A Masoni

Kinetic Analysis of Plasma Insulin Disappearance in Nonketotic Diabetic Patients and in Normal Subjects: A TRACER STUDY WITH 125I-INSULIN

The studies so far reported on the metabolic clearance rate of insulin in human diabetes mellitus have given conflicting results, probably because they have been conducted on few patients and have used a variety of experimental techniques and data treatments. We investigated the kinetics of insulin distribution and degradation in 35 normal subjects and in 42 nonketotic, nonobese, overtly diabetic patients, of whom 26 were above 40 yr old and 16 were 40 yr old or less at diagnosis. The design of the study combined (a) the use of a tracer to perturb minimally the steady state and to avoid glucose infusion; (b) the preparation of purified [(125)I]-monoiodoinsulin, which has a metabolic behavior similar to that of native insulin; and (c) noncompartmental analysis of the plasma immunoprecipitable (125)I-insulin disappearance curves, which were recorded for 2 h after pulse i.v. injection of the tracer.Metabolic clearance rate was found to be similar in diabetics (404+/-18 ml/min.m(2), mean+/-SEM) and in normals (420+/-14), although the latter-onset patients had slightly, if not significantly, lower metabolic clearance rate values than the earlier-onset diabetics (385+/-19 and 443+/-36, respectively). The initial distribution volume of the hormone also did not significantly differ in diabetics and normals and was similar to plasma volume. The reentry rate into the initial distribution volume of the hormone and the total, plasma-equivalent distribution volume of insulin were both significantly raised in diabetics (251+/-12 ml/min.m(2) and 10.3+/-0.5 liters/m(2)) in comparison with normals (195+/-8 and 7.5+/-0.3). The posthepatic delivery rate of insulin was found to be slightly raised in later-onset diabetics (194+/-20 mU/h.m(2)), but somewhat reduced in earlier-onset diabetics (133+/-15) in comparison with normals (172+/-14); these differences reflected the different basal plasma insulin concentrations in these three groups. Chronic treatment with oral hypoglycemic drugs, age, duration of the disease, and degree of metabolic control appeared to have only little effect on the kinetics of insulin.On the basis of these results, we conclude that insulin-independent adult diabetics show, already in the fasting state, a combination of insulin resistance and insulin deficiency and a derangement in insulin distribution, the precise significance of which is uncertain.

Effect of Insulin on Systemic and Renal Handling of Albumin in Nondiabetic and NIDDM Subjects

Insulin resistance and hyperinsulinemia cluster with microalbuminuria in both diabetic and nondiabetic subjects, but the mechanism underlying this association is unknown. To test the hypothesis that insulin influences protein permeability, we measured the albumin transcapillary escape rate (TER) by the 131I-labeled albumin technique in 12 healthy volunteers and 12 normoalbuminuric NIDDM patients (fasting plasma glucose, 10.9 ± 1.3 mmol/l) during 4 h of isoglycemia with high (1.1 mU · min−1 · kg−1) or, on a different day, low (0.1 mU · min−1 · kg−1) insulin infusion. In both patients and control subjects, high insulin was associated with a 7% decrease in blood volume (P = 6.006) and a 6% decrease in diastolic blood pressure (P < 0.02), these two changes being related to one another (r = 0.56, P < 0.01). Basal albumin TER was similar in patients (8.4 ± 0.5% · h−1) and control subjects (7.7 ± 0.7% · h−1) and was not significantly changed by high insulin in either group (patients vs. control subjects, 7.3 ± 0.9 vs. 6.2 ± 0.4% · h−1; NS vs. low insulin). In contrast, high insulin increased renal albumin excretion (from 3.6 ± 0.8 to 5.4 ± 1.1 μg/min, P < 0.01) and clearance rate (0.09 ± 0.02 to 0.13 ± 0.03 μl/min, P < 0.001) in patients but not in control subjects. To localize the effect of insulin along the nephron, we measured the urinary excretion of N-acetyl-β-D-glucosaminidase (β-NAG), released by the proximal tubule; retinol-binding protein (RBP), reabsorbed by the proximal tubule; and Tamm-Horsfall protein (THP) and epidermal growth factor (EGF), both secreted by the distal tubule. For both β-NAG and RBP, but not EGF or THP, insulin enhanced urinary excretion (diabetics vs. controls: β-NAG, 0.48 vs. −0.15 μU/min [P = 0.03]; RBP, 78 vs. −32 ng/min [P = 0.05]). In conclusion, physiological hyperinsulinemia does not affect systemic albumin permeability in healthy subjects or normoalbuminuric NIDDM patients. In contrast, in NIDDM patients, but not in healthy subjects, insulin increases the urinary excretion of albumin and protein markers of proximal tubular function. The significance of this finding for the pathogenesis of diabetic nephropathy remains to be established.

Acute insulin administration does not affect plasma leptin levels in lean or obese subjects

Abstract. Whether leptin levels are related to insulin sensitivity or subject to acute regulation by insulin is not known. In 12 obese [body mass index (BMI) = 34.0 ±1.5 kg m‐2] and 12 lean (BMI = 22.2 ±0.6 kg m‐2) non‐diabetic subjects, plasma leptin concentrations were measured in the fasting state and during 2 hours of euglycaemic hyperinsulinaemia (˜600 pmol L‐2). Fasting plasma leptin was significantly higher in obese (26.6 ±3.2) than in lean subjects (6.4 ±1.2 ng mL‐1, P= 0.0001), and in women (21.1 ±3.3) than in men (7.3 = 2.3 ng mL‐1, P= 0.01). In univariate analysis, fasting plasma leptin was strongly related to all anthropometric measures (body weight, fat mass, percent fat mass, waist and hip circumferences). In multiple regression, per cent adiposity, hip circumference and duration of obesity explained 90% of the variability in fasting leptin concentrations. Fasting and stimulated (OGTT) insulin levels, insulin sensitivity (22.6 ±1.9 vs 36.7 ±2.0 μmol min‐1 kg‐1 in lean and obese subjects, respectively, P < 0.0001), glucose area, and serum triglycerides were positively related to fasting plasma leptin concentrations; none of these associations, however, was statistically significant after adjusting for BMI. During the clamp, plasma leptin concentrations remained constant in both lean and obese subjects. We conclude that neither insulin levels nor sensitivity relate to leptin levels independently of fat mass, and that leptin is not subject to acute (2 hours) regulation by insulin in lean or obese humans.

Influence of duration of obesity on the insulin resistance of obese non-diabetic patients

OBJECTIVE: To investigate whether duration of obesity has an independent impact on insulin resistance.DESIGN: Case-control study.SUBJECTS: 30 non-diabetic obese subjects (age, 34±2 y, body mass index (BMI), 33.5±0.8 kgċm−2) with a range (1–35 y) of self-reported duration of obesity, and 12 age- and gender-matched non-obese controls (BMI, 22.1±0.6 kgċm−2).MEASUREMENTS: Oral glucose tolerance (40 gċm−2), insulin sensitivity (by the euglycaemic insulin clamp technique), and insulin secretion (as the product of post-hepatic insulin clearance and plasma insulin concentration).RESULTS: The obese group presented hyperinsulinaemia in the basal state and after glucose loading (insulin area=58±5 vs 33±3 nmolċl−1ċ2 h, P=0.005), insulin resistance (M value=37.4±4.8 vs 50.6±2.6 μμmolċmin−1 ċkg FFM−1, P=0.002), and insulin hypersecretion (61.9±6.0 vs 33.9±4.0 nmolċ2 h, P=0.007); endogenous glucose production was similar in the two groups. In the whole dataset, insulin resistance was directly related to BMI, the waist-to-hip ratio (WHR), endogenous glucose production, insulin secretion, and fasting serum triglycerides and uric acid concentrations. When the obese subjects were stratified by duration of obesity, insulin resistance was progressively lower with longer obesity duration (P=0.04). When simultaneously adjusting by age, gender and BMI, obesity duration was independently associated with greater insulin sensitivity (P=0.003), lower plasma insulin response to oral glucose (P=0.001), and lower fasting and glucose-stimulated insulin release (P=0.01 for both).CONCLUSIONS: In obese subjects with preserved glucose tolerance, duration of obesity is associated with better insulin sensitivity irrespective of the degree of overweight.

Salivary insulin concentrations in type 2 (non-insulin-dependent) diabetic patients and obese non-diabetic subjects: relationship to changes in plasma insulin levels after an oral glucose load

SummaryThe presence of immunoreactive insulin in saliva and its relationship to plasma immunoreactive insulin was investigated in healthy subjects, newly diagnosed non-obese Type 2 (non-insulin-dependent) diabetic patients and obese non-diabetic subjects, basally and after an oral glucose tolerance test. The mean ± SEM fasting values of plasma and salivary immunoreactive insulin were significantly higher in diabetic patients and obese non-diabetic subjects than in normal volunteers (p<0.05). During the glucose challenge, the increase of salivary insulin was related with that of plasma in the three groups of subjects, with a time lag in normal and obese subjects. In normal volunteers, plasma and salivary peak values were respectively 49.5 ± 13.4 μU/ml (p<0.05 vs obese subjects) at 60 min and 12.0±3.3μU/min (p<0.05 vs obese subjects) at 120 min; in diabetic patients, the values were 51.7 ± 5.6 μU/ml (p<0.05 vs obese subjects) and 14.6±4.1 μU/min at 120 min; in obese subjects, the peak value for plasma insulin was 111.5±40.1 μU/ml at 90 min and for salivary insulin 15.6 ± 5.1 μU/min at 120 min. A positive linear relationship was shown between plasma and salivary insulin during the oral glucose tolerance test. The identity of salivary insulin was assessed by reversed-phase HPLC. We conclude that salivary immunoreactive insulin can be found in Type 2 diabetic patients and in obese non-diabetic subjects, as well as normal volunteers, that plasma and salivary insulin are related after a glucose load, and that differences exist in salivary insulin secretion patterns among the three groups of subjects.

Reciprocal association between insulin sensitivity and the haematocrit in man

In epidemiological studies, a high haematocrit has been associated both with increased cardiovascular risk and with hyperinsulinaemia, a surrogate of insulin resistance. To examine directly the relationship between the haematocrit and insulin sensitivity, we studied 12 healthy volunteers and 12 patients with non-insulin-dependent diabetes mellitus (NIDDM) with the use of a 4-hour hyperinsulinaemic [1 mU min-1 kg-1] isoglycaemic clamp. In the whole group, insulin sensitivity (as the ratio of insulin-mediated glucose clearance to steady-state plasma insulin concentrations) was inversely related to the haematocrit (r = 0.50, P < 0.01). To test whether acute changes in the haematocrit affect insulin sensitivity, in two NIDDM patients and three healthy subjects the clamp study was repeated after lowering (-18%) the haematocrit by erythro-apheresis. In all five subjects, the lower haematocrit was associated with slightly reduced (-7% on average, P = NS) rather than increased insulin sensitivity. We conclude that insulin sensitivity is inversely related to the haematocrit independently of the glucose tolerance status. The association does not result from acute haemodynamic effects on insulin sensitivity, and may therefore reflect an action of insulin resistance/ hyperinsulinaemia on blood viscosity, or the presence of a common determinant.

Insulin sensitivity in familial hypercholesterolemia

Insulin resistance is found in association with obesity, non-insulin-dependent diabetes mellitus, and essential hypertension, which are all risk factors for atherosclerotic cardiovascular disease. Furthermore, hyperinsulinemia has been reported in familial combined hyperlipoproteinemia and endogenous hypertriglyceridemia. Finally, relatively high serum triglyceride and low high-density lipoprotein (HDL) cholesterol concentrations invariably accompany hyperinsulinemia. Whether insulin sensitivity is affected by the isolated presence of high levels of serum low-density lipoprotein (LDL) cholesterol has not been clearly established. We studied 13 subjects with heterozygous familial hypercholesterolemia (FHC) and 15 normocholesterolemic subjects selected to be free of any other known cause of insulin resistance. Thus FHC patients and controls had normal body weight and fat distribution, glucose tolerance, blood pressure, and serum triglyceride and HDL cholesterol concentrations, but were completely separated on plasma LDL cholesterol concentrations (6.05 +/- 0.38 v 3.27 +/- 0.15 mmol/L, P < .0001). Fasting plasma levels of glucose, insulin, free fatty acids (FFA), and potassium and fasting rates of net carbohydrate and lipid oxidation were superimposable in the two study groups. During a 2-hour euglycemic (approximately 5 mmol/L) hyperinsulinemic (approximately 340 pmol/L) clamp, whole-body glucose disposal rates averaged 30.4 +/- 2.3 and 31.1 +/- 3.0 mumol.kg-1 x min-1 in FHC and control subjects, respectively (P = 0.88). The ability of exogenous hyperinsulinemia to stimulate carbohydrate oxidation and energy expenditure and suppress lipid oxidation and plasma FFA and potassium levels was equivalent in FHC and control subjects.(ABSTRACT TRUNCATED AT 250 WORDS)

Inappropriate growth hormone response to luteinizing hormone-releasing hormone in diabetes mellitus

We randomly administered luteinizing hormone-releasing hormone (LHRH) or thyrotropin releasing hormone (TRH) (25 micrograms and 200 micrograms, respectively, as a bolus), to 16 diabetic male subjects (9 type I, 7 type II) and to 9 healthy male controls in two different mornings. While GH in the basal state was similar in type I, type II, and normal subjects, LHRH administration surprisingly evoked a significant GH release in 7 (5 type 1, 2 type II) diabetic patients. GH-responders had higher glycated hemoglobin than non-responders (11 +/- 1 nu 8.3 +/- 0.5%) but superimposable fasting and intratest average glucose levels. Only one patient among the GH-responders to LHRH showed a GH release also after TRH. These data support the hypothesis that GH secretion in diabetes, especially when poorly controlled, is abnormal.

Metabolic effects of combined antihypertensive treatment in patients with essential hypertension

Single-drug treatment of essential hypertension (HT) is often insufficient to normalize blood pressure (BP), and high doses of antihypertensive agents can have adverse effects on glucose tolerance (GT) and insulin sensitivity. This study tested whether aggressive BP lowering with combination treatment had any influence on GT or insulin action. In all, 29 nonobese (body mass index [BMI], <30 kg/m2), normolipidemic patients with established HT (159 ± 3/99 ± 1 mm Hg) but normal GT were recruited. Eleven normotensive (125 ± 3/85 ± 1 mm Hg) subjects were matched to the patients for both anthropometric and metabolic variables. Following baseline studies (serum lipid profile, oral GT, insulin release, and insulin sensitivity assessed by the insulin clamp technique), patients were randomized in a double-blind fashion to two combination regimens (verapamil 180 mg/day + trandolapril 2 mg/day or atenolol 50 mg/day + nifedipine 20 mg/day) and restudied 3 months later. Blood pressure was normalized in both groups (with decrements of 25 ± 5/17 ± 2 and 29 ± 3/15 ± 2 mm Hg, respectively). Lipid profile, GT, insulin release, and insulin sensitivity of both glucose uptake and lipolysis were unchanged following both treatments. The authors conclude that in nonobese, normolipidemic, glucose-tolerant hypertensive patients, BP normalization with combination therapy is feasible at no cost in terms of undesired effects on glucose and lipid metabolism and insulin sensitivity.

Free insulin concentrations in immediately extracted plasma samples and their relationships to clinical and metabolic parameters in insulin-treated diabetic patients.

SummaryThe relationships between free insulin and various clinical and metabolic parameters in insulin-treated diabetic patients are still not clear, possibly because of the technical difficulties in measuring free insulin. Recently, it has been demonstrated that in the presence of insulin antibodies only immediate centrifugation of blood and extraction of insulin antibodies provide an accurate evaluation ofin vivo free insulin concentrations. In this study we evaluated the relationships between free and bound insulin levels, insulin antibodies, metabolic control and insulin requirement in 38 insulin-treated diabetic patients, in whom plasma free insulin was assayed in immediately processed samples. The main findings of our study are as follows. Free insulin concentrations ranged from 2.5 to 54 µU/ml; no difference was found between males and females; the unbound hormone level was inversely correlated to fasting plasma glucose (p<0.01) and HbAlc (p<0.02); a positive correlation was shown between free insulin and daily insulin dose; finally, free insulin concentrations were not correlated with insulin antibody binding.