Search

Due to a longer plasma half-life and half-time of action on glucose metabolism biosynthetic human proinsulin was thought to be an alternative to long-acting insulin preparations. To test this hypothesis we studied 23 type 2 diabetic patients who could no longer be treated sufficiently with oral hypoglycaemic agents. After an initial 1 week phase during which all patients received protamine bound insulin twice daily, the patients either continued on NPH insulin (Group A, n= 11) or were randomly switched to human proinsulin (Group B, n= 12). Glucose profiles and peripheral and hepatic insulin sensitivity (euglycaemic clamp: 120 mU m-2 min-1) were measured at the end of the initial period (Time 1) and 1 week later (Time 2). The insulin-mediated glucose disposal (RD) was not changed after either treatment (group A: 176±18 vs. 192±19 mg m-2 min-1; group B: 175 ± 15 vs.174±12 mg m-2 min-1 for times 1 and 2, respectively, NS). Suppression of hepatic glucose output (HGO) was complete in both groups at both times. Fasting blood glucose levels (FBG) and basal HGO were equally low at times 1 and 2 (group A: FBG 118 vs. 123 mg dl-1, BHGO 81 vs. 79 mg m-2 min-1; group B: FBG 118 vs. 106 mg dl-1, BHGO 87 vs. 84 mg m-2 min-1; NS). Mean blood glucose levels (MBG) were unchanged in the group receiving NPH insulin (164 vs. 162 mg dl-1; NS) but improved in group B (182 vs. 142 mg dl-1; P < 0.001). Blood glucose levels were lower in group B, expecially during the afternoon (from 12.00 to 19.00 h). Insulin requirement was the same in group A at times 1 and 2; in group B the proinsulin dosage was reduced significantly to 33 U day-1 at time 2 as compared to an insulin dose of 41 U day-1 at time 1 (P < 0.01). In summary, equal metabolic control can be achieved with proinsulin compared to protamine bound insulin with a lower dose on a unit base for proinsulin. Peripheral and hepatic insulin sensitivity remain unchanged during proinsulin therapy compared to NPH insulin treatment.

Concentrations of HDL cholesterol, apolipoprotein (apo) A-I and apo A-II were found to be significantly decreased in patients with insulin-dependent diabetes (IDD) and non-insulin-dependent diabetes (NIDD) compared with carefully selected controls matched for sex, age and body weight. LDL cholesterol and apo B levels did not differ significantly between diabetics and controls. Concentrations of lipoprotein Lp(a), an independent risk factor for coronary artery disease in non-diabetics, were above 20 mg/dl in only 14% of diabetics and in 5% of controls. LCAT activity was normal in diabetics, irrespective of type of diabetes, sex and age of patients. No correlation between HbAj and either HDL cholesterol or A-I and A-II was found in IDD and NIDD. A positive correlation between HbA 1 and either triglyceride or VLDL triglyceride was noted in IDD and NIDD. There was also a positive correlation between insulin dosage in IDD and HDL cholesterol, apolipoprotein A-I and A-II.

Patients from England, Austria, and Australia with recently diagnosed juvenile-onset insulin-dependent diabetes (type 1) mellitus (IDDM) and matched controls were tested for specific IgM responses to Coxsackie B1-5 viruses. 37 of 122 (30%) patients aged less than 15, but only 15 of 204 (6%) controls, were positive (p less than 0.005). Differences in Coxsackie B virus specific IgM responses between patients and controls were statistically significant for patients in England and Austria (p less than 0.005). Coxsackie B virus specific IgM responses were detected in only 3 of 31 patients aged greater than 16. Virus-specific IgM responses were directed against a single serotype, usually Coxsackie B4 or 5, in 23 of 37 (62.5%) children aged less than 15; 10 of 13 (77%) of children aged less than 7 had monotypic responses. Among families of Austrian patients with IDDM, 8 of 79 (10%) siblings had Coxsackie B virus specific IgM responses, 1 of whom subsequently had IDDM, but none of the 80 parents was positive. In contrast, there was no evidence of recent infection by mumps, rubella, or cytomegalovirus (CMV), since mumps-virus specific IgM was present in only 2 of 100 children with IDDM and 5 of 139 controls; no rubella or CMV specific IgM responses were detected in 60 sera from patients with IDDM.

Plasma β -Thromboglobulin levels were determined in 22 multiple myeloma patients, in 15 patients with polycythaemia vera and in 70 healthy controls. In both multiple myeloma and poly

The influence of age and sex on human GH secretion is controversial. In previous studies, serum GH responses to arginine and insulin-induced hypoglycemia were significantly higher in pre- and postovulatory women than in men. In contrast, recent studies suggest that GH responsiveness to GHRH is higher in normal young men than in age-matched women. To clarify the question of sex and age influence on GHRH-(1-44)-stimulated GH secretion, we studied 116 normal women and men (with body mass indexes of 18-25 and 19-26, respectively) between the ages of 18 and 95 yr. The peak serum GH increments after GHRH administration were significantly higher in premenopausal women than in age-matched men (P less than 0.003 for the age group 18-30 yr and P less than 0.03 for the age group 30-50 yr, as assessed by analysis of variance). The responses were not different in postmenopausal women and age-matched men. Multiple regression analysis revealed a significant negative correlation between GHRH-induced GH responses (integrated area under the curve) and age in both women (P less than 0.002) and men (P less than 0.001). In addition, we determined basal serum testosterone, estradiol, cortisol, and PRL levels in all subjects. Multivariate regression analysis of the GH responses to GHRH administration revealed a significant positive correlation (P less than 0.01) between serum estradiol and both GH increase and the area under the GH response curve. No correlation was found between GHRH-stimulated GH secretion and basal serum cortisol, testosterone, or PRL concentrations. Our data clearly demonstrate a marked influence of both sex and age on GHRH-stimulated GH secretion. We found a higher GH increase in premenopausal women compared with age matched-men and an age-dependent decrease in GHRH-stimulated GH secretion in both sexes. Furthermore, in women a significant influence of estradiol on GH secretion after GHRH administration could be demonstrated.

Depending on their symptomatology 152 cured (i.e., normocalcemic) patients with surgically proven primary hyperparathyroidism (pHPT) showed typical symptoms preoperatively. Besides hypercalcemia and elevated parathyroid hormone levels, 15 patients suffered only from hypertension and/or diffuse osteoporosis and/or complaints caused by the hypercalcemic syndrome (oligosymptomatic patients). Nine patients had no complaints (asymptomatic patients). The long-term clinical course of all patients was analyzed up to 22 years. Although the formation of urinary calculi was stopped in 94% of cases, a deterioration of renal function and hypertension was seen in symptomatic (12.5% and 9.2%, respectively) and oligosymptomatic patients (6.7% and 13.3%, respectively). Renal function and hypertension were unpredictable despite normalization of the hyperactive parathyroid metabolism and were of decisive prognostic significance; 6% died of acute or chronic renal failure, or of the consequences of hypertension. Multiple bone lesions, even large, healed functionally and were of no prognostic significance. In the majority of symptomatic patients gastrointestinal manifestations held postoperatively, but two patients died of acute pancreatitis without gastrointestinal complaints preoperatively. Almost all symptoms of the hypercalcemic syndrome disappeared immediately and permanently in symptomatic and oligosymptomatic patients. No deterioration of renal function and no elevation of blood pressure was observed in cured asymptomatic patients postoperatively. Immediate surgical treatment even in asymptomatic patients may have avoided complications of chronic renal failure or of hypertension. As soon as organic manifestations, even in a mild form, have been established, it seems impossible to predict the course and to prevent an unfavorable clinical outcome.

Summary Recent resorption studies in healthy subjects suggest that intermediate human zinc insulin preparations might diminish the absorption and activity of human short-acting insulin when the two insulins are administered as a single, combined preparation. This study was designed to investigate whether combined and separate administration of human zinc or human NPH insulin with soluble human insulin have different pharmacokinetic characteristics, as evaluated by glucose clamp studies and determination of free insulin levels. Eight type 1 diabetic patients received, in random order, four different, subcutaneously injected preparations of human insulin. Zinc insulin (Monotard HM, Novo-M) and protamine insulin (Protaphan HM, Novo-P) were each given with short-acting insulin (Actrapid HM, Novo-A). These insulins were administered either as a single combined preparation (MA; PA) or as two separate injections (M + A; P + A). Prior to the insulin injection euglycemia was achieved by an overnight intravenous insulin infusion. After the subcutaneous injection of insulin, glucose was monitored at 10-min intervals and euglycemia was maintained by a variable glucose infusion rate for 6 h. The total glucose infusion rate during this period was significantly lower following MA compared with M + A (total glucose infusion: 643 ± 117 vs. 817 ± 130 mg/kg, P = 0.009) whereas the glucose infusion rate did not differ between PA and P + A (878 ± 122 vs. 914 ± 118 mg/kg, NS). Free insulin levels after combined administration of MA were significantly lower at time 60–140 compared with separate administration of M + A ( P

Hyperlipidamien sind ein haufiger Befund bei Diabetes mellitus. Da neben der Leber auch die Dunndarmmukosa endogene Lipoproteine synthetisiert, war es von Interesse, bei 11 Erwachsenen mit juvenilem Diabetes und bei 7 Patienten mit Altersdiabetes den Lipidgehalt der Dunndarmmukosa zu bestimmen. Als Kontrolle dienten 11 nicht diabetische Patienten. Nach einer Nuchternperiode von 12–14 h erfolgte zunachst eine Blutabnahme zur Bestimmung von Nuchternblutzucker, Serumlipiden und glykosyliertem Hamoglobin AI, daraufhin wurden mittels einer hydraulischen Biopsiesonde oder endoskopisch mehrere Dunndarmbiopsien entnommen und zur biochemischen, histochemischen und elektronenoptischen Auswertung entsprechend aufgearbeitet.

Die cellulare (mittels Migrations-inhibitionstest, MT) und humorale (mittels Immunfluorescenztechnik) Immunreaktion gegen Nebennieren-Antigene wurde bei 19 Patienten mit idiopathischer Nebennierenrindeninsuffizienz (INI) und 19 Kontrollpersonen untersucht. Bei 12 Patienten konnte eine ausgepragte Hemmung der Migration mononuclearer Zellen (MM) in Gegenwart von NN-Mikrosomen beobachtet werden; dagegen lag bei 18 der 19 Kontrollpersonen die MM im Normbereich. Zusatzlich konnten bei 11 (53%) der Patienten Nebennierenrinden-Antikorper (NNR-AK) festgestellt werden. In einer weiteren Untersuchungsreihe wurden NN-Mikrosomen mit NNR-AK vorinkubiert, im MT eingesetzt und die erhaltenen Migrationsindices mit denen durch NN-Mikrosomen allein erzielten verglichen. Bei 6 der 10 NNR-AK positiven Patienten konnte eine Hemmung der MM mit NN-Mikrosomen durch spezifische AK blockiert werden. Bei den NNR-AK negativen Patienten war kein einheitlicher Trend zu einer negativen oder positiven Beeinflussung der MM nachweisbar. Eine Blockierung der cellularen Immunreaktion durch spezifische Antikorper in diesem System erscheint wahrscheinlich. Mogliche Mechanismen, die dazu fuhren konnten, sowie die Bedeutung der NNR-AK werden diskutiert.

The binding of 125I-insulin to insulin receptors on circulating mononuclear leukocytes was studied in ten patients with hyperthyroidism and 20 euthyroid normal volunteers. The hyperthyroid patients demonstrated significantly elevated glucose levels following an oral glucose load, despite normal insulin secretion. The infusion of insulin resulted in a delayed hypoglycaemic effect in the hyperthyroid patients; however, the inhibition of the endogenous insulin secretion as indicated by suppression of C-peptide levels was not different from euthyroid control subjects. Insulin binding to monocytes was significantly decreased in the hyperthyroid patients. Scatchard analysis of binding data indicates that a decrease of receptor number rather than receptor affinity seems to be the cause of the lowered insulin binding in hyperthyroid patients with diffuse toxic goitre. The findings of decreased insulin receptor number, mild degree of glucose intolerance despite normal insulin secretion and the delayed hypoglycaemic effect following insulin infusion suggest that peripheral insulin resistance could be involved in the highly complex pathophysiology of glucose intolerance in hyperthyroidism.

The present prospective follow-up study was made to study the effect of glycaemic regulation on levels of factor VII, protein C and protein S in 15 insulin-dependent diabetic patients without manifestations of vascular disease. Patients were tested before and after 8 weeks of 'metabolic' intervention, whereby a near-normoglycaemic state was achieved. At baseline, values of cross-linked fibrin degradation products (XL-FDP) and levels of 'total' protein S were significantly increased and protein C values were decreased in the diabetic patients when compared to control subjects, whereas levels of factor VII and 'free' protein S were near normal. After 'metabolic' intervention a decrease of all haemostatic parameters were recorded, however XL-FDP levels did not decline to control levels and the imbalance of factor VII and protein C persisted. When patients with newly diagnosed diabetes (n = 8) were compared to those with long-term disease (n = 7) higher levels of factor VII, protein C and protein S were recorded in the latter group before and after metabolic intervention; at baseline the differences reached statistical significance for factor VII and protein S, and remained significant for factor VII after metabolic intervention. Before and after intervention XL-FDP levels were higher in patients with newly diagnosed disease than in patients with long-term diabetes. The correlation analysis revealed positive correlations of factor VII, protein C and protein S to cholesterol and triglycerides, of protein S to all glycaemic control parameters, negative correlations of protein C to glucose, and of XL-FDP to factor VII, protein C and protein S. The results indicate an imbalance of haemostasis towards thrombophilicity in insulin-dependent diabetic patients, not completely correctable by glycaemic control.

Moderate insulin deficiency was reported to be accompanied by an increased production of intestinal very low density lipoprotein (VLDL) triglyceride in the rat. Because plasma free fatty acids (FFA) are incorporated into triglyceride by intestinal mucosa of rats and humans and plasma FFA are increased in insulin-deficient diabetes mellitus, we investigated several aspects of the intestinal metabolism of plasma FFA in diabetic rats. All experiments were performed on the third day following the i.v. injection of streptozotocin (45 mg/kg body weight) or buffer alone. A (14 C)palmitic acid-rat serum complex was rapidly injected intravenously and its initial uptake by small bowel mucosa, the intracellular incorporation into lipids and water soluble metabolites and the specific radioactivity of triglycerides of mucosal homogenates was determined. No significant differences could be found between diabetic and control rats at 2 and 5 min after 14C-palmitate i.v., suggesting that neither the influx of plasma free fatty acids into intestinal mucosal cells nor their initial intracellular metabolic pathways are significantly altered in moderately diabetic rats. A pronounced decrease in intestinal mucosal triglyceride at 10 min after 14C-palmitate i.v. might be interpreted as indirect evidence for an enhanced triglyceride efflux from intestinal mucosa into mesenteric lymph in diabetic rats.

Terbutaline, a beta 2-adrenergic agonist, has been shown to cause hypokalemia and an increase of plasma glucose and serum insulin concentrations. We considered that terbutaline-induced hypokalemia may be due to the insulin-induced shift of potassium (K+) from the extracellular to the intracellular space. If so, then inhibition of insulin secretion by somatostatin would prevent terbutaline-induced hypokalemia. Further, we wondered whether oral potassium pretreatment could prevent terbutaline-induced hypokalemia. Therefore, 10 healthy volunteers (5 men, 5 women; mean age, 23 yr +/- 3 SD) received either sodium chloride (NaCl) or somatostatin intravenously together with 0.25 mg terbutaline subcutaneously in a double-blind crossover design. On a third test day, they received 39 mval of K+ powder orally before terbutaline injection in an open trial. Terbutaline caused a significant decrease of K+ (from 3.96 +/- 0.08 to 3.3 +/- 0.13 mmol/L +/- SEM; p less than 0.0005), accompanied by a significant increase in plasma glucose (from 83 +/- 3.6 to 101 +/- 4.4 mg/dl +/- SEM; p less than 0.01) and serum insulin concentrations (from 11.7 +/- 0.9 to 19.9 +/- 1.1 microU/ml +/- SEM; p less than 0.001), confirming earlier data. Somatostatin pretreatment inhibited the terbutaline-induced hypokalemia; the small fall of K+ (from 3.7 +/- 0.08 to 3.5 +/- 0.2 mmol/L) was no longer significant. Insulin secretion was completely blocked by somatostatin, leading to an even more pronounced increase of blood glucose. Hypokalemia after terbutaline injection was not prevented by oral potassium pretreatment. In summary, the present findings confirm that terbutaline-induced hypokalemia is associated with increased plasma glucose and insulin levels.(ABSTRACT TRUNCATED AT 250 WORDS)

In 9 newly diagnosed type I diabetic children the residual beta-cell secretory capacity was examined after stimulation with oral glucose load, glucagon and iv glucose plus arginine hydrochloride administration shortly after diagnosis and in the partial remission phase. A significant C-peptide secretion induced by these substances except by iv glucose was found at both investigation times. Whereas beta-cell function did only slightly increase from the initial testing to the measurements in the partial remission, beta-cell sensitivity increased significantly (p less than 0.05). The data suggest that "partial remission" referred to C-peptide secretion starts very early after insulin treatment and that other factors, possibly a decrease of peripheral insulin resistance, are involved in the improved metabolic control in partial remission phase.

Cell-mediated immunity to various adrenal antigen preparations - crude extract, mitochondria and microsomes - has been investigated by means of the migration inhibition of mononuclear cells in 19 patients with established diagnosis of idiopathic Addison's disease (IAD), in 1 patient with suspected Addison's disease and in 20 controls.Adrenal antibodies were determined by immunofluorescence technique. In 13 of the IAD patients significant migration inhibition (MI) could be observed with mitochondria and in 12 patients with crude extract.In addition, MI, although less pronounced, could be detected with microsomes in 12 IAD patients.In one of the controls slight inhibition was observed with all the antigens used and in another stimulation of lymphocyte migration with crude extract could be observed.Adrenal antibodies were detected in 11 of the patients investigated.No correlation could be found between duration of the disease and humoral or cellular immune reactions to adrenal antigens.

Recently, conflicting results have been published about a possible relationship between platelet activity and exercise-induced myocardial ischemia. The present study was performed to investigate platelet behavior during a graded symptom-limited bicycle ergometer test both in relation to the intensity of exercise and to exercise-induced myocardial ischemia. Plasma concentrations of platelet factor 4 (PF4) and β-thromboglobulin (β-TG) were measured by radioimmunoassays in 53 patients who had had acute myocardial infarction 10 weeks before the study and, for comparison, in 9 healthy individuals. In the whole group of the 53 patients there was no significant alteration in platelet-specific proteins during exercise, whereas physical activity induced a 2- to 3-fold increase in β-TG and PF4 levels in the controls. However, on differentiation of the patients as to their individual exercise performance, significant exercise-associated platelet activation was demonstrable in those who reached more than 75% of their calculated maximal working capacity, whereas no correlation was found between platelet activity and exercise-induced myocardial ischemia. Thus, the results from this study indicate that in vivo platelet activation is a physiological phenomenon which occurs when a certain degree of physical intensity is exceeded, independent of the precipitation of myocardial ischemia.

Patients who had been included in a randomized double-blind placebo-controlled trial on the efficacy of cyclosporin A (CyA) in producing remissions in insulin-dependent diabetes mellitus (IDDM) type I were investigated for humoral and cellular immunologic parameters. Whereas metabolic derangement before the initiation of insulin treatment led to small but significant decreases in the percentage of CD4-positive lymphocytes as well as of the activity of natural killer (NK) cells and antibody-dependent cellular cytotoxicity (ADCC), the administration of CyA did not influence any of the immunologic parameters tested, which included proliferative lymphocyte responses to mitogens and alloantigens and serum concentrations of immunoglobulins G, A and M. Thus NK cell activity, ADCC as well as the percentage of CD4-positive lymphocytes returned to normal levels in parallel with the normalization of glycosylated haemoglobin (HbAlc), but were not further influenced in their course by the administration of CyA, as compared with patients receiving placebo. Interferon-induced augmentation of NK cell activity did not differ between patients with IDDM on placebo and those under CyA therapy. All other investigated parameters also remained unchanged during the time of CyA therapy. We conclude that metabolic derangement leads to a reversible disturbance of certain cellular immune functions, but their normalization achieved by insulin treatment and their further course remains uninfluenced by the administration of CyA. Journal of Endocrinology (1989) 121, 177–183

In patients with Graves' hyperthyroidism, the relapse rate after antithyroid drug treatment is in the range of about 30–70%. Different attempts have been made to obtain criteria for the prediction of the clinical outcome after drug therapy, especially HLA-DR typing and measurement of TSH receptor antibodies. So far, very conflicting results have been reported. This is not surprising in view of the many genetically controlled and environmental factors that play a role in the pathogenesis of this disease. Moreover, most reports are based on retrospective studies with a relatively small number of patients. Our own data, obtained in a prospective multicenter study, yield strong evidence against the relevance of HLA-DR3 typing (n = 187, sensitivity = 0.38, specificity = 0.67) or measurement of TSH receptor antibodies at the end of therapy (n = 269, sensitivity = 0.49, specificity = 0.72) for the prediction of the clinical course after drug treatment.

Autoantibodies to adrenal medulla that gave a diffuse immunofluorescent staining pattern were detected in 17 out of 107 (16%) patients with newly diagnosed Type I diabetes mellitus, in 13 out of 178 (7%) patients with long lasting disease but in none of 80 mixed control sera tested. The antibodies were of IgG class and 31 of the 33 positive sera also fixed complement. In 32 out of 34 cases, detection of the antibodies was correlated with the presence in the serum of pancreatic islet cell antibodies (ICA). The specificity of adrenal medullary antibodies is distinct from ICA and from C-cell antibodies since their reactivity was not abolished by preabsorption with extracts from human insulinoma or thyroid C-cell carcinoma. The presence in the serum of antibodies to adrenal medulla is not related to a functional defect of the adrenal medulla, but this new specificity indicates a further autoimmune reaction related to the natural history of Type I diabetes.

In the present study insulin binding properties of human semi-synthetic and porcine insulin were compared in Type 1 (insulin-dependent) diabetic patients treated from the onset of their disease either with human semi-synthetic insulin (n = 12) or porcine insulin (n = 12) and control subjects (n = 12). In all three groups, insulin binding to circulating monocytes revealed no difference between human semi-synthetic and porcine insulin (specific insulin binding at tracer concentration: 5.7 +/- 0.5% versus 5.4 +/- 0.5% in control subjects, 5.5 +/- 0.4% versus 5.4 +/- 0.4% in Type 1 diabetic patients on porcine insulin, 5.3 +/- 0.4% versus 5.6 +/- 0.4% in Type 1 diabetic patients on human insulin). Treatment with human or porcine insulin did not have any significant influence on receptor binding properties of the two diabetic groups investigated. Absolute receptor number and affinity of both diabetic groups were within the range of healthy control subjects irrespective of treatment with human or porcine insulin.

Growth hormone levels following an intravenous bolus injection of 1 micrograms/kg body weight growth hormone releasing hormone were measured in 21 non-obese and 26 obese patients with Type 2 (non-insulin-dependent) diabetes mellitus and in 13 control subjects. Growth hormone responses in non-obese Type 2 diabetic patients were not statistically different from control subjects. However, obese Type 2 diabetic patients had significantly decreased growth hormone responses to growth hormone releasing hormone when compared with non-obese Type 2 diabetic patients (p less than 0.02). In 9 Type 2 diabetic patients growth hormone releasing hormone tests were performed both during hyperglycaemia and after metabolic improvement by insulin treatment. Growth hormone responses before and after insulin treatment were not statistically different. Our data demonstrate that growth hormone responses to growth hormone releasing hormone in non-obese Type 2 diabetic patients do not differ significantly from control subjects; obesity blunts growth hormone responses to growth hormone releasing hormone in Type 2 diabetes mellitus; and growth hormone responses following growth hormone releasing hormone administration in Type 2 diabetes mellitus are not influenced by the state of metabolic control.

Bay m 1099 is a newly developed inhibitor of intestinal alpha-glucosidase. Its ability to lower postprandial plasma glucose, serum insulin and C-peptide levels in Type II diabetics has been investigated. Fifteen obese Type II diabetic patients with inadequate metabolic control during sulphonylurea treatment received a standardized diet and were treated either with Bay m 1099, b.d. (100 mg before breakfast and dinner) or placebo for 3 days, according to a double-blind cross-over design. The postprandial blood glucose level was significantly lower during Bay m 1099 treatment compared to placebo after breakfast and dinner (AUC after breakfast p less than 0.001). The reduced postprandial hyperglycaemia was associated with a decrease in meal stimulated serum insulin and C-peptide levels. Thus, Bay m 1099 may be a useful addition in the treatment of Type II diabetic patients.

One hundred fifty patients with toxic and scintigraphically diffuse goiter were HLA typed (A, B, C, DR). One group consisted of 101 patients with concomitant Graves' ophthalmopathy and/or TSH-binding inhibiting antibodies (TBIAb). Forty nine patients had neither ophthalmopathy nor TBIAb. The former group showed a higher prevalence of HLA-B8 and DR3 compared to a normal control group. The latter group showed a higher frequency of HLA-DR5, whereas the HLA-B8 and DR3 antigens were slightly below normal prevalence. These data indicate an immunogenetic heterogeneity in patients with toxic diffuse goiter. A group of 47 hyperthyroid patients with single autonomous thyroid adenoma had no increased prevalence of any HLA-antigens. Patients with long term remission did not show an altered prevalence of any of the HLA antigens compared to controls. In contrast, patients with Graves' ophthalmopathy and/or TBIAb activity who relapsed had a significantly higher prevalence of HLA-B8 DR3, whereas patients without TBIAb and eye signs who relapsed had a significantly higher prevalence of HLA-DR5 than the control group.

Platelet dysfunction may play an important role in diabetic microvascular disease. We therefore studied prostacyclin (PGI2) production in the forearm veins of patients with juvenile-onset diabetes (JOD; n = 15) and in 15 healthy subjects. In 10 male Wistar rats diabetes was induced by a single i. v, dose of streptozotooin and in a further 10 male Wistar rats diabetes was induced an alloxan diabetes. From these animals, as well as from 10 control rats abdominal aortic tissue was removed for PGI2-estimation. PGI2-formation was studied using Moncada’s bioassay based upon its potent platelet aggregation inhibiting effect (the standard was kindly supplied by Dr. John E. Pike, The Upjohn Company, Kalamazoo, Michigan, U.S.A.). Prostacyclin generation of the tissue was significant (2p < 0.02) diminished in the JOD-patients as well as in experimental diabetes compared to the respective control groups. The decrease in PGI2-synthesis might play an important role in initiating and/or promoting the vascular complications of the disease

In order to evaluate the potential role of parathyroid hormone on glucose metabolism in patients on chronic hemodialysis hyperglycemic clamp studies were performed in 7 parathyroidectomized and 11 nonparathyroidectomized patients on chronic hemodialysis and in healthy controls. There were no significant differences in the peripheral glucose uptake of the 3 groups. The beta cell response to hyperglycemia during the early phase as well as during the steady state was almost identical in controls and in nonparathyroidectomized uremics, whereas in the parathyroidectomized group a markedly enhanced insulin secretion was found. Calculated tissue sensitivity to insulin therefore was equal in controls and in nonparathyroidectomized uremics, whereas patients after parathyroidectomy had peripheral insulin resistance. Our results demonstrate that patients on chronic hemodialysis apparently have normal peripheral glucose uptake. The subgroup of patients who have undergone parathyroidectomy, however, show an enhanced insulin response to hyperglycemia suggesting peripheral insulin resistance. We conclude that longstanding and severe secondary hyperparathyroidism—the usual cause for parathyroidectomy in these patients—results in irreversible insulin resistance with a compensatory increase of insulin secretion.

We studied insulin receptor-binding and carbohydrate and metabolism in 15 patients with symptomatic primary hyperparathyroidism in comparison with 20 healthy controls. Insulin binding to monocytes and erythrocytes was measured by radioreceptor-ligand-assay. Furthermore, patients and controls were characterized by testing oral (100 g glucose load) glucose tolerance as well as insulin tolerance (0.1U insulin/kg body weight). Compared with controls, patients with primary hyperparathyroidism exhibited marked hyperinsulinemia (P less than 0.01) and significantly higher glucose levels (P less than 0.01) after an oral glucose load. The glucose lowering effect of intravenous insulin was significantly diminished in primary hyperparathyroidism compared with controls (P less than 0.01). Receptor studies revealed a significantly lower (P less than 0.01) insulin binding to monocytes and to erythrocytes in patients with primary hyperparathyroidism compared with controls. The present data indicate an insulin-resistant state in primary hyperparathyroidism, which is caused at least in part, by a downregulation of insulin receptors.

A high prevalence of left ventricular dysfunction in insulin-dependent (type-I) diabetics has been reported. However, the exact influence of metabolic control and/or the coexistence of early diabetic microangiopathy is unknown. Thus, we assessed left ventricular function by echophonocardiography in 50 type-I diabetics (mean age 26 +/- 7.9 years), who showed a fairly good metabolic long-term control (mean hemoglobin A1: 8.8%) after the introduction to intensified insulin therapy in comparison with 50 age- and sex-matched controls. Type-I diabetics did not differ from controls in their left ventricular internal diameters, mean wall thickness, ratio of pre-ejection period to left ventricular ejection time and systolic shortening fraction. Isovolumetric relaxation period reflecting an early diastolic event was slightly but significantly prolonged in diabetic subjects, independent of metabolic control status or existence of early microangiopathy. Isovolumetric relaxation period showed a statistically significant correlation to age in type-I diabetics, but not in controls. Possibly, the diabetic status--although well-controlled, but not normalized--may biochemically alter the myocardium and might influence its diastolic properties.

Vitamin E deficiency is associated with increased platelet aggregation, which can be normalized through vitamin E supplementation. In diabetes, increased platelet thromboxane A2 (TXA2) production is correlated with decreased platelet vitamin E content. We therefore investigated the effect of 400 mg DL-α-tocopherol acetate daily for 4 wk on ADP- and collagen-induced platelet aggregation and platelet TXA2 production in 22 type I (insulin-dependent) diabetic patients without macroangiopathy and with no or only minimal microangiopathy by a double-blind placebo-controlled crossover study. Platelet aggregation was induced in platelet-rich plasma by two or three different concentrations of ADP and collagen. TXA2 was measured by the stable spontaneous breakdown product thromboxane B2 by a specific radioimmunoassay. Whereas metabolic control remained unchanged during the study period, platelet TXA2 production was significantly (P < .05 and P < .01) reduced at each ADP concentration and at two of three collagen concentrations. Because increased TXA2 production of diabetic platelets is thought to play an important pathogenetic role in diabetic angiopathy, we conclude that vitamin E treatment could be beneficial with respect to platelet–vessel-wall interaction and thus might be promising for the prevention of diabetic angiopathy.

Diabetic patients have elevated plasma levels of factor VIII/von Willebrand factor (F VIII/vWF), and such elevations have been linked to vascular endothelial injury. In a prospective study we investigated the effect of metabolic regulation on the plasma levels of F VIII/vWF and cross-linked fibrin degradation products (XL-FDP), an indicator of intravascular coagulation, in 15 insulin-dependent diabetic patients who had no demonstrable vascular abnormalities. Eight patients had newly diagnosed diabetes, and 7 had been diabetic for an average of 12 yr. The patients were tested before and 1, 2, 4, and 8 weeks after the start of a structured diabetes education and care program, including introduction of a basal-bolus form of insulin treatment. Treatment for 8 weeks resulted in a highly significant improvement of metabolic control [hemoglobin Aic, 11.1 +/- 1.3% (+/- SD) vs. 6.8 +/- 1.0%; plasma fructosamine, 4.8 +/- 1.0 vs. 2.9 +/- 0.7 mmol/L; plasma glucose, 13.5 +/- 4.2 vs. 6.3 +/- 2.2 mmol/L; P less than 0.0001, respectively]. Compared to age- and sex-matched normal subjects, plasma activity of factor VIII (F VIII:C) was significantly elevated in the diabetic patients initially (1.5 +/- 0.6 vs. 1.0 +/- 0.1 x 10(3) U/L; P less than 0.01). After 2 weeks of intensified therapy it was 1.1 +/- 0.4 x 10(3) U/L. The mean plasma vWF value also was significantly elevated initially [vWF antigen, 1.8 +/- 0.7; normal group, 0.9 +/- 0.1 x 10(3) U/L (P less than 0.01); vWF ristocetin cofactor activity, 1.9 +/- 0.9; normal group, 1.0 +/- 0.3 x 10(3) U/L (P less than 0.001)] and decreased significantly after only 1 week of therapy. In the following 7-week period plasma vWF remained near normal. Plasma XL-FDP levels were elevated in all patients initially (190 +/- 150; normal group, 35 +/- 30 micrograms/L): the value was most abnormal in the patients with newly diagnosed disease (300 +/- 150 micrograms/L), indicating intravascular fibrin formation. The mean XL-FDP level declined significantly in the patients with newly diagnosed diabetes after 1 week of therapy; in the other patients, however, XL-FDP levels remained slightly elevated. In all 15 patients the plasma F VIII:C and XL-FDP levels were correlated significantly at all times. The plasma vWF and XL-FDP levels were correlated after 1, 2, 4, and 8 weeks of treatment as were the plasma vWF levels and glucose concentrations before and 1 and 2 weeks after the start of treatment program.(ABSTRACT TRUNCATED AT 400 WORDS)

In 70 patients with juvenile-onset, insulin-dependent (type I) diabetes and 75 age- and sex-matched controls the reversible platelet aggregates expressed as platelet count ratio (PCR) and the ADP-induced platelet aggregation were studied. Retinal microangiopathy was staged by retinal fluorescein angiography. The mean PCR of the patients (0.82 +/- 0.02) was statistically significantly lower than that of the controls (0.97 +/- 0.01). However, in different stages of retinopathy no significantly different PCR could be observed. ADP-induced platelet aggregation (0.5 and 1.0 micromol/l) exhibited a higher reactivity of diabetic platelets, but with the exception of tangent alpha (see later), the differences were not statistically significant in comparison to the controls. After collagen-induced platelet aggregation (0.5 and 1 microgram/ml) the lag time in diabetics was significantly (p less than 0.001) lower than in the controls, whereas the other quantitative parameters exhibited higher platelet reactivity in general, though not statistically significant. No relationship between PCR and the in vitro induced aggregation was found. The degree of retinopathy had no significant influence on platelet aggregation. In general, the data demonstrate an increase in sensitivity of platelets in juvenile-onset diabetics, whereas no influence of stage of microangiopathy could be detected.

The binding properties of human insulin (recombinant DNA) and human proinsulin were compared in seven healthy volunteers. Specific cell binding of human proinsulin was significantly lower compared with the human insulin receptor binding with an approximately 100-fold lower average affinity (3.71 mol−1 × 108 for human insulin versus 0.042 mol−1 × 108 for human proinsulin). Native human proinsulin at low concentrations had no significant effect on specific human insulin receptor binding. Only at high hormone concentrations human proinsulin could displace human insulin from the insulin receptor. We conclude that in vivo proinsulin-insulin interactions at the receptor do not possess major clinical relevance.

Recent studies indicate that serum levels of osteocalcin, a 49-aminoacid bone matrix protein, are a biochemical marker of bone formation. In order to study bone metabolism in diabetes mellitus, in 28 patients with Type 1 (insulin-dependent) diabetes mellitus, in 38 patients with Type 2 (non-insulin-dependent) diabetes mellitus and two control groups, matched for Type 1 and Type 2 diabetic patients, respectively, serum levels of osteocalcin, parathyroid hormone and 25 hydroxy vitamin D were measured by radioimmunoassay. Whereas in Type 1 diabetic patients and control subjects serum levels of osteocalcin and 25 hydroxy vitamin D were not statistically different, serum osteocalcin and 25 hydroxy vitamin D levels were significantly decreased in Type 2 diabetic patients when compared with corresponding control subjects (p less than 0.03 and p less than 0.001, respectively). Independent of the type of diabetes, serum parathyroid hormone levels were comparable in diabetic patients and matched control subjects. Serum osteocalcin levels were significantly lower in Type 1 diabetic patients with retinopathy and/or proteinuria than in Type 1 diabetic patients without microangiopathy (p less than 0.05). Whereas serum parathyroid hormone levels in Type 2 diabetic patients with retinopathy and/or proteinuria were significantly increased (p less than 0.02), 25 hydroxy vitamin D levels were decreased (p less than 0.02) when compared with Type 2 diabetic patients without microangiopathy. Our data give evidence of a vitamin D deficiency and a decreased bone formation in patients with Type 2 diabetes mellitus. In Type 1 diabetes mellitus bone formation as reflected by serum osteocalcin levels is influenced by the presence or absence of microangiopathic complications.

Because of the frequency of late cardiovascular complications in maturity onset non-insulin-dependent (Type II) diabetes mellitus, there have been few studies regarding nephropathy in this patient population. The authors have analyzed the prevalence of microalbuminuria and the nature of clinical manifestations associated with elevated albumin excretion rate (AER) in a large population presenting with Type II diabetes. Among 318 patients studied during 1986, pathologically elevated 24 h AERs were found in 59%. The rate of microalbuminuria among 205 Type I diabetic patients screened during the same interval was 43%. AER was found to be positively correlated with duration of disease (p less than 0.0008) and metabolic control as determined by measurement of glycosylated hemoglobin (HbA1c) (p less than 0.002). There was only a modest agreement between AER and mean systemic blood pressure. The high prevalence of microalbuminuria in Type II diabetic patients and its known association with increased mortality emphasize the need for long-term follow up studies in order to clarify whether elevated AER in this patient population is predictive for overt diabetic nephropathy.

Bei Patienten mit insulinabhangigem Diabetes mellitus (IDM) wird seit langem — insbesondere beim Auftreten einer metabolischen Dekompensation — eine erhohte Infektions-anfalligkeit diskutiert, wahrend Infektionen ihrerseits zu einer betrachtlichen Verschlech-terung der Stoffwechsellage fuhren [2]. Da die neutrophilen Granulozyten in der Infektabwehr eine zentrale Stellung einnehmen, war es von Interesse, die Funktionskapazitat dieser Zellen zu studieren.

Carbohydrate metabolism was investigated in 9 patients with symptomatic primary hyperparathyroidism. Before and after parathyroidectomy intravenous and oral glucose tolerance test, tolbutamide test, arginine infusion test and insulin tolerance test were performed. During intravenous and oral glucose tolerance tests, patients with primary hyperparathyroidism exhibited hyperinsulinemia and impaired glucose tolerance without normalization after surgery. Tolbutamide-induced induced insulin release did not differ pre- or postoperatively. After restoration of normocalcemia and normocalcemia and normophosphatemia we found significantly lower glucose and insulin levels following arginine infusion and a significantly increased hypoglycemic response to parenterally administered insulin, probably indicating partial improvement of glucose tolerance after surgery. Our findings suggest that biochemical abnormalities associated with primary hyperparathyroidism, like hypercalcemia, hypophosphatemia, and elevated parathyroid hormone levels may cause and sustain a form of endogenous insulin resistance, which consequently leads to hyperinsulinemia and to impaired glucose tolerance. Since hyperinsulinemia as well as impaired glucose tolerance seem to be only slowly and partially reversible in symptomatic primary hyperparathyroidism, these data could be considered as an additional argument for early surgical intervention in this disorder.

In two hospitals an identical diabetes teaching and treatment programme (in-patient, Monday to Friday, group teaching) was set up. Seventy-eight consecutive, conventionally treated Type 1 diabetic patients (duration of diabetes 10 +/- 6 years), referred during a certain period, were reinvestigated after 1 year, and again (for assessment of metabolic control only) 22 months after the teaching and treatment programme. Initially, mean glycosylated haemoglobin was 2.6%, after one year 1.0%, and after 22 months 1.5% above the upper limit of the normal range (p less than 0.001). Hospital admissions were reduced from a mean of 10 to a median of 1 day per patient per year (p less than 0.001). The long-term quality of diabetes care achieved by the diabetes teaching and treatment programme was unrelated to intelligence quotient, diabetes duration, or diabetes-related knowledge. Patients with normal levels of glycosylated haemoglobin on follow-up (33% of all patients) had particularly good compliance rates, and significantly lower initial values of glycosylated haemoglobin than patients with glycosylated haemoglobin levels greater than or equal to 10%. The data indicate that the diabetes teaching and treatment programme resulted in a substantial long-term improvement of metabolic control and a striking reduction of hospital admissions. The study substantiates the feasibility of applying this teaching and treatment programme on a large scale to other hospitals, so as to improve the quality of diabetes care and decrease health care costs.

The number of thyroglobulin-binding peripheral blood cells (TG-BL) was determined in 24 patients with Hashimoto thyroiditis: 12 non-Hashimoto, non-Graves disease goiter patients; and 10 unrelated controls using the fluoroimmunocytoadherence (FICA) technique. Hashimoto patients showed significantly elevated numbers of TG-BL as compared to members of the two other groups. For further characterization of TG-BL, inhibition experiments were performed by preincubation of peripheral blood lymphocytes with TG, normal human serum, rabbit-γ-globulin, or bovine serum albumin. The results of these experiments indicate that the total number of TG-BL in Hashimoto patients consists of a majority of cells actively synthesizing their TG receptors and a minority adhering to TG-coated beads due to passive adsorption of TG autoantibody onto their surface or in a nonspecific fashion. No correlation between the total number of TG-BL and the presence and/or titer of autoantibodies to TG, the second colloid antigen, or microsomal antigens was found. Evidence is presented that the determination of TG-BL provides a specific tool for the diagnosis of Hashimoto thyroiditis superior to conventional thyroid autoantibody analysis.

Our own data presented in this paper are taken from investigations of a multi center prospective study*, in which the following colleagues participate: Althoff (Frankfurt), Badenhoop (Mannheim), Benker (Essen), Beyer (Mainz), Bd’rner (Wiirzburg), Bogner (Berlin), Bretzel (GieBen), Fiek (Berlin), Finke (Berlin), GrSf (Berlin), Grebe (GieBen), Ifengst (Miinster), Hensen (Berlin), Holl (Berlin), Hopf (Berlin), Hufner (Heidelberg), Joseph (Marburg), Jungmann (Frankfurt), Kahaly (Mainz), Kotulla (Berlin), Koppenhagen (Berlin), Mtiller-Eckardt (GieBen), Pickardt (Miinchen), Raue (Heidelberg), Reiners (WCirzburg), Reinwein (Essen), Schatz (GieBen), Schleusener (Berlin), Schoffling (Frankfurt), Schumm (Frankfurt), Schwander (Berlin), Schwedes (Mannheim), Seif (TUbingen), Usadel (Mannheim), WLtte (Miinchen), Ziegler (Heidelberg)

Antibody-dependent killer-cell activity (ADCC) was determined in 36 insulin-dependent diabetics (IDD) and 32 controls. The medians of cytotoxic indices obtained by using either antibody coated chicken red blood or HeLa cells as targets were statistically significantly reduced in the diabetics (P less than 0.05 for both systems). However, due to the wide range and considerable overlap of the cytotoxic indices observed in patients and controls, the biological significance of these mathematical differences remains to be determined. The duration of the disease did not have any influence on killer (K) cell function and only a slight tendency for decreased ADCC during episodes of poor metabolic control was noted. Further analysis of the influence of diabetes-associated factors did not reveal any definite correlation between the functional K cell deficit, the insulin dosage administered, the insulin antibody titers, the blood glucose at the time of sampling, the 24 hour glucosuria and IDD-associated immunogenetic factors.

Humoral immunity to bacterial antigens was tested in 49 tissue typed patients with juvenile onset diabetes mellitus (JOD) and in 50 healthy controls. The number of patients with agglutinins to E. coli and staphylococci was significantly lower compared to controls (p less than 0.001, p less than 0.01 respectively). Missing antibody formation to pertussis and diphtheria toxoid could also be detected in a higher percentage of JOD patients than of controls (p less than 0.05; p congruent to 0.05, respectively). By contrast heteroagglutinins to sheep and rabbit erythrocytes were found in similar proportion in both groups and the values of immunoglobulin serum concentrations showed no difference between patients and controls. In addition no correlation between antibody formation and genes of the HLA complex was found. It is suggested that the severely reduced agglutinin formation to bacteria antigens might be partly responsible for susceptibility to bacterial infections in juvenile diabetics.

Several studies report increased growth hormone (GH) responses to provocative stimuli in patients with diabetic retinopathy. We studied GH responses to 1 μg/ kg body wt human pancreatic GH-releasing hormone 1-44 (hpGHRH 1-44) in 33 patients with type I diabetes mellitus, 31 patients with type II diabetes mellitus, and 2 control groups (N = 11 and 8). Based on the results of fundoscopy and fluorescein angiography, the diabetic patients were subdivided into 1) patients without diabetic retinopathy, 2) patients with nonproliferative diabetic retinopathy, and 3) patients with proliferative diabetic retinopathy. Growth hormone responses to hpGHRH 1-44 in diabetic patients with proliferative or nonproliferative retinopathy or without retinopathy were not significantly different regardless of the type of diabetes. Remarkably, GH responses to hpGHRH 1-44 in type I diabetic patients without retinopathy were significantly higher than the matched controls. Our data suggest that diabetic retinopathy in type I and in type II diabetes isnot associated with increased GH responsiveness to hpGHRH 1-44, whereas in type I diabetes mellitus without diabetic retinopathy, a GH hyperresponsiveness to hpGHRH seems to occur.

Fifty-four thyrotoxic patients (23 with and 31 without endocrine ophthalmopathy EOP) were HLA typed for A, B and C locus antigens. The frequency of the third locus antigen CW3 was found to be significantly increased in patients with EOP compared with those thyrotoxic patients without EOP. These findings point to a possible genetic heterogeneity in thyrotoxic patients with or without EOP. HLA B8 was observed in only 10 of the 54 patients studied, which is not in accordance with the previously reported statistically significant increased frequency of this B locus antigen in thyrotoxic patients.

There is ample evidence that cell-mediated immune mechanisms are crucial in the initiation of insulin-dependent diabetes mellitus (IDDM). Therefore, the role of cytokines in the pathogenesis of IDDM was investigated in 51 patients with IDDM, in comparison with 20 normal controls. The patients were divided into three groups, group 1 consisting of 31 newly diagnosed type 1 diabetics, in group 2 IDDM had been diagnosed for between 2 months and 2 years, and in group 3 onset had occurred 2–20 years before. Interleukin 1 (IL 1) activity was measured by the thymocyte co-stimulator assay, and interleukin 2 (IL 2) using IL 2 dependent cell lines. Peripheral blood monocyte IL 1 production was not altered under basal conditions. However, silica-stimulated IL 1 release was normal in patients with newly diagnosed or short-term disease, but was significantly decreased in long-term diabetics. Peripheral blood T-lymphocyte IL 2 production at onset of IDDM was normal under basal conditions, and upon optimal stimulation with concanavalin A (ConA) and phorbol myristate acetate (PMA). However, in the two groups with longer standing diabetes, basal and stimulated IL 2 release was decreased. We conclude that monocytes and T-lymphocytes from patients with diabetes mellitus have a diminished capacity to release IL 1 and IL 2 only later in the course of the disease. At the time of manifestation of disease, IL 1 and IL 2 production is normal in type-I diabetes mellitus.

The affinity of human (recombinant DNA) insulin and porcine insulin to preformed IgG-insulin antibodies of insulin-treated diabetic individuals was studied in 29 insulin-treated diabetic patients. The binding of 125I-human insulin and 125I-porcine insulin with antibodies was similar in the group of patients without insulin resistance (N = 25). The sera of insulin-resistant diabetic patients (N = 4), containing very high IgG-insulin immunoglobulins, showed a significantly lower affinity for human insulin compared with porcine insulin (P < 0.01). All four patients with insulin-antibody-mediated insulin resistance were positive for HLA-DR4, but negative for -DR3, supporting the concept of an immunogenetically transferred anti-insulin immune response in insulin-treated diabetic individuals. Based on the reduced binding of human insulin to IgG-antibodies of very high titers in patients with insulin resistance, a potential therapeutic advantage of human insulin therapy can be expected in such infrequent cases of immunologic insulin resistance.