decreased in type 2 diabetics, and the subjects with IGT showed a similar tendency. Serum apolipoprotein A-II levels were lower in the male subjects with type 2 diabetes or IGT than in controls. Insulin reponse, i.e., sum of immunoreactive insulin (IRI) levels at basal, 30, 60, 90 and 120 min after a 75-g oral glucose load, negatively correlated to HDL and HDL₂ cholesterol levels (r = −0.396, P < 0.05; r = −0.482, P < 0.001, respectively), and positively correlated to VLDL triglyceride values (r = 0.485, P < 0.001) in the male subjects with type 2 diabetes or IGT. In the female subjects, fasting plasma IRI values significantly correlated to HDL cholesterol (r = −0.496, P < 0.05). There was a significant negative correlation between the concentrations of HDL₂ cholesterol and VLDL trgglyceride. These data show that lipoprotein metabolism, not only in type 2 diabetics, but also in IGT tends to show changes such as decreased HDL₂ cholesterol and increased VLDL triglyceride levels, and which might be related to the hypersecretion of endogenous insulin.     

Quantitation of apo b in human aortic fatty streaks A comparison with grossly normal intima and fibrous plaques

The content of apolipoprotein B (apo B)-containing lipoproteins was measured in aortic fatty streak lesions of 18 male individuals between the ages of 21 and 67 years, and compared to the values found in adjacent grossly normal intima. Extraction of apo B was accomplished by sequential treatment of aortic tissue homogenates with a standard buffer and one containing the detergent Triton X-100. Mean apo B values (μg per mg tissue dry weight) in fatty streaks were: BUFFER-EXTRACTED = 4.67 ± 0.51, Triton-extracted = 1.88 ± 0.39; while in adjacent grossly normal intima: BUFFER-EXTRACTED = 6.51 ± 0.92, Tritonextracted = 0.37 ± 0.15. Using a paired t-test, buffer-extracted apo B was marginally significantly greater in the adjacent normal intima than fatty streaks (P < 0.05), whereas Triton-extracted apo B was highly significantly greater in fatty streaks than adjacent normal intima (P < 0.0005). When the mean apo B values of these 18 fatty streaks and 23 fibrous plaques from separate cases were compared in a non-paired t-test, buffer-extracted apo B was slightly higher in fatty streaks than fibrous plaques (P < 0.025), whereas Triton-extracted apo B was much higher in fibrous plaques than in fatty streaks (P < 0.0005). The intermediate position of fatty streaks between grossly normal and fibrous plaques with respect to buffer- and Triton-extracted apo B content, gives additional support to the contention that this lesion is an intermediate step in the progression of the grossly normal intima to a fibrous plaque. Assuming this sequence of progression to occur, our results demonstrate a marginally significant decrease in buffer-extracted apo B but a highly statistically significant increase in Triton-extracted apo B with lesion development.     

Abnormal diurnal changes in in-vivo platelet activation in patients with atherosclerotic diseases

We measured the urinary excretion of beta-thromboglobulin in timed urine samples collected by 2 groups of healthy volunteers, (group I, N = 20, mean age 34 years, group II, N = 15, mean age 64 years) and by patients (n = 40) with symptomatic atherosclerotic diseases. Older healthy subjects were found to excrete high amounts of BTG in comparison to young subjects (302.25 ± 50.61 vs 219.65 ± 59.31 ng/day, P < 0.05). Higher (P < 0.01) levels of urinary BTG were observed in patients with coronary (427.61 ± 179.96 ng/day), cerebral (422.13 ± 223.2 ng/day) and peripheral (454.16 ± 269.05 ng/day) arterial diseases and in diabetic patients with diffuse vascular complications (613.71 ± 253.07 ng/day). The diurnal variability of BTG excretion, measured as coefficient of variation (C.V. %) of the mean daily excretion rate, was higher (P < 0.001) in atherosclerotic patients (70.59 ± 26.57) as compared with the similar values observed in the control groups of young (32.05 ± 14.54) and older subjects (26.38 ± 8.4). Comparable diurnal variabilities of the creatinine excretion rate were observed in the control groups and in patients. These data indicated that in vivo platelet activation may occur in atherosclerotic patients with a distinctive high fluctuation rate.     

Favorable effects of oral maintenance digoxin therapy on left ventricular performance in normal subjects: Echocardiographic study

Left ventricular performance was assessed with echocardiography in 10 normal subjects before and during maintenance therapy with digoxin (0.5 mg/day orally) in the basal state and after acute pressure loading with intravenously administered phenylephrine. During digoxin therapy, despite a decrease in mean heart rate of 5 beats/min in the basal state, mean left ventricular ejection fraction increased from 74 ± 2 to 79 ± 1 percent (standard error, P < 0.03); percent shortening of a left ventricular minor dimension increased from 37 ± 2 to 41 ± 1 percent (P < 0.04) and the mean rate of left ventricular dimension shortening increased from 5.66 ± 0.22 to 6.31 ± 0.23 cm/sec (P = 0.05). During acute pressure loading with phenylephrine there was no change in mean heart rate after digoxin and mean ejection fraction increased from 69 ± 3 to 75 ± 2 percent; mean percent shortening increased from 33 ± 2 to 38 ± 2 percent; mean rate of shortening increased from 5.46 ± 0.32 to 6.48 ± 0.33 cm/sec and mean normalized rate of shortening increased from 1.11 ± 0.06 to 1.29 ± 0.05 sec⁻¹ (all P < 0.01). In a few subjects the response to digoxin did not coincide with the mean data for the whole group. This variability was largely due to difficulties in exactly matching heart rate between the control and digoxin studies. These data (1) support the concept that long-term oral digoxin therapy exerts a positive inotropic effect on the normal left ventricle, and (2) demonstrate the usefulness of echocardiography in noninvasive assessment of the effects of drugs on left ventricular performance.     

The effects of oophorectomy and female sex steroids on glucose kinetics in the rat

In order to clarify the roles played by female sex steroids on glucose metabolism, basal glucose kinetics were studied in control sham operated (C), oophorectomised (O), 17-β-oestradiol treated oophorectomised (1.5 μg/day) (E) and progesterone treated oophorectomised (1.5 mg/day) (P) female rats. Hormone (or vehicle only) delivery was via osmotic pumps which were inserted at the time of oophorectomy (or sham operation) 7 days prior to metabolic testing. In fasted anaesthetised rats, hepatic glucose production (HGP), plasma glucose metabolic clearance rate (MCR) and glucose uptake indices (GUI) of selected peripheral tissues were measured using radioactive tracer methodology. Following surgery, the O rats significantly gained and the E rats significantly lost weight compared to the C rats. Plasma insulin and glucose were not different between groups. HGP and MCR were increased by 24–29% (P < 0.005) and 19–28% (P < 0.001), respectively, in the O compared to the C, E and P rats. The GUI of brown adipose tissue was significantly reduced in the P compared to the C rats (3 ± 1 vs 25 ± 10 μmol/100 g/min). In conclusion, female sex steroid hormones significantly influence rat body weight, hepatic glucose metabolism and the metabolism of brown adipose tissue.