Early expression and high prevalence of islet autoantibodies for DR3/4 heterozygous and DR4/4 homozygous offspring of parents with Type I diabetes: the German BABYDIAB study.

AIMS/HYPOTHESIS: Islet autoantibodies precede the clinical onset of Type I (insulin-dependent) diabetes mellitus. The cumulative development of such autoantibodies in infants followed from birth and in particular infants with high-risk HLA genotypes is poorly defined, but such information is essential to design trials to prevent islet autoimmunity. METHODS: HLA genotypes were determined in offspring of parents with Type I diabetes who were followed from birth for at least 2 years (median follow-up: 3.1 years) and who were characterised for the expression of insulin, GAD65, IA-2 and islet cell autoantibodies at birth, 9 months, 2 and 5 years of age. RESULTS: The HLA genotypes DRB1*03/04(DQB1*57non-Asp) and DRB1*04/04(DQB1*57non-Asp) were present in 7.1% and 5.0% of offspring of parents with Type I diabetes. The frequency of both genotypes was increased in offspring who developed islet autoantibodies within the first 2 years of life (27.3% vs 5.5%, odds ratio 6.3 [p = 0.002] and 22.7% vs 4.2%, odds ratio 6.6 [p = 0.003]) and half of all offspring who developed antibodies had these genotypes. Other genotypes were not associated with an increase in risk. By life-table analysis, the cumulative risk of developing islet autoantibodies by the age of 2 years was 20% (95% CI 9.4,30.6) for offspring carrying either the DRB1*03104(DQB1*57non-Asp) or the DRB1*04/04(DQB1*57non-Asp) genotype compared with 2.7% (95% CI 1.2,4.2) for offspring without these genotypes (p < 0.0001). CONCLUSION/INTERPRETATION: These data show that early appearance of islet autoantibodies is remarkably frequent for DR3/4 heterozygous and DR4/4 homozygous offspring and indicate that primary prevention could be considered once available in an offspring cohort selected for these genotypes.

Blood glucose determinations in newborns: four instruments compared.

Four portable analyzers, HemoCue B-Glucose (I), Accu-Check III (II), One-touch II (III), and Glucometer Elite (IV), with different measuring principles were tested for their suitability for measuring blood glucose in neonates. Precision of all instruments is satisfactory. In the analysis of capillary blood from newborns, two instruments show an excellent accuracy; however, the scatter of the results for instrument (II) is about 1.6 times greater than for instrument (I). The inaccuracy of instruments (III) and (IV) is not acceptable from a clinical point of view. All devices show an influence of hematocrit, the magnitude of which varies between 5% (I) and 12% (III) for every 10% change of hematocrit. Instruments II and IV show that temperature has a marked influence on the readings; the same is true for oxygen in instrument IV. In conclusion, only instrument (I) has met the requirements of accurate and precise blood glucose determinations in neonates.

Platelet Na+/H+ antiport activity in patients with insulin-dependent diabetes mellitus with and without diabetic nephropathy.

The incidence of diabetic nephropathy in patients with insulin-dependent diabetes mellitus (IDDM) may depend on factors other than the quality of diabetes control. Hypertension is an additional factor associated with a high degree of renal involvement in IDDM. One abnormality consistently observed in various tissues of patients with essential hypertension is enhanced activity of the Na+/H+ antiport. In the present study we have therefore studied platelet antiport activity in 41 healthy subjects (control), in 22 patients with untreated essential hypertension (EH), and in 35 normotensive IDDM patients (type 1). Of these patients 17 exhibited signs of diabetic nephropathy (group 1) while 18 had no evidence for renal involvement of IDDM in spite of a duration of IDDM of at least 10 years (group 2). The two IDDM patient groups were undistinguishable with respect to age, body mass index, and arterial blood pressure (group 1, 117.9 +/- 2.4/78.4 +/- 1.5 mmHg; group 2, 113.9 +/- 3.6/76.1 +/- 1.8 mmHg). Antiporter activity was determined from the rate of cell volume changes induced by propionic acid. Platelet Na+/H+ exchange activity averaged 23.43 +/- 0.43 10(-3).s-1 in control subjects and was markedly elevated in EH (28.38 +/- 0.62 10(-3).s-1; P < 0.01). Antiport activity in group 2 patients without nephropathy averaged 24.54 +/- 0.57 10(-3).s-1 and was undistinguishable from the control group. However, platelet Na+/H+ antiport activity was significantly stimulated in group 1 patients with nephropathy as compared to group 2 (26.95 +/- 0.73 10(-3). s-1; P < 0.025). Our results show that renal involvement in IDDM is associated with enhanced activity of the platelet Na+/H+ antiport.

[Serum fructosamine in healthy and diabetic children and adolescents]. / Fructosamin im Serum gesunder und diabetischer Kinder und Jugendlicher.

The determination of fructosamine in serum of healthy newborns, children and adolescents by a new colorimetric method leads to an age-dependent reference range. Correction of the values for total protein yields a median of the results, which is not dependent on age and the upper limit of the reference range is not significantly different from that of healthy adults; this does not hold true for referral to albumin. As the half-life time of glycated serum proteins is shorter (mean 20 days) than that of hemoglobin A1c, fructosamine can provide useful additional informations about the diabetic control of children and adolescents (medium-term record of blood glucose).

Atrial natriuretic peptide in patients with diabetes mellitus type I. Effects on systemic and renal hemodynamics and renal excretory function.

In the present study the effects of 1 h intravenous infusion of alpha-human atrial natriuretic peptide (24 ng/min/kg) on systemic and renal hemodynamics and on renal excretory function were studied in six insulin-treated and metabolically well-controlled patients with diabetes mellitus (DM) type I and in six healthy control subjects (C). Basal plasma atrial natriuretic peptide (ANP) concentration was 14.6 +/- 2.0 in DM patients and 14.9 +/- 1.3 pmol/L in C and rose similarly in both groups to 87.1 +/- 22.1 and to 86.9 +/- 11.1 pmol/L, respectively, during alpha-hANP infusion (P less than .05). Maximal effects of alpha-hANP occurred between 30 and 60 min after the start of the infusion. Mean arterial pressure (MAP) (83 +/- 5 v 81 +/- 3 mm Hg), heart rate (HR) (63 +/- 2 v 64 +/- 4/min) and total peripheral resistance (TPR) (11 +/- 1 v 10 +/- 1 mm Hg.min/L) remained unaltered in patients with DM. In contrast, in C MAP and TPR decreased from 83 +/- 3 to 77 +/- 2 mm Hg and from 12 +/- 1 to 10 +/- 1 1 mm Hg.min/L, respectively (P less than .05), whereas HR increased from 53 +/- 2 to 59 +/- 3 beats/min (P less than .05). Cardiac output (CO) rose initially by 11% and by 9% in DM and C, respectively. Urine flow increased from 4.1 +/- 0.9 to 11.3 +/- 1.5 mL/min in DM patients and from 3.9 +/- 1.0 to 8.4 +/- 0.8 mL/min in C (P less than .05).(ABSTRACT TRUNCATED AT 250 WORDS)

[Transdermal administration of insulin in type II diabetics. Results of a clinical pilot study]. / Transdermale Applikation von Insulin bei Typ-II-Diabetikern. Ergebnisse einer klinischen Pilotstudie.

In 6 type II diabetic patients, which showed no satisfactory blood sugar profiles under oral sulfonylurea monotherapy, a placebo controlled cross over pilot trial was performed to evaluate the effect of additive transdermal insulin application. In comparison to the monotherapy with sulfonylurea, the combination with transdermal insulin showed in 4 of the 6 patients a significant reduction of the daily mean blood sugar values as well as a slight increase of insulin serum concentrations. The 2 patients, who had no glucose reductions also showed a slight increase of insulin levels during the combination phase. Relevant adverse reactions were not seen. The results suggest, that in suited patients an improvement of sulfonylurea therapy by combination with transdermal insulin is possible.

[Fructosamine reference ranges for pregnant patients and children determined using an improved NBT method]. / Fructosamin-Referenzbereiche für Schwangere und Kinder bestimmt mit einer verbesserten NBT-Methode.

Reference values for fructosamine in pregnancy show a decrease with progressing pregnancy, which can be explained by pregnancy-associated hemodilution. A normalization to 7.0 g/dl total protein leads to values independent of gestational age. For children and adolescents age-dependency of the reference range is abolished if values are related to total protein. More plausible values are obtained in longitudinal profiles if fluctuations of protein concentration are taken into account.

[Severe periodic hypokalemic paralysis. Prevention using beta-receptor blockade]. / Schwere periodische hypokaliämische Lähmung. Prophylaxe durch beta-Rezeptorenblockade.

For ten years, severe physical exercise in a 24 year old male patient had been an almost constant trigger of frequent attacks of pareses which were mostly accompanied by complete tetraplegia and once by the occurrence of cardiac arrest with atrial fibrillation. During the attack, the serum potassium concentration fell to 1.2 mmol/l, whereas the intraleukocytic potassium concentration rose from 136 mmol/l to 149 mmol/l. The catecholamine excretion in the urine was raised during the first 24 hours after admission as an emergency (189 micrograms noradrenalin and 54 micrograms adrenalin). After intravenous adrenalin infusion (0.01-0.1 microgram/kg X min) during the symptom-free interval, there was a major fall of the serum potassium concentration from 3.9 mmol/l to 3.1 mmol/l. This was not accompanied by a raised insulin excretion and could be prevented by prior administration of the nonselective beta blocker propranolol. On the basis of these results, the patient was treated prophylactically with three times 40 mg/d p.o. propranolol. Pareses requiring treatment no longer occurred under this therapy.

Studies on the role of sodium- and potassium-activated adenosine triphosphatase inhibition in the pathogenesis of human hypertension. Changes in vascular and cardiac function following inhibition of the sodium pump in normotensive subjects and effects of calcium entry blockade.

An endogenous humoral factor which inhibits the sodium- and potassium-activated adenosine triphosphatase (Na-K-ATPase) enzyme in vitro has been incriminated recently of playing a pathogenetic role in experimental and human hypertension. The present study was therefore performed in six healthy volunteers to investigate the hemodynamic consequences of an inhibition of this enzyme by ouabain, a potent and specific inhibitor of Na-K-ATPase. In addition, the role of intracellular calcium as a potential mediator was studied indirectly by the administration of nifedipine, a potent calcium entry blocker with predominant vasodilator properties. Intravenous administration of 8.5 micrograms ouabain/kg body weight inhibited red blood cell (RBC) - Na-K-ATPase by 49% which was accompanied by a significant increase in RBC - ATP and a decrease in intracellular potassium concentrations. This enzyme inhibition resulted in a 24% increase in peripheral vascular resistance. The parallel decrease in cardiac output and heart rate, however, prevented a rise in arterial pressure. This increase in vascular resistance was completely abolished by pretreatment with nifedipine (10 mg orally). In the absence of an effect of nifedipine on Na-K-ATPase, its attenuation of the vasoconstrictor effect of ouabain suggests that the effects of ouabain on the vascular smooth muscle cell are mediated by intracellular calcium. These results demonstrate that inhibition of the Na-K-ATPase enzyme in vivo causes a marked peripheral vasoconstriction. They are also compatible with the concept that an endogenous inhibitor of Na-K-ATPase - in the presence of decreased baroreceptor reflex sensitivity due to blood volume expansion - may play a role in the pathogenesis of human arterial hypertension.

The role of endogenous inhibition of Na-K-ATPase in human hypertension--sodium pump activity as a determinant of peripheral vascular resistance.

High sodium intake in the presence of an intrinsic or acquired defect in renal sodium excretion will result in extracellular fluid volume (ECFV) expansion which is accompanied by decreased baroreceptor reflex sensitivity. We have shown that ECFV-expansion also stimulates the secretion of an endogenous inhibitor of the Na-K-ATPase enzyme and high activity of this sodium transport inhibitor was detected in plasma of patients with primary aldosteronism, the most classical type of volume-dependent hypertension. Thus, vasoconstriction due to inhibition of sodium pump activity of the vascular smooth muscle cell may contribute to the pathogenesis of human arterial hypertension. In analogy, ouabain (8.5 micrograms/kg) when administered i.v. to healthy volunteers inhibited RBC - Na-K-ATPase by 49% and significantly increased peripheral vascular resistance by 24 - 36%. The calcium entry blocker nifedipine (10 mg orally) completely prevented ouabain-induced vasoconstriction suggesting that the action of ouabain was mediated by a rise in intracellular calcium. High potassium intake partially abolished the vasoconstrictor effect of ouabain and also significantly increased baroreceptor reflex sensitivity. The results of these studies support the concept that inhibition of the sodium and potassium pump of vascular smooth muscle cells by a yet putative endogenous inhibitor of Na-K-ATPase (natriuretic hormone) may represent a crucial mechanism in the pathogenesis of at least certain forms of essential and secondary hypertension in man.

[Comparison of various methods for determining glycosylated hemoglobins]. / Vergleich verschiedener Methoden zur Bestimmung glykosylierter Hämoglobine.

Determination of glycosilated haemoglobin (HbA1) has become an important parameter for the control of diabetes mellitus. Although several methods are available today, some are time consuming and complicated and may lead to differing results. Two methods, the thiobarbituric-acid (TBA) method and microcolumn chromatography, were compared with the reference method, high performance liquid chromatography (HPLC), with respect to precision, accuracy and practicability. Seventy different blood samples from diabetics were analysed. Using the TBA method, good results were achieved which were generally consistent with those of the reference method (r = 0.90); there were no significant differences in values determined with the two methods. However, the TBA method requires an inordinate amount of work. Microcolumn chromatography is better suited to the needs of physicians in private practice. Results with this method also correlate well with those of the reference method (r = 0.92) when the labile aldimine fraction has been removed by dialysis of the sample. Quality control can be performed using either lyophilized or deep-frozen control samples.

Effects of potassium on blood pressure regulation.

Short-term changes (1 week) of potassium intake had no effect on elevated or normal blood pressure of 18 subjects. Potassium supplementation (100 mmol KCl/day) for 8 weeks caused a fall in blood pressure in 16 patients with mild hypertension. After cessation of potassium supplementation, blood pressure returned to "prepotassium" levels. In healthy volunteers, high potassium intake for 1 week resulted in a marked increase in intraleukocytic concentration of potassium. No change was observed in mean arterial pressure, cardiac index, or total peripheral resistance. The hemodynamic response to an intravenous infusion of ouabain was reduced during high potassium intake. Baroreceptor sensitivity rose during high potassium intake as demonstrated by the infusion of norepinephrine.

Influence of intravenous Mg++ solutions on renal excretion of potassium, sodium, calcium, chloride, intraleukocytic potassium and peripheral vascular resistance: a metabolic and hemodynamic study in normal volunteers.

In an open randomized crossover trial 8 healthy male volunteers received an intravenous infusion of potassium chloride, potassium/magnesium chloride, potassium-(D,L)-aspartate, and potassium/magnesium-(D,L)-aspartate. Equimolar amounts of potassium (27.75 mmol) and magnesium (13.9 mmol) were given in a 500-ml volume during 24 h. During two 9-day periods subjects were maintained on a constant diet with a daily intake of 80 mmol potassium and 60 mmol magnesium. Infusions were administered on day 5 and 7 of each period. Serum and urine electrolyte concentrations as well as intraleukocyte potassium were measured before, during, and after the tests; cardiac output and systemic vascular resistance were determined by impedance cardiography. Potassium and magnesium containing solutions did not influence renal elimination of potassium, and also the circadian rhythm of potassium excretion did not show any change. The elimination of sodium, calcium, potassium, and chloride rose significantly over the corresponding control values during magnesium infusions, but not when potassium salts were given. The increase of calcium excretion after Mg++ is most probably due to suppression of parathyroid hormone. Intraleukocyte potassium was not affected significantly by the various infusions, indicating that intracellular compartments are completely filled. There was no evidence that the anion (D,L-aspartate or chloride) had a significant effect on all measured variables. Mean arterial blood pressure and peripheral vascular resistance were not altered significantly during the infusions.

An improved method for the determination of potassium in leucocytes.

1. In twenty normal subjects and five patients with disturbances of potassium balance, the potassium concentration in leucocytes was measured by a modified technique. 2. The precision of the method was three to four times greater than that of techniques previously described, with a coefficient of variation for duplicate analyses of 2.3%. 3. A comparison between intraleucocyte potassium concentration and total body potassium in five patients with pathological alterations in their potassium balance showed that intracellular potassium concentration may reflect the clinical state better than total body potassium.

[Determination of glucose in hemolysed blood samples (author's transl)]. / Glucosebestimmung in hämolysierten Blutproben

The determination of glucose in hemolysed and stabilized blood samples by the hexokinase/glucose-6-phosphate-dehydrogenase-method is described. The glucose concentration in hemolysed blood samples was stable for 7 days. Even at high glucose concentrations (linear range up to 60 mmol/l), the reaction came to completion within 5 minutes. No interference by lipemia, bilirubin and drugs was observed; the interference of fructose was slight. Compared with deproteinized samples there was a very good correlation between this method and the reference method. Precision and recovery were good. This method is also suited for the analysis of few samples and offers the possibility of blood sugar self-profiles in diabetic out-patients and gives an increasing improvement of diabetic control.

[Semiquantitative determination of glucose in urine with a new test kit]. / Halbquantitative Glucose-Bestimmung im Urin mit einem neuen Testbesteck.

A new testing set for diluting urine allows to determine glucose in urine with the Diabur-test strip up to a concentration of 8.0 g/dl. The dilution by means of a pipette is absolutel;y practicable at a distinguished precision; the results show an excellent correlatiopn with the quantitative hexokinase method. Of all possible interfering substances tested only ascorbic acid influenced the reaction which, however, interfered only when minor glucosuria was present.

[A simple method for determining blood-glucose levels in diabetic out-patients (author's transl)]. / Eine einfache Methode zur Blutglucose-Bestimmung bei ambulant betreuten Diabetikern.

24 hour blood-sugar profiles were obtained in 25 diabetic out-patients. The samples were obtained by the patients themselves even when at work, the glucose-level measurements in the laboratory. The relative differences between duplicate values was less than 10%. The results obtained made it possible to alter the treatment regimen so that, on average, there was a marked reduction in blood-sugar variations during the day.