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Showing papers in "Diabetologia in 1992"


Journal ArticleDOI
TL;DR: It is proposed that one of the major long-term consequences of inadequate early nutrition is impaired development of the endocrine pancreas and a greatly increased susceptibility to the development of Type 2 diabetes.
Abstract: In this contribution we put forward a novel hypothesis concerning the aetiology of Type 2 (non-insulin dependent) diabetes mellitus. The concept underlying our hypothesis is that poor foetal and early post-natal nutrition imposes mechanisms of nutritional thrift upon the growing individual. We propose that one of the major long-term consequences of inadequate early nutrition is impaired development of the endocrine pancreas and a greatly increased susceptibility to the development of Type 2 diabetes. In the first section we outline our research which has led to this hypothesis. We will then review the relevant literature. Finally we show that the hypothesis suggests a reinterpretation of some findings and an explanation of others which are at present not easy to understand.

3,107 citations


Journal ArticleDOI
TL;DR: Evidence is provided for endothelial and smooth muscle dysfunction in diabetes which may have important therapeutic implications in patients with Type 2 (non-insulin-dependent) diabetes mellitus and in control subjects, using venous occlusion plethysmography.
Abstract: The endothelium plays a pivotal role in modulating the reactivity of vascular smooth muscle through the formation of several vasoactive substances. We examined the effects of endothelium-dependent and independent vasodilators on forearm blood flow in 29 patients with Type 2 (non-insulin-dependent) diabetes mellitus and in 21 control subjects, using venous occlusion plethysmography. Via a brachial artery cannula, increasing amounts of acetylcholine and glyceryl trinitrate were infused in doses of 60, 120, 180 and 240 mmol per min and 3, 6 and 9 nmol per min respectively. NG monomethyl-l-arginine, a stereospecific inhibitor of endothelium derived relaxing factor, was infused to inhibit basal and stimulated release of this dilator substance. Reactive hyperaemic forearm blood flow did not differ between groups. Forearm blood flow responses to each dose of acetylcholine were significantly greater in control than diabetic subjects (p<0.01 for all doses). NG monomethyl-l-arginine attenuated forearm blood flow from maximal stimulated values when responses were compared with the natural decline to acetylcholine in forearm flow in both control and diabetic subjects (p<0.05 for both groups), but had no effect on basal blood flow responses. Forearm blood flow responses to each dose of glyceryl trinitrate were significantly greater in control than diabetic subjects (p<0.05 for all). These data provide evidence for endothelial and smooth muscle dysfunction in diabetes which may have important therapeutic implications.

896 citations


Journal ArticleDOI
TL;DR: Heritability for Type 1 diabetes was greater than that for Type 2 where both genetic and environmental effects seemed to play a significant role, according to computerized record linkage from death certificates, the National Hospital Discharge Register and the National Drug Register.
Abstract: We studied the cumulative incidence, concordance rate and heritability for diabetes mellitus in a nationwide cohort of 13,888 Finnish twin pairs of the same sex. The twins were born before 1958 and both co-twins were alive in 1967. Data on diabetes were derived through computerized record linkage from death certificates, the National Hospital Discharge Register and the National Drug Register. Records were reviewed in order to assign a diagnostic category to the 738 diabetic patients identified. Of these patients 109 had Type 1 (insulin-dependent) diabetes, 505 Type 2 (non-insulin-dependent) diabetes, 46 gestational diabetes, 24 secondary diabetes, 38 impaired glucose tolerance and 16 remained unclassified. The cumulative incidence of diabetes was 1.4 % in men and 1.3 % in women aged 28–59 years and 9.3 % and 7.0 % in men and women aged 60 years and over, respectively. The cumulative incidence did not differ between monozygotic and dizygotic twins. The concordance rate for Type 1 diabetes was higher among monozygotic (23 % probandwise and 13 % pairwise) than dizygotic twins (5 % probandwise and 3 % pairwise). The probandwise and pairwise concordance rates for Type 2 diabetes were 34% and 20% among monozygotic tiwns and 16% and 9 % in dizygotic twins, respectively. Heritability for Type 1 diabetes was greater than that for Type 2 where both genetic and environmental effects seemed to play a significant role.

657 citations


Journal ArticleDOI
TL;DR: It is shown for the first time in a prospective study that high plantar foot pressures in diabetic patients are strongly predictive of subsequent plantar ulceration, especially in the presence of neuropathy.
Abstract: Foot ulceration results in substantial morbidity amongst diabetic patients. We have studied prospectively the relationship between high foot pressures and foot ulceration using an optical pedobarograph. A series of 86 diabetic patients, mean age 53.3 (range 17–77) years, mean duration of diabetes 17.1 (range 1–36) years, were followed-up for a mean period of 30 (range 15–34) months. Clinical neuropathy was present in 58 (67%) patients at baseline examination. Mean peak foot pressure was higher at the follow-up compared to baseline (13.5 kg·cm−2±7.1 SD vs 11.2±5.4, p 12.3) being present in 55 patients at follow-up and 43 at the baseline visit (p=NS). Plantar foot ulcers developed in 21 feet of 15 patients (17%), all of whom had abnormally high pressures at baseline; neuropathy was present in 14 patients at baseline. Non-plantar ulcers occurred in 8 (9%) patients. Thus, plantar ulceration occurred in 35% of diabetic patients with high foot pressures but in none of those with normal pressures. We have shown for the first time in a prospective study that high plantar foot pressures in diabetic patients are strongly predictive of subsequent plantar ulceration, especially in the presence of neuropathy.

656 citations


Journal ArticleDOI
TL;DR: The full blown syndrome of Type 2 (non-insulin-dependent) diabetes mellitus requires the simultaneous presence of two defects, insulin resistance and impaired Beta-cell function.
Abstract: Following an overnight fast the majority of glucose disposal occurs in insulin-independent tissues, the brain (-50 % ) and splanchnic organs (-25 %), while only 25 % occurs in insulin-dependent tissues, primarily muscle [14]. Basal glucose utilization (-2 mg.kg -~.min 1) is precisely matched by glucose production by the liver [1-4]. Following glucose ingestion, the balance between uptake and output is disrupted and maintenance of glucose homeostasis depends upon three processes that must occur in a co-ordinated fashion: (1) insulin secretion; (2) stimulation of glucose uptake by splanchnic (liver and gut) and peripheral (primarily muscle) tissues in response to hyperinsulinaemia plus hyperglycaemia; (3) suppression of hepatic glucoseproduction. It logically follows that abnormalities at the level of the Beta cell, muscle, and/or liver can lead to the development of glucose intolerance. The full blown syndrome of Type 2 (non-insulin-dependent) diabetes mellitus requires the simultaneous presence of two defects, insulin resistance and impaired Beta-cell function. In Type 2 diabetes the primary or inherited defect most likely represents impaired tissue (muscle and/or liver) sensitivity to insulin. Eventually, however, the Beta cell fails to maintain a sufficiently high rate of insulin secretion to compensate for the insulin resistance, and overt diabetes mellitus ensues.

427 citations


Journal ArticleDOI
TL;DR: Elevated levels of glucagon-like peptide-1 in patients with increased gastric emptying rate (post-gastrectomy syndromes) may be responsible for the exaggerated insulin secretion seen in these patients, and is likely to be a new incretin.
Abstract: The post-translational processing of proglucagon in the small intestine gives rise to glucagon-like peptide-1 (PG 78–107 amide) which has profound effects on the endocrine pancreas, and in many species also on the stomach Glucagon-like peptide-1 (PG 78–107 amide) is secreted in man in response to physiological stimuli eg a mixed meal Glucagon-like peptide-1, in concentrations corresponding to those observed in response to meals, strongly stimulates insulin secretion, in all mammals studied, even more potently than the gastric inhibitory peptide Thus, glucagon-like peptide-1 fulfills the classic criteria for being a hormone and is likely to be a new incretin The glucagon inhibitory effect of glucagon-like peptide-1 (PG 78–107 amide) probably further potentiates the effect of glucagon-like peptide-1 on glucose metabolism and distinguished this peptide from other intestinal peptides which have been proposed as incretins Glucagon-like peptide-1 also inhibits gastric acid secretion and gastric emptying in man The latter delays nutrient entry to the intestine and thereby diminishes meal-induced glucose excursions Elevated plasma concentrations of immunoreactive glucagon-like peptide-1 have been reported in Type 2 (noninsulin-dependent) diabetic patients, however, the consequences of the elevation are not yet known However, elevated levels of glucagon-like peptide-1 in patients with increased gastric emptying rate (post-gastrectomy syndromes) may be responsible for the exaggerated insulin secretion seen in these patients

302 citations


Journal ArticleDOI
TL;DR: In this article, the effect of insulin by direct microneurographic muscle and skin nerve sympathetic activity recordings during euglycaemic insulin clamps in healthy subjects was examined.
Abstract: Sympathetic nervous system activation by insulin has been suggested as a mechanism explaining the association between insulin resistance and hypertension. We further examined the effect of insulin by direct microneurographic muscle and skin nerve sympathetic activity recordings during euglycaemic insulin clamps in healthy subjects. The mean plasma insulin level was elevated from 5.3±0.7 to 92.2±2.2 mU/l in seven subjects during a 90-min one-step clamp. In six other subjects plasma insulin was further raised from 85.7±4.0 mU/l to 747±53 mU/l between 45–90 min (two-step clamp). Four of the latter subjects received a sham clamp with NaCl infusions only on a second recording session. At the low dose of insulin muscle nerve sympathetic activity increased from a resting level of 22.7±5.0 bursts per min to 27.7±5.0 bursts per min at 15 min (p<0.05). The increases in muscle nerve sympathetic activity were significant (p<0.001; ANOVA) throughout insulin infusion, with a slight further increase (from 29.2±1.6 to 32.3±1.9 bursts per min) at the supraphysiological insulin concentration. During sham clamps muscle nerve sympathetic activity did not increase. Both insulin clamps induced minor, but significant, increases in forearm venous plasma noradrenaline concentrations. Skin nerve sympathetic activity (n=3) did not change during insulin infusions. Heart rate increased slightly but significantly (p<0.005), during the insulin clamps. Blood pressure was not notably affected. In conclusion, hyperinsulinaemia was associated with increased vasoconstrictor nerve activity to skeletal muscle and with no change of sympathetic outflow to skin.

295 citations


Journal ArticleDOI
TL;DR: In both groups glucose intolerance was more strongly associated with waist-hip girth ratio than with skinfolds or body mass index, and the association between hyperinsulinaemia and obesity is less specific for centrally-distributed fat.
Abstract: Type 2 (non-insulin-dependent) diabetes mellitus and insulin resistance are associated with centrally-distributed obesity. These disturbances are especially prevalent in people of South Asian (Indian, Pakistani and Bangladeshi) descent. We examined the relationship of glucose intolerance to body fat pattern in a population survey of 2936 men and 537 women of South Asian and European origin living in London, UK. In both groups glucose intolerance (defined as diabetes or impaired glucose tolerance) was more strongly associated with waist-hip girth ratio than with skinfolds or body mass index. The associations between body mass index and glucose intolerance were fully accounted for by waist-hip ratio. In European men with normal glucose tolerance fasting insulin levels were more strongly correlated with body mass index than with waist-hip ratio. Physical activity scores were lower in South Asians than in Europeans but no statistically significant associations between glucose intolerance and low physical activity were detectable. Leisure-time physical activity scores were inversely correlated with 2 h insulin levels in both groups. In contrast with other studies these results suggest that a specific effect of intra-abdominal fat deposition underlies the association between glucose intolerance and obesity. The association between hyperinsulinaemia and obesity is less specific for centrally-distributed fat. When measured appropriately waist-hip ratio is the most valid anthropometric index for identifying individuals whose obesity predisposes them to glucose intolerance.

282 citations


Journal ArticleDOI
TL;DR: It is concluded that this miniaturized glucose sensor, whose size makes it easily implanted, works for at least ten days after implantation into rat subcutaneous tissue.
Abstract: Summary A miniaturized amperometric, enzymatic, glucose sensor (outer diameter 045 ram) was evaluated after implantation in the subcutaneous tissue of normal rats A simple experimental procedure was designed for the long-term assessment of the sensor's function which was performed by recording the current during an intraperitoneal glucose load The sensor was calibrated by accounting for the increase in the current during the concomitant increase in plasma glucose concentration, determined in blood sampled at the tail vein This made it possible to estimate the glucose concentration in subcutaneous tissue During the glucose load, the change in subcutaneous glucose concentration followed that in blood with a lag time consistently shorter than 5 rain The estimations of subcutaneous glucose concentration during these tests were compared to the concomitant plasma glucose concentrations by using a grid analysis Three days after implantation (n = 6 experiments), 79 estimations were considered accurate, except for five which were in the acceptable zone Ten days after implantation (n = 5 experiments), 101 estimations were accurate, except for one value, which was still acceptable The sensitivity was around 05 nA mmol-l1-1 on day 3 and day 10 A longitudinal study on seven sensors tested on different days demonstrated a relative stability of the sensor's sensitivity Finally, histological examination of the zone around the implantation site revealed a fibrotic reaction containing neocapillaries, which could explain the fast response of the sensor to glucose observed in vivo, even on day 10 We conclude that this miniaturized glucose sensor, whose size makes it easily implanted, works for at least ten days after implantation into rat subcutaneous tissue

209 citations


Journal ArticleDOI
TL;DR: It is concluded that there are polyol pathway related abnormalities for contraction, some aspects of endothelium-independent relaxation, but particularly for endot helium-dependent relaxation in aorta from chronic streptozotocin-diabetic rats.
Abstract: The effects of 3 months streptozotocin-induced diabetes mellitus on contraction and relaxation of aorta were examined in vitro. A further diabetic group was treated with a novel sulphonylnitromethane-based aldose reductase inhibitor for 3 months following diabetes induction. Diabetes resulted in reduced maximal tension production, particularly for responses to phenylephrine (p < 0.001) and serotonin (p < 0.001). However, with aldose reductase inhibitor treatment, responses were in the non-diabetic range. The ratio of maximum contractions to noradrenaline and phenylephrine were 28 % elevated by diabetes (p < 0.01), which may suggest increased α2-adrenoreceptor-mediated responses. Endothelium-independent relaxation to glyceryl trinitrate was unaffected by diabetes or treatment. By contrast, there were 38 % deficits in endothelium-dependent relaxation to acetylcholine (p < 0.001) and Ca2+ ionophore A23187 (p < 0.001) with diabetes which were prevented by aldose reductase inhibitor treatment (p < 0.001). A 121 % shift in the concentration giving a 50% maximum effect for acetylcholine towards lower sensitivity with diabetes (p < 0.001) was also largely corrected by treatment (p < 0.001). A non-diabetic group treated with aldose reductase inhibitor showed a 30 % decrease in the 50 % effective concentration for acetylcholine (p < 0.05). A 15 % deficit in maximum relaxation to the ATP-sensitive K+ channel opener cromakalim for the diabetic group (p < 0.001) was prevented by aldose reductase inhibitor treatment (p < 0.01). We conclude that there are polyol pathway related abnormalities for contraction, some aspects of endothelium-independent relaxation, but particularly for endothelium-dependent relaxation in aorta from chronic streptozotocin-diabetic rats. If found in the appropriate circulatory beds, these could potentially contribute to the putative vascular basis of some of the complications of diabetes. Their amelioration could account for many of the beneficial effects of aldose reductase inhibitors.

207 citations


Journal ArticleDOI
TL;DR: It is shown that transplantation of purified freshly-prepared and cryopreserved islets into Type 1 diabetic patients results in prolonged insulin secretion, and that sufficient function could be provided in one patient to sustain euglycaemia in the absence of insulin therapy at 1 year of follow-up.
Abstract: Purified human islets and a kidney from the same donor were transplanted into four patients with Type 1 (insulin-dependent) diabetes mellitus. Two of the patients received additional islets that were isolated from multiple donors, cryopreserved, and stored in a tissue bank. The islets were embolized into the liver via the portal vein. Immunosuppression was induced with antilymphocyte globulin and maintained with azathioprine, prednisone and cyclosporine. In the first two patients, fasting serum C-peptide rose to levels of 0.5–2.0 ng/ml during the first 4–8 weeks and mixed meal feeding elicited increases to 2–3 ng/ml. C-peptide secretion persisted for 8 months, but at progressively lower levels and insulin therapy could not be withdrawn. In the next two patients who received cryopreserved islets in addition to fresh islets, serum C-peptide levels (fasting/post-meal) rose to 4–7 ng/ml and serum glucose was more stable, allowing withdrawal of insulin therapy after 69 days in one patient, and reduced insulin doses in the other. The insulin-independent patient has maintained normal fasting glucose, glycosylated haemoglobin, and oral glucose tolerance at 1 year following cessation of daily insulin therapy. Episodes of renal graft rejection occurred in three patients, including the insulin-independent patient. High-dose steroid therapy reversed the rejection in all instances, with apparent preservation of C-peptide secretion. These data show that transplantation of purified freshly-prepared and cryopreserved islets into Type 1 diabetic patients results in prolonged insulin secretion, and that sufficient function could be provided in one patient to sustain euglycaemia in the absence of insulin therapy at 1 year of follow-up.

Journal ArticleDOI
TL;DR: It is concluded that short-term administration of C-peptide in physiological amounts to patients with Type 1 diabetes may reduce the glomerular filtration rate and increase whole-body glucose utilization.
Abstract: The possible influence of C-peptide administration on renal function and whole body glucose utilization was examined in 11 patients (Group 1) with Type 1 (insulin-dependent) diabetes mellitus. They were given an i. v. insulin infusion during the night before the study and were euglycaemic at the time of examination. The glomerular filtration rate and effective renal plasma flow were measured by clearance techniques using constant-rate infusions of inulin and sodium para-aminohippurate. After baseline measurements C-peptide was infused during two periods of 60 min at rates of 5 and 30 pmol·kg−1·min−1. In a control study 0.9% NaCl was infused during two 60 min periods in ten Type 1 diabetic patients (Group 2), Glomerular filtration rate decreased by 7%(p<0.001), effective renal plasma flow increased by 3%, (p<0.05) and whole-body glucose utilization rose by approximately 25%(p<0.05) above basal during low-dose C-peptide infusion. Group 2 showed an unaltered glomerular filtration rate, effective renal plasma flow and glucose utilization during 60 min of NaCl infusion. The differences between Group 1 and Group 2 in glomerular filtration rate and glucose utilization were statistically significant. It is concluded that short-term administration of C-peptide in physiological amounts to patients with Type 1 diabetes may reduce the glomerular filtration rate and increase whole-body glucose utilization. The results suggest the possibility that short-term C-peptide administration may exert a regulatory influence on renal function and stimulate glucose utilization in Type 1 diabetic patients.

Journal ArticleDOI
TL;DR: Present knowledge on the regulation of beta-cell growth, with emphasis on recent studies of Beta-cell DNA replication in vitro, is reviewed and appears appropriate for the understanding of the aetiology and pathogenesis of diabetes.
Abstract: Glucose homeostasis is tightly controlled by, first and foremost, insulin. There is a minute-to-minute regulation of insulin output from the Beta cell to meet changing demands at and between meals. There is also a long-term adaptation of insulin production by changes in total Betacell mass. Diabetes mellitus develops if any one of these processes is insufficient and causes absolute or relative insulin deficiency. The regulation of insulin biosynthesis and release in relation to the aetiology of diabetes has been intensely studied, while the role of Beta-cell growth has met with less interest until recent years. In Type 1 (insulin-dependent) diabetes there is a loss of Beta cells and decompensation of metabolism following autoimmune aggression [1]. Insulin production often reccurs shortly after onset of clinical disease ("honeymoon period") suggesting an effort by the reduced Beta-cell mass to meet insulin demands. In Type 2 (non-insulin-dependent) diabetes pathogenesis is less clear and probably multifactorial but there is evidence to suggest that a reduced insulin secretory response to glucose and a limited capacity for Beta-cell replication predisposes to the disease [2, 3]. Studies of the regulation and limitations of Beta-cell growth thus appear appropriate for the understanding of the aetiology and pathogenesis of diabetes. Present knowledge on the regulation of Beta-cell growth, with emphasis on recent studies of Beta-cell DNA replication in vitro, is reviewed in this paper.

Journal ArticleDOI
TL;DR: This review focuses on four potential bio-chemical pathways linking hyperglycaemia to changes within the kidney which can plausibly be linked to the functional and structural changes characterising diabetic nephropathy.
Abstract: A large number of experimental studies in animals and retrospective or non-randomised prospective studies in humans provide support for the concept that the microvascular complications of diabetes mellitus are dependent on hyperglycaemia. This review focuses on four potential bio-chemical pathways linking hyperglycaemia to changes within the kidney which can plausibly be linked to the functional and structural changes characterising diabetic nephropathy. These four pathways are the polyol pathway, non-enzymatic glycation, glucose autoxidation and de novo synthesis of diacylglycerol leading to protein kinase C and phospholipase A2 activation. Rather than being independent, there are several potential interactions between these four pathways which may explain confusing and overlapping effects observed in studies examining inhibitors of individual pathways. As many of the steps which follow on glucose metabolism are subject to modification by dietary and pharmacological means, the further delineation of the pathogenetic sequence leading to tissue damage in diabetes should allow a logical and effective approach to the prevention or treatment of the complications of diabetes.

Journal ArticleDOI
TL;DR: The prevalence of Type 1 diabetes in the parents of these newly-diagnosed diabetic children was higher in fathers (5.7%) than in mothers (2.6%) and the total incidence was about 35.2 per 100,000 per year during 1987–1989.
Abstract: A nationwide study of childhood Type 1 (insulin-dependent) diabetes mellitus was established in 1986 in Finland, the country with the highest incidence of this disease worldwide. The aim of the project called “Childhood Diabetes in Finland” is to evaluate the role of genetic, environmental and immunological factors and particularly the interaction between genetic and environmental factors in the development of Type 1 diabetes. From September 1986 to April 1989, 801 families with a newly-diagnosed child aged 14 years or younger at the time of diagnosis were invited to participate in this study. The vast majority of the families agreed to participate in the comprehensive investigations of the study. HLA genotypes and haplotypes were determined in 757 families (95%). Our study also incorporates a prospective family study among non-diabetic siblings aged 3–19 years, and two case-control studies among the youngonset cases of Type 1 diabetes. During 1987–1989, the overall incidence of Type 1 diabetes was about 35.2 per 100,000 per year. It was higher in boys (38.4) than in girls (32.2). There was no clear geographic variation in incidence among the 12 provinces of Finland. Of the 1,014 cases during these 3 years only six cases were diagnosed before their first birthday. The incidence was high already in the age group 1–4-years old: 33.2 in boys and 29.5 in girls. Of the 801 families 90 (11.2%) were multiple case families, of which 66 had a parent with Type 1 diabetes at the time of diagnosis of the proband. The prevalence of Type 1 diabetes in the parents of these newly-diagnosed diabetic children was higher in fathers (5.7%) than in mothers (2.6%).

Journal ArticleDOI
C Meyerhoff1, F Bischof1, F Sternberg1, Horst Zier1, Ernst-Friedrich Pfeiffer1 
TL;DR: It is concluded that changes in blood glucose could be monitored in the subcutaneous tissue by the microdialysis technique in a continuous on line manner.
Abstract: For the normalisation of blood glucose levels in diabetic patients by feedback controlled insulin delivery, a self-manageable and reliable method for continuous glucose estimation is still not available. By combining a commercially available needle type dialysis probe (molecular cutoff 20,000 Da) with a sensitive glucose sensor, we obtained a device for continuous glucose measurement in dialysate. This device was tested in healthy volunteers during a 75-g oral glucose tolerance test and in Type 2 (non-insulin-dependent) diabetic patients. Venous glucose and subcutaneous sensor signal were followed for 300 min (ten healthy subjects), 21 h (three healthy subjects) or 9 h (seven Type 2 diabetic patients). The recovery of the microdialysis was interindividually different, but after calibration, glucose levels in the dialysate and subcutaneous glucose sensor signal correlated well (r = 0.84–0.95). Under the assumption of a physiologic and technical delay between intravenous and subcutaneous glucose, correlation coefficient between intravenous glucose and subcutaneous sensor signal ranged from 0.60 to 0.93. We conclude that changes in blood glucose could be monitored in the subcutaneous tissue by the microdialysis technique in a continuous on line manner.

Journal ArticleDOI
TL;DR: An early immunological event due to maternal-child blood group incompatibility, known to be associated with neonatal Beta-cell dysfunction, represents an increased risk for Type 1 diabetes in young children.
Abstract: The nationwide Swedish Childhood Diabetes Registry, which ascertains 99% of recent-onset Type 1 (insulin-dependent) diabetic children (0–14 years) in Sweden, was linked with the Swedish Medical Birth Registry. A matched case-control study was carried out analysing about 20 perinatal variables concerning mother and child. A total of 2757 infants who became diabetic during the period 1978–1988 were analysed. For each case infant three control children were randomly selected from among all infants born in the same year and at the same delivery unit as the case infant. The following statistically significant risk factors were identified for Type 1 diabetes with an onset before 15 years of age: maternal diabetes (OR=3.90), maternal age above 35 (OR=1.36), maternal non-smoking (OR=1.54), pre-ec-lamptic toxaemia (OR=1.19), caesarian section (OR=1.32), and maternal-child blood group incompatibility (OR=1.61). When the analysis was restricted to Type 1 diabetes with an onset before the age of 5 years, most odds ratios were increased — for blood group incompatibility OR=3.86 (95% confidence interval 1.54–9.65). Icterus without blood group incompatibility was not a significant risk factor. When each risk factor was analysed after standardization for all other risk factors, the odds ratios remained significantly increased. Scrutiny of medical records for cases and control children with a diagnosis of blood group incompatibility verified the diagnosis in close to 90% of children. The more severe cases needing phototherapy and/or blood transfusion were found to have a greater risk than milder cases. In conclusion, an early immunological event due to maternal-child blood group incompatibility, known to be associated with neonatal Beta-cell dysfunction, represents an increased risk for Type 1 diabetes in young children. Other stressful perinatal events may also be risk factors for Type 1 diabetes.

Journal ArticleDOI
TL;DR: The heated hand technique using the warm-air box sufficiently arterializes venous blood so that the glucose measurement in the arterialized blood provides a reasonable estimate of the arterials value and that the venousBlood from the contralateral forearm is also markedly arterialization, probably reflecting a vasodilator effect of heating.
Abstract: The purpose of this study was to evaluate the effectiveness of the warm-air box method on the arterialization of venous blood during euglycaemia and hypoglycaemia. Six healthy male volunteers were studied using an i.v. infusion of insulin (144 mU·kg−1·h−1). Arterial blood glucose was clamped at the baseline level for the first 30 min and subsequently reduced to 3.2 and to 2.5 mmol/l for 20 min. At each stage, including prior to insulin infusion, arterial, arterialized venous (heating the hand in a warm-air box set to 55–60°C), venous and capillary blood samples were taken simultaneously for analyses of blood glucose and oxygen saturation (not for capillary blood). The oxygen saturations in arterialized blood were approximately 3% below the arterial values. The arterial-arterialized difference of blood glucose was about 0.1 mmol/l (the 95% confidence interval: from −0.19 to 0.41 mmol/l), which tended to correlate with the difference in oxygen saturations between the arterial and arterialized blood samples (r=0.25, p=0.08). During the test the forearm venous blood oxygen saturation increased by 9% and the arteriovenous difference in blood glucose ranged from 0.2 to 0.5 mmol/l which correlated significantly with the difference in oxygen saturations (r=0.48, p<0.001). Capillary glucose was similar to the arterialized value. Rectal temperature was stable during the experiment. We conclude that the heated hand technique using the warm-air box sufficiently arterializes venous blood so that the glucose measurement in the arterialized blood provides a reasonable estimate of the arterial value and that the venous blood from the contralateral forearm is also markedly arterialized, probably reflecting a vasodilator effect of heating.

Journal ArticleDOI
TL;DR: It is possible, using microdialysis, to directly determine the absolute glucose concentration in subcutaneous adipose tissue, and this technique may be used for continuous glucose monitoring in diabetic patients.
Abstract: The possibility of continuously monitoring the absolute glucose concentration in subcutaneous adipose tissue, using microdialysis of the extracellular water space, was investigated in six Type 1 (insulin-dependent) diabetic patients. By using a large microdialysis probe (30×0.62 mm), and by perfusing with a low flow rate (0.5 μl/min), complete recovery of glucose was attained in vitro. In the patients the dialysis probe was implanted subcutaneously, perfused by a wearable microinfusion pump, and dialysate samples were collected in 60-min fractions over 10 h. The absolute glucose concentration in the tissue dialysate was the same or almost the same as the blood glucose concentration (range 87–101 % of the blood glucose value). The changes in blood glucose were closely paralleled by the variations in adipose tissue glucose (r=0.93, p<0.01), and the recovery of glucose in the microdialysate remained constant during the 10-h study period. In conclusion, it is possible, using microdialysis, to directly determine the absolute glucose concentration in subcutaneous adipose tissue. Hence, this technique may be used for continuous glucose monitoring in diabetic patients.

Journal ArticleDOI
TL;DR: The results are the reverse of the positive association of androgens with insulin in women and suggest alternative possible explanations for the effect of hyperinsulinaemia on cardiovascular disease risk.
Abstract: Plasma insulin is a risk factor for diabetes mellitus and cardiovascular disease in men. We investigated the association between plasma testosterone and plasma insulin in an occupational sample of 1292 healthy adult men. Total plasma testosterone decreased with each decade of age and insulin increased with each decade of age. In these cross-sectional data, this significant graded inverse association between testosterone and insulin was independent of age. The association was reduced but not explained by the addition of obesity and subscapular skinfold to the model. Adjustment for alcohol consumption, cigarette smoking and plasma glucose did not materially alter the association. These results are the reverse of the positive association of androgens with insulin in women and suggest alternative possible explanations for the effect of hyperinsulinaemia on cardiovascular disease risk. Prospective studies will be necessary to determine the direction and causal nature of this association.

Journal ArticleDOI
TL;DR: Repeated encouragement and follow-up using exercise records was not sufficient to induce a significant increase in physical activity and an improvement in aerobic capacity in diabetic patients, and the results suggest that high aerobic capacity is beneficial for glycaemic control, and on the other hand, even slight increase in aerobic Capacity is associated with an increase in HDL-cholesterol level.
Abstract: The aim of this study was to assess the effects of a 1-year intensified diet and exercise education regimen on habitual physical activity and aerobic capacity in middle-aged, obese patients with newly-diagnosed Type 2 (non-insulin-dependent) diabetes niellitus. In addition, we analysed whether the level and the changes in physical activity and aerobic capacity are related to the metabolic control of diabetes. After a 3-month basic education programme, 78 patients (45 men, 33 women) were randomly placed in an intervention or conventionally treated group. The intervention group received intensified diet education and continuous encouragement to increase physical activity which was monitored using exercise records and questionnaires. Aerobic capacity was assessed by measuring oxygen uptake at anaerobic threshold and at peak exercise. The proportion of patients with regular recreational exercise increased from 24% to 38% in the intervention men (0.10

Journal ArticleDOI
TL;DR: It is concluded that diabetic boys tend to be taller and grow faster than referent boys for several years preceding the disease, and rapid linear growth is a risk factor for Type 1 diabetes in childhood.
Abstract: Insulin release and growth are intimately connected. The aim of the present study was to investigate height and weight in diabetic children from birth to onset of Type 1 (insulin-dependent) diabetes mellitus compared to that in referent children. Data on height and weight were collected from mailed questionnaires and from growth records obtained from the child health clinics and schools in 337 recentonset diabetic children, 0–14 years old, and from 517 age-, sex-, and geographically matched referent children. A total of 9002 paired height and weight observations were collected. The anthropometric development of the children was expressed as standard deviation scores using the National Center for Health Statistics/Centers for Disease Control (NCHS/CDC) growth reference material. On the average, the diabetic children were consistently taller than the referent children, a finding more pronounced among the boys. The diabetic boys were significantly taller from 7 to 1 years before the clinical onset of the disease, regardless of age at onset. A similar tendency was found for the girls. When mean height from 5 to 1 years before onset was used as a possible risk factor for diabetes, a linearly increasing trend in the odds ratio was found for diabetes in boys (odds ratio = 1.0; 1.57; 2.46 for height standard deviation score values 1, respectively; p=0.002 for trend). A similar, but statistically not significant, tendency was found for girls (odds ratio = 1.0; 1.44; 1.43). As regards height increment from birth similar trends in odds ratios were found. Weight-for-height was similar among diabetic and referent children of both sexes. We conclude that diabetic boys tend to be taller and grow faster than referent boys for several years preceding the disease. A similar, but not statistically significant tendency was found among diabetic girls. Our findings indicate that rapid linear growth is a risk factor for Type 1 diabetes in childhood, and may be either a promoter of Type 1 diabetes or else a marker of a physiological mechanism that affects both growth and the pathogenesis of Type 1 diabetes.

Journal ArticleDOI
TL;DR: The MTT assay provides a convenient tool for the rapid assessment of Beta-cell metabolism and viability and was found that the rate of formazan production correlated with glucose oxidation and glucose utilization at glucose concentrations which also stimulated insulin secretion.
Abstract: Insulin secretion depends critically on glucose metabolism. We investigated whether a rapid viability test could be established for assessing glucose metabolism in insulin secreting cells. The MTT (C,N-diphenyl-N′-4,5-dimethyl thiazol 2 yl tetrazolium bromide) colorimetric assay (reduction of tetrazolium salt to formazan) was applied to rat islets and rat insulinoma cell lines. It was found that the rate of formazan production correlated with glucose oxidation and glucose utilization at glucose concentrations which also stimulated insulin secretion. In differentiated insulinoma INS-1 cells, salt reduction paralleled the insulin release, at glucose concentrations of up to 8.3 mmol/l. The glucose-induced formazan production in INS-1 cells and islets was abolished by exposure to the Beta-cell cytotoxic agents, streptozotocin or alloxan. The MTT assay thus provides a convenient tool for the rapid assessment of Beta-cell metabolism and viability.

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TL;DR: It was concluded that the beneficial effect of preventive lisinopril treatment is likely to depend upon a reduction of peripheral vascular resistance and improvement of tissue blood flow, which implicates relative hypoxia as an important factor in the development of myopathy and neuropathy in experimental diabetes.
Abstract: The effects of the angiotensin converting enzyme inhibitor lisinopril on slow and fast twitch muscle contractile properties, nerve conduction and hypoxic resistance, and muscle and nerve capillary density were examined in streptozotocin-diabetic rats. Prolongation of soleus contraction and relaxation were partially prevented by treatment (p<0.01). A 22% deficit in fast twitch extensor digitorum longus tetanic tension production was also ameliorated (p<0.01). Sciatic motor and sensory conduction velocity, 25% and 12% reduced by diabetes respectively, were 75% normalized by lisinopril (p<0.01). There was a 47% increase in resistance to hypoxic conduction block with diabetes (p<0.01). Lisinopril treatment resulted in normal hypoxic resistance. Capillarisation of nerve and muscle was little affected by diabetes; however, there was a 17% increase in capillary density in sciatic nerve, and a 40% increase in extensor digitorum longus muscle with lisinopril (p<0.01). For soleus, a smaller treatment-induced increase in capillary density led to an elevated capillary/muscle fibre ratio (p<0.01). These results suggest that lisinopril promoted angiogenesis. It was concluded that the beneficial effect of preventive lisinopril treatment is likely to depend upon a reduction of peripheral vascular resistance and improvement of tissue blood flow, which implicates relative hypoxia as an important factor in the development of myopathy and neuropathy in experimental diabetes.

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TL;DR: The notion that advanced glycation end products contribute to the aetiology of early diabetic neuropathy, possibly acting via a vascular mechanism, and that aminoguanidine treatment may have therapeutic applications are supported.
Abstract: The effect of 2 months aminoguanidine treatment on nerve conduction abnormalities was studied in streptozotocin-diabetic rats. Treatment with aminoguanidine from the induction of diabetes mellitus prevented a 22% decrease in sciatic motor nerve conduction velocity (p <0.001), and a 10% deficit in sensory saphenous conduction velocity (p <0.01). There was a 49% increase in resistance of sciatic nerve to hypoxic conduction failure in vitro. This was not significantly affected by aminoguanidine treatment. Sciatic nerve polyol pathway metabolites, sorbitol and fructose, were elevated 10-fold by diabetes (p <0.001). Myo-inositol levels were 18% decreased by diabetes. Aminoguanidine treatment had no significant effect on sorbitol, fructose or myo-inositol levels. Aminoguanidine has been identified as both an inhibitor of the formation of advanced glycation end products, and an aldose reductase inhibitor. The data suggest that beneficial actions on nerve function do not depend on the latter property. They support the notion that advanced glycation end products contribute to the aetiology of early diabetic neuropathy, possibly acting via a vascular mechanism, and that aminoguanidine treatment may have therapeutic applications.

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TL;DR: Plasma glucose levels 30 min and 2 h after a 75-g glucose load were inversely related to birthweight, independent of gestational age, and current body mass, height and social class.
Abstract: In a study of men aged 59 to 70 years plasma glucose levels 30 min and 2 h after a 75-g glucose load were inversely related to birthweight. To determine whether there are similar relations at a younger age the 30-min plasma glucose levels of 40 men aged 21 years, who were born in one hospital in the United Kingdom, were measured. Lower birthweight was associated with higher 30-min plasma glucose levels. This trend was independent of gestational age, and current body mass, height and social class.

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TL;DR: Findings do not support the hypothesis that hyperinsulinaemia is a major risk factor for coronary heart disease in elderly men and Hyperglycaemia (or diabetes mellitus) seems to be the most important risk factor.
Abstract: Insulin and insulin resistance have attracted considerable interest as possible risk factors for coronary heart disease during the last decade. We therefore examined the 8 year incidence of coronary heart disease in 595 67-year-old men in relation to baseline insulin and other risk factors. The incidence of coronary heart disease increased from 9% among non-diabetic men to 13.5% among those with impaired glucose tolerance, 12.9% among newly-detected diabetic men and up to 31.3% among men with known diabetes. The incidence of coronary heart disease was related to fasting blood glucose and 1 h and 2 h blood glucose during the oral glucose tolerance test and to serum cholesterol and serum triglycerides. Fasting serum insulin was of borderline significance for the risk of coronary heart disease. When known diabetic subjects were excluded only serum cholesterol and serum triglycerides remained as statistically significant risk factors. Among diabetic subjects (known and newly-detected) only blood glucose was related to the risk of coronary heart disease. In multivariate analyses the different degrees of glucose intolerance or fasting blood glucose were independently related to the risk of coronary heart disease (p=0.008–0.010). Serum triglycerides were also an independent risk factor in three out of four multivariate models (p=0.02–0.09). Fasting serum insulin was not an independent risk factor. These findings do not support the hypothesis that hyperinsulinaemia is a major risk factor for coronary heart disease in elderly men. Hyperglycaemia (or diabetes mellitus) seems to be the most important risk factor.

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R. Østerby1
TL;DR: No supporting evidence of a relationship with glomerular hyperfunction or hypertrophy was observed, but the structural parameters may be useful tools in clinical trials aiming at arresting the development of glomerulopathy and thereby providing a prevention of diabetic nephropathy.
Abstract: Diabetic nephropathy is caused primarily by advanced glomerulopathy, the renal expression of diabetic microangiopathy. With stereological methods a quantitative description of the structural changes is achieved. The glomerulopathy is characterized by an increase in basement membrane material: thickening of the capillary wall and an increase in mesangial volume relative to glomerular volume, comprising increase in matrix. Among groups of patients conformity between renal function stage and structure exists. The parameters measuring glomerulopathy are normal at the onset of diabetes; patients with normoalbuminuria may show slight basement membrane thickening, or normal parameters; the microalbuminuric group shows a measurable, but moderate glomerulopathy; patients with overt nephropathy have advanced lesions; at this stage heterogeneity among glomeruli makes the estimates weaker. Recent data indicate that the changes in peripheral basement membrane and in mesangial matrix develop in concert and both contribute to the early stage of glomerulopathy in patients with microalbuminuria. As to the consequences of the structural changes the mechanism of albuminuria is not clear. It is suggested that the early glomerulopathy entails other structural modifications, including formation of new vessels which may be the site of leakage. The marked deviations in glomerular filtration rate correspond well with estimates of filtration surface area: in the early hyperfunction state it is increased; in advanced nephropathy it is decreased, due to advanced glomerulopathy in conjunction with glomerular occlusion. The diabetic state is the necessary condition for the glomerulopathy. In relating structural changes to presumed contributing causes no supporting evidence of a relationship with glomerular hyperfunction or hypertrophy was observed. The structural parameters may be useful tools in clinical trials aiming at arresting the development of glomerulopathy, and thereby providing a prevention of diabetic nephropathy.

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TL;DR: Alginate-polylysine microencapsulation has been proposed as a method of protecting transplanted pancreatic islets against immunological attack, but in the spontaneously diabetic insulindependent BB/E rat it is found that intraperitoneal implantation of microencapulated islets had only a short-lived effect on hyperglycaemia.
Abstract: Alginate-polylysine microencapsulation has been proposed as a method of protecting transplanted pancreatic islets against immunological attack. Using this technique, prolonged graft survival has been reported in some diabetic animals. However, in the spontaneously diabetic insulin-dependent BB/E rat we found that intraperitoneal implantation of microencapsulated islets had only a short-lived effect on hyperglycaemia. Recovered microcapsules (both those implanted empty and containing islets) were surrounded by a foreign body type cellular overgrowth and, although many capsules remained intact, encapsulated islets were observed to be disintegrating. Loss of Beta cells was confirmed by immunohistology. Various polymer materials used in artificial membranes have been shown to activate macrophages involved in foreign body reactions and induce synthesis of interleukin-1 beta, a known Beta-cell toxin. Reduced secretion of insulin and progressive islet damage (indicated by a significant reduction in residual islet insulin and DNA content) were demonstrated when microencapsulated islets were incubated with interleukin-1 beta in vitro for 9 days. Similar effects were seen following exposure to a combination of gamma interferon and alpha tumour necrosis factor. Successful use of microencapsulation in islet transplantation depends upon the development of biocompatible membranes. The exclusion of smaller molecules, such as cytokines, which may be involved in foreign body mediated damage and microencapsulated islet graft rejection, could also be important.

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TL;DR: Reports on malondialdehyde in rat islets incubated with cytokines suggest that the cytotoxic action of cytokines on islet Beta cells may result from free radical production and lipid peroxidation in the islet cells.
Abstract: We have previously reported that oxygen free radical scavengers protect rat islet cells from damage by cytokines and we interpreted these findings as suggesting the involvement of oxygen free radicals but did not directly measure indices of free radical activity. In this study, we report on malondialdehyde, an end product of lipid peroxidation, in rat islets incubated with cytokines. The individual cytokines, interleukin 1 (1 U/ml), tumour necrosis factor (102 U/ml), and interferon gamma (102 U/ml) inhibited insulin release but did not increase islet malondialdehyde levels. Combination of these cytokines however, produced significant increases in islet malondialdehyde and this was accompanied by islet necrosis. Furthermore, an inhibitor of lipid peroxidation, U78518E, significantly decreased the cytokine-induced increase in islet malondialdehyde and protected islet Beta cells from destruction by the cytokine combination of interleukin 1, tumour necrosis factor and interferon gamma. These findings suggest that the cytotoxic action of cytokines on islet Beta cells may result from free radical production and lipid peroxidation in the islet cells.