Showing papers in "Diabetologia in 1986"

Reduced incretin effect in type 2 (non-insulin-dependent) diabetes.

Abstract: Integrated incremental immunoreactive insulin and connecting peptide responses to an oral glucose load of 50 g and an "isoglycaemic" intravenous glucose infusion, respectively, were measured in 14 Type 2 (non-insulin-dependent) diabetic patients and 8 age- and weight-matched metabolically healthy control subjects. Differences between responses to oral and intravenous glucose administration are attributed to factors other than glucose itself (incretin effect). Despite higher glucose increases, immunoreactive insulin and connecting peptide responses after oral glucose were delayed in diabetic patients. Integrated responses were not significantly different between both groups. However, during "isoglycaemic" intravenous infusion, insulin and connecting peptide responses were greater in diabetic patients than in control subjects as a consequence of the higher glycaemic stimulus. The contribution of incretin factors to total insulin responses was 72.8 +/- 6.9% (100% = response to oral load) in control subjects and 36.0 +/- 8.8% in diabetic patients (p less than or equal to 0.05). The contribution to connecting peptide responses was 58.4 +/- 7.6% in control subjects and 7.6 +/- 14.5% (p less than or equal to 0.05) in diabetic patients. Ratios of integrated insulin to connecting peptide responses suggest a reduced (hepatic) insulin extraction in control subjects after oral as compared to intravenous glucose. This was not the case in diabetic patients. Immunoreactive gastric inhibitory polypeptide responses were not different between control subjects and diabetic patients.(ABSTRACT TRUNCATED AT 250 WORDS)

The histopathology of the pancreas in type 1 (insulin-dependent) diabetes mellitus: a 25-year review of deaths in patients under 20 years of age in the United Kingdom.

Abstract: A 25-year computerised survey of deaths in the United Kingdom among diabetic patients of 19 years of age and under was performed. Suitable pancreatic material was available in 119 out of the 498 identified patients. The duration of diabetes was known in 95 of the 119 patients. In 60 patients it had been present for less than 1 year. Insulitis was present in 47 of the 60 patients (78%) with recent onset disease, and was also found in 3 patients who had been treated for diabetes for between 1 and 6 years. In cases in which it was identified, insulitis affected 23% of islets containing insulin, but affected only 1% of islets which were insulin deficient, thus supporting the concept that insulitis represents an immunologically mediated destruction of insulin secreting B cells. Four patients appeared to have a different disease from classical Type 1 (insulin-dependent) diabetes in that there was no evidence of insulitis and all islets contained insulin. The age of onset of diabetes was eighteen months or less in these patients.

Affinity-purified human Interleukin I is cytotoxic to isolated islets of Langerhans

Abstract: Addition of highly purified human Interleukin-1 to the culture medium of isolated rat islets of Langerhans for 6 days led to 88% inhibition of glucose-induced insulin-release, reduction of islet contents of insulin and glucagon to 31% and 8% respectively, and disintegration of the islets. These effects were dose-dependent and reproducible when using three different Interleukin-1 preparations. Highly purified human Interleukin-2, Lymphotoxin, Leucocyte Migration Inhibitory Factor and Macrophage Migration Inhibitory Factor were ineffective. These findings suggest that Interleukin-1 may play an important role in the molecular mechanisms underlying autoimmune B-cell destruction leading to Type 1 (insulin-dependent) diabetes mellitus.

Neuropeptidergic versus cholinergic and adrenergic regulation of islet hormone secretion.

Abstract: Augmentation des connaissances sur l'importance du controle nerveux des fonctions des ilots sous certaines conditions physiologiques: le systeme cholinergique est implique avant et pendant l'alimentation et peut-etre aussi dans l'insulino-secretion de l'obesite; le systeme nerveux sympathique controle les ilots pendant le stress; quant aux neuropeptides, leur etude vient a peine de commencer

Effects of vitamin D deficiency and repletion on insulin and glucagon secretion in man

Abstract: We have studied the effects of vitamin D deficiency on pancreatic A- and B-cell function. Four subjects with vitamin D deficiency and 10 healthy subjects were studied. Pancreatic B-cell function was assessed by the insulin response to an oral glucose tolerance test. An insulin tolerance test was used to evaluate pancreatic A-cell function. The patients were then treated with 2000 U/day of vitamin D3 for 6 months, after which the clinical, metabolic, biochemical and radiological features of vitamin D deficiency resolved, and pancreatic A-and B-cell function was repeated. In the vitamin D-deficient subjects pre-treatment and post-treatment serum calcium levels (mean +/- SEM) were 2.22 +/- 0.01 mmol/l and 2.24 +/- 0.01 mmol/l respectively, and 2.27 +/- 0.02 mmol/l in healthy subjects (NS). The pre-treatment level of 1,25-dihydroxy vitamin D (1,25-(OH)2D) of 29.7 +/- 3.3 pg/ml in the vitamin D deficient subjects rose to 70.3 +/- 10.3 pg/ml after treatment (p less than 0.05). The 1,25-(OH)2D level in the healthy subjects was 50.0 +/- 13.7 pg/ml (p less than 0.05 versus pre- and post-treatment values in the patients). Insulin secretion, calculated by the area under the insulin curve, was significantly lower before vitamin D3 treatment in the patients (9.09 +/- 0.7 mU X min, p less than 0.05) compared with the healthy subjects (11.9 +/- 0.5 mU X min) and post-treatment values of the patients with vitamin D deficiency (13.7 +/- 0.5 mU X min). Similar changes were seen in the insulogenic indices (delta I/delta G).(ABSTRACT TRUNCATED AT 250 WORDS)

Increased transcapillary escape rate of albumin in Type 1 (insulin-dependent) diabetic patients with microalbuminuria

Abstract: The transcapillary escape rate, intravascular mass and outflux of albumin were measured in 75 Type 1 (insulin-dependent) diabetic patients. The groups were defined as: group 1: normal urinary albumin excretion, <30 mg/24 h (n=21); group 2: microalbuminuria, 30–300 mg/24 h (n=36); group 3: diabeticnephropathy, <300 mg/24 h (n=18). Fifteen sex- and age-matched non-diabetic persons served as control subjects. The diabetes duration was: group 1: 20±9 years, group 2: 17±5 years, group 3: 19±7 years. The transcapillary escape rate of albumin was similar in controls and group 1 (5.0±1.8 versus 5.2±1.5%) and was significantly higher in the microalbuminuric group 2 and group 3 (8.1±2.2 versus 8.1±2.3 %). The differences were not explained by differences in metabolic control or blood pressure at the time of investigation. The outflux of albumin was also higher in group 2 than in group 1 and controls (7.1 ± 2.0 versus 5.3±1.5 and 5.1±2.0 g/h × 1.73 m2). It was indistinguishable from controls in group 3 (5.8±1.5 g/h × 1.73 m2) because of a reduced intravascular mass of albumin (p<0.01) in group 3. In conclusion, a universal vascular leakage of albumin is an early event in the development of diabetic nephropathy, with the leakage of albumin being fully developed in the microalbuminuric patient. In contrast, long-term diabetic patients with normal urinary albumin excretion have a normal transcapillary escape rate of albumin.

Heterogeneity of insulin responses: phases leading to Type 2 (non-insulin-dependent) diabetes mellitus in the rhesus monkey

Abstract: To determine the natural history of the development of Type 2 (non-insulin-dependent) diabetes mellitus, basal plasma insulin and glucose levels and responses to intravenous glucose tolerance tests were determined over a period of 6 years in 42 adult male rhesus monkeys (Macaca mulatta). Among the 28 obese monkeys (percent body fat > 22%) over the age of 10 years, 9 developed overt Type 2 diabetes (fasting plasma glucose, > 7.8 mmol/l; and reduced glucose disappearance rates, KG < 1.5), and 14 monkeys have shown progressive changes which suggest that they may also become diabetic. Application of a highly constant antecedent diet and a consistent 16-h fast minimized experimental variability, and permitted the identification of 8 phases in the progression from normal lean young adult to overt Type 2 diabetes. The earliest changes which could be detected were a slight increase followed by a progressive rise in fasting plasma insulin levels and an increased insulin secretion in response to a glucose stimulus. These events preceded by several years the onset of a gradual deterioration of glucose tolerance. We found that hyper-, normo-, or hypoinsulinaemia could be associated with normoglycaemia or varying degrees of hyperglycaemia; however, the prospective longitudinal study of individual monkeys clearly identified this apparent heterogeneity of plasma insulin and glucose levels as reflecting sequential changes in a continuum of events preceding or accompanying the development of impaired glucose tolerance and Type 2 diabetes mellitus.

In vivo insulin resistance in individual peripheral tissues of the high fat fed rat: assessment by euglycaemic clamp plus deoxyglucose administration.

Abstract: We have examined peripheral insulin action in conscious rats chronically fed high fat (60% calories as fat) or high carbohydrate (lab chow) diets using the euglycaemic clamp plus 3 H-2-deoxyglucose technique. A response parameter of individual tissue glucose metabolic rate (the glucose metabolic index, based on tissue deoxyglucose phosphorylation) was used to assess diet effects in eight skeletal muscle types, heart, lung and white and brown adipose tissue. Comparing high fat with high carbohydrate fed rats, basal glucose metabolism was only mildly reduced in skeletal muscle (only diaphragm was significant,p<0.05), but was more substantially reduced in other tissues (e.g. white adipose tissue 61% and heart 33%). No evidence of basal hyperinsulinaemia was found. In contrast, widespread insulin resistance was found during the hyperinsulinaemic clamp (150 mU/l) in high fat fed animals; mean whole body net glucose utilization was 34% lower (p<0.01), and the glucose metabolic index was lower in skeletal muscle (14 to 56%,p< 0.05 in 6 out of 8 muscles), white adipose (27%,p<0.05) and brown adipose tissue (76%,p<0.01). The glucose metabolic index was also lower at maximal insulin levels in muscle and fat, suggesting the major effect of a high fat diet was a loss of insulin responsiveness. White adipose tissue differed from muscle in that incremental responses (maximal insulin minus basal) were not reduced by high fat feeding. The heart showed an effect opposite to other tissues, with an increase in insulin-stimulated glucose metabolism in high fat versus chow fed rats. We conclude that high fat feeding, without a major increase in body weight or basal hyperinsulinaemia, causes widespread but varying degrees of in vivo insulin resistance in peripheral tissues, with major effects in principally oxidative skeletal muscle.

Serum immunoreactive insulin responses to a glucose load in Asian Indian and European type 2 (non-insulin-dependent) diabetic patients and control subjects.

Abstract: The serum immunoreactive insulin response to an oral glucose load was estimated in 15 Asian Indian and 29 European non-diabetic subjects, and in 45 Asian Indian and 72 European Type 2 (non-insulin-dependent) diabetic patients. In the non-diabetic group, basal insulin values were higher in the Asian Indians than the Europeans (16.7 +/- 3.0 vs. 6.9 +/- 0.7 mU/l, p less than 0.001), and remained higher throughout the glucose tolerance test. Total insulin response was also higher in the Asian Indians (p less than 0.001), and linear regression analysis revealed basal insulin, body mass index and race to be important predictors of insulin response. Amongst the diabetic patients, basal insulin values were again higher in the Asian Indians compared with the Europeans (18.0 +/- 5.0 vs. 11.5 +/- 0.9 mU/l, p less than 0.05). Total insulin response was also greater (p less than 0.01). Linear regression analysis revealed the basal insulin value to be the only significant predictor of insulin response. The results demonstrate higher insulin levels in Asian Indians than Europeans in both normal subjects and Type 2 diabetic subjects. The insulin response to a glucose load is also greater in the Asian Indians. In the control subjects, ethnic differences contribute to this response, whereas in the diabetic patients this is a function of the elevated basal insulin values of the Asian Indians.

Diabetic control and microvascular complications: the near-normoglycaemic experience.

Abstract: Les benefices du meilleur controle metabolique possible dans le diabete de type 1 sont maintenant bien documentes et prouves ; par contre les methodes pour arriver a ce but meritent d'autres etudes

Cigarette-smoking as a risk factor for macroproteinuria and proliferative retinopathy in type 1 (insulin-dependent) diabetes.

Abstract: In a case control study 192 cigarette-smoking patients with Type 1 (insulin-dependent) diabetes were compared with 192 non-cigarette-smoking patients pair-matched for sex (90 females), duration of diabetes (mean 14 years), and age (mean 32 years). Macroproteinuria was found in 19.3% of the smoking and in 8.3% of the non-smoking patients (p less than 0.001). Proliferative retinopathy was present in 12.5% of the smoking and in 6.8% of the non-smoking patients (p less than 0.025). The percentages of patients with normal proteinuria or without retinopathy were comparable between the two groups. In addition, glycosylated haemoglobin values and the prevalence of hypertension were similar between smoking and non-smoking patients. Thus, cigarette-smoking appears to be a risk factor for the progression of incipient to overt nephropathy and of background to proliferative retinopathy in Type 1 diabetes.

Effect of past and concurrent body mass index on prevalence of glucose intolerance and type 2 (non-insulin-dependent) diabetes and on insulin response. The Israel study of glucose intolerance, obesity and hypertension.

Abstract: A representative sample (n=2140) of the Israeli Jewish population aged 40–70 (excluding known diabetic patients), whose body mass index had been measured 10 years earlier, underwent an oral glucose tolerance test and redetermination of body mass index. Irrespective of weight changes, high concurrent and high past body mass index values (≥ 27) were associated with similarly increased rates of glucose intolerance as compared with body mass index values < 27 at both time-points (rate ratio 1.76, 90% confidence limits 1.56–1.99). Glucose intolerance here includes borderline and impaired tolerance as well as Type 2 diabetes. The rate of Type 2 diabetes increased only with increasing past body mass index, while concurrent body mass index had no effect [rate ratios: 2.36 (1.48–3.75) and 1.99 (1.48–2.68) respectively for the medium-(23–26.9) versus-low (<23) and high- (≥ 27) versus-medium past body-mass-index categories]. Weight reduction was associated with only slightly reduced rate of glucose intolerance and had no effect on the rate of diabetes. Mean sum insulin (summed 1 and 2 h levels, mU/l) increased significantly with increasing concurrent body mass index (123, 150 and 190 in the low, medium and high categories) with no effect of past body mass index. It also increased significantly (p < 0.001) in all concurrent body mass index categories from normal tolerance through borderline to impaired tolerance, and decreased significantly (p < 0.001) in diabetes relative to impaired tolerance, although it remained above normal. Means of sum insulin within each glucose tolerance level were similar in the two lower concurrent body mass index categories, with markedly higher (p < 0.001) levels in the high body mass index category. All these findings held after accounting for age, sex, ethnic group and use of antihypertensive medications. We conclude that body mass index ≥ 27 leads to early impairment in glucose tolerance. A prolonged period of obesity is apparently required for the development of Type 2 diabetes and its associated reduced insulin response. The reversibility of the deterioration of glucose tolerance seems to be limited.

Preventive effects of cyclosporin on diabetes in NOD mice.

Abstract: Non-obese diabetic mice aged 30 to 60 days were treated orally with Cyclosporin at doses of 25, 15 and 2.5 mg/kg every 2 days until 160 days of age. Diabetes developed in 12 out of 18 oil-treated mice (67%), with partial to complete Langerhans' islet destruction associated with lymphocytic infiltration. The non-obese diabetic mice showed a plasma glucose concentration of 6.62 +/- 0.92 mmol/l (mean +/- SD) at 50 days of age. The plasma glucose level of oil-treated non-obese diabetic mice gradually increased after 130 days of age and reached 14.0 to 19.0 mmol/l at 160 days of age, while Cyclosporin-treated non-obese diabetic mice showed neither clear increase of plasma glucose levels nor development of insulitis. The cumulative incidence of diabetes in Cyclosporin-treated mice was significantly lower than that in oil-treated mice (p less than 0.01). Subsequently, Cyclosporin treatment was started after development of glucose intolerance. Twenty-five mg/kg of Cyclosporin was administered every 2 days for 35 days. Cyclosporin appeared to have little therapeutic effect on diabetes in non-obese diabetic mice.

Immunology and diabetes workshop: Report on the third international (Stage 3) workshop on the standardisation of cytoplasmic islet cell antibodies

Abstract: Ce troisieme workshop s'est attache a determiner la precision des differents laboratoires, la specificite des anticorps anti-ilots, l'amelioration des concordances interlaboratoires en utilisant les standards JDF, et l'expression des resultats avec des unites arbitraires

Subcutaneous implantation of a ferrocene-mediated glucose sensor in pigs.

Abstract: Miniature, amperometric glucose sensors were constructed using entrapped 1,1'-dimethylferrocene to mediate electron transfer between immobilised glucose oxidase and a carbon base electrode. Electrodes were calibrated in buffered glucose solutions and then implanted in the subcutaneous tissue of anaesthetised, non-diabetic pigs. Subcutaneous tissue glucose concentrations, as measured by the sensor, were about 20% of blood glucose values, measured by a conventional glucose oxidase assay. After an intravenous 0.07 mol bolus glucose injection, electrode responses increased with almost no time lag, but the subsequent rates of rise and fall of electrode-measured tissue glucose concentrations were slower than that of the blood values. After an intravenous 0.2 U/Kg bolus short-acting insulin injection the electrode response was also rapid, but decreased at a slower rate than the blood glucose concentrations. We conclude that this is a feasible technology for future development as an implantable glucose sensor for use in diabetic man.

Longitudinal studies on the development of diabetes in individual Macaca nigra.

Abstract: Development of spontaneous diabetes has been monitored in individual Macaca nigra. In this study, pancreatic biopsies were taken, islets were assessed morphologically, and results were related to the metabolic/clinical status. A biopsy or autopsy sample was obtained 4 to 10 years later, and the islet morphological state was again related to the metabolic/clinical status. Metabolic deterioration was correlated to the islet lesion, in which there was gradual loss of islet secretory cells and concurrent amyloid deposition. As nondiabetic monkeys with 0 to 3% islet amyloid progressed up to 20 to 40% amyloid, the insulin secretion and glucose clearance were both decreased (p<0.01), and the glucose and glucagon levels increased (p=0.05). Impaired monkeys progressed to overt diabetes when islet amyloid exceeded 50 to 60%. Diabetic monkeys developed hyperglycaemia, along with impaired insulin secretion and glucose clearance (p<0.04). Loss of islet cells results in metabolic deterioration. The lesion precedes development of overt diabetes in Macaca nigra.

Insulin autoantibodies in the pre-diabetic period: correlation with islet cell antibodies and development of diabetes.

Abstract: IgG and IgM class insulin autoantibodies were measured by an enzyme-linked immunosorbent assay in sera from members of the Barts-Windsor-Middlesex prospective family study for Type 1 (insulin-dependent) diabetes. One hundred and twelve individuals from 28 families were selected for study on the basis of a clearly defined islet cell antibody status. IgG insulin autoantibodies were found to be significantly associated with islet cell antibody positive (n=30) versus islet cell antibody negative (n= 57) first degree family relatives (p=0.002), with increased significance (p=0.0003) if complement-fixing (CF)-islet cell antibody individuals (n=20) only were considered. In addition, a significant association of IgG insulin autoantibodies with subsequent development of diabetes was observed within the CF-islet cell antibody positive group (p<0.0003). No such associations were found for IgM insulin autoantibodies, but a higher prevalence of these autoantibodies was observed in islet cell antibody negative first degree relatives (n=57) compared with a control group of 73 Blood Bank donors (p=0.00007), and they were significantly associated with siblings (n=48) rather than parents (n=39), (p=0.001). We conclude that the presence of IgG insulin autoantibodies and CF-islet cell antibodies confer more risk for future development of diabetes than the presence of either marker alone.

Prevalence of microalbuminuria in children with Type 1 (insulin-dependent) diabetes mellitus

Abstract: The prevalence of microalbuminuria was determined in children aged 7 to 18 years with Type 1 (insulin-dependent) diabetes of more than 2 years' duration. All patients (n =102) attending 2 diabetes clinics were asked to collect 2 overnight timed urine samples for albumin analysis by radioimmunoassay. Complete urine collection was obtained in 97 patients (95%). Overnight urinary albumin excretion rates were also measured in 36 healthy children matched for age and sex. Nineteen of the 97 patients (20%) had microalbuminuria, i. e. overnight urinary albumin excretion rates above the upper normal level (14 μg/min) in both urine collections. Microalbuminuria was only demonstrated in patients aged ≥ 15 years, prevalence 37% (19/52 patients). Arterial blood pressure was elevated, mean 122/84±11/9mmHg, in the microalbuminuric group (19 patients) compared to the age-matched normoalbuminuric diabetic group (33 patients), mean 117/74±10/10 mm Hg,p < 0.001. The prevalence of simplex retinopathy was identical in these two groups, i. e. 25%. Glycosylated haemoglobin was slightly higher in the microalbuminuric patients,p < 0.10. Our cross-sectional study reveals a high prevalence (37%) of persistent microalbuminuria, a stage highly predictive of later development of diabetic nephropathy, in Type 1 diabetic children aged ≥ 15 years.

The renal subcapsular site offers better growth conditions for transplanted mouse pancreatic islet cells than the liver or spleen.

Abstract: In order to investigate the importance of the transplantation site for the replication of grafted islet cells, we implanted syngeneic mouse pancreatic islets intrasplenically, intraportally and subcapsularly in the kidney. Fourteen days later the alloxan-diabetic mice were killed after an injection of tritiated thymidine, and the graft-bearing organs fixed and processed for autoradiography. The highest labelling indices were recorded for subcapsularly grafted islets, followed by intraportal and intrasplenic islets in that order. In separate experiments some islet-containing kidney sections were immune stained for insulin before the autoradiographic process. The labelling index of the insulin-positive cells was as high as in the entire islet cell population of the sections from the same mice stained with haematoxylin only. This indicates that the B cells of the islets replicate as often as the other islet cell types. The present data also suggest that the renal subcapsular space offers better growth conditions for transplanted islet cells than the liver or spleen.

Glycosylation of low density lipoprotein in patients with type 1 (insulin-dependent) diabetes: correlations with other parameters of glycaemic control.

Abstract: Glycosylation of low density lipoproteins obtained from 16 patients with Type 1 (insulin-dependent) diabetes and from 16 age-, sex-, and race-matched controls, was determined. The diabetic patients were normolipaemic and were in good or fair glycaemic control. Eleven patients performed home blood glucose monitoring. Glycosylation of low density lipoproteins in the diabetic patients was significantly higher (p < 0.001) than in the control subjects, and was significantly correlated with haemoglobin A1c, (p < 0.01), glycosylation of plasma proteins, (p < 0.001), and mean home blood glucose, (p < 0.01). This study confirms that, in diabetic patients, increased glycosylation of low density lipoprotein occurs to an extent which correlates closely with other commonly used indices of glycaemic control.

Risk factors for the development of retinopathy in children and adolescents with Type 1 (insulin-dependent) diabetes mellitus

Abstract: In our preceding paper, the prevalence and development of retinopathy in 231 Type 1 diabetic children and adolescents were reported to be associated with the duration of diabetes and its age at onset. This paper analyses the relationships between the development of retinopathy and the following factors: age, sex, puberty, blood pressure, insulin dosage, HLA antigens, long-term glycaemic control, and serum cholesterol and triglycerides. All these variables were longitudinally evaluated in a cohort of 322 insulin-dependent patients aged 16.2 ± 4.9 years with diabetes for 7.4 ± 5.2 years, including those 231 subjects whose eyes were examined once or repeatedly by ophthalmoscopy and fluorescein angiography. Long-term glycaemic control from the onset of diabetes to the retinal examination was assessed by both an arbitrary score comprising different parameters and by mean values of glycosylated haemoglobin, and was categorised as good, fair, and poor. With life-table analysis, the overall median individual risk for developing early retinal changes (9.1 years) was found to be significantly influenced by glycaemic control. Minimal lesions developed earlier (8.0 years) with poor control, but later with fair (10.5 years) and good glycaemic control (12.5 years) (p < 0.01). Mean HbA1 values below 10% delayed the onset of both incipient (10.8 years) and background retinopathy (16.6 years), while values above 10% advanced it (8.0 and 11.8 years respectively) (p < 0.05 and < 0.008). By multivariate regression and stepwise discrimination analyses, only 4 out of 14 variables were found to exert significant independent influences on the development of retinopathy: diabetes duration, long-term glycaemic control, serum triglycerides and age. The correlation coefficients with retinopathy cumulatively increased fromr=0.78 for duration of diabetes only tor=0.81 for the sum of these four factors. None of the other variables was found to increase this value any further.

Prevalence and development of retinopathy in children and adolescents with type 1 (insulin-dependent) diabetes mellitus. A longitudinal study

Abstract: In 231 subjects with Type 1 diabetes mellitus aged 17.6 ± 4.0 years, with a diabetes duration of 8.5 ± 4.9 years at the end of the study, the prevalence and the development of retinopathy during a period of 5 years were studied. All patients were examined between one and six times both by ophthalmoscopy and fluorescein angiography. A total of 626 fluorescein angiographies were evaluated. By the end of the study, 109 out of 231 patients (47%) had developed retinal changes, half of which were classified as minimal (<5 microaneurysms). Thirty-eight patients (35% of those affected) had background (n = 28) or proliferative (n = 10) retinopathy. In subjects less than 15 years of age and diabetic for less than 5 years, retinal lesions were rare. With increasing age and duration of diabetes, both the prevalence and severity of retinal changes increased markedly. Life-table analysis was used to calculate the median individual risk for the development of early retinal changes, which was 9.1 years of diabetes duration. This risk differed in sub-groups with different ages at onset of diabetes, i. e. 12.1, 8.9 and 6.6 years (p < 0.0001), with diabetes starting below 4, between 5 and 9, and after 10 years of age respectively. After 18 years of diabetes, every patient demonstrated at least incipient structural changes. Fluorescein angiography allowed the detection of retinopathy, on average, four years earlier than with ophthalmoscopy. The median interval between the ‘onset’ of retinopathy, as indicated by a few microaneurysms, and background retinopathy was 5 years.

The effects of sorbinil on peripheral nerve conduction velocity, polyol concentrations and morphology in the streptozotocin-diabetic rat.

Abstract: This study examined the effects of an aldose reductase inhibitor, Sorbinil, on neuropathy over a 6-month period in streptozotocin-diabetic rats. Sorbinil treatment prevented the 10-fold increase in nerve sorbitol found with diabetes. It produced a 60% improvement in tibial nerve motor conduction velocity after 6 months. Morphometric profiles of nerves were also normalised. Axon area was reduced by 14% in untreated diabetic rats compared to age-matched controls, whereas Sorbinil-treated animals showed normal age-related axon growth. Myelin area was increased by 28% in untreated diabetic animals, but was the same as age-matched controls with Sorbinil treatment. Nervemyo-inositol levels were reduced by 45% after three months of untreated diabetes, but were normal after ix months. Sorbinil treatmend tended to restore myo-inositol levels toward normal over the shorter time period. It was concluded that axon growth retardation is the most likely cause of the conduction deficit seen in longterm experimental diabetes.

Sucrose in the diet of diabetic patients--just another carbohydrate?

Abstract: The effects of regularly eating sucrose were studied in 23 diabetic patients, 12 Type 1 (insulin-dependent) and 11 Type 2 (non-insulin-dependent), with differing degrees of glycaemic control. Two diets, each lasting 6 weeks, were compared in a randomised cross-over study. Both diets were high in fibre and low in fat. In one diet 45 g of complex carbohydrate was replaced by 45 g of sucrose taken at mealtimes. There were no significant biochemical differences between the two diets in either Type 1 or Type 2 patients. In Type 1 patients the mean (+/- SEM) fasting plasma glucose was 10.5 (1.8)mmol/l on the control diet and 10.3 (1.5) mmol/l on sucrose. In Type 2 patients the levels were 9.1 (0.8) mmol/l and 8.9 (0.8) mmol/l respectively. Glycosylated haemoglobin for the Type 1 patients was 9.9% on control and 10.3% on sucrose; for Type 2 patients the figures were 9.3% and 9.0% respectively. There were no differences in mean daily plasma glucose levels or diurnal glucose profiles. Cholesterol (total and in lipoprotein fractions) was unchanged, as were diurnal triglyceride profiles and plasma insulin profiles in the Type 2 patients. There were no changes in medication or body weight. We conclude that a moderate amount of sucrose taken daily at mealtimes does not cause deterioration in metabolic control in diabetic patients following a high fibre/low fat diet.

HLA-DR 3 is associated with a more slowly progressive form of type 1 (insulin-dependent) diabetes.

Abstract: The presence of HLA-DR 3 was analysed in 745 patients with Type 1 (insulin-dependent) diabetes with age at diagnosis between 1–19 years. HLA-DR 3 and/or 4 was found in 678/745 (91%) of the patients. Presence of DR 2 with neither DR 3 nor 4 was demonstrated in 15 patients. Patients with HLA-DR 3 without DR 4 presented with Type 1 diabetes more evenly over the year; they also presented without incidence peaks at 7 years or 10–11 years, as seen especially in DR 3/4 patients. The DR 3 patients more often had mild disease with less ketonuria at diagnosis, less often ketoacidotic symptoms and more often a subsequent partial remission. The apparently more severe disease among diabetic girls may, at least to some extent, be explained by their higher prevalence of HLA-DR4. The differences found were similar in North America and Europe. The results suggest that Type 1 diabetes is a genetically heterogenous disease and that HLA-typing may be a useful marker of this heterogeneity.

Insulin induces opposite changes in plasma and erythrocyte magnesium concentrations in normal man

Abstract: Plasma and erythrocyte magnesium levels were measured by atomic absorption spectrophotometry in 10 healthy volunteers during an oral glucose tolerance test and during an euglycaemic hyperinsulinaemic glucose clamp. At min 180 and 210 of the oral glucose tolerance test, a significant decline in plasma magnesium levels (p less than 0.01 and p less than 0.05 respectively) and a significant increase in erythrocyte magnesium levels (p less than 0.01 and p less than 0.05 respectively) were observed. Similar changes were seen during the second hour of the glucose clamp, during which euglycaemia (4.1 +/- 0.4 mmol/l) was maintained despite hyperinsulinaemia (110-130 mU/l). During in vitro incubations, glucose (5 mmol/l) did not modify erythrocyte magnesium levels. In contrast, erythrocyte magnesium levels were significantly increased (p less than 0.01) by insulin (100 mU/l), an effect entirely abolished by ouabain (5 X 10(-4) mol/l). These results suggest that insulin induces a shift of magnesium from the plasma to the erythrocytes both in vivo and in vitro. These data may help to interprete the abnormalities in magnesium circulating levels frequently reported in diabetic patients.

The effect of metabolic control on leucine metabolism in Type 1 (insulin-dependent) diabetic patients

Abstract: Leucine production rate, metabolic clearance rate and oxidation rate were measured in 10 Type 1 (insulin-dependent) diabetic patients after (1) 24 h insulin withdrawal, (2) conventional insulin therapy and (3) an overnight insulin infusion to maintain normoglycaemia, and in 10 control subjects. In the insulin-withdrawn patients, leucine concentration (259 ± 17 μmol/1), production rate (2.65 ± 0.29 p mol·min−1 kg−1) and oxidation rate (0.69 ± 0.10 μmol · min−1 · kg−1) were significantly greater (p < 0.001;p < 0.05;p < 0.005 respectively) than corresponding values in control subjects (127±6; 1.81 ± 0.12; 0.19 ± 0.02). Following conventional insulin therapy, leucine concentration (162 ± 12 μmol/1) and oxidation rate (0.43 ± 0.05 μmol · min−1 · kg−1) were lower than after insulin withdrawal but were still significantly greater than in control subjects (p<0.05;p<0.005). Although leucine concentration, production rate and metabolic clearance rate were normal after an overnight insulin infusion, leucine oxidation rate was still greater than normal (0.34 ± 0.06 μmol · min−1 kg−1;p<0.05). These results suggest that increased leucine concentration in insulin deficiency is due to elevated leucine production rate caused by increased proteolysis, and that leucine concentration is restored to normal by insulin treatment.

Progression of subclinical polyneuropathy in young patients with type 1 (insulin-dependent) diabetes: associations with glycaemic control and microangiopathy (microvascular complications).

Abstract: The progression of subclinical polyneuropathy over 2.5 years has been studied in a representative group of 75 young patients with Type 1 (insulin-dependent) diabetes (initial age 16–19 years). The relationships between changes in nerve function, glycaemic control and concurrently developing microvascular complications (retinopathy, microproteinuria) were investigated. Deterioration of motor, sensory and autonomic nerve function, retinopathy and microproteinuria was related to poor glycaemic control. In addition, there was an association between developing neural and microvascular complications which was not diminished when their common relationship to hyperglycaemia was taken into account. These findings suggest that, although poor glycaemic control is an essential permissive factor in the early development of diabetic polyneuropathy, other influences, shared with microvascular complications, must also be important.

The serum insulin and plasma glucose responses to milk and fruit products in type 2 (non-insulin-dependent) diabetic patients.

Abstract: The plasma glucose and serum insulin responses were determined in untreated Type 2 (non-insulin-dependent) diabetic patients following the ingestion of foods containing sucrose, glucose, fructose or lactose in portions that contained 50 g of carbohydrate. The results were compared to those obtained following the ingestion of pure fructose, sucrose, glucose + fructose and lactose. The objectives were to determine 1) if the glucose response to naturally occurring foods could be explained by the known carbohydrate content, and 2) whether the insulin response could be explained by the glucose response. The glucose response was essentially the same whether the carbohydrate was given as a pure substance, or in the form of a naturally occurring food. The glucose response to each type of carbohydrate was that expected from the known metabolism of the constituent monosaccharides. The glucose areas following the ingestion of the foods were: Study 1: glucose 11.7, orange juice 7.3, sucrose 5.2, glucose + fructose 6.3, and fructose 0.7 mmol X h/l; Study 2: glucose 14.6, orange juice 7.3, apples 5.5, and apple juice 4.7 mmol X h/l; Study 3: glucose 12.6, ice cream 8.1, milk 3.7, and lactose 4.1 mmol X h/l. The insulin response was greater than could be explained by the glucose response for all meals except apples. Milk was a particularly potent insulin secretagogue; the observed insulin response was approximately 5-fold greater than would be anticipated from the glucose response. In summary, the plasma glucose response to ingestion of fruits and milk products can be predicted from the constituent carbohydrate present. The serum insulin response cannot.

Mortality of type 1 (insulin-dependent) diabetes mellitus in Denmark: a study of relative mortality in 2930 Danish type 1 diabetic patients diagnosed from 1933 to 1972.

Abstract: This study included 2930 (1642 male, 1288 female) Type 1 (insulin-dependent) diabetic patients diagnosed before the age of 31 years and between 1933 to 1972. The patients were followed from first admission to Steno Memorial Hospital until death, emigration, or until 1 January 1983. Relative mortality was studied, and the influence of calendar year of diagnosis, diabetes duration, age at diagnosis, current age and sex were studied. Relative mortality decreased continuously during the period, and patients diagnosed after 1956 had a relative mortality 30–40% lower than patients diagnosed from 1933 to 1946. Relative mortality increased with increasing diabetes duration until about 20 years of duration, after which it declined. It also increased with increasing age until 31–40 years. It decreased with increasing age at diabetes onset. Factors like calendar year of diabetes onset, age at diagnosis, current age and sex had no influence on relative mortality within the first 15 years of duration, although the relative mortality increased with diabetes duration. In the interval of 16 to 40 years of diabetes duration, the relative mortality decreased with increasing calendar year of diagnosis and age at diagnosis. In patients with a diabetes duration of more than 40 years, the relative mortality decreased with increasing age and diabetes duration. These results show that the prognosis of Type 1 diabetic patients has improved considerably during the last 40 years. Furthermore, they show that diabetes duration is the most important determinant of relative mortality.