Reproducibility of insulin dosage on consecutive days of blood glucose control by an artificial beta-cell in brittle diabetic patients.

The profiles of blood glucose and of insulin dosage were compared between the first and second of 2 consecutive days of Biostator administration under constant conditions in 12 brittle type I diabetic inpatients. All blood glucose criteria and the daily insulin doses were reproducible between these 2 days for the entire group of patients. In nearly all patients, however, there were distinct but unsystematic differences between the 2 days in the diurnal patterns of insulin dose distribution. These differences could be ascribed to some stress reaction or inherent metabolic lability. It is concluded that, in these extremely labile diabetic patients, due to the insufficient short-term reproducibility of the outcome of an extracorporal artificial beta-cell, caution must be used when constant profiles are to be predicted from these doses for open-loop insulin delivery systems or for conventional subcutaneous injection therapy.

Age-dependent insulin secretion of the endocrine pancreas in vitro from fetuses of diabetic and nondiabetic patients.

Fetal hyperinsulinemia is assumed to play a key role in the pathogenesis of diabetic fetopathy. To investigate the role of enhanced fetal B-cell mass as one cause of fetal hyperinsulinemia during diabetic pregnancy, we studied human fetal pancreatic slices from diabetic women (FDW) with poor metabolic control and nondiabetic women (FNDW) between 11 and 26 wk of pregnancy, morphometrically and by in vitro incubation experiments. Abortions had been performed due to different medical indications. We found a good correlation between the calculated B-cell mass and the gestational age in both FDW and FNDW, but the increase in FDW was much more pronounced. Such a correlation was also found in vitro regarding the insulin response to glucose and IBMX. The FDW had significantly higher values than FNDW of the same age range. In contrast to this, we found in two diabetic patients with tight metabolic control during the whole pregnancy results similar to those in FNDW. Therefore, we assume that it could be possible to prevent fetal hyperinsulinemia and perhaps even diabetic fetopathy in diabetic women by tight metabolic control during the whole pregnancy, but further investigations are necessary.

Different frequencies of diabetic complications in insulin-treated patients with diabetes of comparable duration, in relation to age at onset of diabetes.

Diabetic complications such as retinopathy and nephropathy affect the quality of life of diabetic patients. The aim of this study was to find out whether there are differences in the development of these complications associated with the age at onset of diabetes and the different effects of diabetes onset before, during or after puberty. Therefore, we tested the hypothesis whether onset of insulin dependent diabetes in puberty was connected with an increased risk of developing diabetic microangiopathy. We found a significantly increased risk in patients with diabetes onset in puberty up to a diabetes duration of 20 years if compared with diabetes onset before but not with that after puberty. It seems that diabetes onset before puberty delays the development of early diabetic complications and that changes of the hormonal status during puberty may be responsible for an earlier development of retinopathy. After about 20 years of diabetes there are no significant differences between the groups. Our results emphasize the necessity of early ophthalmological diagnosis and adequate metabolic control, especially in patients with diabetes onset during or after puberty, in order to prevent or delay the development of diabetic complications.

Trends in mortality rates in the diabetic population of the GDR.

Based upon the National Diabetes Registry the mortality rates were assessed annually between 1961 and 1987 in the total diabetic population of the GDR. The rise of diabetes prevalence from 724/10(5) up to 3988/10(5) during the 27-year observation period was associated with an increase of relative mortality rates from 466% to 600% in insulin-treated diabetics, from 352% up to 528% in non-insulin-treated diabetics. By calculation of standardized mortality ratios (SMR) it could be shown that excess mortality is dependent on age but not at all on sex. Insulin-treated diabetics exhibited their maximum SMR of 650% to 750% at ages 25 to 45 years, while in non-insulin-treated diabetics the maximum SMR amounted to 450% at ages 25 to 35 years. In contrast to trends of the total relative mortality rates that of the overall age structure adjusted SMR of diabetics was characterized by a declining tendency, which may be a reflection of the improvement in diabetes care in our country, and which underscores the dependence of mortal, ty rates on the methods used for evaluation.

Epidemiology of insulin-treated diabetes mellitus in the East-German population: differences in long-term trends between incidence and prevalence rates.

In order to evaluate temporal trend variations of incidence and prevalence rates of Type 1 (insulin-treated) diabetes mellitus in the East-German population (19.6 million) 85,904 incidence cases, recorded by the Diabetes Registry between 1960 and 1989, were analyzed by calculating the regression coefficients for defined time intervals. The total incidence trend was characterized by a rise from 18/10(5) in 1960 to 29/10(5) in 1965, a decrease to 14/10(5) in 1975, and a slight increase to 15/10(5) in 1989. This trend was reflected only by patients with insulin treated diabetes mellitus aged > or = 30 yrs. Patients of the age groups 0-9 yrs., 10-19 yrs., and 20-29 yrs. exhibited increasing rates of 0.21/10(5)/year (1960-75), 0.22/10(5)/year, and 0.08/10(5)/year (1960-89), respectively. The rise in the prevalence rate from 187/10(5) (1960) to 658/10(5) (1989) demonstrated temporal trend variations during the periods 1960-71 (+19.3/10(5)/year), 1972-77 (-0.8/10(5)/year), and 1978-89 (+25.6/10(5)/year). The age-specific increasing prevalence trend varied between +0.81/10(5)/year (0-9 yrs.) and +48.89/10(5)/year (60-69 yrs.). The differences observed between incidence and prevalence trends were mainly due to changes in relative mortality rates of patients with insulin treated diabetes and the percentage of secondarily insulinized Type 2 diabetic patients. In summary, the incidence of Type 1 diabetes mellitus in East-Germany increased over the past 3 decades of registration by about 94% in children and adolescents, by 38% in adults aged 20-29 yrs., but not in people aged > or = 30 yrs.(ABSTRACT TRUNCATED AT 250 WORDS)

Survival time after onset of diabetes: 29-year follow-up mortality study in a diabetes cohort from a rural district.

UNLABELLED: In order to evaluate various influences on survival time after onset of diabetes, a 29-year follow-up study was conducted in the 166 diabetic patients who were newly diagnosed between May 1st, 1962, and April 30th, 1963, in the rural district of Neustrelitz. Their mean age at onset was 63 (15-81) years, sex ratio was 2.5 (females: males). 27% of the patients were initially treated with insulin, 73% were on diet alone or on diet plus oral antidiabetic drug. There were 18 drop-outs. Check-up of mortality was performed at 3-year intervals. Shortening of life expectancy was calculated by comparison of their survival time to the life expectancy of the general population of the former German Democratic Republic with reference upon age and sex. RESULTS: Seven out of the remaining 148 study patients (4.7%) with an age at onset between 15 and 60 were alive. 19% of the patients had either reached or exceeded the life expectancy of the general population. The average loss in life expectancy in the decreased patients amounted to 5.3 years in males and to 6.4 years in females. The shortening of life expectancy decreased with increasing age at onset. Both underweight (BMI < 20) and extreme obesity (BMI > 40) were associated with a higher loss in life expectancy (14.7 vs. 10.8 yrs.) Also the survival time was not significantly different in dependence on the nature of treatment and on the circumstances of detection of the disease. CONCLUSION: only 19% of diabetic patients may expect a "normal" survival time.(ABSTRACT TRUNCATED AT 250 WORDS)

Prevalence and incidence trends of non-insulin-dependent diabetes mellitus (NIDDM) in the population of the GDR.

Trends of prevalence and incidence rates of non-insulin-dependent diabetes mellitus (non-insulin-treated diabetes mellitus) were assessed in the population of the GDR based upon the National Diabetes Register and the Official Statistical Year Book as sources for the calculations. Within the 25-year follow-up period 1960-1984 the prevalence rose from 4.39%; to 31.95%; the incidence rate from 1.04%; to 3.57%. Age-dependence of the specific rates is characterized by their continuous rise above the age of 30 years reaching the peak prevalence of 146.6%; in 75- to 80-year-olds, that of 14.1%, for the incidence in people aged 70 to 75 years. A significant male preponderance was confirmed between the ages of 30 and 50 years, a significant overwhelming of female NIDDM in the age groups 60 to 90 years. Based on demonstrated correlations between the changes of living standard parameters and the epidemiological trend of NIDDM the conclusion is drawn that overnutrition and reduced muscular activity mainly account for the rise of diabetes morbidity in the population of the GDR.

Treatment of diabetic coma with low-dose injections of insulin.

Twenty-one patients in severe diabetic coma were treated with small doses of insulin at a rate of 4.1 units per hour (total dose about 100 units per 24 hours). Using single doses of 4 to 10 units by the intravenous or intramuscular routes the fall of blood glucose was steady in all cases. In the treatment of diabetic coma this regimen of insulin administration has proved simple, safe and effective since 1946. Main dangers during recompensation of diabetic coma are: hypovolaemia with oliguria -- anuria, dysequilibrium syndrome with cerebral edema and hypokalaemia. Therefore early intensive and adequate intravenous fluid and electrolyte replacement is the most important part of treatment. Most of the cases in this study were undiagnosed diabetics (14) and elderly patients (9). Three patients older than 65 years and a 56-year old diabetic died. In this context the most important aspects of treatment to avoid death are: prevention of diabetic coma and adequate fluid and electrolyte replacement especially in geriatric patients.

Derivation and experimental proof of a new algorithm for the artificial B-cell based on the individual analysis of the physiological insulin-glucose relationship.

Normal dogs were submitted to oral glucose loads or to intravenous glucose infusions. Insulin secretion rates (CISR) were calculated considering the resulting peripheral venous concentration differences in short intervals and the experimentally determined half life and apparent distribution space of exogenous insulin. Multiple regression analysis was done between CISR and both the level and the rate of change of plasma glucose. The regression coefficients were used as algorithm parameters for continuous plasma glucose dependent intravenous insulin administration in the same animals after induction of an insulin-dependent diabetes. Normal glycemic regulation over the day could be resotred by this sytem. The insulin responsiveness, however, varies from day to day; tusing this insulin dosage pattern we observed nearly normal plasma glucose curves and slightly elevated insulin reactions after glucose loading. This kind of algorithm could also be used in diabetic humans.

Estimation of pancreatic IRI output rate and its relations to glucose tolerance in normal anasthetized dogs.

The pancreaticoduodenal and portal venous blood flows were recorded electromagnetically in anaesthetized dogs. Blood glucose and IRI were measured in the arterial, portal, and peripheral venous as well as in the intestinal venous blood. By a mathematical model the actual net IRI output of the whole pancreas was estimated. Under basal conditions it is 10.2 +/- 2.4 mU/min (n = 30; 26 kg mean body wt.). After i.v. glucose injection, IRI output is rapidly enhanced. The biphasic nature of this reaction was unequivocally demonstrated by consideration of the ratio IRI output : blood glucose. Pancreaticoduodenal blood flow increases transiently in relation to the increased blood glucose concentration. The IRI secretion rate is well correlated with the blood glucose concentration and to the amounts of glucose or of blood reaching the whole pancreas. It is also correlated with the portal IRI Concentration. The overall peripheral venous or arterial IRI concentrations are correlated with the IRI secretion rate, but not in all individual experiments. The different phases of IRI output (basal rate, stimulated output 1-10 min and 10-60 min) show no influence on each other, nor are they correlated with the peripheral IRI concentration area. Basal IRI output is negatively correlated with the glucose assimilation constants. These constants or the peripheral BG areas, however, are independent of the stimulated IRI output rate. However, both the assimilation constants and the peripheral BG areas are related to the peripheral IRI concentration areas. Hepatic uptake of insulin and dynamics of pancreatic blood flow seem to contribute considerably to the estimated correlation pattern.

[Fetal hyperinsulinism in early pregnancy--a cause of diabetic fetopathy?]. / Der fetale Hyperinsulinismus in der Frühsehwangerschaft--eine Ursache der diabetischen Fetopathie?

The influence of fetal hyperinsulinemia on the development of diabetic fetopathy was investigated. Human fetal pancreatic slices of fetus between the 12th and 26th weeks of pregnancy from non diabetic (n = 32) and diabetic (n = 18) women were incubated in vitro for one hour. The insulin secretion results clearly demonstrate an age dependent increase in both groups investigated, but the increase is much more pronounced in fetuses from diabetic women. The differences between the groups are present already during the 12th week of pregnancy. The results support the concept to normalize the metabolic control in pregnancy as early as possible in order to prevent the diabetic fetopathy.

Studies on the clinical importance of the constants used in the algorithm of an artificial B-cell (Biostator).

The clinical importance of different constants used in the algorithm of a glucose-controlled insulin infusion system (Biostator) with respect to insulin requirement was studied in 9 insulin-dependent juvenile-onset type diabetics. After normalizing the fasting blood glucose level (around 4.5 mmol/l), 3 consecutive glucose infusions (12 mg . kg-1 . min-1) followed by a 1 h post-infusion period were carried out in all individuals. The blood glucose was controlled by the Biostator using three sets of constants: A (KR = 160, KF = 50, QI = 30, RI = 12), B (KR = 70, KF = 50, QI = 40, RI = 12) and C (KR = 20, KF = 50, QI = 50, RI = 20). The algorithm constants were changed in an arbitrary order before the start of each glucose infusion in the same patient. Mean blood glucose profiles were comparable whereas the mean total insulin dose infused by the Biostator amounted to 13 +/- 1.3 U/h, 7.8 +/- 1.2 U/h and 7.0 +/- 1.0 U/h when sets A, B and C were applied (A versus B and C p less than 0.01). The higher insulin amount during control of set A was mainly due to a high insulin infusion during the first 20 min. In summary, the results emphasize the clinical importance of appropriate algorithm constants of a glucose-controlled insulin infusion system for evaluation of the insulin requirement in insulin-dependent diabetics.

Pancreatic B-cell behaviour after changing the natural environment of sand rats (Psammomys obesus.

On the basis of the blood glucose increase during the capitivity sand rats born in the desert were classified as normals, protodiabetics and diabetics, indicating a different adaptation to the new environment within a definite period. Isolated islets of animals, which did not develop a hyperglycemia, enhanced their insulin content during the adaptation period. The absolute insulin secretion rates in response to 16.5 mM glucose were rather similar between the three investigated groups and not modified by the insulin as well as glucagon content of pancreatic islets. But, since islets of hyperglycemic sand rats could not increase the insulin content, a significantly enhanced fractional secretion (as % of the content) could be observed. The results let us assume that the B-cell reaction during the adaptation period can be modified by further factors additionally to the changed environment.

"Catheter-pens"--an alternative to insulin pump treatment?

Two types of insulin pens MADI and MD, were connected to subcutaneous catheters. These "catheter-pens" were used like hand-driven insulin pumps. Results after 1 year of treatment in 30 type 1 diabetics (HCP-negative; age at onset of diabetes 16.5 +/- 1.7 years; duration of diabetes 18.5 +/- 1.6 years, on multiple insulin injections before catheter-pen application): 1. better quality of life (reduction of frequency of needle pricks, more flexibility, inconspicuous application of insulin in public); 2. daily insulin--increased number of "injections" (4.2 +/- 0.1 vs 5.8 +/- 0.1, p less than 0.01), reduction of units per kg BW (0.70 +/- 0.02 vs 0.60 +/- 0.01, p less than 0.01), reduction of intermediate-acting insulin (14.1 +/- 1.3 vs 9.2 +/- 1.2 U/d, p less than 0.05); 3. no change of HbA1 (10.8 +/- 0.8 vs 10.2 +/- 0.2%, normal range 7.7 to 8.4%), mean blood glucose (MBG) in stress situation (8.4 +/- 0.4 vs 7.7 +/- 0.3 mmol/l), serum cholesterol and body weight, both within normal range; 4. improvement (p less than 0.05) of serum triglycerides, serum HDL-cholesterol, ratio of apolipoprotein A1/B; 5. rare skin reactions at the needle site. Conclusion. Catheter-pens offer a very convenient alternative for insulin administration in intensified conventional insulin treatment with multiple injections in type 1 diabetics.

Estimation of individually adapted control parameters for an artificial beta cell.

For optimum long-term glycemic regulation using a miniaturized artificial beta cell it is indispensible to estimate control parameters suited to the individual requirements of each diabetic patient. To solve this problem, a strategy has been developed which is based on engineering optimum-control theory with a model involving glucose and insulin interactions. The model considers physiologically relevant unit processes like endogenous glucose production, insulin-independent glucose uptake from its apparent distribution space, insulin-dependent glucose utilization, glucose-dependent insulin supply, and insulin catabolism. The assumed model structure is validated by results obtained in experimentally diabetic dogs using partition analysis. The individual parameter values of the model are obtained by a digital computer procedure based on a simple test which involves a bolus injection of glucose + insulin when a constant basal insulin dose is being administered in the diabetic in whom normoglycemia was re-established before the test. The method presented is recommended for future use in all cases where an optimized insulin regimen is to be worked out.

Ergometric heart rate, blood pressure and work capacity (PWC170) in type I diabetics with diabetes-specific microangiopathy.

118 male and 68 female type I diabetics and 25 male and 23 female nondiabetic healthy controls were compared during submaximal bicycle ergometer tests using four work stages (duration: 6 min each) of 50 W, 75 W, 100 W and a submaximal stage producing a heart rate of 170 min-1. We found that male type I diabetics with and without retinopathy who had significantly higher than normal heart rates both at the start and during the ergometer test also had above normal ergometric blood pressures. Female type I diabetics, in contrast, did not differ significantly from the controls in terms of heart rate before and during the ergometer tests. The PWC170 of all male type I diabetics was, in contrast to that of the female patients, lower than that of the controls. In diabetics with diabetic nephropathy there was no correlation between exercised acceleration of the heart rate and the degree of nephropathy despite their higher heart rates at the beginning and during the ergometer test, but a correlation was found between the ergometrically increased blood pressure and the severity of the diabetic nephropathy. In male type I diabetics cardiocirculatory adaptation to muscular work was reduced, and this reduction became more marked as the degree of diabetic microangiopathy increased. Compared with the controls, the increase in systolic blood pressure evoked by activity on the ergometer in male and female type I diabetics was disproportionate to the actual load and correlated with the degree of diabetic microangiopathy.

[Measurement of uteroplacental circulation with 113m indium in diabetic pregnancy]. / Die Messung der uteroplazentaren Durchblutung mit 113m In in der diabetischen Schwangerschaft.

In 122 diabetic pregnancies the placental blood flow has been estimated determining the half life of the activity inflow (2 MBq 113 m In labelled transferrin) into the placental bed. We used a highly sensitive detector (modified pinhole collimator) and a computer supported evaluation, free from subjective influences. 259 flow measurements were compared to the risk of complication in the course of a diabetic pregnancy. - The half life values in the diabetic group, calculated by a gamma camera computer system by means of an iterative regression analysis, were significantly different compared to a control group (12 pregnancies without risk.) - Severe diabetic angiopathic complications (White classes D, F, and R) are accompanied by higher half life values (placental blood flow reductions) and perinatal complications. - Even in pregnant women with gestational diabetes or disturbances of the carbohydrate metabolism a disturbed placental hemodynamic is to be found.

The progression of diabetic nephropathy in type I diabetics: relationship to metabolic control and blood pressure.

This study was designed to investigate the importance of risk factors such as hyperglycemia and elevated systolic and diastolic blood pressures on the progression of renal insufficiency in diabetics suffering from diabetic nephropathy. Seventeen patients with Type I, insulin-dependent diabetes mellitus (IDDM) (8 women and 9 men) undergoing chronic hemodialysis were investigated by retrospective follow-up and compared with 17 age and sex matched IDDM patients without diabetic nephropathy (controls). According to the time interval of creatinine increase from 200 to 600 mumol/l, the patients were divided arbitrarily into two groups with rapidly (group I less than 20 months) or slowly progressive (group II greater than or equal to 20 months) renal insufficiency. This period was 13.4 +/- 2.05 months in group I (age 36.67 +/- 2.47 years, diabetes duration 23.55 +/- 2.37 years) and 32.75 +/- 4.34 months in group II (age 40.62 +/- 2.63 years, diabetes duration 26.62 +/- 2.63 years, P.n.s.), respectively. The IDDM patients studied exhibited individually differing progressions of renal insufficiency at different times after manifestation of diabetes. After 15 years of diabetes duration, both risk factors, that is blood pressure and blood glucose concentrations, were elevated in nephropathic diabetics when compared with controls (p less than 0.01). During the phase of declining kidney function, mean blood pressures were found to be higher in IDDM patients with rapid progression of renal insufficiency when compared with slowly progressing diabetics. Although both risk factors were related to diabetic nephropathy, during the phase of renal insufficiency hypertension appeared to be more closely related to the further deterioration of kidney function.