Showing papers in "Diabetologia in 1985"

Homeostasis model assessment : insulin resistance and beta-cell function from fasting plasma glucose and insulin concentrations in man

Abstract: The steady-state basal plasma glucose and insulin concentrations are determined by their interaction in a feedback loop. A computer-solved model has been used to predict the homeostatic concentrations which arise from varying degrees beta-cell deficiency and insulin resistance. Comparison of a patient's fasting values with the model's predictions allows a quantitative assessment of the contributions of insulin resistance and deficient beta-cell function to the fasting hyperglycaemia (homeostasis model assessment, HOMA). The accuracy and precision of the estimate have been determined by comparison with independent measures of insulin resistance and beta-cell function using hyperglycaemic and euglycaemic clamps and an intravenous glucose tolerance test. The estimate of insulin resistance obtained by homeostasis model assessment correlated with estimates obtained by use of the euglycaemic clamp (Rs = 0.88, p less than 0.0001), the fasting insulin concentration (Rs = 0.81, p less than 0.0001), and the hyperglycaemic clamp, (Rs = 0.69, p less than 0.01). There was no correlation with any aspect of insulin-receptor binding. The estimate of deficient beta-cell function obtained by homeostasis model assessment correlated with that derived using the hyperglycaemic clamp (Rs = 0.61, p less than 0.01) and with the estimate from the intravenous glucose tolerance test (Rs = 0.64, p less than 0.05). The low precision of the estimates from the model (coefficients of variation: 31% for insulin resistance and 32% for beta-cell deficit) limits its use, but the correlation of the model's estimates with patient data accords with the hypothesis that basal glucose and insulin interactions are largely determined by a simple feed back loop.

The effect of proteinuria on relative mortality in Type 1 (insulin-dependent) diabetes mellitus

Abstract: We followed 1, 134 patients with Type 1 (insulin-dependent) diabetes, diagnosed between 1933 and 1952, until 1982 or death or until their emigration. Their age at onset of diabetes was under 31 years. Information concerning the development of persistent proteinuria was sought in every case. In 104 cases, the data were either questionable or the patient could not be traced. Twenty-nine patients developed non-diabetic proteinuria. Among the remaining 1,001 patients, 406 developed persistent proteinuria (350 died) and 595 did not (166 died). The incidence of persistent proteinuria was highest among men; it decreased with increasing year of diabetes onset from 1933 to 1952, and decreased with increasing age at onset. The relative mortality was extremely high among patients with persistent proteinuria, increasing to a maximum of about 100 at age 35 years. Patients not developing proteinuria had a relatively constant low relative mortality of about 2. The decreasing incidence of persistent proteinuria and the decreasing mortality with increasing calender year of diabetes onset resulted in a 50% increase in life-expectancy among patients diagnosed in 1950 compared with patients diagnosed in 1935. In patients who developed persistent proteinuria, relative mortality was higher in women than men at all ages. In patients who did not develop proteinuria, relative mortality was similar in men and women after the age of 35. Uraemia was the main cause of death in patients with persistent proteinuria, although cardiovascular deaths were more frequent than in patients without proteinuria. Thus, proteinuria is associated not only with death from uraemia but also from cardiovascular disease. It is concluded that the development of persistent proteinuria is a major life-threatening complication in patients with early-onset Type 1 diabetes. Patients who do not develop proteinuria have almost a normal life expectancy.

Hyperglycaemia as an inducer as well as a consequence of impaired islet cell function and insulin resistance: implications for the management of diabetes.

Abstract: It is postulated that hyperglycaemia influences the natural history of Type 1 (insulin-dependent) and Type 2 (non-insulin-dependent) diabetes mellitus. Hyperglycaemia, even when mild, can attenuate the secretory response of pancreatic β and α cells to increments in glucose and can impair insulin-mediated glucose transport, thus impeding its own correction and initiating a cycle of progressive self-exacerbation and metabolic deterioration. Both reduced islet function and insulin action may be the consequence of a generalized down-regulation and/or occupation of glucose transporters by hyperglycaemia so that the islets respond less to further increments in glycaemia. The postulated hyperglycaemic cycle can be initiated by any environmental perturbation that increases insulin demand in previously normoglycaemic patients in whom insulin secretion has already reached a maximum level of compensation for peripheral insulin resistance (as in obese pre-Type 2 diabetes) or for a reduced β-cell mass (as in pre-Type 1 diabetes). Elimination of hyperglycaemia by any means can halt this cycle of progressive metabolic deterioration and may restore transiently metabolic recompensation both in Type 1 and Type 2 diabetes. There is experimental evidence that long-standing severe hyperglycaemia may irreversibly damage β cells.

Glucagon physiology and pathophysiology in the light of new advances.

Abstract: Recent advances in the understanding of glucagoninsulin relationships at the level of the islets of Langerhans and of hepatic fuel metabolism are reviewed and their impact on our understanding of glucagon physiology and pathophysiology is considered. It now appears that α cells can respond directly to hyperglycaemia in the absence of insulin and β cells, but that antecedent hyperglycaemia masks or attenuates this response. Insulin appears to exert ongoing release inhibition upon glucagon secretion, probably via the intra-islet microvascular system that connects β cells to α cells. Diabetic hyperglucagonemia in insulin deficient states appears to be secondary to lack of the restraining influence of insulin. The α cell response to glucopenia, by contrast, may be in large part mediated by release of noradrenaline from nerve endings in contact with α cells. Glucagon's action on glucose and ketone production by hepatocytes is mediated by increase in cyclic-AMP-dependent protein kinase. The opposing action of insulin upon glucagon-mediated events probably occurs largely at this level. Consequently, when glucagon secretion or action is blocked, cyclic-AMP-dependent protein kinase activity is low even in the absence of insulin, explaining why marked glucose and ketone production is absent in bihormonal deficiency states.

Glucagon-like peptide-1 but not glucagon-like peptide-2 stimulates insulin release from isolated rat pancreatic islets.

Abstract: Glucagon-like peptide-1 and glucagon-like peptide-2 are encoded by the m-RNA of pancreatic preproglucagon. They show high conservation in different species and substantial sequence homology to glucagon. Because no definite biological activity of these peptides has been reported, we investigated the effect of synthetic C-terminally amidated glucagon-like peptide-1 [1–36] and synthetic human glucagon-like peptide-2 [1–34] with a free C-terminus on insulin release from isolated precultured rat pancreatic islets in the presence of glucose. Glucagon-like peptide-1 stimulates insulin release at 10 and 16.7 mmol/l glucose in a dose-dependent manner. Significant stimulation starts at 2.5 nmol/l in the presence of 10 mmol/l glucose and near maximal release is observed at 250 nmol/l, with approximately 100% increase over basal at both glucose concentrations. The peptide reaches 63% of the maximal stimulatory effect of glucagon. No stimulation occurs in the presence of 2.8 mmol/l glucose. Glucagon-like peptide-2 has no effect on insulin secretion at any glucose concentration tested. It is concluded that glucagon-like peptide-1, in contrast to glucagon-like peptide-2, exhibits a glucose-dependent insulinotropic action on isolated rat pancreatic islets similar to that of glucagon and gastric inhibitory polypeptide.

Continuous infusion of glucose with model assessment: measurement of insulin resistance and beta-cell function in man.

Abstract: Continuous infusion of glucose with model assessment (CIGMA) is a new method of assessing glucose tolerance, insulin resistance and beta-cell function. It consists of a continuous glucose infusion 5 mg glucose/kg ideal body weight per min for 60 min, with measurement of plasma glucose and insulin concentrations. These are similar to postprandial levels, change slowly, and depend on the dynamic interaction between the insulin produced and its effect on glucose turnover. The concentrations can be interpreted using a mathematical model of glucose and insulin homeostasis to assess insulin resistance and beta-cell function. In 23 subjects (12 normal and 11 with Type 2 (non-insulin-dependent diabetes) the insulin resistance measured by CIGMA correlated with that measured independently by euglycaemic clamp (Rs = 0.87, p less than 0.0001). With normal insulin resistance defined as 1, the median resistance in normal subjects was 1.35 by CIGMA and 1.39 by clamp, and in diabetic patients 4.0 by CIGMA and 3.96 by clamp. In 21 subjects (10 normal and 11 Type 2 diabetic) the beta-cell function measured by CIGMA correlated with steady-state plasma insulin levels during hyperglycaemic clamp at 10 mmol/l (Rs = 0.64, p less than 0.002). The CIGMA coefficient of variability was 21% for resistance and 19% for beta-cell function. CIGMA is a simple, non-labour-intensive method for assessing insulin resistance and beta-cell function in normal and Type 2 diabetic subjects who do not have glycosuria during the test.

Production of insulin resistance by hyperinsulinaemia in man.

Abstract: It has been proposed that hyperinsulinaemia may cause or exacerbate insulin resistance. The present studies were undertaken to test this hypothesis in man. Glucose utilization, glucose production, and overall glucose metabolism at submaximally and maximally effective plasma insulin concentrations (approximately 80 and approximately 1700 mU/l), and monocyte and adipocyte insulin binding were measured in normal volunteers on two occasions: once after 40 h of hyperinsulinaemia (25-35 mU/l) produced by infusion of insulin and once after infusion of saline (75 mmol/l; plasma insulin approximately 10 mU/l). After 40 h of hyperinsulinaemia, glucose utilization and overall glucose metabolism at submaximally and maximally effective plasma insulin concentrations were both slightly, but significantly, reduced compared with values observed after the infusion of saline (p less than 0.05), whereas glucose production rates were unaffected. Monocyte and adipocyte binding were also unaffected. These results indicate that hyperinsulinaemia of the magnitude observed in insulin resistant states, such as obesity, can produce insulin resistance in man. Assuming that human insulin sensitive tissues possess spare insulin receptors and that monocyte and adipocyte insulin binding accurately reflect insulin binding in insulin-sensitive tissues, the decreased maximal responses to insulin and the lack of change in insulin binding suggest that this insulin resistance occurred at a post-binding site.

New developments in the incretin concept

Abstract: Experimental and clinical work over the last 6 years has confirmed and broadened, but also challenged, the incretin concept. The nervous component of the entero-insular axis is still poorly defined, especially the peptidergic nerves, of which several contain insulinotropic regulatory peptides. The incretin effect is preserved after complete denervation of the porcine pancreas. Type 2 (non insulin-dependent) diabetic patients have a significantly decreased incretin effect. GIP (gastric inhibitory polypeptide; glucose dependent insulin releasing peptide) remains the strongest incretin factor. Its secretion depends on the absorption of nutrients. However, the correlation between the GIP response and disturbances of the entero-insular axis in some gastrointestinal diseases and, in particular, Type 2 diabetes, is poor. Furthermore, physiological concentrations of exogenous GIP do not produce fully the incretin effect and injection of GIP antibodies does not abolish the incretin effect. This suggests the existence of additional humoral incretin factors. On the other hand, GIP seems to have direct metabolic effects independent of its insulinotropic activity. The incretin effect of oral glucose is smaller if plasma levels of C-peptide rather than insulin are measured. However, decreased hepatic extraction of insulin after glucose ingestion only accounts partially for the incretin effect. GIP is unlikely to be the gut factor which regulates hepatic insulin extraction.

Patient education as the basis for diabetes care in clinical practice and research

Abstract: Despite the obvious improvements made in the field of diabetes therapy during this century [1] the quality of diabetes care has, in general, remained poor. The widespread failure to acknowledge the impact of patient education appears to evolve as the primary reason for this unsatisfactory situation. Despite the firm and well founded recommendations put forward by some of the pioneers of modem diabetology, e.g. Drs. E.P.Joslin and R.D. Lawrence in the 1920s, it has taken almost 50 years for the beneficial effects of patient education to have finally and unequivocally been proven. The recently developed strategies for a global approach to diabetes therapy which combines biomedical, psychosocial and educational elements represents an exemplary therapeutic model for the care of many chronic diseases.

Insulin-like growth factors and insulin: comparative aspects

Abstract: IGF I and IGF II are two insulin-like growth factors resembling insulin in many respects. They stem from a common precursor, act through receptors similar to the insulin receptor with which they cross-react. When administered in large amounts they produce hypoglycemia. Their major effects, however, are on replication and differentiation of cells of mesodermal origin. IGF I is the major growth promoting factor in vivo. The synthesis and secretion of IGF I by the liver depend on the growth hormone status, insulin and nutrition. In contrast to insulin, the IGFs circulate in blood bound to the carrier proteins. Their half-life in man is in the order of 16 h. IGF I deficiency results in dwarfism (pygmy, Laron dwarf, toy poodle) despite normal or elevated growth hormone secretion. The anabolic actions of insulin and of the IGFs appear to complement each other as shown in Figure 7.

Evaluation of thermal and vibration sensation in diabetic neuropathy.

Abstract: Sensory evaluation of diabetic neuropathy was undertaken by a new technique for assessment of thermal sensitivity The method is simple and reproducible, and the mean normal value of the lateral border of the foot was 60 °C (36–98 °C, 95% confidence limits) Four groups of patients with diabetic neuropathy were examined: 22 with neuropathic ulcers and/or Charcot joints (groups 1 and 2); all showed severe abnormalities (range 108->30 °C), frequently more than three times the upper limit of normal In contrast thermal sensitivity in 15 patients with painful neuropathy (group 4) varied from normal to grossly abnormal (range 39->30 °C) confirming this form of neuropathy as a distinct entity The majority of those 10 patients with autonomic neuropathy alone (group 3) had abnormal thermal sensitivity (range 64->30 °C) Comparison of thermal sensitivity (a small fibre modality) with vibration perception threshold (a large fibre modality) showed that thermal sensitivity is sometimes selectively affected, especially in those with painful neuropathy, suggesting that the small fibres are more vulnerable in diabetes Frequent involvement of the hands confirms the “stocking and glove” distribution of diabetic neuropathy We conclude that impairment of thermal sensivity is the rule in symptomatic diabetic neuropathy and its assessment provides a simple quantitive measurement suitable for long-term studies of its natural history

The epidemiology of diabetes in Swedish children 0-14 years--a six-year prospective study.

Abstract: Since 1 July 1977, all newly diagnosed diabetic children in Sweden aged 0–14 years have been reported to a central register. During the first 6 years, 2300 newly diagnosed diabetic children out of a population of 1.6 million children were registered. The degree of certainty was close to 100%. The mean of the yearly incidence rate for the whole 6 year period was 23.6 per 100000. The prevalence of insulin dependent diabetes mellitus on 1 July 1980 was 1.48 per 1000 and 1.52 on 1 July 1983. Comparing the first and second 3-year periods, an increase was found (22.7–25.1 per 100000). This increase was consistent when analyzing incidence rates by age, sex, and geographical distribution. Cumulative incidence rates revealed a risk of developing diabetes by the age of 15 years of 3.6 per thousand for boys and 3.2 per thousand for girls. The higher incidence for boys was consistent throughout the study period. Seasonal variations in the incidence rate were also consistent, showing yearly incidence peaks in the autumn and winter months. Incidence peaks were noted for both sexes in the pubertal ages. Age- and sex-standardized morbidity ratios varied significantly within the country. 12.8% of the probands had a first degree relative with Type 1 diabetes, and it was twice as common that this relative was a father as a mother. The high and rapidly increasing incidence of Type 1 diabetes in a genetically stable population such as Sweden calls for case-control studies directed towards the identification of environmental pathogens.

Reduction of diabetes incidence of BB Wistar rats by early prophylactic insulin treatment of diabetes-prone animals.

Abstract: A group of 36 diabetes-prone BB Wistar rats were given prophylactic insulin treatment with heat-treated bovine ultralente insulin (15 IU · kg−1 · day−1) from 50 to 142 days of age The incidence of Type 1 (insulin-dependent) diabetes at the end of the treatment period was compared to that of 36 control animals given insulin only from the first day of glycosuria At withdrawal of the prophylactic insulin treatment, 6 of 36 treated animals were insulin-dependent, while 15 of 36 control animals had developed diabetes (p<002) One control animal (day 153) and 2 insulin-treated animals (day 172 and 186) subsequently developed diabetes, yielding an overall diabetes incidence of 16 of 36 controls against 8 of 36 insulin treated (p<005) The finding that prophylactic insulin treatment of diabetes-prone BB Wistar rats reduced the incidence of diabetes suggests a relationship of the immune destruction of B cells to the endogenous insulin production/secretion rate

Prevalence of coronary heart disease, left ventricular failure and hypertension in middle-aged, newly diagnosed Type 2 (non-insulin-dependent) diabetic subjects

Abstract: The prevalence of coronary heart disease, left ventricular failure and hypertension was examined in a representative group of 133 newly diagnosed Type 2 (non-insulin-dependent) diabetic subjects (70 men, 63 women), aged 45 to 64 years, and in a group of 144 randomly selected non-diabetic control subjects (62 men, 82 women) of the same age group. The prevalence of previous myocardial infarction (major Q-QS abnormalities in resting ECG and/or myocardial infarction verified at hospital) was increased 1.7-fold in male (NS) and 4.4-fold in female (p = 0.007) diabetic patients compared with that found in non-diabetic subjects. Chest pain symptoms and ischaemic ECG abnormalities were about twice as common among diabetic than among non-diabetic subjects. The frequency of coronary heart disease defined by chest pain symptoms and ECG abnormalities was 3.5 times higher in male (p = 0.001) and 3.1 times higher in female (p = 0.001) diabetic patients than in the respective non-diabetic subjects. The frequency of current digitalis therapy was increased 3.3-fold in male (p = 0.006) and 3.9-fold in female (p = 0.001) diabetic patients suggesting an increased frequency of left ventricular failure among diabetic subjects. The prevalence of hypertension, based on the elevated blood pressure levels and/or current use of antihypertensive drugs, was increased 1.6–1.7-fold among the diabetic patients.

The effects of physical training on insulin secretion and effectiveness and on glucose metabolism in obesity and Type 2 (non-insulin-dependent) diabetes mellitus

Abstract: Obese subjects with normal glucose tolerance (n = 55), and, in another study, a group of patients with Type 2 (non-insulin-dependent) diabetes (n = 33), and controls (n = 13) matched for body weight and age but with normal glucose tolerance, participated in an individualized physical training program for 3 months. Under controlled dietary conditions, metabolic studies were performed before and in steady state after the last exercise session after training in the subjects showing signs of physical training in VO2 max and heart rate measurements. No changes occurred in body weight, body cell mass, body fat or adipose tissue cellularity. Oral glucose tolerance was improved in the patients with diabetes mellitus only. In both diabetic and control subjects initially elevated C-peptide concentrations decreased, while low C-peptide values increased and which was particularly pronounced in diabetic subjects with subnormal values. Peripheral insulin values did not change. Glucose disposal rate measured with the glucose clamp technique was similar in diabetic patients and control subjects. An improvement was seen at both submaximal and maximal insulin levels in both groups, correlating with improvement in glucose tolerance in the diabetic subjects. No changes were found in adipocytes in insulin binding or the antilipolytic effect of insulin at submaximal insulin levels, but there was a normalization of a decreased glucose incorporation into triglycerides. These results indicate that both insulin secretion and effectiveness are altered by physical training in different ways in different clinical entities. They suggest that in insulin resistant conditions with high insulin secretion (as indicated by high C-peptide concentrations) the increased peripheral insulin sensitivity is followed by a decreased insulin secretion. This is not associated with an improvement of glucose tolerance. In Type 2 diabetes with low insulin secretion, an increased insulin secretion results from physical training, perhaps due to accompanying sensitization of the autonomic nervous system. Peripheral insulin concentrations are not altered, suggesting that the extra insulin produced is captured by the liver. This mechanism, as well as the improved peripheral insulin responsiveness seen in the whole body and also seen at the cellular level, probably both contribute to an improvement in glucose tolerance.

The insulin factory: a tour of the plant surroundings and a visit to the assembly line. The Minkowski lecture 1973 revisited.

Abstract: Le point sur les recents resultats du point de vue morphologique sur la biosynthese, la maturation et la degradation de l'insuline et sur l'organisation des cellules endocrines au sein des ilots de Langerhans

Blood pressure and metabolic control as risk factors for nephropathy in type 1 (insulin-dependent) diabetes.

Abstract: The respective roles of arterial blood pressure and metabolic control in different stages of diabetic nephropathy were analyzed retrospectively in 52 sequentially-followed Type 1 (insulin-dependent) diabetic patients. A negative correlation was found between median post-prandial blood glucose and median duration of diabetes until onset of persistent proteinuria (p<0.01). Systolic blood pressure was higher in patients who subsequently developed persistent proteinuria than those who did not (140 versus 121 mmHg; p<0.05), but duration of the interval until onset of persistent proteinuria was not related to blood pressure. After onset of persistent proteinuria, hypertensive diabetic patients developed elevated serum creatinine concentrations more frequently than normotensive diabetic patients (67% versus 14%, p<0.05). In these patients, the delay until elevation of serum creatinine concentration was negatively correlated with blood glucose (p<0.01). Once serum creatinine was raised, decay of renal function occurred faster in patients with persistent than intermittent hypertension (p<0.05). No effect of metabolic control was demonstrable at this stage of nephropathy. It is concluded that metabolic control determines the early course of diabetic nephropathy, whereas blood pressure is more important in advanced stages of nephropathy.

Near normoglycaemia improved nerve conduction and vibration sensation in diabetic neuropathy

Abstract: Twelve C-peptide deficient Type 1 (insulin-dependent) diabetic patients with abnormal peripheral nerve function were randomly assigned to continuation of conventional insulin therapy (CIT) or to continuous subcutaneous insulin infusion (CSII). There were no statistically significant differences at entry to the study between the two treatment groups in nerve function assessed by neurologic disability score, computer assisted sensation examination and measurements of amplitudes, distal latencies, F-wave latencies and somatosensory evoked potential latencies over the spine and conduction velocities of motor and sensory fibers of ulnar, median, peroneal, tibial, plantar and sural nerves. In addition, mean plasma glucose from 24 h profiles (12.5 vs 10.6 mmol/l, respectively) and HbA1 (11.0 vs 11.6%, respectively) did not differ significantly between the two treatment groups at entry. Despite improved glycaemia from CSII in 5 patients (one dropped out of the study after 2 months) contrasted to CIT in 6 patients (5.3 vs 9.9 mmol/l, respectively, p=0.002) and HbA1 (8.5 vs 10.7%, respectively, p=0.002), there were no significant differences in measurements of peripheral nerve function after 4 months. After 8 months of improved glycaemia (4.4 vs 10.2 mmol/l, p=0.004) and improved HbA1, (8.3 vs 10.5%, p=0.002), nerve conduction (p=0.03) and vibratory sensation threshold (p=0.002) were significantly better in patients treated with CSII than those who received CIT. The improvements in nerve function, although small, provide further evidence that some clinical endpoints of neuropathy are favorably influenced by improved control of glycaemia.

Tropical pancreatic diabetes in South India: heterogeneity in clinical and biochemical profile.

Abstract: Clinical and biochemical studies were carried out in 33 patients with diabetes secondary to chronic calcific, non-alcoholic pancreatitis (tropical pancreatic diabetes) and in 35 Type 2 (non-insulin-dependent) diabetic patients and 35 nondiabetic subjects. Despite lower body mass indices, only 25% of patients with tropical pancreatic diabetes had clinical evidence of malnutrition. There was no history of cassava ingestion. Mean serum cholesterol concentration was significantly lower in the tropical pancreatic diabetic patients (p<0.01) in comparison with the Type 2 diabetic patients or non-diabetic subjects, due to a significantly decreased concentration of LDL cholesterol (p<0.01) and VLDL cholesterol (p<0.05). Basal and post-glucose stimulated concentrations of serum C-peptide were highest in those pancreatic diabetic patients (n=11) who responded to oral hypoglycaemic drugs, intermediate in the majority (n=17), who were insulin dependent and ketosis resistant and negligible in a small sub-group (n=5) who were ketosis prone. The occurrence of microangiopathy in pancreatic diabetic patients was common and similar to that in Type 2 diabetic patients. Thus, tropical pancreatic diabetes in South India appears to be heterogenous with respect to level of nutrition, severity of glucose intolerance, B-cell function, response to therapy and the occurrence of microvascular complications.

Pre-diabetes in the spontaneously diabetic BB/E rat: lymphocyte subpopulations in the pancreatic infiltrate and expression of rat MHC class II molecules in endocrine cells

Abstract: Use of monoclonal antibodies specific for rat lymphocyte subsets and an anti-insulin marker has allowed us to document the following sequence of events leading to the development of clinical diabetes in this animal model. The first change observed in the pancreas is increased expression of MHC class II molecules on vascular endothelium and this precedes lymphocytic infiltration. Next, T cells of the T helper phenotype infiltrate the pancreas around blood vessels. Many of the infiltrating T cells show class II expression indicating that they are activated. A few cytotoxic and suppressor cells and B lymphocytes are also present and their numbers increase proportionately with rat age. Some macrophages are also seen. Finally, at a late stage class II MHC molecules can be detected in partially destroyed islets on β cells which are still actively synthesising insulin. We have never observed expression of class II molecules on glucagon or somatostatin secreting cells which are invariably well preserved.

High prevalence of type 2 (non-insulin-dependent) diabetes among the offspring of conjugal type 2 diabetic parents in India.

Abstract: The prevalence of Type 2 (non-insulin-dependent) diabetes among offspring of conjugal Type 2 diabetic parents in India was determined by performing oral glucose tolerance tests. Diabetes was present in 50% of offspring, and 12% had impaired glucose tolerance according to the National Diabetes Data Group criteria. Thus, 62% of all offspring had abnormal glucose tolerance tests. This is the highest prevalence rate for diabetes among offspring of conjugal diabetic parents and might represent an ethnic variation of the genetic factors operating in Indian patients with Type 2 (non-insulin-dependent) diabetes.

Immunoisolation of pancreatic B cells by microencapsulation. An in vitro study.

Abstract: The selective permeability of alginate microcapsules, containing isolated rat islets of Langerhans or insulin secreting RINm5F cells, was investigated in vitro. An increase in insulin release was observed when microencapsulated islets were stimulated by glucose+theophylline, and when microencapsulated RINm5F cells were stimulated by arginine+theophylline. These findings demonstrate the permeability of the microcapsule membrane to these B-cell secretagogues and to insulin. Immunoisolation of RINm5F cells by microencapsulation was assessed using a 51chromium cytotoxicity test. Significant 51Cr release was observed when nonencapsulated cells were incubated with complement and either the serum of a rabbit immunized with RIN cells or the sera of two patients with recently diagnosed Type 1 (insulin-dependent) diabetes. This effect was not observed with encapsulated cells. Both free and encapsulated cells released 80% of their initial radioactivity when incubated in the presence of HC1. These results clearly demonstrate pancreatic cell immunoisolation by microencapsulation. They also provide a method for the in vitro evaluation of the functional characteristics of microcapsules, in terms of both insulin permeability and immunoprotection.

An hypothesis on the aetiology of obesity: dysfunction of the central nervous system as a primary cause.

Abstract: L'obesite, l'insulino-resistance et l'evolution vers le diabete de type II pourraient avoir la meme base conceptuelle neurologique

Limited benefit of treatment of diabetic polyneuropathy with an aldose reductase inhibitor: a 24-week controlled trial

Abstract: The effects of the aldose reductase inhibitor, sorbinil, on symptomatic symmetrical diabetic polyneuropathy were studied during a 6-month period in a double-blind parallel group placebo-controlled trial. Twenty-seven patients received sorbinil and 28 placebo. The patients were assessed by clinical examination, neurophysiological measurements, sensory threshold determinations and tests of autonomic nerve function. No major clinical benefit was seen in the sorbiniltreated patients and no differences in sensory thresholds were observed. In three out of nine neurophysiological tests (motor nerve conduction velocity of the posterior tibial nerve, F-wave latency and sensory distal latency of the ulnar nerve) and one out of five tests of autonomic nerve function (heart rate variation during deep breathing) significant differences between the patient groups evolved in favour of sorbinil treatment. An overall evaluation of the temporal development of these and remaining neurophysiological and autonomic variables suggested a small but significant benefit from sorbinil treatment. There was no evidence of continuing improvement throughout the treatment period and beneficial effects observed were no greater than those seen in previous trials of considerably shorter treatment periods. It is concluded that sorbinil treatment results in some improvement in peripheral nerve function in symptomatic diabetic polyneuropathy, but that the long-term effect may be of limited value.

Type 1 (insulin-dependent) diabetes and a highly variable locus close to the insulin gene on chromosome 11

Abstract: A polymorphic DNA sequence in the 5'-flanking region of the human insulin gene was studied in relation to Type 1 (insulin-dependent) diabetes. In 141 Caucasoid subjects analysed by Southern blot hybridisation techniques, two major DNA insertions were observed: a Class 1 allele or a Class 3 allele. The Class 2 allele was not observed in this group of subjects. Genotype frequencies in a control population (n = 88) were: homozygous 1/1, 42%; heterozygous 1/3, 50%; and homozygous 3/3, 8%. Corresponding genotype frequencies in 53 Type 1 diabetic patients were 79%, 21% and 0%, respectively (p less than 0.0005 from chi 2 test). This confirms prevalence data reported by Bell et al. [16]. There appeared to be no coinheritance with HLA-DR3/DR4 related antigens, nor with autoimmune features. Analysis of 17 Type 1 diabetic pedigrees including 34 diabetic and 69 non-diabetic subjects did not demonstrate genetic linkage of these DNA inserts with diabetes, using an autosomal recessive, single locus model of inheritance.

On the mechanism of the hypoglycaemic effect of a plant extract.

Abstract: The efficacy of a hypoglycaemic plant extract, in common use by Kuwaiti diabetic individuals, was evaluated using both streptozotocin-induced diabetic and normal rats. A significant decrease in blood glucose concentration was demonstrated on glucose tolerance tests, as compared to untreated animals. The sum of the fasting, 1 and 2 h blood glucose values, decreased from 18.5 +/- 0.72 to 13.6 +/- 0.62 mmol/l (p less than 0.001) and from 58.6 +/- 2.83 to 44.5 +/- 3.12 mmol/l (p less than 0.005) in normal and diabetic animals treated for 1 week, respectively. Treatment with the extract was not found to significantly alter insulin levels or intestinal glucose absorption. The mode of action of the hypoglycaemic preparation remains to be elucidated.

Rat hepatic microsomal glucose-6-phosphatase protein levels are increased in streptozotocin-induced diabetes.

Abstract: Hepatic microsomal glucose-6-phosphatase activity levels and the hepatic output of glucose are increased in diabetes. We have used protein chemistry and immunological techniques to determine the mechanism by which the activity levels of the glucose-6-phosphatase system are increased in streptozotocin-induced diabetic rats. In the streptozotocin-induced diabetic rats, the activity of the glucose-6-phosphatase enzyme increased four-fold without appreciably altering the transport capacity of the glucose-6-phosphatase system. The solubilized diabetic rat liver glucose-6-phosphatase enzyme appeared to be very similar to the solubilized enzyme from control rat liver microsomes. They exhibit the same Km, are labile at 30 °C, are stabilized by sodium fluoride and they migrate to the same position during density gradient centrifugation. Immunological studies demonstrated that a greater amount of hepatic microsomal glucose-6-phosphatase enzyme protein is present in diabetic rats than in control rats. Thus, we have determined for the first time that increased levels of the glucose-6-phosphatase protein are present in streptozotocin-induced diabetes. The significance of this finding in relation to the regulation of the hepatic microsomal glucose-6-phosphatase system is discussed.

Sucrose or honey at breakfast have no additional acute hyperglycaemic effect over an isoglucidic amount of bread in type 2 diabetic patients.

Abstract: Exclusion of simple sugars from the diabetic diet is not always followed by patients and may not even be as crucial as was hitherto thought. We tested three types of mixed breakfasts (400 kcal, 50 g HCO) including an isoglucidic amount either of white bread (30 g), honey (20 g) or sucrose (15 g), at the critical morning period i.e. for breakfast, in a group of 21 Type 2 (non-insulin-dependent) diabetic patients (6 well- and 15 badly controlled). Mean plasma glucose and insulin levels were comparable on the three occasions: respectively with bread, sucrose and honey, peak glucose values were 18 mmol/l, 17.7 mmol/l and 17.5 mmol/l in the uncontrolled group versus 13.9 mmol/l, 12.8 mmol/l and 12.7 mmol/l in the well-controlled group. Peak insulin values were 33.6 mU/l,34.0 mU/l and 36.3 mU/l (p>0.05) in uncontrolled patients against 57.5 mU/l, 54.8 mU/l and 52.5 mU/l in well-controlled subjects (p>0.05). The mean increment in peak plasma glucose values for the three breakfasts was as follows: 6.9 mmol/l, 6.3 mmol/l and 6.2 mmol/l for the uncontrolled group against 7.2 mmol/l, 5.9 mmol/l and 6.2 mmol/l in well-controlled subjects; the mean increment in peak plasma insulin levels was 21.8 mU/l, 22.0 mU/l and 24.2 mU/l in the controlled group versus 38.2 mU/l, 32.0 mU/l and 34.7 mU/l in the well-controlled subjects, all values being non-significantly different (p>0.05). We conclude that, in acute conditions, simple sugars have no additional hyperglycaemic effect over an isoglucidic amount of bread in well- and in badly controlled Type 2 diabetic patients, even at breakfast.

Measurement of free insulin concentrations: the influence of the timing of extraction of insulin antibodies.

Abstract: Plasma insulin concentrations of insulin-treated diabetic patients must be measured after removal of insulin antibodies, usually by precipitation with polyethylene glycol (PEG). Details of the procedure vary between laboratories; commonly, frozen plasma is thawed and incubated at 37 °C to restore a presumed equilibrium between free and antibody bound insulin before extraction. The present study was designed to investigate methodological factors that could affect the measured free insulin concentration. In normal subjects PEG extraction of globulins did not disturb measurement of insulin concentrations, whether carried out after incubation for 2 h at 37 °C, or storage at -20 °C, in either order. Freezing or incubation of PEG extracts of plasma from insulin-treated patients also failed to disturb the measured concentrations of free insulin. When plasma from patients was incubated for 2 h after storage, a marked scatter (51–272%) of measured results occurred when compared to bedside extraction. This problem was not overcome by buffering with HEPES or storage at a lower temperature (-40 °C). Incubation at 0 °C also severely disturbed the apparent concentrations. Incubation of plasma before extraction and freezing also disturbed the measured result, a problem not corrected by maintaining near physiological pH. Total insulin concentrations measured on acid extracts were not disturbed by any of these manoeuvres. The temperature of centrifugation of blood at the time of venepuncture did not influence the result. Furthermore, when insulin concentrations were rising or falling similar percentage changes were seen over a 30-min incubation of plasma before extraction on the day of venepuncture, suggesting that equilibrium between free and bound insulin is maintained in vivo. We suggest that, for accurate estimation of free insulin concentrations in insulin-treated diabetic patients, immediate centrifugation of blood and extraction of insulin antibodies is mandatory.

Relative mortality of Type 1 (insulin-dependent) diabetes in Denmark: 1933–1981

Abstract: The relative mortality of Type 1 (insulin-dependent) diabetes in Denmark during the period 1933–1981 was studied using a modification of Cox's regression model on the basis of two patient populations, ascertained in different ways and independently of each other. Initial analysis showed that the two groups could be combined completely into one common analysis. Relative mortality was the same for both sexes. The additional variables studied were age at diagnosis, current age, calendar year at diagnosis and calendar time during follow-up. All these interrelated variables were accounted for in the analysis. The analysis showed that relative mortality (a) decreased with increasing age at diagnosis; (b) increased from 1933 to a maximum in about 1965, after which it decreased; (c) increased with increased duration of diabetes to a maximum at 15–25 years, after which it declined.