Genetic susceptibility to non-insulin dependent diabetes mellitus and glucose intolerance are located in HLA region.

OBJECTIVES--To test the hypothesis that the genetic susceptibility to non-insulin dependent diabetes mellitus is the same as that to insulin dependent disease and to see whether glucose intolerance is associated with specific HLA haplotypes. DESIGN--Population based study of men in 1989 first tested for glucose tolerance in 1984. HLA haplotypes, including HLA-A, C, B, DR, and DQ, were defined serologically. HLA haplotype data from a population based Finnish study of childhood diabetes were used for predicting non-insulin dependent diabetes and impaired glucose tolerance. SETTING--Two communities in Finland. SUBJECTS--Representative cohort of Finnish men aged 70-89, comprising 98 men with non-insulin dependent diabetes mellitus and a randomly selected group of 74 men, who served as controls, who were tested for glucose tolerance twice within five years. MAIN OUTCOME MEASURES--Non-insulin dependent diabetes, impaired glucose tolerance, blood glucose concentration. RESULTS--Diabetes associated HLA haplotypes were present in 94% (85/90) of diabetic subjects, 79% (27/34) of subjects with impaired glucose tolerance, and only 13% (3/23) of non-diabetic subjects. In this group of elderly men sensitivity of the diabetes associated HLA haplotypes for non-insulin dependent diabetes and impaired glucose tolerance was 90%, specificity 87%, and predictive power 97%. Mean fasting blood glucose concentration was only just significantly higher in men with diabetes associated haplotypes than in men with no such haplotypes, but there was a substantial difference in blood glucose values two hours after glucose loading (10.4 and 6.4 mmol/l in men with diabetes associated HLA haplotypes and men with no such haplotypes, respectively (p < 0.0001)). CONCLUSIONS--These findings support the hypothesis that specific HLA haplotypes exhibit a common genetic determinant for insulin dependent and non-insulin dependent diabetes. Furthermore, HLA is a major genetic determinant of glucose intolerance in elderly Finnish men. The belief that the HLA predisposition to diabetes is specific for insulin dependent diabetes mellitus is largely incorrect.     

Relation of size at birth to non-insulin dependent diabetes and insulin concentrations in men aged 50-60 years.

OBJECTIVE: To establish whether the relation between size at birth and non-insulin dependent diabetes is mediated through impaired beta cell function or insulin resistance. DESIGN: Cohort study. SETTING: Uppsala, Sweden. SUBJECTS: 1333 men whose birth records were traced from a cohort of 2322 men born during 1920-4 and resident in Uppsala in 1970. MAIN OUTCOME MEASURES: Intravenous glucose tolerance test at age 50 years and non-insulin dependent diabetes at age 60 years. RESULTS: There was a weak inverse correlation (r=-0.07, P=0.03) between ponderal index at birth and 60 minute insulin concentrations in the intravenous glucose tolerance test at age 50 years. This association was stronger (r=-0.19, P=0.001) in the highest third of the distribution of body mass index than in the other two thirds (P=0.01 for the interaction between ponderal index and the body mass index). Prevalence of diabetes at age 60 years was 8% in men whose birth weight was less than 3250 g compared with 5% in men with birth weight 3250 g or more (P=0.08; 95% confidence interval for difference -0.3% to 6.8%). There was a stronger association between diabetes and ponderal index: prevalence of diabetes was 12% in the lowest fifth of ponderal index compared with 4% in the other four fifths (P=0.001; 3.0% to 12.6%). CONCLUSION: These results confirm that reduced fetal growth is associated with increased risk of diabetes and suggest a specific association with thinness at birth. This relation seems to be mediated through insulin resistance rather than through impaired beta cell function and to depend on an interaction with obesity in adult life.     

Fetal and infant growth and impaired glucose tolerance at age 64.

OBJECTIVE--To discover whether reduced fetal and infant growth is associated with non-insulin dependent diabetes and impaired glucose tolerance in adult life. DESIGN--Follow up study of men born during 1920-30 whose birth weights and weights at 1 year were known. SETTING--Hertfordshire, England. SUBJECTS--468 men born in east Hertfordshire and still living there. MAIN OUTCOME MEASURES--Fasting plasma glucose, insulin, proinsulin, and 32-33 split pro-insulin concentrations and plasma glucose and insulin concentrations 30 and 120 minutes after a 75 g glucose drink. RESULTS--93 men had impaired glucose tolerance or hitherto undiagnosed diabetes. They had had a lower mean birth weight and a lower weight at 1 year. The proportion of men with impaired glucose tolerance fell progressively from 26% (6/23) among those who had weighted 18 lb (8.16 kg) or less at 1 year to 13% (3/24) among those who had weighed 27 lb (12.25 kg) or more. Corresponding figures for diabetes were 17% (4/23) and nil (0/24). Plasma glucose concentrations at 30 and 120 minutes fell with increasing birth weight and weight at 1 year. Plasma 32-33 split proinsulin concentration fell with increasing weight at 1 year. All these trends were significant and independent of current body mass. Blood pressure was inversely related to birth weight and strongly related to plasma glucose and 32-33 split proinsulin concentrations. CONCLUSIONS--Reduced growth in early life is strongly linked with impaired glucose tolerance and non-insulin dependent diabetes. Reduced early growth is also related to a raised plasma concentration of 32-33 split proinsulin, which is interpreted as a sign of beta cell dysfunction. Reduced intrauterine growth is linked with high blood pressure, which may explain the association between hypertension and impaired glucose tolerance.     

Metabolic abnormalities in children of non-insulin dependent diabetics.

Non-insulin dependent diabetes appears to be an inherited condition. A study of young offspring of non-insulin dependent diabetics was conducted to determine whether metabolic abnormalities could be found at a young age before clinical diabetes developed. Thirteen patients with non-insulin dependent diabetes were selected who fulfilled the following criteria: they had a sibling who also had non-insulin dependent diabetes, their spouse was non-diabetic, and the offspring were aged between 12 and 45 years, not diabetic, and available for study. All 32 offspring had a 75 g oral glucose tolerance test, and results in 13 of them, one randomly selected from each family, were compared with 13 controls of similar age, sex, and weight. The offspring had significantly higher fasting concentrations of glucose, higher proportions of haemoglobin A1, and higher concentrations of insulin, C peptide, and glucagon. After glucose challenge the increases in both glucose and C peptide concentrations were significantly greater in the offspring. These differences were maintained in all 32 offspring when compared with 18 controls of similar age, sex, and weight; seven of the 32 offspring had impaired glucose tolerance. These results indicate that young offspring of selected non-insulin dependent diabetics can show extensive metabolic changes including impaired glucose tolerance. These changes are associated with hyperinsulinaemia and hyperglucagonaemia.     

Metabolic abnormalities in first-degree relatives of type 2 diabetics

Diabetic relatives and obese subjects are at increased risk for development of diabetes mellitus, and therefore are classed as potential abnormality of glucose tolerance (POT-AGT). Disturbances of lipid and purine metabolisms have been reported in diabetic and obese non-diabetic subjects. In obese subjects above alterations are probably due to hyperinsulinemia. This study aimed at verifying whether similar metabolic abnormalities could be found in relatives of non-insulin dependent diabetic patients and whether they could be related to possible glucose intolerance. We have studied 10706 outpatients and 95 hospitalized subjects, aged between 20 and 50 years. We have selected 4 groups according to diabetic relationship and body mass index: A (normal weight subjects), B (obese subjects), C (normal weight NIDDM-relatives), D (overweight NIDDM-relatives). The NIDDM-relatives showed higher prevalence of hyperglycemia, as expected; furthermore the relatives with normal glucose tolerance had higher glucose area during OGTT. Serum levels of uric acid and insulin response to oral glucose were increased in all obese subjects, but abnormalities of lipid metabolism and fasting hyperinsulinemia were found only in obese NIDDM-relatives. These results suggest that family history of diabetes mellitus can be a risk for metabolic disturbance even in absence of glucose intolerance. Furthermore some metabolic disorders observed in obese subjects could be due to an associated and not sufficiently investigated family history of diabetes.     

Birth weight and non-insulin dependent diabetes: thrifty genotype,thrifty phenotype,or surviving small baby genotype?

OBJECTIVE--To determine the prevalence of diabetes in relation to birth weight in Pima Indians. DESIGN--Follow up study of infants born during 1940-72 who had undergone a glucose tolerance test at ages 20-39 years. SETTING--Gila River Indian community, Arizona. SUBJECTS--1179 American Indians. MAIN OUTCOME MEASURE--Prevalence of non-insulin dependent diabetes mellitus (plasma glucose concentration > or = 11.1 mmol/l two hours after ingestion of carbohydrate). RESULTS--The prevalence was greatest in those with the lowest and highest birth weights. The age adjusted prevalences for birth weights < 2500 g, 2500-4499 g, and > or = 4500 g were 30%, 17%, and 32%, respectively. When age, sex, body mass index, maternal diabetes during pregnancy, and birth year were controlled for, subjects with birth weights < 2500 g had a higher rate than those with weights 2500-4499 g (odds ratio 3.81; 95% confidence interval 1.70 to 8.52). The risk for subsequent diabetes among higher birthweight infants (> or = 4500 g) was associated with maternal diabetes during pregnancy. Most diabetes, however, occurred in subjects with intermediate birth weights (2500-4500 g). CONCLUSIONS--The relation of the prevalence of diabetes to birth weight in the Pima Indians is U shaped and is related to parental diabetes. Low birth weight is associated with non-insulin dependent diabetes. Given the high mortality of low birthweight infants selective survival in infancy of those genetically predisposed to insulin resistance and diabetes provides an explanation for the observed relation between low birth weight and diabetes and the high prevalence of diabetes in many populations.     

Retinal blood flow in diabetic retinopathy.

OBJECTIVES--(a) To report on the basic parameters of retinal blood flow in a population of diabetic patients with and without retinopathy and non-diabetic controls; (b) to formulate a haemodynamic model for the pathogenesis of diabetic retinopathy from this and other studies. DESIGN--Laser-Doppler velocimetry and computerised image analysis to determine retinal blood flow in a large cross sectional study. SETTING--Diabetic retinopathy outpatient clinic. SUBJECTS--24 non-diabetic controls and 76 diabetic subjects were studied (63 patients with insulin dependent diabetes, 13 with non-insulin dependent diabetes). Of the diabetic subjects, 12 had no diabetic retinopathy, 27 had background retinopathy, 13 had pre-proliferative retinopathy, 12 had proliferative retinopathy, and 12 had had pan-retinal photocoagulation for proliferative retinopathy. MAIN OUTCOME MEASURES--Retinal blood flow (microliters/min) and conductance (rate of flow per unit of perfusion pressure). RESULTS--In comparison with non-diabetic controls (9.52 microliters/min) and diabetic patients with no diabetic retinopathy (9.12 microliters/min) retinal blood flow was significantly increased in all grades of untreated diabetic retinopathy (background 12.13 microliters/min, pre-proliferative 15.27 microliters/min, proliferative 13.88 microliters/min). There was a significant decrease in flow after pan-retinal photocoagulation in comparison with all the other groups studied (4.48 microliters/min). Conductance of the retinal circulation was higher in the untreated diabetic retinopathy groups. These results were independent of age, sex, type of diabetes, duration of diabetes, glycated haemoglobin concentration, blood glucose concentration, blood pressure, and intraocular pressure. CONCLUSIONS--Retinal blood flow is significantly increased in diabetic retinopathy in comparison with non-diabetic controls and diabetic subjects with no retinopathy. This has implications for controlling hypertension and hyperglycaemia as a strategy in reducing morbidity from diabetic retinopathy.     

Transient impaired glucose tolerance in Pima Indians: is it important?

As part of a continuing epidemiological study of non-insulin dependent diabetes among Pima Indians 154 subjects who had had a transient impairment of glucose tolerance were followed up for 1.2-16.9 (median 5.8) years after their glucose tolerance had returned to normal. Of these, 49 subsequently developed diabetes; 26 subsequently developed impaired glucose tolerance; and 79 had normal glucose tolerance at the last examination. The cumulative incidence of diabetes was 16% and 48% at five and 10 years of follow up respectively, compared with 3% and 8% for a control group of 1245 members of the same population. After adjustment for age, sex, body mass index, and plasma glucose concentration two hours after glucose loading the incidence of diabetes among the subjects who had had transient impaired glucose tolerance was 3.0 times that among the controls (95% confidence interval 2.1 to 4.3). Proportional hazards function analysis indicated that obesity was the most important predictor of subsequent development of diabetes. The results suggest that transient impairment of glucose tolerance indicates, at least in some subjects, a predisposition to diabetes and should not be considered clinically unimportant.     

Diabetes in prison: can good diabetic care be achieved?

OBJECTIVE--To investigate the clinical characteristics and metabolic control of diabetic patients given structured diabetic care in prison. DESIGN--Survey of diabetic men serving prison sentences during a 22 month period in a large British prison. SETTING--HM Prison, Walton, Liverpool. SUBJECTS--42 male diabetic prisoners, of whom 23 had insulin dependent and 19 non-insulin dependent diabetes. MAIN OUTCOME MEASURES--Episodes of diabetic instability, glycated haemoglobin concentrations, body mass index. RESULTS--No serious diabetic instability occurred. Between the initial assessment by the visiting consultant diabetologist and a second assessment 10 weeks later glycated haemoglobin concentrations had fallen from 10.8 (SD 2.9)% to 9.8 (2.4)% (p less than 0.05) in prisoners with insulin dependent diabetes and from 8.7 (1.9)% to 7.6 (1.2)% (p less than 0.05) in those with non-insulin dependent diabetes. Good glycaemic control continued, a mean glycated haemoglobin concentration of 7.6 (1.5)% being recorded in seven men remaining in prison for six to 18 months. Mean body mass index (weight (kg)/(height(m))2) did not change during the study (insulin dependent prisoners 23.3 (SD 2.1), non-insulin dependent prisoners 27.9 (3.8)). CONCLUSIONS--Good diabetic metabolic control is usual in prison, probably due to the rigid dietary regimen, no alcohol, and compliance with treatment. Many younger men had defaulted from their home diabetic clinics, and imprisonment allowed screening for diabetic complications and reassessment of treatment. Structured diabetic care should be offered in all prisons.     

Evidence of beta cell dysfunction which does not lead on to diabetes: a study of identical twins of insulin dependent diabetics.

Ten non-diabetic identical twins of insulin dependent diabetics were studied to see whether they showed changes in insulin secretion. The twins were selected because more than 11 years had elapsed since the diagnosis of the diabetic twin and they were therefore unlikely to develop diabetes, and they had had islet cell antibodies. Despite similar glucose concentrations to the controls the twins had greater total immunoreactive insulin responses to both oral (mean 3280 (SD 699) versus 2338 (1110) pmol/dl at 180 minutes; p less than 0.05) and intravenous (1346 (690) versus 699 (294) pmol/dl at 30 minutes; p less than 0.05) glucose challenge. The C peptide responses to intravenous glucose were also increased consistent with increased insulin secretion. In addition, basal serum proinsulin concentrations in the twins were increased (2.1 (1.2) versus 1.0 (0.3) pmol/dl; p less than 0.01) and remained so throughout both tests. These twins, who were unlikely to develop insulin dependent diabetes, showed evidence of beta cell dysfunction which does not progress to diabetes.     

Risk factors for early death in non-insulin dependent diabetes and men with known glucose tolerance status.

OBJECTIVE--To identify risk factors for all cause mortality according to glucose tolerance status. DESIGN--Cohort study with an average 15.6 years'' follow up. SETTING--Paris, France. SUBJECTS--7166 working men aged 44-55 in 1968-72 in the Paris prospective study cohort, with non-insulin dependent diabetes or known result of two hour 75 g oral glucose tolerance test. MAIN OUTCOME MEASURES--Risk factors for death from all causes. RESULTS--128 men were known to be diabetic, 180 had diabetes diagnosed, and 697 had impaired glucose tolerance diagnosed. Compared with normoglycaemic men the relative risks of death in these groups were 2.0 (95% confidence interval 1.4 to 3.0), 2.7 (2.0 to 3.6), and 1.6 (1.3 to 2.0) respectively. Obesity, smoking, high blood pressure, and high non-esterified fatty acid concentration were risk factors for death in all subjects and were unaffected by glucose tolerance. The risks for fasting and two hour insulin concentrations and mean corpuscular volume were two times higher in known diabetic men than in men not known to be diabetic. Central obesity was significant only in men not known to be diabetic (1.6 (1.4 to 1.9)). In known diabetic men a two hour glucose concentration higher than 11.1 mmol/l carried a relative risk of death of 3.8 (1.4 to 9.4). CONCLUSIONS--Diabetic men have similar risk factors for early mortality to other men but are at higher risk from hyperinsulinaemia, hyperglycaemia, and high mean corpuscular volume.     

Diabetic dyslipidaemia and coronary heart disease: new perspectives.

Atherosclerotic macrovascular disease is the leading cause of both morbidity and mortality in non-insulin dependent diabetes mellitus. Endothelial dysfunction is a key, early and potentially reversible event in pathogenesis of atherosclerosis. Its occurrence in non-insulin dependent diabetes mellitus is well supported by both in-vitro and in-vivo studies. Non-insulin dependent diabetes mellitus results in diverse abnormalities of lipid and lipoprotein metabolism, in particular hypertriglyceridaemia, low levels of high density lipoprotein and abnormalities of post-prandial lipaemia. A variety of studies demonstrate the presence of enhanced oxidative stress in non-insulin dependent diabetes mellitus, with recent data implying an association between oxidative stress, post-prandial lipaemia and endothelial dysfunction in non-diabetic subjects. In this article based on in-vitro and human studies, we develop the hypothesis that endothelial dysfunction in non-insulin dependent diabetes mellitus is the consequence of the diabetic dyslipidaemia, in particular post-prandial lipaemia, and of oxidative stress on the action of nitric oxide. The practical applications of this theory provide potential therapeutic options which may reduce the risk of vascular disease in non-insulin dependent diabetes mellitus.     

Relation of coronary heart disease and apolipoprotein E phenotype in patients with non-insulin dependent diabetes.

OBJECTIVES--To examine the relation between coronary heart disease and the apolipoprotein E phenotypes in patients with non-insulin dependent diabetes mellitus. DESIGN--Cross sectional study. SETTING--District around Kuopio University Central Hospital, East Finland. SUBJECTS--138 men with non-insulin dependent diabetes and 64 men without diabetes as controls. MAIN OUTCOME MEASURE--Apolipoprotein E phenotype, electrocardiographic abnormalities, other signs of coronary heart disease. RESULTS--The prevalences of definite myocardial infarction and ischaemic electrocardiographic changes were highest in the diabetic men with the phenotypes E4/4 or E4/3 (25% (95% confidence interval 18% to 32%) and 50% (42% to 58%) respectively), although the difference between the phenotype groups was not significant. The prevalence of angina pectoris was 69% (61% to 77%) in men with the phenotypes E4/4 or E4/3 (p = 0.005 compared with other phenotypes), 41% (33% to 49%) in men with phenotype E3/3, and 47% (39% to 55%) in those with phenotypes E2/2 or E2/3. Similarly, the simultaneous presence of angina pectoris and ischaemic electrocardiographic changes was highest in the diabetic men with the phenotypes E4/4 or E4/3 (42% v 22% in those with E3/3 and 29% in those with E2/2, E2/3; p = 0.038). Overall, the prevalence of any evidence of coronary heart disease among the diabetic subjects with the phenotypes E4/4 or E4/3 was 81% (p = 0.011 compared with other phenotypes), 58% in those with phenotype E3/3, and 53% in those with phenotypes E2/2 or E3/3. CONCLUSION--Apolipoprotein E phenotypes E4/4 and E4/3 modulate the risk of coronary heart disease in men with non-insulin dependent diabetes.     

Diabetic cataract of the musk shrew (Suncus murinus, Insectivora) exhibiting spontaneous non-insulin dependent diabetes mellitus (NIDDM).

The EDS colony, developed as a new laboratory colony of the musk shrew, is characterized by a high incidence of early-onset spontaneous non-insulin dependent diabetes mellitus (NIDDM). In this colony, a few diabetic shrews exhibited a cataract at 1 month after the onset of diabetes, and all diabetic shrews had bilateral cataracts at 5 months after the onset of diabetes. In contrast, cataractous animals were never observed among non-diabetic shrews. These results suggest that the cataract in the EDS colony is a diabetic complication.     

Effect of insulin on von Willebrand factor release in normal and diabetic subjects: in vivo and in vitro studies.

The aim of this study was to evaluate the effect of insulin on the release of vWf in vivo during an oral glucose tolerance test (OGTT) performed in normal, glucose-intolerant and diabetic subjects and in vitro on human endothelial cells. Twenty-eight subjects exhibiting risk factors for diabetes underwent an OGTT: 11 subjects proved to be normal, 7 were glucose-intolerant and 10 diabetic. In each group, the vWf and PAI-1 plasmatic levels were measured at t = 0, 30 min and 180 min after the beginning of the test. Human endothelial cells from non-diabetic and diabetic subjects were incubated in the presence of human insulin at various concentrations (0.25, 2.5, 25 and 250 mUI/ml). After 1, 4, and 24 hours of incubation, the release of vWf and endothelin 1 was measured in the cell supernatant and the intracellular amount of vWf in the cell lysate. During the OGTT, the vWf levels in plasma were not affected despite a 4.5-, 6-, and 2.5-fold increase in insulin levels in normal, glucose-intolerant and diabetic subjects, respectively. Although raised in all three groups, PAI-1 plasmatic levels remained constant during the test. After 24 hours of exposure to insulin (0.25 mU/ml), the release of vWf by endothelial cells reached 35.94 +/- 23.08 % of the basal value for non-diabetic subjects, and 27.57 +/- 10.05 % for diabetic patients. Similar results were observed in non-stimulated cells. Insulin had no influence on intracellular vWf content, which remained comparable to control values. Regardless of its concentration, insulin failed to stimulate the release of vWf by endothelial cells of non-diabetic and diabetic subjects, while its ability to stimulate the release of endothelin 1 was preserved. In conclusion, hyperinsulinemia had no adverse effect on circulating vWf in normal or diabetic subjects. Neither release nor intracellular vWf content in non-diabetic or diabetic endothelial cells was influenced by insulin in vitro.     

Renal replacement treatment for diabetic patients in Newcastle upon Tyne and the Northern region, 1964-88.

OBJECTIVES--To review the experience of renal replacement treatment in diabetic patients treated in Newcastle upon Tyne and the Northern region from 1964 to 1988, and to compare the morbidity and mortality of diabetic patients treated with dialysis or transplantation with those of matched controls of non-diabetic patients. DESIGN--Retrospective study of clinical case notes. SETTING--Renal units of the Northern region, particularly that in Newcastle upon Tyne. PATIENTS--All 65 diabetic patients treated by renal replacement treatment in Newcastle upon Tyne from 1964 to 1987; 42 diabetic patients were matched with 42 non-diabetic patients according to age, sex, year of starting treatment, and type of treatment (dialysis or transplantation). MAIN OUTCOME MEASURES--Sex, age, renal biopsy findings, blood pressure, history of diabetic treatment, and plasma creatinine concentration at the start of renal replacement treatment. History of renal replacement treatments, suitability for transplantation, history of transplantation, cumulative survival, and cause of death during follow up. Survival of technique, cumulative survival of the first peritoneal catheter and history of peritonitis in patients treated with continuous ambulatory peritoneal dialysis; source of graft, histocompatibility antigens, duration of associated stay in hospital, and graft survival in patients receiving renal or pancreatic transplant. RESULTS--1259 Patients with chronic renal failure were accepted for renal replacement treatment in Newcastle upon Tyne, of whom 65 (5%) had diabetes. The first was accepted in 1974, and between 1974 and 1980 another 15 were treated (mean age 42 years; 4% of new patients). From 1981 to 1987, 49 diabetic patients (mean age 44; 9% of new patients) were treated. Fifty patients (77%) had insulin dependent diabetes and the remaining 15 (23%) non-insulin dependent diabetes. On average, the patients were aged 25 (range 5-57) when diabetes was first diagnosed and 44 (range 24-70) at the start of renal replacement treatment. The mean age at the start of treatment was 40 for patients with non-insulin dependent diabetes and 58 for patients with non-insulin dependent diabetes. Transplantation was performed in 33 of the diabetic patients, whose mean age was lower than that of those who did not receive a transplant (41 v 48 respectively, p less than 0.05). Comparison between the 42 diabetic patients and matched controls showed that the overall survival at five years was 46% and 77% respectively. The three year survival of the diabetic patients who did not receive a transplant was poor (41% v 79% respectively). Of patients transplanted, survival at five years was 73% in the diabetic patients and 90% in the controls. However, there was no significant difference in the five year graft survival (64% v 46% respectively). CONCLUSIONS--Diabetes adversely affects morbidity and mortality in patients having renal replacement treatment, but renal transplantation seems to be the best option for treating diabetic patients with end stage renal failure.     

Acute effects of valsartan on insulin sensitivity in obese, non-hypertensive subjects with and without type 2 diabetes.

BACKGROUND: Two studies were designed to determine whether a single dose (80 mg) of the angiotensin II receptor blocker (ARB), valsartan, alters insulin sensitivity in obese, non-hypertensive subjects with and without Type 2 diabetes. METHODS: Insulin sensitivity (S(I)), glucose effectiveness (S(G)), and acute insulin response (AIR(0-10 min)) were measured by means of a 3-hour insulin-modified frequently sampled intravenous glucose tolerance test (FSIVGTT) before and after a single dose of valsartan. Study 1: obese, normotensive non-diabetic male subjects (n = 12), mean (SD) age 37.2 +/- 11.2 years, BMI 32.8 +/- 6.8 kg/m (2); Study 2: obese, normotensive Type 2 diabetic patients (n = 12), mean age 55.7 +/- 6.9 years, BMI 35.0 +/- 6.8 kg/m (2)/l. Both studies were randomised, double-blind, placebo-controlled, single-dose crossover group studies involving subjects in two study days, two weeks apart. After fasting samples were taken, a 300 mg/kg iv glucose bolus was injected at 0 min, and 0.05 U/kg iv insulin was given 20 min later. Blood samples for analysis of glucose and insulin were taken throughout the 3-hour study period. RESULTS: Study 1 (non-diabetic subjects) S(I) 2.81 vs. 2.63 x 10 (-4) min (-1) per microU/ml (p = 0.54), S(G) 0.020 vs. 0.020 min (-1) (p = 0.90), AIR(0-10) min 3305 vs. 3450 microU/min/ml (p = 0.71); Study 2 (patients with type 2 diabetes) S(I) 0.59 vs. 0.85 x 10 (-4) min (-1) per microU/ml (p = 0.15), S(G) 0.013 vs. 0.014 min (-1) (p = 0.71), AIR(0-10) min 65 vs. 119 microU/min/ml (p = 0.14), placebo vs. valsartan, respectively. CONCLUSION: In obese, non-hypertensive non-diabetic and Type 2 diabetic subjects a single dose of valsartan does not alter insulin sensitivity.     

Delta aminolevulinate dehydratase (ALA-D) activity in human and experimental diabetes mellitus

The haem pathway is impaired in porphyrias and a frequent coexistence of diabetes mellitus and porphyria disease has been reported. We have therefore decided to investigate delta-aminolevulinate dehydratase, one of the more sensitive enzymes in the haem pathway, in both human diabetic patients and diabetic rats. We have studied 131 diabetes mellitus patients, 32 insulin dependent and 99 non-insulin dependent. The latter group was further subdivided according to treatment: diet alone (n = 24), diet plus oral hypoglycemic agents (n = 28) and diet plus insulin (n = 47). We have also performed similar studies in the rat model of diabetes mellitus, induced in 11 Wistar rats by streptozotocin. Control groups of both humans and animals were used. Erythrocytic aminolevulinate dehydratase activity was reduced in both insulin dependent and non-insulin dependent diabetic patients as compared to their controls (p < 0.001). This activity was only partially restored by addition of zinc and thiols to the incubation media. In insulin-dependent diabetes mellitus, reduction of enzyme activity was related to the glycosilated hemoglobin concentration (p < 0.05) and in non-insulin dependent diabetes mellitus to the glycemia (p < 0.01). In the diabetic rat, aminolevulinate dehydratase activity was diminished on both erythrocytes (p < 0.01) and hepatic tissue (p < 0.01) when compared to the control group. The decrease in activity of erythrocyte aminolevulinate dehydratase observed in diabetic patients, may represent an additional and useful parameter for the assessment of the severity of carbohydrate metabolism impairment.     

Plasma non-cholesterol sterols in patients with non-insulin dependent diabetes mellitus.

Plasma plant sterol concentrations (an index of cholesterol absorption efficiency) and plasma lathosterol concentration (an index of cholesterol synthesis rate) were measured in 52 patients with non-insulin dependent diabetes mellitus (NIDDM) and 36 non-diabetic controls. Plasma plant sterol concentrations were significantly (P less than 0.01) lower in diabetic patients (campesterol: men -36%, women -48%; betasitosterol: men -35%, women -42%). Fasting serum insulin levels were inversely correlated with plasma plant sterol concentrations in diabetic patients (campesterol: r = -0.347, P = 0.012; betasitosterol: r = -0.345, P = 0.012) and in non-diabetic men (campesterol: r = -0.578, P = 0.039; betasitosterol: r = -0.702, P = 0.008). Serum insulin levels were also correlated significantly with plasma lathosterol concentration in diabetic patients (r = 0.295, P = 0.034). The results of this study suggest that absorption of plant sterols and possibly cholesterol from the diet may be reduced in hyperinsulinemic diabetics.     

Possible involvement of corticosterone in bone loss of genetically diabetic db/db mice.

The etiology of bone loss in non-insulin dependent diabetes mellitus is still unknown. We compared serum biochemical parameters and bone parameters of genetically diabetic db/db mice with those of their control non-diabetic +/+ mice. We found that serum corticosterone levels of the db/db mice were significantly elevated after 5 weeks while bone mineral density of femur metaphysis significantly decreased in the db/db mice after 12 weeks of age compared with age matched +/+ mice. To explore the causal relationship between the serum corticosterone levels and the bone loss, metyrapone (100 mg/kg, p.o., twice a day), a glucocorticoid synthesis inhibitor, was administered to these mice for 4 weeks after the age of 8 weeks. The compound significantly decreased serum corticosterone levels in both strains. Metyrapone prevented bone loss by increasing the bone mineral content of the metaphysis in the db/db mice. In addition, the treatment slightly improved the ratio of ash weight to dry weight in the db/db mice. These results suggest that increased serum corticosterone levels are concerned with the etiology of bone loss in non-insulin dependent diabetic db/db mice.