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Biomedical subjects

U Keller

Publications and source records attributed to U Keller.

At least 235 records · Page 13Linked to original sources
PubMed1986

Biosynthesis of cyclosporin A: partial purification and properties of a multifunctional enzyme from Tolypocladium inflatum.

An enzyme fraction most probably involved in the biosynthesis of cyclosporin A was purified 540-fold from Tolypocladium inflatum. The enzyme was capable of forming covalent enzyme-substrate complexes and catalyzed the ATP-pyrophosphate exchange reactions dependent on the unmethylated constituent amino acids of cyclosporin A. Evidence was obtained that covalent binding of substrate amino acids occurred via thioester linkage. Furthermore, the N-methylation of thio-esterified valine, leucine, and glycine residues with S-adenosyl-L-methionine was demonstrated. De novo synthesis of cyclosporin A was not observed but the formation of the diketopiperazine cyclo-(D-Ala-MeLeu) from D-alanine and L-leucine under the consumption of ATP and S-adenosyl-L-methionine. This cyclodipeptide represents a partial sequence of cyclosporin A. Molecular mass determinations revealed the enzyme activity to be lying in the range of about 700 kDa.

Carbon Radioisotopes↗
PubMed1986

[New findings on the pathogenesis of diabetes mellitus].

Diabetes mellitus is a heterogeneous syndrome. Insulin-dependent type 1 diabetes is characterized by progressive deterioration of B-cells in the islets of Langerhans resulting in a fall in insulin secretion. According to recent studies, autoimmune mechanisms are the reason for the B-cell destruction. These mechanisms can be triggered by viral infections which result in expression of HLA-DR antigens in macrophages and possibly in B-cells of the islets. B-cells are destroyed by cytotoxic T-lymphocytes; plasma cells form islet cell antibodies. The autoimmune process probably starts months to years before clinical manifestation of the disease. A viral infection immediately before clinical manifestation may reactivate the autoimmune process and lead to overt diabetes. T-lymphocytes reject pancreatic B-cells in type 1 diabetics throughout life. Pilot studies using cyclosporin as immunosuppressive agent in newly diagnosed type 1 diabetics have demonstrated that after discontinuation of this treatment diabetics again became insulin-dependent. Type 2 diabetics are usually elderly and non-insulin-dependent; there is a predominant defect in insulin action on peripheral tissues but also a concomitant impairment of B-cell secretion. Fasting plasma insulin levels are normal or increased; fasting C-peptide concentrations may be used to distinguish this type of diabetes from type 1 diabetes. Plasma fasting C-peptide concentrations less than 300 pmol/l usually indicate type 1 diabetes and levels above 300 pmol/l type 2 diabetes. Classification of diabetics according to pathogenesis is important, since different therapeutic and preventive measures are necessary.

Autoimmune Diseases↗
PubMed1986

Acute cortisol excess results in unimpaired insulin action on lipolysis and branched chain amino acids, but not on glucose kinetics and C-peptide concentrations in man.

To assess whether acute cortisol excess impairs insulin action on lipolysis, plasma amino acids, endogenous insulin secretion, and glucose kinetics, nine normal subjects were studied after acute cortisol excess (80 mg hydrocortisone by mouth) and after placebo. Insulin sensitivity was assessed 6 hours after hydrocortisone using the glucose clamp technique (insulin infusion of 20 mU/m2 X minute for 120 minutes, plasma insulin levels of approximately equal to 50 mU/L). Hyperinsulinemia suppressed plasma free fatty acids (FFA) similarly by 75 and 76%, respectively. Most plasma amino acid concentrations were increased after hydrocortisone; however, the insulin-induced decrease of branched chain amino acids, serine, threonine, and tyrosine was unimpaired after hydrocortisone. Plasma C-peptide concentrations were less suppressed during hyperinsulinemia after hydrocortisone than after placebo (by 0.15 +/- 0.03 v 0.25 +/- 0.02 nmol/L, P less than 0.01), suggesting diminished insulin-induced suppression of insulin secretion. The glucose infusion rates required to maintain euglycemia were 35% lower (P less than 0.01) after hydrocortisone due to decreased insulin effects on metabolic clearance rate of glucose and diminished suppression of hepatic glucose production (0.4 +/- 0.1 v -0.1 +/- 0.1 mg/kg X minute, p less than 0.05, 3-3H-glucose infusion method). The data demonstrate that acute elevation of plasma cortisol to levels near those observed in severe stress results in insulin resistance of peripheral and hepatic glucose metabolism but in unimpaired insulin effects on plasma FFA and branched chain amino acids, suggesting that cortisol's lipolytic and proteolytic effects are antagonized by elevated plasma insulin levels.

Aged↗
PubMed1986

Sulfonylurea therapy fails to diminish insulin resistance in type I-diabetic subjects.

To assess whether extrapancreatic effects of sulfonylureas in vivo are detectable in the absence of endogenous insulin secretion, insulin sensitivity was determined in six insulin-deficient type 1-diabetic subjects. Peripheral uptake and hepatic production of glucose and lipolysis were measured during hyperinsulinemia using the euglycemic clamp technique and 3-3H-glucose infusions twice, once during a period with glibornuride treatment (50 mg b.i.d.), and once without. Hepatic glucose production decreased in diabetic subjects during hyperinsulinemia (insulin infusion of 20 mU/m2 X min; plasma free insulin levels of 40 +/- 4 mU/l) from 2.9 +/- 0.6 mg/kg min to 0.2 +/- 0.1 mg/kg X min after 120 min, and plasma free fatty acid (FFA) concentrations decreased from 1.33 +/- 0.29 to 0.38 +/- 0.08 mmol/l. Hepatic production, peripheral uptake of glucose and plasma FFA concentrations before and during hyperinsulinemia were not influenced by pretreatment with glibornuride. Compared to 8 non-diabetic subjects, type 1-diabetics demonstrated a diminished effect of hyperinsulinemia on peripheral glucose clearance (2.4 +/- 0.04 vs 4.2 +/- 0.5 ml/kg X min, P less than 0.01), whereas hepatic glucose production and plasma FFA levels were similarly suppressed by insulin. The data indicate that sulfonylurea treatment did not improve the diminished insulin sensitivity of peripheral glucose clearance in type 1-diabetic subjects; insulin action on hepatic glucose production and lipolysis was unimpaired in diabetics and remained uninfluenced by glibornuride. Thus, extrapancreatic effects of sulfonylureas in vivo are dependent on the presence of functioning beta-cells.

Adult↗
PubMed1986

[Early prognosis of intracranial hemorrhage in premature infants].

Between July 1979 and June 1984 an intracerebral haemorrhage developed in 87 premature infants (mean gestational age 29.5 weeks, mean birth weight 1156g). 46 of these died, 41 infants survived. Their psychomotoric development was followed up to a mean age of 19 months. In 63% of the patients the haemorrhage occurred during the first four days of life. Its frequency was highest in premature infants of 27 to 30 weeks of gestation. The survival rate was influenced by the gestational age and by the grade of haemorrhage. Early complications such as ventricular dilatation, hydrocephalus occlusus and porencephaly were seen especially in very immature infants (less than 31 weeks). The frequency of abnormal psychomotoric development in 55% of these infants contrasts with 13.5% in premature infants (less than 1 500 g) without intracerebral haemorrhage.

Birth Weight↗
PubMed1985

[HLA-antigens and islet cell antibodies in type-1 diabetics of various age groups and their first-degree relatives].

140 type 1 diabetics from Basle and vicinity were HLA-typed. 89% had HLA-haplotypes DR3, DR4, or DR3/DR4. The frequency of these antigens was significantly increased compared to normal controls. The HLA antigens DR2 and DR5 were significantly diminished in diabetics. The increase in diabetes-associated HLA antigens differed within the diabetics according to the age of diabetes manifestation. Diabetes onset before age 40 was associated with increased frequency of HLA DR4 and HLA DR3/DR4. In contrast, patients with diabetes onset after age 40 exhibited an increased prevalence of HLA DR3. The combination HLA B7/DR4 was only observed when diabetes onset was below age 20. Islet cell antibodies (ICA) were determined in 124 of the 140 type 1 diabetics. ICA were found in 40% of patients who had had diabetes for less than 2 years, but in only 21% when diabetes had lasted more than 10 years. There was no association between certain HLA haplotypes and presence of ICA. HLA antigens and the presence of ICA were also investigated in 117 first-degree relatives of the type 1 diabetics. Compared to the latter, the relatives had a significantly diminished prevalence of the HLA DR3/DR4 combination. Compared to healthy controls, these relatives had a significantly increased frequency of positive ICA (in 12% compared to 2% in nondiabetic controls). These findings demonstrate that the genetic (HLA-antigens) and immunological (ICA) background of type 1 diabetes is heterogenous. A clinical feature of the genetically determined subtypes is the age of diabetes onset.

Adolescent↗