Inhaled insulin as adjunctive therapy in subjects with type 2 diabetes failing oral agents: a controlled proof-of-concept study.

AIM: This controlled proof-of-concept study investigated inhaled insulin (INH) as adjunctive therapy to existing oral antidiabetic agents in subjects with type 2 diabetes. METHODS: Twenty-four subjects with type 2 diabetes [19 men and 5 women, 56.1 +/- 6.6 years, body mass index 32.7 +/- 4.2 kg/m(2), glycosylated haemoglobin (HbA1c) 8.4 +/- 0.8% (mean +/- s.d.)] inadequately controlled by metformin and/or sulfonylureas were randomized to receive additional therapy with either INH administered preprandially using a metered-dose inhaler (MDI), or insulin glargine (GLA) injected subcutaneously at bedtime for 4 weeks. Both inhaled and injected insulin doses were titrated to predefined blood glucose (BG) targets. RESULTS: INH and GLA improved metabolic control to a similar extent. Mean daily BG decreased by 2.8 mmol/l in the INH group (p < 0.001) and by 2.4 mmol/l in the GLA group (p < 0.001). Accordingly, fasting BG (-2.7 vs. -3.6 mmol/l for INH vs. GLA), preprandial- and 2-h postprandial BG, HbA1c (-1.23 vs. -1.05%), body weight (-1.9 vs. -2.3 kg) and serum fructosamine were similarly and significantly reduced in both groups (p < 0.05). Triglycerides decreased significantly with INH (-1.15 micromol/l; p < 0.001) but not with GLA [-0.52 micromol/l; not significant (NS)]. Incidence rates of adverse events did not differ significantly, and there were no indications of respiratory tract irritation. CONCLUSIONS: In subjects with type 2 diabetes inadequately controlled by oral agents, preprandial administration of INH delivered by a MDI provided a comparable metabolic control to bedtime GLA and did not show any safety concerns during a 4-week treatment. These results warrant a more extensive investigation of preprandial treatment with INH in longer term studies.

A randomized multicentre trial of insulin glargine compared with NPH insulin in people with type 1 diabetes.

BACKGROUND: To compare insulin glargine with NPH human insulin for basal insulin supply in adults with type 1 diabetes. METHODS: People with type 1 diabetes (n = 585), aged 17-77 years, were randomized to insulin glargine once daily at bedtime or NPH insulin either once- (at bedtime) or twice-daily (in the morning and at bedtime) according to their prior treatment regimen and followed for 28 weeks in an open-label, multicentre study. Both groups continued with pre-meal unmodified human insulin. RESULTS: There was no significant difference between the two insulins in change in glycated haemoglobin from baseline to endpoint (insulin glargine 0.21 +/- 0.05% (mean +/- standard error), NPH insulin 0.10 +/- 0.05%). At endpoint, self-monitored fasting blood glucose (FBG) had decreased similarly in each group (insulin glargine -1.17 +/- 0.12 mmol/L, NPH insulin -0.89 +/- 0.12 mmol/L; p = 0.07). However, people on >1 basal insulin injection per day prior to the study had a clinically relevant decrease in FBG on insulin glargine versus NPH insulin (insulin glargine -1.38 +/- 0.15 mmol/L, NPH insulin -0.72 +/- 0.15 mmol/L; p < 0.01). No significant differences in the number of people reporting >or=1 hypoglycaemic episode were found between the two groups, including severe and nocturnal hypoglycaemia. Insulin glargine was well tolerated, with a similar rate of local injection and systemic adverse events versus NPH insulin. CONCLUSIONS: A single, bedtime, subcutaneous dose of insulin glargine provided a level of glycaemic control at least as effective as NPH insulin, without an increased risk of hypoglycaemia.

No evidence for accumulation of insulin glargine (LANTUS): a multiple injection study in patients with Type 1 diabetes.

AIMS: Insulin glargine is a long-acting insulin analogue that is metabolically active for at least 24 h. We investigated the multiple-dose pharmacokinetic properties of insulin glargine to determine whether daily injections lead to the accumulation of circulating insulin levels and a corresponding decrease in blood glucose levels in patients with Type 1 diabetes. METHODS: Fifteen patients using preprandial insulin lispro (mean age 36 +/- 9 years, body mass index 24.6 +/- 2.2 kg/m(2)) completed the study. Each patient's optimal insulin glargine dose was determined during a dose-finding phase. After a washout period, patients were treated over 12 days with a constant daily dose of insulin glargine injected in the abdominal subcutaneous adipose tissue at 22:00 h, and with preprandial insulin lispro. Free serum insulin (FSI) and blood glucose concentrations were assessed hourly after the first, fourth, and eleventh injection, after which patients fasted for 24 h and did not use any other insulin preparation. RESULTS: There were no changes in daily insulin doses during the dose-finding phase (insulin glargine: initial dose 24 +/- 6 IU, mean change 0 +/- 3 IU; insulin lispro: 18 +/- 9 IU, 0 +/- 7 IU). The time course of FSI was comparable on the three pharmacokinetic study days. Notably, the trough FSI at the end of the sampling periods was almost identical (day 1, 79 +/- 56 pmol/l, day 4, 77 +/- 56 pmol/l, day 11, 86 +/- 60 pmol/l). No changes occurred in any of the pharmacokinetic parameters studied. CONCLUSIONS: There is no evidence that insulin glargine accumulates after multiple injections over 12 days. These results indicate that the predetermined dose of insulin glargine will not need to be reduced after commencing treatment because of a risk of accumulation.

Long-acting insulin analogs.

Once daily injection of existing intermediate/long-acting insulin preparations does not provide a 24-h basal insulinemia in most patients. High variability, pronounced insulin peaks, and (as a result) a high risk of nocturnal hypoglycemia only poorly simulate normal physiology. One principle to prolong insulin action is the shift of the isoelectric point of insulin towards neutral. One example is HOE 901, which shows in healthy volunteers a constant peakless profile over the entire 24-h clamp period. In 4-week trials in comparison to NPH insulin, significant lower fasting plasma glucose levels were achieved with lower rates of nocturnal hypoglycemia. Another principle to prolong insulin action is the use of soluble fatty acid acylated insulins that are bound to albumin after absorption. The combination of long- and short-acting insulins might provide the tools towards the final goal of achieving sustained normoglycemia in diabetic patients.

Long-term treatment of type 2 diabetic patients with the new oral antidiabetic agent glimepiride (Amaryl): a double-blind comparison with glibenclamide.

An international, prospective, double-blind trial compared the long-term therapeutic value of glimepiride with glibenclamide in patients with Type 2 diabetes mellitus. Patients stabilised on glibenclamide were randomised to 1 mg glimepiride (524 patients) or 2.5 mg glibenclamide (520 patients). The treatment groups were comparable at baseline with respect to age (60.2 years), body mass index (26.5 kg/m2), duration of diabetes (5.0 years) and fasting blood glucose levels (163 mg/dl [9.0 mmol/l]). Doses were increased stepwise, up to 8 mg for glimepiride (once-daily) and 20 mg for glibenclamide (> 10 mg as divided dose), until metabolic control (fasting blood glucose < or = 150 mg/dl [8.3 mmol/l]), or maximum dose was achieved. After one year of treatment, patients entered a long-term follow-up study. Primary endpoints for evaluation of metabolic control, mean glycated haemoglobin and mean fasting blood glucose, were 8.4% and 174 mg/dl (9.7 mmol/l) for glimepiride and 8.3% and 168 mg/dl (9.3 mmol/l) for glibenclamide. Differences between treatment groups were not considered clinically relevant (95% confidence intervals (-0.05, 0.19%) for glycated haemoglobin and (2, 11 mg/dl) [0.1, 0.6 mmol/l] for fasting blood glucose). Statistically significant lower fasting insulin and C-peptide values were observed in glimepiride patients compared with glibenclamide (differences: insulin, -0.92 microU/ml [p = 0.04]; C-peptide, -0.14 ng/ml [p = 0.03]). Both treatment groups showed an equivalent safety profile. Adverse events were consistent with the nature of the diabetic patient population studied. Fewer hypoglycaemic reactions occurred with glimepiride than with glibenclamide (105 versus 150 episodes). The long-term follow-up (457 patients) confirmed that glimepiride (1-8 mg) once daily provides equivalent metabolic control to a higher dosage (2.5-20.0 mg) of glibenclamide. Both treatments were well tolerated.

Clinical profile of the novel sulphonylurea glimepiride.

Glimepiride is a new generation sulphonylurea being prudently characterized in more than 2000 NIDDM patients. It has a short onset of action and a long duration of action. The same pharmacodynamic effect as with traditional sulphonylureas is achieved with secretion of less insulin, suggesting a possible extrapancreatic action. Glimepiride is given once daily in doses from 1-8 mg/day. 100% absolute bioavailability and the absence of a food interaction guarantee highly reproducible pharmacokinetics. Glimepiride is a remarkably safe drug especially in NIDDM patients at high risk e.g. the renally impaired, elderly or physically very active person. Hypoglycemia is less frequent in the first weeks of treatment than with glibenclamide. Ongoing studies are investigating the possible beneficial clinical effect of its different binding behavior to the potassium channel, especially in the heart.

[Erythropoietin as a biochemical parameter for fetal hypoxia]. / Erythropoietin als biochemischer Parameter für fetale Hypoxie.

The ability of parameters like umbilical arterial pH and Apgar-score to predict and/or to reflect fetal distress is limited. It is known that erythropoietin (EPO) increases due to hypoxic stimulation. Therefore we studied the levels of EPO in the cord blood of stressed neonates (n = 75). In addition, reference values for EPO were established in a group of healthy term infants (n = 54) (mean +/- SD: 20.02 +/- 6.4; median 17.8; range 8.7-40.3 (mU/ml]) and in premature infants (n = 77) according to gestational age (median/range: < 30 weeks 11.0, 5.5-17.5; 30-32 weeks 18.1, 5.5-136; 33-34 weeks 17.7, 8.3-422.9; 35-37 weeks 17.3, 5.5-272 [mU/ml]). EPO concentrations significantly increased in the stressed group: in acute stress (n = 27): mean 153.4, range 6.5-641.7 [mU/ml], p < 0.003; and in chronic stress (n = 48): mean 102.6, range 12.4-544 [mU/ml], p < 0.002. However, parameters like hemoglobin, hematocrit, umbilical arterial pH and Apgar-score did not correlate with EPO values. A sensitivity of 59% and a specificity of 92% was calculated. We conclude that serum EPO concentrations are capable of detecting acute and chronic stress. In part EPO also allows to grade stress in pregnancies, which are complicated by diseases like preeclampsia.

Syndrome of developmental retardation, facial and skeletal anomalies, and hyperphosphatasia in two sisters: nosology and genetics of the Coffin-Siris syndrome.

We report on 2 sisters, 3 and 6 years old, with a possible new syndrome consisting of developmental retardation, facial and skeletal anomalies, and hyperphosphatasia. This disorder closely resembles the Coffin-Siris syndrome (McKusick number 135900). We describe the difficulties in achieving a diagnosis. A major diagnostic clue was the radiological recognition of hypoplasia/aplasia of the terminal phalanx of the 5th finger. Minor facial anomalies and mental retardation alone had not led to the proper diagnosis. Still, several diagnostic possibilities remain. For unknown reasons both children have an increased level of serum alkaline phosphatase activity.

Constitutional delay of growth and puberty: do they really reach their target height?

We compared the final adult height (FH) of patients with classic constitutional delay of growth and puberty with their target height (TH) and with the height prediction by the Bayley-Pinneau method (BP). 20 patients and their parents were included in our study: 6 females (mean age 19.1 years) and 14 males (mean age 20.6 years). No significant difference could be detected between TH, FH and BP prognosis. This is in contrast to recent studies using height data partly obtained by self-estimation. We measured our patients and their parents ourselves and were accurately able to calculate their genetically determined TH. This proceeding could explain our results. Our study shows that adolescents with true constitutional delay do not need treatment and that height prediction seems to be accurate.

The effect of cyproheptadine on plasma growth hormone (GH) and on somatostatin response to GH-releasing hormone in man.

Cyproheptadine (CPH)--a putative serotonin antagonist--is known to inhibit growth hormone (GH) response to various pharmacological stimuli, as well as during sleep. To elucidate the possible site at which this drug takes effect, we examined plasma GH and somatostatin response to i.v. GHRH1-44 (1 microgram/kg body wt.) before and after CPH treatment in 10 healthy volunteers. The oral administration of CPH (8-12 mg daily for 5 days; total dose 56 mg) significantly curbed GH response to GHRH as expressed in peak plasma GH values (32.0 +/- 6.1 micrograms/l vs. 12.6 +/- 3.2 micrograms/l; P less than 0.01) and in integrated GH response area (2368 +/- 517 micrograms x l-1 x 2 h vs. 744 +/- 172 micrograms x l-1 x 2 h; P less than 0.01). Plasma somatostatin levels did not change in response to GHRH.

Three sibs with achalasia and alacrimia: a separate entity different from triple-A syndrome.

We report on two brothers and one sister with achalasia and alacrimia born to consanguineous unaffected parents. The combination of achalasia and alacrimia may represent an entity different from the triple-A syndrome in showing normal adrenal function.

Rapid effect of intravenous growth hormone (GH)-releasing hormone 1-44 on plasma GH levels in children.

Growth hormone releasing hormone (GHRH)-testing was performed in 24 short normal children (16 male, 8 female). Before and after administration of GHRH1-44 (1 microgram/kg body weight i.v.) blood samples for growth hormone (GH) determination were drawn at -30, 0, 1, 2, 3, 4, 6, 8, 10, 15, 30, 45, 60, and 90 min. Plasma GH increase was apparent 1 min after injection and in 12 patients (7 female) peak plasma GH values were reached within 15 min. In all patients plasma GH levels were greater than 10 ng/ml within the first 8 min following GHRH injection, but in 4 patients this level was not attained when considering only GH values obtained after 15 min. These results demonstrate the capability of the pituitary to rapidly secrete GH in response to GHRH1-44 in children. Therefore, in this age group blood samples for GH determination should be taken earlier when testing with GHRH1-44.

Plasma growth hormone-releasing hormone levels in type 1 (insulin-dependent) diabetic children following a mixed meal.

Following a mixed meal, plasma hormone responses were measured in four type 1 diabetic children and in eight short normal children. Between 60 and 150 min after ingestion of the mixed meal there was a significant increase in circulating growth hormone-releasing hormone values both in diabetic and in normal children. Mean plasma GHRH peak values were not different between diabetic patients (27.0 +/- 3.9 ng/l) and controls (24.6 +/- 4.9 ng/l). No time relationship to spontaneous growth hormone peaks was observed. Whereas normal children showed a characteristic biphasic plasma somatostatin response, somatostatin plasma levels in diabetic children did not change. In normal children plasma insulin values increased between 30 and 150 min, but remained unchanged in type 1 diabetic patients. Blood glucose response was more pronounced in diabetic children than in short normal children. These results indicate that circulating growth hormone-releasing hormone does not play a dominant role in the regulation of insulin and somatostatin.

[Growth hormone releasing hormone. Review]. / Wachstumshormon-Releasinghormon. Ubersicht.

Growth hormone-releasing hormone was isolated 1982 from human pancreatic tumours. They were found to consist of three peptides (GHRH1-44, GHRH1-40, GHRH1-37) which in vivo and in vitro were specific stimulators of pituitary growth hormone secretion. These tumor-derived GHRHs were demonstrated to be identical to human hypothalamic GHRHs. Extrahypothalamic GHRH is present in some brain regions and in the gastrointestinal tract. Circulating GHRH is detectable in human plasma, but little is known about its function. Above all binding of GHRH to a specific receptor stimulates growth hormone secretion through formation of cyclic AMP. GHRH secretion is modulated by somatostatin, the somatomedins and growth hormone itself. Following single injection of GHRH1-44 i.v. the equilibration half-time is 1.0 +/- 0.2 min and elimination half-time is 6.8 +/- 1.2 min. Maximal growth hormone response is achieved after injection of 1 microgram/kg GHRH. Using higher GHRH-doses growth hormone can be stimulated via subcutaneous or intranasal application. A single i.v. GHRH-test is not sufficient to prove a pituitary defect since growth hormone can be stimulated following repetitive injections in some cases. About 50% of patients with growth hormone deficiency have a hypothalamic defect of GHRH release. In some of these patients GHRH s.c. can promote linear growth to the same degree as growth hormone treatment.

Serum vitamin D metabolites do not change in response to intravenous injection of thyrotropin releasing hormone (TRH) and growth hormone releasing factor (GHRF 1-44) in children.

Several reports claim that thyroid hormones and growth hormone participate in the regulation of vitamin D synthesis. We investigated whether there was a direct effect of their releasing hormones on vitamin D metabolism. TRH (7 micrograms/kg) was injected iv in 8 children with euthyroid diffuse goiter and GHRF (1 microgram/kg) in 10 short normal children. TRH injection induced significant TSH elevations but no changes in serum vitamin D metabolites, calcium and phosphorus. GHRF administration resulted in marked growth hormone elevations without alterations in the serum vitamin D metabolites, calcium and phosphorus. These results indicate no direct effect of TRH or GHRF itself on vitamin D metabolism, as well as a lack of very short term effect of growth hormone and TSH.

Plasma levels of growth hormone-releasing hormone and somatostatin in response to a mixed meal and during sleep in children.

Following a mixed meal, plasma levels of GHRH, GH, SRIH and insulin were measured in 7 prepubertal children with constitutional delay of growth and adolescence (CDGA) and in 3 children with proven GH-deficiency which responded to GHRH-injection. In children with CDGA, plasma levels of GHRH increased between 60 and 120 min (10.1 +/- 1.2 ng/l vs 25.5 +/- 4.4 ng/l; P less than 0.01). Although no GH increase occurred in patients with GH-deficiency, their plasma GHRH increases were comparable to those in CDGA children. No time relationship was present between circulating GHRH and GH, SRIH, or insulin, nor was there any correlation between their integrated hormone response areas. Sleep-induced plasma GHRH, GH and SRIH values were determined in 10 prepubertal children with CDGA. Spontaneous variations of plasma GHRH and GH values occurred with no temporal or quantitative relationship. SRIH values did not change during nocturnal sleep. In one child with GH-deficiency, comparable GHRH plasma fluctuations occurred, although GH values were all below 1 microgram/l. Our results support the concept that circulating GHRH does not only represent hypothalamic GHRH, but derives mainly from extrahypothalamic sources, possibly from the gastrointestinal tract.

[Idiopathic juvenile osteoporosis--report of 2 cases]. / Idiopathische juvenile Osteoporose--Bericht über zwei Fälle.

Idiopathic juvenile osteoporosis appears in temporal coherence with puberty leading to a reversible generalized osteoporosis of the skeletal system, spontaneous fractures and skeletal deformities. First symptoms in a 14 years old boy occurred as muscle pareses. A lymphocytic pleocytosis could be detected in cerebrospinal fluid. The next two years more than 20 spontaneous fractures occurred. Height was reduced by 15 cm. We first saw the boy at 17 years and could find decreased serum concentrations of calcitriol. Substitution with calcitriol resulted in regression of the pareses within days. Spontaneous fractures did not develop during the next two years of therapy. Subsequently serum calcitriol level was normalized. In a 10 years old boy first symptom occurred as fractures resulting from minimal traumas. In this case also during previous calcitriol therapy no new fractures occurred.

Insulinhypoglycemia but not arginine infusion stimulates circulating plasma growth hormone-releasing hormone (GHRH) concentrations in children.

The effect of insulinhypoglycemia and arginine infusion on circulating concentrations of plasma growth hormone-releasing hormone (GHRH) and growth hormone (GH) has been studied in 24 children (4.4 to 14.3 years). Plasma GH and GHRH concentrations were determined by RIA. Basal plasma GHRH levels were detectable in the plasma of all patients ranging from 6.8 to 27.1 pg/ml. Injection of 0.1 U/kg body wt. insulin i.v. resulted in an increase of plasma GHRH levels (11.1 +/- 1.4 pg/ml vs. 18.8 +/- 2.6 pg/ml; P less than 0.01) preceding that of plasma GH (1.5 +/- 0.4 ng/ml vs. 13.6 +/- 1.3 ng/ml; P less than 0.01). Infusion of 0.5 gm/kg body wt. arginine hydrochloride did increase GH concentrations (2.0 +/- 0.6 ng/ml vs. 13.9 +/- 2.3 ng/ml; P less than 0.01) but did not change circulating plasma GHRH levels. Since the source of peripheral GHRH concentrations is not known the importance of these findings remains to be determined.