Search

The aim of the present study was to elucidate the pathophysiologic significance of circulating ouabain as a link between insulin resistance (IR) and hypertension (HT) in NIDDM. Euglycaemic (4.5 mmol/l) hyperinsulinaemic (360-580 pmol/l) clamping was performed using an artificial endocrine pancreas. Plasma ouabain-like immunoreactivity (OLI) was determined by radioimmunoassay using a highly specific antibody to ouabain. HT was defined as systolic blood pressure > 140 mm Hg and/or diastolic > 90 mm Hg or being treated with antihyper-tensive agents. The values (mean±SEM) of glucose infusion rate (GIR) and plasma OLI were compared among the four groups classified using IR and HT as factors. Group I (IR-/HT- n = 15):GIR 7.20 ± 0.36 mg · kg · min, OLI 130.8±20.9 pmol/1, which was not different from that in eight normal control subjects (7.69 ± 0.40 mg · kg · min and 142.6± 32.3 pmol/l, respectively); Group II (IR-/HT+, n = 13): 5.89±0.36 mg · kg · min, 172.5±35.0 pmol/1; Group III (IR+/HT- n = 14) 1.91± 0.28 mg · kg · min, 576.6±161.5 pmol/l (p<0.01 vs Group I and II); Group IV (IR+/HT+, n = 15) 1.79±0.22 mg · kg · min, 703.1±170.1 pmol/l (p < 0.01 vs Group I and II), respectively. Six of 57 NIDDM patients studied exhibited very high (> 1500 pmol/l) plasma OLI concentrations, showed marked insulin resistance and were all hypertensive. When analysed as a whole, plasma OLI was negatively correlated with GIR (p < 0.001), but was not correlated with arterial blood pressure. These results demonstrate that plasma concentration of OLI is closely associated with the severity of IR but not with blood pressure elevation. It is, however, possible that in some fraction of NIDDM patients with insulin resistance, the elevation of blood pressure may be causally related to circulating OLI. [ABSTRACT FROM AUTHOR]

Nuclear families of non-insulin-dependent diabetic (NIDDM) patients are uncommon, as usually one or both parents have died. In order to aid identification of complete nuclear families, we have ascertained the disease process at a younger age by studying subjects with previous gestational diabetes. One hundred women who had had gestational diabetes, age (±SD) 38 (6) years, were screened by fasting plasma glucose (fpg). Sixty-one were found to have either fasting hyperglycaemia (5.5≤fpg<7.8 mmol/l) or diabetes. Of these women 35 had both parents alive and the parents of 14 of these women agreed to the assessment of their metabolism by a continuous infusion of glucose with model assessment (CIGMA). Seven probands had impaired glucose tolerance (IGT) and seven were diabetic. They were age 35 (4) years and had body mass index (BMI) 26 (5) kg/m. The parents were aged 62 (6) years and had BMI 29 (6) kg/m and their affection status was defined as presence of glucose intolerance (fpg or post-infusion achieved plasma glucose level >2 SD of an age and obesity matched population). In the 14 families, five probands (36%) had neither parent affected, six (43%) had one parent affected and three (21%) had both parents affected. Only three probands had a parent with diabetes as defined by World Health Organisation criteria. We concludes that the study of women who have had gestational diabetes allows detection of probands with diabetes or impaired glucose tolerance, who have both parents available for study. A substantial proportion had neither parent affected with impaired glucose tolerance or diabetes, similar to the nuclear families of NIDDM patients. The results are in accord with studies of nuclear families of NIDDM patients in suggesting polygenic inheritance or environmental influences rather than autosomal dominant inheritance with high penetrance. [ABSTRACT FROM AUTHOR]

Increased erythrocyte sodium-lithium countertransport rate is found in non-diabetic subjects with essential hypertension, and in insulin-dependent diabetic subjects with nephropathy. However, relationships between these variables in non-insulin-dependent diabetic subjects are ill-defined. In order to characterise the relationships between blood pressure, urinary albumin excretion, and erythrocyte sodium-lithium countertransport, 66 subjects with non-insulin-dependent diabetes were studied. Urinary albumin excretion rate correlated with mean 24-h ambulatory systolic blood pressure ( r=0.57; p<0.001), but not with sodium-lithium countertransport ( r=0.06; p=0.31). No significant relationship was observed between 24-h systolic blood pressure and erythrocyte sodium-lithium countertransport ( r = 0.16; p=0.17). The principal differences between microalbuminuric and normoalbuminuric subjects (albumin excretion rate >15 Μg·min [ n=20], and <15 Μg·min, [ n=46]) were: higher 24-h systolic blood pressure (145.9 [16.8] mm Hg vs 131.9 [16.8] mm Hg; p=0.006), nocturnal heart rate (72.4 [8.9] vs 67.4 [8.9] beats·min; p=0.042), and HbA (11.3 [1.5]% vs 10.1 [2.0]%; p=0.028), and a longer median duration of diabetes (10.0 vs 5.0 years; p = 0.02). In contrast, there was no significant difference in sodium-lithium countertransport rate between microalbuminuric (0.41 [0.18] mmol·l·h) and normoalbuminuric subjects (0.39 [0.15] mmol·l· h; p=0.687). In multiple regression analysis controlling for race, age, body mass index and HbA, the significant determinants of albumin excretion rate were 24-h systolic blood pressure (B [regression coefficient]=0.029, SE[B] [standard error of B]=0.009, t=2.95, p=0.005), duration of diabetes (B=0.430, SE[B]=0.169, t=2.54, p=0.016) and male gender (B=−1.170, SE[B]=0.457, t=−2.56, p=0.015). In conclusion, albumin excretion rates in non-insulin-dependent diabetic subjects are linked to hypertension and glycaemic exposure, but show no relationship to erythrocyte sodium-lithium countertransport. [ABSTRACT FROM AUTHOR]

Cholesterol absorption and metabolism and LDL and HDL kinetics were investigated in 11 hypercholesterolaemic non-insulin-dependent diabetic men off and on a hypolipidaemic treatment with sitostanol ester, (3 g sitostanol daily) dissolved in rapeseed oil margarine, by a double-blind crossover study design. Serum total, VLDL and LDL cholesterol and apoprotein B fell significantly by 6±2, 12±6, 9±3 and 6±2%, mean ±SEM, and HDL cholesterol was increased by 11±4% ( p<0.05) by sitostanol ester. LDL cholesterol and apoprotein B were significantly decreased in the dense (1.037-1.055 g/ml), but not light, LDL subfraction due to a significantly diminished transport rate for LDL apoprotein B, while the fractional catabolic rate was unchanged. HDL kinetics, measured with autologous apoprotein AI, was unaffected by sitostanol ester. Cholesterol absorption efficiency was markedly reduced from 25±2 to 9±2% ( p<0.001) during sitostanol ester followed by proportionately decreased serum plant sterol proportions. Cholesterol precursor sterol proportions in serum, fecal neutral sterol excretion, and cholesterol synthesis, cholesterol transport, and biliary secretion were all significantly increased by sitostanol ester. We conclude that the sitostanol ester-induced decrease in cholesterol absorption compensatorily stimulated cholesterol synthesis, had no effect on fractional catabolic rate, but decreased transport rate for LDL apoprotein B so that serum total, VLDL and LDL cholesterol levels were decreased. Dietary rapeseed oil margarine rich in sitostanol ester was well tolerated, appears to be safe from the nutritional point of view and effective for lowering VLDL and LDL cholesterol and increasing HDL cholesterol in hypercholesterolaemic non-insulin-dependent diabetic subjects. [ABSTRACT FROM AUTHOR]

Mortality among 4740 diabetic men and women aged 35-55 years participating in the WHO Multinational Study of Vascular Disease in Diabetics has been studied. Ten of the original centres (Warsaw, Berlin, Havana, Arizona, Oklahoma, Hong Kong, Switzerland, London, Tokyo, Zagreb) were able to identify the life/death status of their study participants on 1 January 1983, giving an average follow-up period of six to seven years. All-cause mortality rates in males varied about threefold among the ten participating centres with the highest rates in Warsaw, Berlin and Havana and the lowest rates in Tokyo and Zagreb. All-cause mortality rates for females varied about fourfold with the highest rates in Warsaw and Oklahoma and the lowest rates in Tokyo. The proportion of deaths ascribed to circulatory disease varied among the centres ranging from 32% for males and 0% for females in Tokyo to 67% for males and 47% for females in London. There was an excess all-cause mortality in males compared to females for all centres except Zagreb. This excess also applied to circulatory diseases in general, ischaemic heart disease in particular and occurred in both insulin-dependent and non-insulin-dependent diabetic patients. Death rates for insulin-dependent diabetic patients were generally higher than those for non-insulin-dependent patients. [ABSTRACT FROM AUTHOR]

Genetically obese fatty (fa/fa) male rats with abnormal oral glucose tolerance associated with initial hyperinsulinaemia as well as control lean (FA/FA) rats were investigated for the development of retinal microangiopathies. The animals were kept on a standard or sucrose supplemented diet. When tested at 60 weeks, the glucose intolerance of fa/fa rats was accompanied by an insulin response that was now either comparable to that of lean rats (standard diet) or close to nil (sucrose supplemented diet). At killing (68 weeks of age), retinal vasculature was examined by electron microscopy and morphological changes were quantitatively assessed by ultrastructural morphometry. A retinal microangiopathy was observed in all mutant animals which was more pronounced in the sucrose fed group, and which was characterized by: (1), an increase in focal thickenings and in nodules of the basement membrane adjacent to the perivascular glial cells; (2), a decrease in the number of pericyte nulei with concomitant signs of early degenerative cytoplasmic changes of pericytes; (3), an increase in the pinocytic activity of endothelial cells, indicative of presumptive changes in vascular permeability; (4), an increase in the number of intercellular endothelial junctions; (5), the presence of numerous stimulated platelets within capillaries. The fa/fa rat may thus be considered as a suitable model for studying the pathophysiology of ocular complications, in particular retinopathy accompanying non-insulin-dependent diabetes. [ABSTRACT FROM AUTHOR]

Mild diabetes was induced in adult rats with streptozotocin (45 mg/kg body weight), and insulin sensitivity, glycogen deposition and glycogen synthase activity assessed in liver and muscle 5 weeks later. Diabetic rats had significantly elevated fasting blood glucose concentrations (5.6±0.1 versus 3.6±0.1 mmol/l, p<0.001), and blood glucose concentrations 2 h after a 1 g/kg glucose load (12.0±0.6 versus 3.7±0.2 mmol/l, p<0.001). After a 20-h fast hepatic glucose output was significantly elevated (58±3 versus 47±3 μmol·min·kg, p<0.05), and failed to suppress at high insulin concentrations during a euglycaemic clamp (hepatic glucose output 21±4 versus 2±4 μmol·min·kg, p<0.02). Liver glycogen was lower in the diabetic rats by the end of the clamp (16±3 versus 38±6 μmol/g wet wt, p<0.05). At the end of the clamp total glucose turnover was lower in the diabetic rats (107±4 versus 161±17 μmol·min· kg, p<0.01), as was skeletal muscle glycogen synthase activity (0.46±0.04 versus 0.67±0.05 U/g wet wt, p<0.01) and glycogen concentration (22±2 versus 33±3 μmol/g wet wt, p<0.05). Blood lactate and pyruvate responses suggested that glycolytic pathways were similarly affected. Thus, insulin insensitivity develops in both liver and skeletal muscle after 5 weeks of mild streptozotocin-induced diabetes. [ABSTRACT FROM AUTHOR]

Non-insulin-dependent diabetes was obtained in adult rats by neonatal administration of streptozotocin (100 mg/kg). Obesity was obtained in the same animals either by a ventromedial hypothalamic lesion in adult non-insulindependent diabetic Wistar rats, or by using genetically obese Zucker rats. In diabetic rats, weight gain was similar to that in non-diabetic rats, whether hyperphagia was due to a ventromedial hypothalamic lesion or to a genetic factor. Glucose-induced insulin release in vivo was increased in obese diabetic rats compared with non-diabetic rats. Despite this enhanced insulin secretion, both diabetic 'fatty' Zucker rats and diabetic rats with hypothalamic obesity showed a deterioration of glucose tolerance. Moreover, about one-third developed overt diabetes with permanent or transient glycosuria. We conclude that when insulin-deficient rats are made hyperphagic, they are able to increase their insulin secretion and become obese. In some of these animals the occurrence of obesity aggravates the diabetes. The obese diabetic rat appears to be a suitable laboratory model for the study of the relationship between obesity and diabetes. [ABSTRACT FROM AUTHOR]

The insulin response of isolated islet cells to glucose and theophylline in vitro was studied after incubation with lymphocytes. The test was employed to explore cell-mediated immunity in diabetics. A significant inhibition of insulin response to glucose and theophylline as compared to insulin release in a 'basal' medium was found after incubation with blood lymphocytes from 21 out of 23 insulin-dependent diabetics (mean secretion index 18±8 versus 118±8 (SEM) % in control subjects). Most of the patients studied had associated autoimmune diseases: all of these displayed inhibition of insulin release. In six cases, the diabetes had a recent onset with no associated autoimmune disease: four of them displayed the same inhibition. No inhibition was found in the 26 control subjects and in seven non-insulin-dependent diabetics (mean secretion index 134±17 versus 145±23 (SEM) % in four control subjects). Lymphocytes inhibiting islet cell response were not cytotoxic against mouse fibroblasts. Twenty-two insulin-dependent diabetics showed islet cell antibodies to human and/or mouse pancreatic islets.. However, an inhibition of insulin release was found with no detectable islet cell antibodies in one case, and the converse in two cases. Lymphocyte cytotoxicity to islet cells could play a role in the natural history of insulin-dependent diabetes. [ABSTRACT FROM AUTHOR]

Since intrinsic cellular abnormalities have previously been reported in diabetes mellitus, skin fibroblasts from patients with insulin-dependent diabetes and non-insulin-dependent diabetes, and from age-matched young and old controls, were examined for stimulation by insulin (4-4000 ng/ml) of glucose uptake, leucine incorporation into protein, and uridine incorporation into RNA. No differences in insulin-stimulated glucose uptake were seen between donor types. At 40 and 400 ng/ml, insulin did not stimulate as much leucine incorporation into protein in insulin-dependent diabetics as in young controls (p<0.05) and at 4000 ng/ml, less insulinstimulated leucine incorporation was seen in insulindependent diabetics than in young controls or noninsulin dependent diabetics (p<0.01). Lower insulin-stimulated uridine incorporation into RNA in old controls than in other cell lines appeared to be largely secondary to a two-fold increase in basal incorporation in these old controls. These results provide additional evidence for intrinsic cellular abnormalities in diabetes mellitus. Whether the differences in basal or insulin-stimulated response between fibroblasts of different donor types are attributable to alterations in protein or RNA synthesis, metabolite pool size or turnover have yet to be determined. [ABSTRACT FROM AUTHOR]

In order to study the lipoprotein pattern in diabetes mellitus, plasma lipoproteins were isolated by rate zonal centrifugation in 12 control subjects (median fasting blood glucose level: 80 mg/dl (range: 74-86)), 14 diabetic patients treated by diet alone 104 mg/dl (76-153), 27 patients treated by diet plus insulin (180 mg/dl (106-404)), and 32 patients treated by diet plus sulphonylurea [178 mg/dl (103-361)]. No significant differences of median relative body weight existed between the four groups. Neither the diabetic group on diet alone nor the insulin-treated group differed significantly from control subjects with respect to lipid and lipoprotein concentrations. Diabetics treated with diet plus sulphonylurea, however, differed significantly from the control group with regard to the following parameters (median and range); plasma triglycerides (210 [75-620) mg/dl; p<0.01)] and intermediate density lipoproteins (65 (10-338) mg/dl; p<0.05)) were higher; low density lipoproteins (236 (82-418) mg/ dl; p<0.05)) and high density lipoproteins (HDL) [51 (12-121) mg/dl; p<0.01)] concentrations were lower. When data from all 85 studied individuals were analysed together, significant positive correlations were observed between fasting blood glucose and plasma triglyceride concentration (r = 0.28, p<0.01), and between fasting blood glucose and plasma very low density lipoproteins (VLDL) (r = 0.23, p<0.05). A negative correlation was found between blood glucose and plasma HDL (r = -0.29, p<0.01). In addition, VLDL correlated negatively with HDL (r = -0.89, p<0.001) but not with plasma HDL concentration. It is concluded that the deranged lipoprotein metabolism in diabetes mellitus may be better controlled by insulin than by sulphonylureas. [ABSTRACT FROM AUTHOR]

The activation of glycogen synthase after addition of glucose to isolated hepatocytes became impaired in BB rats after the development of insulin-dependent diabetes. This defect was associated with a decreased hepatic synthase phosphatase activity. Both features correspond closely to previous observations on alloxan-diabetic rats. In contrast, in hyperinsulinaemic db/db mice with a similarly increased plasma glucose concentration (non-insulin-dependent diabetes), the synthase phosphatase activity was essentially normal. We conclude that the decreased hepatic synthase phosphatase activity in insulin-dependent diabetes in rodents is due to the lack of insulin, rather than to the increased intrahepatic glucose concentration. [ABSTRACT FROM AUTHOR]

The effects of the α and β anomers of D-glucose on insulin release were studied in a rat model of non-insulin-dependent diabetes, which was induced by streptozotocin injection at 2 days of age. Glucose tolerance of the streptozotocin-treated rats at 8-10 weeks of age was mildly diabetic. Insulin release from the isolated perfused pancreas of the diabetic rats in response to 10 mmol/l α-D-glucose was markedly impaired, while insulin response to 10 mmol/l β-D-glucose in the diabetic pancreas was only slightly reduced as compared to that in the control pancreas. [ABSTRACT FROM AUTHOR]

A 95% follow-up of all known diabetic patients in one racial group in Papua New Guinea was performed. Mortality was high with an average life-span of 4-5 years from the time of diagnosis. Microvascular diabetic complications were detected in over half of the surviving diabetic patients whose average duration of known disease was 3.8 years. At present, diabetes mellitus is both a rapidly fatal and morbid disease in Papua New Guinea. [ABSTRACT FROM AUTHOR]