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The short-term effect of the glucose-controlled insulin infusion system (GCIIS) Biostator on metabolic and hormonal responses was studied in 10 non-obese subjects with glucose intolerance and insulin low response to glucose. Glucose tolerance characterized by means of a 2 h glucose infusion test (12 mg/kg/min) primed by i.v. injection of 0.33 g glucose/kg body weight was completely normalized by GCIIS. Results provide further support that normalization of glucose tolerance by means of GCIIS is accompanied by peripheral hyperinsulinaemia if compared with 33 non-obese healthy controls. Glucose-induced endogenous insulin secretion (C-peptide) was significantly reduced during the GCIIS study possibly due to inhibition of insulin secretion by exogenous insulin and/or by lower blood glucose concentration after normalization of glucose tolerance. Acute normalization of glucose tolerance in these patients failed to alter pancreatic glucagon, NEFA and glycerol responses but normalized paradoxical growth hormone response to glucose.

Several studies have indicated that the long-term effectiveness of sulfonylurea therapy in the treatment of type-II diabetics is due to a potentiation of insulin action. The present investigation was undertaken in order to elucidate whether or not there is also an acute effect of sulfonylureas on insulin-mediated glucose uptake. Nine non-obese subjects classified as having impaired glucose tolerance formed the study group. In vivo insulin sensitivity was assessed by using the glucose controlled insulin infusion system (Biostator) without or with a contemporary 3-hour tolbutamide infusion. Studies were performed on subsequent days, and each subject served as its own control. Glucose was given at a fixed rate of 0.011 mmol/kg b.w./min. The computer program was set to maintain plasma glucose concentration at 3.89 mmol/l. The amount of exogenous insulin necessary to keep glycemia at this steady-state level has been accepted as an estimate of insulin sensitivity. Mean plasma glucose and insulin concentrations were constant and comparable in control and sulfonylurea treated groups. Under our experimental conditions tolbutamide did not provoke any increase of C-peptide secretion. There was no significant alteration of insulin counterregulatory hormones (glucagon and growth hormone) either. On the other hand, for the disposal of identical quantities of glucose the necessary amount of insulin has been found to be reduced by one third due to tolbutamide treatment indicating a higher insulin sensitivity. The mechanism by which tolbutamide intensifies the insulin effect is unknown. It seems to be that a successful short-term sulfonylurea therapy on glucose utilization is associated with some alterations on the receptor and/or post-receptor level.

In 30 first-degree relatives (siblings or children) of type-I diabetics and 17 relatives (children) of type-II diabetics as well as in 19 healthy subjects a two-hour glucose infusion test (GIT, 12 mg/kg b.w./min) primed by a starting bolus of 0.33 g/kg b.w. was performed to evaluate carbohydrate tolerance (CHT) and insulin secretion pattern. After 4 to 5 years the test was repeated and the results were compared with those of the initial GIT. The glucose-stimulated insulin response of the early secretion phase (0--5 min) decreased during the follow-up study in relatives of type-II diabetics with normal CHT (in tendency) and with glucose intolerance (p less than 0.05) but not in relatives of type-I diabetics. A rightward shift of the glucose-insulin response curve was seen in the former group. Relatives of type-II diabetics with impaired CHT showed a striking abnormality in B-cell responsiveness. In relatives of type-I diabetics a disturbed glucose-insulin response curve could not be observed. The insulin response during the late phase of insulin secretion did not differ significantly among the groups. The conclusion drawn from our findings is that responsiveness of pancreatic B-cells seems to be directly affected genetically in first-degree relatives of type-II but not of type-I diabetics. Thus, diabetes mellitus cannot be regarded as one disorder with a similar genetic background.

The present study focussed on the impact of heavy muscular work upon metabolic homeostasis in insulin dependent (type I) diabetics in situations involving a certain degree of hyper- and hypoinsulinemia. 20 juvenile type I-diabetics were compared with 6 nondiabetic healthy subjects. The diabetics were studied in states of hypo-(trial A) and hyperinsulinemia (trial B) at the start of the exercise. Differences in insulin availability resulted from the different times that had elapsed from the last insulin injection (3 hours in trial A and 1 hour in trial B) before the ergometer test started at 7 a.m. Six diabetics out of 20 patients were studied in both trials A and B to establish the reproducibility of metabolic reactions to the exercise. Bicycle ergometer tests were carried out in the upright position at 5 graded steps of 50 W, 75 W, 100 W, 125 W and a load near to exhaustion. Rest periods of five minutes were allowed between these work periods for taking blood samples before and after each work load. Plasma glucose, FFA, glycerol, lactate, alanine, IRI and HCP concentrations were investigated. The blood pressure at rest and during exercise was measured, and the physical working capacity (PWC170) was calculated according to Wahlund on the basis of the heart rate response to exercise. The results of the exercise tests reflect clearly the different metabolic reactions to heavy muscular work despite the relatively slight differences in insulin availability at the start: --Exhausting muscular work during the hypoinsulinemic state resulted in hyperglycemia and exaggerated lipolysis. --Heavy muscular work in a hyperinsulinemic state resulted in a reduced blood glucose level and antilipolytic reactions in comparison to nondiabetics. These findings suggest the great necessity of an adequate insulin availability during heavy muscular work in juvenile type I-diabetics.

A 66-year-old female patient with a malignant insulinoma was treated with streptozotocin (STZ; Zanosar) in 5 cycles every 4 weeks as 5 day courses with an intravenous dosage of 850 mg per day. Under this treatment hypoglycemic episodes decreased continuously in number as well as severity and - after a delay of 12 months after the last treatment - an overt diabetes mellitus appeared. Plasma insulin concentrations dropped immediately after starting of STZ therapy. On the other hand, islet cell surface antibodies and their complement-dependent cytotoxicity increased continuously, being at their highest 6 months after termination of STZ treatment. Thus, STZ is able to induce a specific immune response against islet cells with a progressive damage of malignant insulin producing cells.

A sensitive and versatile radioimmunoassay (RIA) for insulin was established using human insulin standard, a specific guinea pig anti-insulin antiserum and rabbit anti-guinea pig serum. Radioiodination was performed according to a modified chloramine T method. Tracer preparations were used for as long as 6 weeks after iodination. The standard curve ranges from 0.044 to 1.2 nmol/l. The intra-assay coefficient of variation (CV) was 3-5% and the inter-assay CV was 6-9% in the optimal range between 0.4 and 0.9 nmol/l. The average recovery of human insulin added to plasma or serum samples was 100.2 +/- 2.0% (n = 38) and 100.1 +/- 1.9% (n = 42), respectively. In addition to human insulin, porcine, canine, rabbit and bovine insulin can also be determined but not rat or mouse insulin. The cross-reactivity of the antiserum with porcine proinsulin was found to be 40% on the molar basis. The range of mean fasting plasma insulin concentrations in healthy subjects and under various pathological conditions were estimated.

Diabetic nephropathy is the dominant cause of hypertension in insulin-dependent diabetics, and long-term rigid antihypertensive treatment inhibits the progression of nephropathy, probably even when there is renal insufficiency. In our clinical study 14 insulin-dependent diabetics with diabetic nephropathy and renal failure (glomerular filtration rate [GFR] 0.39 +/- 0.12 ml/sec) underwent rigid blood pressure treatment. Antihypertensive therapy included furosemide, propranolol, dihydralazine and nifedipine. The whole group showed a lowering in mean blood pressures from 150.1 +/- 2.3/91.3 +/- 1.4 mm Hg to 139.8 +/- 3.1/86.5 +/- 2.0 mm Hg (p less than 0.01). During the observation period the mean decline in glomerular filtration rate decreased from -0.022 +/- 0.003 ml/sec per month to -0.010 +/- 0.007 ml/sec per month. In 10 out of 14 patients with very advanced nephropathy the further decline of GFR halted markedly. Thus, vigorous blood pressure control is able to postpone endstage renal disease even in advanced diabetic nephropathy.

To assess pharmacokinetics and biological activity of the new L-SNC insulin (Berlin-Chemie, a low immunogenic pork insulin in neutral solution purified by chromatography) ten healthy male subjects were connected to the BIOSTATOR. After an overnight fast 0.4 U of L-SNC insulin per kg body weight were injected subcutaneously in the thigh of each individual. Plasma insulin concentrations rose gradually reaching their maximum values after 8 hours. According to C-peptide levels there was some inhibition of endogenous insulin secretion. For the evaluation of insulin action we used the closed loop system (BIOSTATOR) which was transformed in its function into a glucose controlled dextrose infusion system. The amount of glucose delivered by the BIOSTATOR in order to maintain blood glucose steady state concentrations at the "basal" level was taken as a measure of biological activity of the injected insulin. The glucose infusion rate increased after insulin administration, reaching statistical significance after 3 hr. The maximum effect of L-SNC insulin was observed between 5 and 12 hours after injection. The overall duration of action of more than 16 hours meets the increasing need for insulin in the early morning in many diabetic patients. Therefore, L-SNC insulin should be recommended for intensified conventional insulin therapy to cover the night and to prevent dawn phenomenon in insulin dependent diabetics.

Since mumps virus seems to be one of the most likely candidates in viral etiology of insulin-dependent diabetes (IDDM) we studied the possible relationship of glucose tolerance (75 g oGTT), beta cell function, diabetes associated HLA antigens, haptoglobin phenotype, islet cell antibodies (ICA) and islet cell surface antibodies (ICSA) in 125 subjects with antecedent mumps infection. Impaired glucose tolerance (IGT) was diagnosed in 3.2% (n = 4) but onset of diabetes did not appear within 14 months after mumps infection. There was no relationship between glucose tolerance and complications of antecedent mumps infection (e.g. pancreatitis, meningitis, orchitis). The prevalence rate of ICA was 76%. ICSA were detectable in about 36% of children and 62% of the adults tested (p less than 0.01). There was no relationship between ICA/ICSA and diabetes-associated HLA antigens, haptoglobin phenotype or beta cell function (fasting C-peptide and insulin response to 75 g oGTT). However, adults with circulating ICA were characterized by a significantly lower insulin response to glucose. Fifty two "risk" subjects characterized by IGT, diabetes associated HLA antigen(s), ICA or ICSA either alone or combined were studied again 26 months after mumps infection. No symptomatic diabetes appeared and IGT was diagnosed in one case only. ICA and ICSA persisted in more than 50% of subjects in whom ICA or ICSA were present 14 months after mumps infection. Since the used immunological techniques do not clearly distinguish organ-specific from non-organ-specific antibodies the results must be interpreted with caution. To summarize, the preliminary results do not support a close temporal relationship between mumps infection and the onset of IDDM. The pathogenetic role of mumps virus and ICA/ICSA and their possible relation to a slow progressive beta cell destruction has still to be determined.

The purpose of the present cross-sectional clinical study was to evaluate the prevalence of retinopathy in Type 1 diabetic patients without nephropathy and with different degrees of nephropathy. In addition we investigated the association between retinopathy, nephropathy, and other variables, and studied the importance of cardiovascular autonomic dysfunction to these conditions. 76 Type 1 diabetic patients were investigated. All patients were initially selected on the basis of body weight, and 47 proteinuric patients were further selected for age, diabetes duration and the duration of insulin treatment (see Table 1). Proteinuric diabetic patients were categorized by degree of nephropathy, i.e. for incipient nephropathy (proteinuria of less than 0.5 g/day), for overt nephropathy (proteinuria of more than 0.5 g/day), and for renal failure (serum creatinine of more than 103 mumol/l). Retinopathy was assessed by ophthalmoscopy. Cardiovascular autonomic dysfunction (CAD) was assessed by heart rate variations, 30:15 ratios, the Valsalva maneuver, and systolic blood pressure fall upon standing. Our findings revealed increased prevalence of retinopathy in patients with more advanced stages of nephropathy. CAD abnormalities exhibited increased prevalence among proteinuric patients. Our data clearly revealed differences between proteinuric and non-proteinuric patients. In both proteinuric and non-proteinuric patients there were found correlations of retinopathy with diabetes duration, and only in proteinurics was retinopathy correlated with kidney function, systolic blood pressure and CAD findings. In patients in identical stages of nephropathy, increased prevalence of CAD abnormalities was shown in patients suffering from proliferative retinopathy. Thus our data suggest that CAD abnormalities might be related in some way to both the proliferative retinopathy and to diabetic nephropathy.