Jürgen Beyer

Biological activity of C-peptide on the skin microcirculation in patients with insulin-dependent diabetes mellitus.

19 insulin-dependent diabetes mellitus (IDDM) patients participated in a randomized double-blind crossover investigation to investigate the impact of human C-peptide on skin microvascular blood flow. The investigation was also carried out with 10 healthy volunteers. Blood pressure, heart rate, blood sugar, and C-peptide levels were monitored during a 60-min intravenous infusion period of C-peptide (8 pmol kg-1 min-1) or saline solution (154 mmol liter-1 NaCl), and 30 min after stopping the infusion. During the same time period, capillary blood cell velocity (CBV), laser Doppler flux (LDF), and skin temperature were assessed in the feet. In the verum arm, C-peptide levels increased after starting infusion to reach a maximum of 2.3+/-0.2 nmol liter-1 after 45 min, but remained below 0. 15 nmol liter-1 during the saline treatment. Baseline CBV was lower in diabetic patients compared with healthy subjects (147+/-3.6 vs. 162+/-4.2 micron s-1; P < 0.01). During C-peptide administration, CBV in IDDM patients increased progressively from 147+/-3.6 to 167+/-3.7 micron s-1; P < 0.001), whereas no significant change occurred during saline infusion or in healthy subjects. In contrast to the CBV measurements, the investigation of LDF, skin temperature, blood pressure, heart rate, or blood sugar did not demonstrate any significant change during the study. Replacement of human C-peptide in IDDM patients leads to a redistribution in skin microvascular blood flow levels comparable to levels in healthy subjects by increasing the nutritive CBV relative to subpapillary arteriovenous shunt flow.

Treatment of Cryptorchidism with Pernasal Gonadotropin-Releasing Hormone Therapy *

Twenty-five boys between 1 and 10 years of age with unilateral or bilateral cryptorchidism were treated with 200 microgram of gonadotropin-releasing hormone (GnRH) pernasally six times daily until descensus was completed, or for 10 weeks at most. Complete descent of the tests occurred in 16 patients, usually after 2 to 5 weeks of treatment. No adverse side effects have been observed. Radioimmunologic measurements of serum luteinizing hormone (LH), follicle-stimulating hormone (FSH), testosterone, and prolactin, carried out before treatment, at the end of treatment, and 6 months after treatment, showed a transitory increase of the LH responsiveness to GnRH in only four of the patients and in the group as a whole a slight but significant decrease of FSH responsiveness. There were no signs of precocious puberty. GnRH antibodies were not found.

Comparison of the microvascular response to transcutaneous electrical nerve stimulation and postocclusive ischemia in the diabetic foot

Neurogenic inflammation, mediated by unmyelinated C-nerve fibers, is part of the acute neurovascular response to injury. Laser doppler flowmetry was used to measure the flare response to transcutaneous electrical nerve stimulation (TENS) and to compare this axon reflex vasodilatation with postischemic hyperemia in the skin of the foot in diabetic and nondiabetic subjects. Twenty-one control subjects and 57 diabetic patients (25 type I; 32 type II; 14 without complications; 14 with neuropathy and without retinopathy; 8 with retinopathy and without neuropathy; 21 with neuropathy and retinopathy) were enrolled in the study. Following TENS, an increase in skin blood flow was found at the dorsum of the foot without any significant difference between the different groups. Compared to the control group, axon reflex vasodilatation was significantly reduced in the group of patients with diabetic neuropathy and in the group of patients with diabetic neuropathy and retinopathy at the pulp of the hallux (61 +/- 15 versus -6 +/- 16; versus 23 +/- 5; p < 0.05, respectively). All investigated groups exhibited a significant increase in skin blood flow after arterial occlusion without any significant difference between the groups. A good association was observed between postocclusive and TENS-induced hyperemia at the dorsum of the foot (r = 0.39; p = 0.0002), but only a weak association was found at the pulp of the hallux (r = 0.24; p = 0.03). TENS-induced hyperemia was associated with a diminished sweat response (p = 0.03), but not with pathological cardiovascular function tests (p = 0.07). Electrical axon reflex vasodilatation is diminished in diabetic patients suffering from peripheral autonomic C-fiber injury, especially in skin rich in thermoregulatory blood flow. The diminished neurovascular response is independent of vascular alterations in diabetes mellitus.

Serum Insulin-like Activity in Hypophysectomized and Depancreatized (Houssay) Dogs

Serum insulin-like activity was measured serially by the epididymal fat pad method in twelve dogs over several weeks. The animals were first hypophysectomized and subsequently pancreatectomized; no insulin was administered at any stage of the experiment. Hypophysectomy resulted in a reduction of serum ILA of some 50 per cent from an average normal fasting value of 420 μU. per ml. Subsequent pancreatectomy caused no further appreciable reduction in serum ILA over the entire observation period of five weeks. In a selected number of serum samples residual ILA was detectable also by the rat hemidiaphragin procedure. None of the Houssay dogs had measurable amounts of insulin in blood by immunoassay. It was considered unlikely that activities measured by the two bio-assays represented insulin.

Influence of Sex Differences in Subcutaneous Fat Mass on Serum Leptin Concentrations

(3-5)—that is potentially applicable in heterogeneous groups of patients (6), has facilitated its extended application. The recent availability of insulin lispro interested us in evaluating the effects of this new insulin on HRQOL in a Spanish population of patients with diabetes. There were 284 patients (138 males and 146 females; 241 type 1 diabetic and 43 type 2 diabetic patients) age 14-66 years, with a mean ± SD of 32.7 ± 13.2 years and treated with at least two insulin injections for >6 months who were invited to participate. At the time of a routine clinical appointment, patients were asked to first answer the DQOL questionnaire whenever insulin lispro treatment was recommended. Those data were considered the patients quality-of-life baseline. A second DQOL questionnaire was answered after a 8to 16-week period of insulin lispro treatment. A preliminary analysis of the responses to the questionnaire showed a slight global quality-of-life improvement after insulin lispro treatment compared with patient baselines (72.2 ± 10.1 vs. 70.1 ± 10.1, P = 0.012) on a transformed scale where 0 represents the lowest possible quality of life and 100 represents the highest possible quality of life (7). In addition, a statistically significant improvement was shown on the satisfaction subscale (69.4 ± 12.7 vs. 65.7 ±13.3, P = 0.001). Interestingly, question 4 of the DQOL questionnaire (How satisfied are you with your current treatment?) showed a statistically significant 8.6-point mean increase (P < 0.001) after insulin lispro treatment period over the patient baselines. Insulin lispro has demonstrated hypoglycemia risk reduction (8-10) and clearly leads to better postprandial glucose control in type 1 and type 2 diabetic patients (8,9). These benefits result from improved pharmacokinetics characterized by a faster and shorter duration of action, which, in addition, allows for close-to-mealtime injections, which may simplify a patients daily life, thereby positively impacting their perception of their own quality of life. Even though the observed differences are slight, this prospective naturalistic analysis supports the results published by Kotsanos et al. (1). Although additional HRQOL evaluation is necessary on the effects of new therapeutic agents, such as insulin lispro, these data suggest that the unique characteristics of insulin lispro shown in clinical trials may readily be translated into clinical practice, making a patients daily life easier in the real world.

Corticotropin-releasing hormone (CRH) is a respiratory stimulant in humans: A comparative study of human and ovine CRH

Previous experimental and clinical studies clearly demonstrated that exogenously administered CRH possesses respiratory properties. Until now, these effects were investigated using human (h) CRH in both healthy volunteers and patients under long-term respiration. We now compared the effects of hCRH with those of ovine (o) CRH in ten healthy young males. In particular it should be evaluated whether oCRH with its longer plasma half-life induces a more profound respiratory stimulation. On two separate days within two weeks, ventilation and cardiac performance were measured during steady state conditions by using a computerized cardio-pulmonary exercise testing system. In this placebo controlled double-blind-crossover study h- and oCRH (100 ug i.v. each) both augmented minute volume significantly during the observation period. Heart rate also increased after both analogues. All effects were comparable without a significant difference between both substances. There were no major side effects observable. Our data thus demonstrate that both analogues might be suitable for both diagnostic (i.e., testing of respiratory and autonomic responses) and therapeutic purposes.

The beta-specific protein kinase C inhibitor ruboxistaurin (LY333531) suppresses glucose-induced adhesion of human monocytes to endothelial cells in vitro.

Aims: Strong evidence shows that late diabetic complications in diabetes mellitus are substantially related to an increased synthesis of diacylglycerol with a subsequent activation of protein kinase C (PKC) β. Several studies have shown that specific inhibition of the PKC isoform β by ruboxistaurin is able to attenuate the development of microvascular complications under diabetic conditions. The aim of this in vitro study was to investigate the effect of ruboxistaurin on glucose-induced adhesion of monocytes to endothelial cells, representing one of the first pivotal steps in the course of atherogenesis. Methods: Human umbilical venous endothelial cells were isolated and cultured to confluence in microtiter plates. After coincubation with monocytes in the presence of 0, 10, or 400 ng ruboxistaurin to achieve PKC β- specific and -unspecific PKC inhibition, cells were fixed and monocyte adhesion was determined by means of a standardized chemiluminescence assay. Expression of adhesion molecules (intercellular adhesion molecule-1, vascular cell adhesion molecule-1, and E-selectin) was also measured by chemiluminescence methods. Results: Adhesion of monocytes to endothelial cells cultured under hyperglycemic conditions (27.7 mM glucose) was increased by 30.9 ± 5.1% (p < 0.001) versus endothelial cells cultured under normoglycemic (NG) conditions (5.5 mM). Pretreatment of endothelial cells with 10 nM (PKC β-specific concentration) and 400 nM (PKC β- unspecific concentration) led to a significant reduction of glucose-induced adhesion of monocytes to endothelial cells that was statistically not different from endothelial adhesion under NG conditions (−7.2 ± 3.1 and −8.1 ± 2.6%, respectively; not significant vs NG). A nonsignificant tendency to lower the expression of adhesion molecules was seen with 10 ng of ruboxistaurin. Conclusions: We conclude that monocyte adhesion to endothelial cells under hyperglycemic conditions is at least mediated by PKC β activation. Ruboxistaurin is able to suppress this monocyte adhesion even in a PKC β-specific concentration. Further studies should evaluate these potential effects of ruboxistaurin in vivo.

Respiratory Parameters after Systemic Corticotropin­ Releasing Hormone Administration

Neuroanatomical studies on the distribution of corticotropin-releasing hormone (CRH) and its receptors (7) as well as physiological data suggest a regulatory function of endogenous CRH in hypothalamic and extrahypothalamic brain areas [1, 4]. Endogenous CRH acts within the endocrine hypothalamo-pituitary-adrenal axis and affects cardiovascular regulation and respiration through extrahypothalamic pathways. CRH also stimulates gluconeogenesis and release of plasma-catecholamines. Our experiments in humans also demonstrate an influence on respiration and on heart rate activity after systemic application of CRH. Respiratory parameters and heart rate were analyzed during steady-state conditions and also under various medications [2, 3] and under CO2-challenge [6]. In order to evaluate whether the effects observed in experimental animals after central application of CRH were also present after peripheral application in man, we focussed our interest on the intraindividual and interindividual changes of minute volume, tidal volume, and on heart rate after systemic CRH-administration. Our findings should provide a deeper insight into mechanisms of neuronal regulation of respiratory and cardiac function. We also intended to find out whether there is a therapeutic effect on disorders of respiratory regulation in humans by CRH. We used two analogues of CRH, human CRH (hCRH) and ovine CRH (oCRH) (Bissendorf Peptide, Wedemark, FRG) with different biological half-life times. We wanted to specify the therapeutic effect of each analogue and to determine possible side effects.

Development and application of insulin infusion profiles for therapy of type I diabetics with portable insulin infusion systems

We studied the insulin requirements of seven insulin-dependent diabetics applying a glucose controlled insulin infusion system. The data were transformed into individually programmed and rectangular profiles. The MAGE, a measure of blood sugar fluctuations, was significantly lower when individually programmed step profiles were used (P less than 0.005) than it was when rectangular profiles were applied: 57.7 +/- 24.8 mg/dl vs 89.0 +/- 42.9 mg/dl. The average of measured blood glucose levels was significantly lower in individually programmed infusion profiles (P less than 0.025). The combination of individually programmed profiles and preprandial insulin bolus significantly reduced the postprandial blood glucose level and increase (P less than 0.001). Our investigations suggest that individually programmed insulin infusion profiles are able to smooth blood glucose fluctuations. When combined with an initial insulin bolus they may lead to a reduced insulin consumption after meals.

Die Entwicklung von Insulininfusionsprofilen zur Therapie insulinpflichtiger Diabetiker mit tragbaren Insulininfusionssystemen

Wir analysieren den Insulinbedarf von 7 insulinpflichtigen Diabetikem am glukosekontrollierten Insulininfusionssystem und ubertrugen die dabei gewonnenen Daten auf ein portables Insulininfusionsgerat, bei dem individuell Insulinabgabeproflle programmiert werden konnen, bzw. ein System mit einfachen Rechteckprofllen. Unsere Untersuchungen ergaben, das mit individuell erstellten Insulininfusionsprofilen eine bessere Glattung der Blutzuckerspiegel zu erreichen ist. Bei Berucksichtigung der kephalen Phase der Insulinsekretion kann offenbar sogar Insulin eingespart werden. We studied the insulin requirement of 7 insulin-dependent diabetics using a glucose-controlled insulin infusion system. The data established by our investigation were then translated, to an individually programmable insulin infusion system developed by ourselves, and also to a system employing simple rectangular profiles.