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Background: Impaired glucose tolerance and secondary diabetes are frequent in older patients with cystic fibrosis (CF), associated with increased frequency of infections and reduced life expectancy. Studies on the pathophysiology of islet cell secretion in CF are a prerequisite for a scientifically based therapeutic approach., Methods: Oral glucose tolerance tests were performed in 71 patients (14.2 +/- 0.5 years; mean +/- SE) and 56 control subjects (16.5 +/- 0.9 years). Glucose, insulin, C-peptide, and proinsulin were measured every 30 min., Results: Glucose tolerance in CF patients was classified as normal (NGT, n = 48), impaired (IGT, n = 14), or diabetic (DM, n = 9). Even in CF patients with NGT, blood glucose was significantly elevated at 30, 60, and 90 min of the test. Surprisingly, the secretory responses of insulin and C-peptide were not reduced in CF patients with IGT or DM compared with both healthy controls or CF patients with normal glucose tolerance. However, peak insulin concentration was reached at 90 min in CF-IGT or CF-DM patients compared with 30 min in controls. The ratio of glucose to insulin, an indicator of insulin resistance, increased in CF patients with progression of carbohydrate intolerance. Proinsulin was significantly reduced in all CF patients compared with controls (p < 0.001; Wilcoxon's rank sum test)., Conclusions: In CF patients with impaired glucose tolerance or diabetes, integrated insulin release is not diminished, indicating that insulin resistance is likely to contribute to hyperglycemia in CF patients with IGT or DM. Reduced proinsulin levels in CF patients are compatible either with enhanced conversion of proinsulin to insulin in compensation for reduced beta-cell mass, or enhanced clearance of proinsulin.

Background and Objective: Weight gain is a common undesirable side effect of insulin treatment in type 1 diabetics. This study tested the assumption that this is due to an increase in fat mass., Patients and Method: Bioelectric impedance measurements were performed on 157 young male and 117 female diabetics (age 17.6 +/- 4.9 years; diabetes duration 8.9 +/- 5.7 years) and the fat-free mass (FFM) calculated according to the equation of Schfer et al. The data of the diabetics were compared with those of healthy controls and normal values published by Barlett et al., Results: The average weight of the diabetic cohort was 2.0 +/- 0.7 kg higher than in the reference groups, adjusted for sex and age. FFM was higher by 2.9 +/- 0.7 kg in diabetics than in the healthy cohort of Barlett et al (P < 0.005), being equally high in males and females (+2.9 +/- 0.7 kg and 2.9 +/- 0.6 kg, respectively). But compared with the values in metabolically normal controls the percentage fat proportion was lower in the diabetics than the controls, but not significantly (-1.3 +/- 0.6%). Weight gain was greater in females than males (+3.8 +/- 0.9 kg vs +1.2 +/- 0.9 kg, P < 0.05). After correcting for age, there was a partial correlation between good metabolic control and FFM in males. The form of treatment had no effect on body composition., Conclusion: These data indicate that weight gain in young diabetics is due not to an increase in fatty tissue but in muscle mass. This is probably the result of peripheral hyperinsulinism combined with hyperglycaemia.

The dawn-phenomenon causes high fasting glucose values in IDDM patients during puberty. Even a bedtime injection of intermediate-acting insulin does not reliably suppress glucose rises during the morning hours. We therefore examined whether Semilente, an amorphous zinc insulin with kinetics different from NPH insulin, is better suited to alleviate the dawn-phenomenon in adolescent patients with long-standing diabetes. This prospective study included 15 adolescent patients (age 15.5 +/- 0.4 years; mean +/- SE) well beyond the remission phase of diabetes (mean duration: 7.5 +/- 0.8 years). On an inpatient basis, blood glucose profiles following bedtime injections of NPH or semilente insulin were compared, using a sequential cross-over design for intra-patient comparison. Fasting blood glucose was significantly lower following bedtime injections of Semilente (183 +/- 21 mg/dL [10.2 +/- 1.1 mmol/L]) compared to nights where NPH had been injected (235 +/- 22 mg/dL [13.1 +/- 1.2 mmol/L]). In addition, the morning postprandial blood glucose was significantly improved. The frequency of nocturnal hypoglycemia was not different, and the dose of Semilente insulin was slightly lower compared to the dose of NPH-insulin injected. For adolescent IDDM patients with suboptimal metabolic control due to a marked dawn-phenomenon, with high fasting glucose concentrations despite a bedtime injection of NPH insulin, bedtime injection of Semilente insulin may result in reduced fasting hyperglycemia on the next morning.

Normal growth and development, as well as the prevention of overweight, are major goals in the treatment of paediatric patients with insulin-dependent diabetes mellitus (IDDM). We therefore evaluated longitudinally the anthropometric measurements of height and weight, as well as bone age, in an unselected group of 389 patients with IDDM treated at one institution. In order to identify genetic influences on these parameters, height and weight were determined in 186 unaffected siblings and 177 pairs of parents. At diagnosis, patients were slightly taller than average (median z score: +0.37). During the subsequent course of diabetes, age-adjusted heights decreased progressively for the first 9 years, catching up again after more than 10 years of diabetes. Bone ages were progressively retarded with increasing duration of diabetes. In 76 patients of 18 years or older, median z-score for height was +0.30, not different from their unaffected siblings (median z-score: +0.22). The correlation with midparental height was identical for diabetic and nondiabetic siblings (r = 0.43). In contrast, children with diabetes were significantly heavier (z-score for weight: +0.74 compared to +0.34 in unaffected siblings; p < 0.002). Obesity developed primarily during and after puberty. We conclude that: 1) during the course of diabetes, longitudinal growth is temporarily reduced and maturation is delayed in children with diabetes compared to unaffected siblings. However, this effect of diabetes is transient and small compared to genetic influences on height in an individual child. 2) As a group, children with IDDM become significantly overweight, which is likely to increase the cardiovascular risk during adulthood.

We studied the influence of fasting serum from nine insulin-dependent diabetic children and adolescents under insufficient metabolic control on normal human bone cells in vitro compared with serum from eight sex- and age-matched controls. Cell number 24 h after plating was significantly less under diabetic serum, indicating impaired cell attachment, spreading and initiation of cell proliferation. Cell number after five days was reduced by 1% diabetic serum, while higher serum concentrations had diverging effects on osteoblast proliferation. Collagen synthesis of human osteoblasts was significantly reduced by 8% diabetic serum compared to 8% control serum, while synthesis of non-collagenous proteins was not affected. Duration of diabetes (several weeks up to 12 years) had no influence on these parameters. The serum from one patient, which was studied a second time under excellent metabolic control three months later, however, had lost its inhibitory influence on collagen synthesis of osteoblasts. The pattern of the interstitial collagen types I, III and V was not altered by diabetic serum. These results indicate that defective regulation of proliferation and collagen synthesis of osteoblasts by components present in human diabetic serum may be an important factor in the development of diabetic osteopenia. The negative influence might be explained in part by reduced levels of IGF-I and elevated levels of IGF binding protein-1 in the diabetic sera.

Increased HbA1c concentrations in diabetic patients indicate retrospectively a poor metabolic control during the preceding 2-3 months. In the present study attempts have been made to use the HbA1c concentration at the time of diagnosis as an indicator of the duration of the remission phase in 23 juvenile diabetic children. The regression analysis revealed a significant negative correlation between the initial HbA1c concentrations and the duration of the remission phase defined as no glucose excretion, an insulin requirement of less than 0.5 U/kg/day and detectable serum C-peptide concentration (r =- 0.84, p < 0.001). The results suggest that the initial HbA1c concentration may serve as a useful indicator to predict the duration of the remission phase in juvenile-onset diabetic patients.

From 1977-1982 47 patients with newly diagnosed type I diabetes mellitus were treated in the department of Pediatrics, University of Ulm . 34 patients had no ketoacidosis. They were treated initially with 1 U/kg bodyweight/day of insulin as a mixture of 1/3 regular and 2/3 NPH. In the morning they received 2/3 and in the evening 1/3 of the total amount of insulin. 13 patients with ketoacidoses initially were treated for 12-36 h with regular insulin either subcutaneously or intravenously and later with the insulin mixture as outlined above. 37 patients received purified porcine and 10 patients biosynthetic human insulin (BHI). The non ketotic patients reached a good metabolic control (= mean blood glucose less than 150 mg/dl) on day 3.1 +/- 1.9 with porcine and on day 2.8 +/- 1.4 with human insulin (M +/- SD). Excellent metabolic control (= all blood glucose concentrations less than 150 mg/dl) was achieved with procine insulin on day 4.6 +/- 1.7 and with BHI on day 4.3 +/- 1.5. 2.6% of 1916 blood glucose determinations ranged less than 50 mg/dl, minimal value: 31 mg/dl. Severe symptomatic hypoglycemias were not observed. All ketoacidotic patients were treated with porcine insulin. They reached good metabolic control on day 6.0 +/- 2.3 and excellent metabolic control on day 7.9 +/- 3.5. It appears that newly diagnosed insulin-dependent-diabetic patients without ketoacidosis can be managed quickly and safely with a mixture of regular and NPH insulin from the very beginning of the disease.

In 35 children with long-standing diabetes mellitus, a significant correlation was found between the hemoglobin A1c (HbA1c)--and the 24-hour urinary glucose excretion. By contrast, 11 newly diagnosed diabetic children had grossly elevated HbA1c-concentrations, but no correlations could be established between the levels of HbA1c and the duration of symptoms, blood glucose, glycosuria, ketonuria and the acid--base status. However, HbA1c and C-peptide were significantly correlated. The elevated HbA1c-concentrations decreased towards normal in all of these 11 children after 2--3 months following adequate therapy. The results suggest that the determination of HbA1c may serve as a valuable metabolic control index in children with long-standing diabetes mellitus, but adds little information in newly diagnosed patients. For the individual diabetic child during the early treatment period, HbA1c may be the index of choice for adequacy of metabolic control.

In 21 newly diagnosed children with type 1 diabetes mellitus initial hemoglobin A1c-concentrations, mean insulin requirements during the first 10 days of treatment to recompensate carbohydrate metabolism, duration of glucosuria after diagnosis and duration of remission were determined. Initial hemoglobin A1c-concentration and both mean insulin requirement during the first 10 days of treatment and duration of initial glucosuria showed a highly significant positive correlation. A highly significant, negative correlation was found between the duration of remission and both the mean insulin requirement during the first 10 days of treatment and the duration of initial glucosuria. Thus the present results together with previous findings suggest that the severity of initial metabolic decompensation in diabetes mellitus type I seems to determine at least in part the duration of remission.

C-peptide secretion was studied in eight juvenile diabetics during the remission phase of the disease. The release of C-peptide was measured after a (1) normal intravenous glucose tolerance test, (2) a double glucose tolerance test, (3) an arginine infusion, and (4) after an intravenous glucose tolerance test followed by an arginine infusion. Under all conditions the intravenous glucose load had only a minimal effect on the secretion of C-peptide, while arginine alone or after the intravenous glucose tolerance test stimulated the release of the peptide in all patients. Pretreatment with glucose did not augment the effect of arginine on C-peptide release. The results indicate that during the remission phase of juvenile-onset diabetes the endocrine pancreas does not recognize glucose as and appropriate signal for C-peptide release and cannot transform the amplifying effect of glucose into a higher hormonal secretion rate.