The effect of growth hormone (GH) replacement therapy in adult patients with type 1 diabetes mellitus and GH deficiency

Specific problems in patients with insulin-dependent diabetes mellitus (IDDM) and GH deficiency are hypoglycaemic attacks, increased insulin sensitivity and loss of energy. These problems may be related to GH deficiency.

Effect of IGF-I therapy on VLDL apolipoprotein B100 metabolism in type 1 diabetes mellitus

Abnormal lipid metabolism may be related to the increased cardiovascular risk in type 1 diabetes. Secretion and clearance rates of very low density lipoprotein (VLDL) apolipoprotein B100 (apoB) determine plasma lipid concentrations. Type 1 diabetes is characterized by increased growth hormone (GH) secretion and decreased insulin-like growth factor (IGF) I concentrations. High-dose IGF-I therapy improves the lipid profile in type 1 diabetes. This study examined the effect of low-dose (40 microg.kg(-1).day(-1)) IGF-I therapy on VLDL apoB metabolism, VLDL composition, and the GH-IGF-I axis during euglycemia in type 1 diabetes. Using a stable isotope technique, VLDL apoB kinetics were estimated before and after 1 wk of IGF-I therapy in 12 patients with type 1 diabetes in a double-blind, placebo-controlled trial. Fasting plasma triglyceride (P < 0.03), VLDL-triglyceride concentrations (P < 0.05), and the VLDL-triglyceride-to-VLDL apoB ratio (P < 0.002) significantly decreased after IGF-I therapy, whereas VLDL apoB kinetics were not significantly affected by IGF-I therapy. IGF-I therapy resulted in a significant increase in IGF-I and a significant reduction in GH concentrations. The mean overnight insulin concentrations during euglycemia decreased by 25% after IGF-I therapy. These results indicate that low-dose IGF-I therapy restores the GH-IGF-I axis in type 1 diabetes. IGF-I therapy changes fasting triglyceride concentrations and VLDL composition probably because of an increase in insulin sensitivity.

Effects of growth hormone (GH) replacement therapy on very low density lipoprotein apolipoprotein B100 kinetics in patients with adult GH deficiency: a stable isotope study

Patients with adult GH deficiency are often dyslipidemic and may have an increased risk of cardiovascular disease. The secretion and clearance of very low density lipoprotein apolipoprotein B 100 (VLDL apoB) are important determinants of plasma lipid concentrations. This study examined the effect of GH replacement therapy on VLDL apoB metabolism using a stable isotope turnover technique. VLDL apoB kinetics were determined in 14 adult patients with GH deficiency before and after 3 months GH or placebo treatment in a randomized double blind, placebo-controlled study using a primed constant [1-(13)C]leucine infusion. VLDL apoB enrichment was determined by gas chromatography-mass spectrometry. GH replacement therapy increased plasma insulin-like growth factor I concentrations 2.9 +/- 0.5-fold (P < 0.001), fasting insulin concentrations 1.8 +/- 0.6-fold (P < 0.04), and hemoglobin A1C from 5.0 +/- 0.2% to 5.3 +/- 0.2% (mean +/- SEM; P < 0.001). It decreased fat mass by 3.4 +/- 1.3 kg (P < 0.05) and increased lean body mass by 3.5 +/- 0.8 kg (P < 0.01). The total cholesterol concentration (P < 0.02), the low density lipoprotein cholesterol concentration (P < 0.02), and the VLDL cholesterol/VLDL apoB ratio (P < 0.005) decreased. GH therapy did not significantly change the VLDL apoB pool size, but increased the VLDL apoB secretion rate from 9.2 +/- 2.0 to 25.9 +/- 10.3 mg/kg x day (P < 0.01) and the MCR from 11.5 +/- 2.7 to 20.3 +/- 3.2 mL/min (P < 0.03). No significant changes were observed in the placebo group. This study suggests that GH replacement therapy improves lipid profile by increasing the removal of VLDL apoB. Although GH therapy stimulates VLDL apoB secretion, this is offset by the increase in the VLDL apoB clearance rate, which we postulate is due to its effects in up-regulating low density lipoprotein receptors and modifying VLDL composition.

[Diabetes update: preventing type 2 diabetes. Individualized stepwise therapy (oral antidiabetic agents). Multifactorial intervention]

Preclinical disorders of glucose metabolism should be systematically included in the high-risk group for diabetes mellitus and affected individuals provided with preventive measures. Their underlying insulin resistance is determined with the help of a checklist and a method called homeostasis model assessment (HOMA). Patients with impaired fasting glucose (IFG) must change their lifestyles. If this does not lead to a response or the patient is unable to modify behavior, medication is required. In the case of manifest type 2 diabetes mellitus, a graded schedule is used for differential management, which should be based on nutritional and exercise therapy. Oral medication with metformin is probably the drug of choice in both obese and non-obese patients. It is crucial not to delay raising the level of treatment until HbA1c has fallen to within an unsatisfactory range (wait-and-see strategy). Rather, the level should be intensified when persistent exacerbation starts to become apparent (proactive therapy). In diabetes mellitus, the same guidelines for secondary prevention apply to the associated cardiovascular risk factors as with coronary heart disease. An intensified and, especially, early treatment is to be preferred over a conservative, wait-and-see approach, in this case as well.

Adjunct prednisone therapy for patients with community-acquired pneumonia: a multicentre, double-blind, randomised, placebo-controlled trial

BACKGROUND Clinical trials yielded conflicting data about the benefit of adding systemic corticosteroids for treatment of community-acquired pneumonia. We assessed whether short-term corticosteroid treatment reduces time to clinical stability in patients admitted to hospital for community-acquired pneumonia. METHODS In this double-blind, multicentre, randomised, placebo-controlled trial, we recruited patients aged 18 years or older with community-acquired pneumonia from seven tertiary care hospitals in Switzerland within 24 h of presentation. Patients were randomly assigned (1:1 ratio) to receive either prednisone 50 mg daily for 7 days or placebo. The computer-generated randomisation was done with variable block sizes of four to six and stratified by study centre. The primary endpoint was time to clinical stability defined as time (days) until stable vital signs for at least 24 h, and analysed by intention to treat. This trial is registered with ClinicalTrials.gov, number NCT00973154. FINDINGS From Dec 1, 2009, to May 21, 2014, of 2911 patients assessed for eligibility, 785 patients were randomly assigned to either the prednisone group (n=392) or the placebo group (n=393). Median time to clinical stability was shorter in the prednisone group (3·0 days, IQR 2·5-3·4) than in the placebo group (4·4 days, 4·0-5·0; hazard ratio [HR] 1·33, 95% CI 1·15-1·50, p<0·0001). Pneumonia-associated complications until day 30 did not differ between groups (11 [3%] in the prednisone group and 22 [6%] in the placebo group; odds ratio [OR] 0·49 [95% CI 0·23-1·02]; p=0·056). The prednisone group had a higher incidence of in-hospital hyperglycaemia needing insulin treatment (76 [19%] vs 43 [11%]; OR 1·96, 95% CI 1·31-2·93, p=0·0010). Other adverse events compatible with corticosteroid use were rare and similar in both groups. INTERPRETATION Prednisone treatment for 7 days in patients with community-acquired pneumonia admitted to hospital shortens time to clinical stability without an increase in complications. This finding is relevant from a patient perspective and an important determinant of hospital costs and efficiency. FUNDING Swiss National Science Foundation, Viollier AG, Nora van Meeuwen Haefliger Stiftung, Julia und Gottfried Bangerter-Rhyner Stiftung.

Treatment intensification with insulin glargine in patients with inadequately controlled type 2 diabetes improves glycaemic control with a high treatment satisfaction and no weight gain

PRINCIPLES We aimed to evaluate the efficacy of, and treatment satisfaction with, insulin glargine administered with SoloSTAR® or ClikSTAR® pens in patients with type 2 diabetes mellitus managed by primary care physicians in Switzerland. METHODS A total of 327 patients with inadequately controlled type 2 diabetes were enrolled by 72 physicians in this prospective observational study, which aimed to evaluate the efficacy of a 6-month course of insulin glargine therapy measured as development of glycaemic control (glycosylated haemoglobin [HbA1c] and fasting plasma glucose [FPG]) and weight change. We also assessed preference for reusable or disposable pens, and treatment satisfaction. RESULTS After 6 months, the mean daily dose of insulin glargine was 27.7±14.3 U, and dose titration was completed in 228 (72.4%) patients. Mean HbA1c decreased from 8.9%±1.6% (n=327) to 7.3%±1.0% (n=315) (p<0.0001), and 138 (43.8%) patients achieved an HbA1c≤7.0%. Mean FPG decreased from 10.9±4.5 to 7.3±1.8 mmol/l (p<0.0001). Mean body weight did not change (85.4±17.2 kg vs 85.0±16.5 kg; p=0.11). Patients' preference was in favour of the disposable SoloStar® pen (80%), as compared with the reusable ClickStar® pen (20%). Overall, 92.6% of physicians and 96.3% of patients were satisfied or very satisfied with the insulin glargine therapy. CONCLUSIONS In patients with type 2 diabetes insulin glargine administered by SoloSTAR® or ClikSTAR® pens, education on insulin injection and on self-management of diabetes was associated with clinically meaningful improvements in HbA1c and FPG without a mean collective weight gain. The vast majority of both patients and primary care physicians were satisfied with the treatment intensification.

Effects of aerobic exercise on ectopic lipids in patients with growth hormone deficiency before and after growth hormone replacement therapy

Growth hormone replacement therapy (GHRT) increases exercise capacity and insulin resistance while it decreases fat mass in growth hormone-deficient patients (GHD). Ectopic lipids (intramyocellular (IMCL) and intrahepatocellular lipids (IHCL) are related to insulin resistance. The effect of GHRT on ectopic lipids is unknown. It is hypothesized that exercise-induced utilization of ectopic lipids is significantly decreased in GHD patients and normalized by GHRT. GHD (4 females, 6 males) and age/gender/waist-matched control subjects (CS) were studied. VO2max was assessed on a treadmill and insulin sensitivity determined by a two-step hyperinsulinaemic-euglycaemic clamp. Visceral (VAT) and subcutaneous (SAT) fat were quantified by MR-imaging. IHCL and IMCL were measured before and after a 2 h exercise at 50-60% of VO2max using MR-spectroscopy (∆IMCL, ∆IHCL). Identical investigations were performed after 6 months of GHRT. VO2max was similar in GHD and CS and significantly increased after GHRT; GHRT significantly decreased SAT and VAT. 2 h-exercise resulted in a decrease in IMCL (significant in CS and GHRT) and a significant increase in IHCL in CS and GHD pre and post GHRT. GHRT didn't significantly impact on ∆IMCL and ∆IHCL. We conclude that aerobic exercise affects ectopic lipids in patients and controls. GHRT increases exercise capacity without influencing ectopic lipids.

Roles of insulin-like growth factor binding protein-3 in gastrointestinal stromal tumors

Imatinib mesylate, a selective inhibitor of KIT, PDGFR, and Abl kinases, has shown significant success as a therapy for patients with advanced gastrointestinal stromal tumors (GISTs). However, the underlying mechanisms of imatinib-induced cytotoxicity are not well understood. Using gene expression profiling and real-time PCR for target validation, we identified insulin-like growth factor binding protein-3 (IGFBP3) to be to be up-regulated after imatinib treatment in imatinib-sensitive GISTs. IGFBP3 is a multifunctional protein that regulates cell proliferation and survival and mediates the effects of a variety of anti-cancer agents through IGF-dependent and IGF-independent mechanisms. Therefore, we hypothesized that IGFBP3 mediates GIST cell response to imatinib. To test this hypothesis, we manipulated IGFBP3 protein levels in two KIT mutant, imatinib-sensitive GIST cell lines and assessed the resultant changes in cell viability, survival, and imatinib sensitivity. In GIST882 cells, endogenous IGFBP3 was required for cell viability. However, inhibiting imatinib-induced IGFBP3 up-regulation by RNA interference or neutralization resulted in reduced drug sensitivity, suggesting that IGFBP3 sensitizes GIST882 cells to imatinib. GIST-T1 cells, on the other hand, had no detectable levels of endogenous IGFBP3, nor did imatinib induce IGFBP3 up-regulation, in contrast to our previous findings. IGFBP3 overexpression in GIST-T1 cells reduced viability but did not induce cell death; rather, the cells became polyploid through a mechanism that may involve attenuated Cdc20 expression and securin degradation. Moreover, IGFBP3 overexpression resulted in a loss of KIT activation and decreased levels of mature KIT. Consistent with this, GIST-T1 cells overexpressing IGFBP3 were less sensitive to imatinib. Furthermore, as neither GIST882 cells nor GIST-T1 cells expressed detectable levels of IGF-1R, IGFBP3 is likely not exerting its effects by modulating IGF signaling through IGF-1R or IR/IGF-1R hybrid receptors in these cell lines. Collectively, these findings demonstrate that IGFBP3 has cell-dependent effects and would, therefore, not be an ideal marker for identifying imatinib response in GISTs. Nevertheless, our results provide preliminary evidence that IGFBP3 may have some therapeutic benefits in GISTs. ^

DIABETIC RETINOPATHY IN NON-INSULIN-DEPENDENT DIABETES MELLITUS IN BLACK WOMEN: A DESCRIPTIVE STUDY OF RISK FACTORS

This cross-sectional study examines the prevalence of selected potential risk factors by stage of diabetic retinopathy (DR) among Black American women with non-insulin-dependent diabetes mellitus (NIDDM) followed at a university diabetes clinic. DR was assessed by ophthalmoscopy and five-field retinography, and graded on counts of microaneurysms, hemorrhages and/or exudates, and presence of proliferative DR. Prevalence of other vascular diseases was assessed from medical records. Potential risk factors included age, known duration of diabetes, type of hypoglycemic treatment, concentrations of random capillary blood glucose, glycosylated hemoglobin, urine protein and fibrinogen, body mass index, and blood pressure. Prevalence of these risk factors is reported for three categories: No DR, mild background DR, severe background or proliferative DR (including surgically treated DR). Duration, age at diagnosis and treatment of diabetes, concentration of urine protein and average blood glucose, hypertension and cardiovascular disease were significantly associated with DR in univariate analysis. The covariance analysis employed stratification on duration, age at diagnosis and therapy of diabetes. The highest DR scores were calculated for those diagnosed before age 45, regardless of duration, therapy, or average blood glucose. Only individuals diagnosed before age 45 had high blood glucose concentrations in all categories of duration. These findings suggest that in this clinic population of Black women, those diagnosed with NIDDm before age 45 who eventually required insulin treatment were at the greatest risk of developing DR and that longterm poor glucose control is a contributing factor. These results suggest that greater emphasis be placed on this subgroup in allocating the limited resources available to improve the quality of glucose regulation, particularly through measures affecting compliance behavior.^ Findings concerning the association of DR with concentration of blood glucose and urine protein, blood pressure/hypertension and weight were compared with those reported from American Indian and Mexican American populations of the Southwestern United States where prevalence of NIDDM, hypertension and obesity is also high. Additional comparative analyses are outlined to substantiate the preliminary finding that there are systematic differences between these ethnic populations. ^

GENETIC PREDICTORS OF HYPERGLYCEMIA DUE TO HYDROCHLOROTHIAZIDE THERAPY

Response to pharmacological treatment is variable among individuals. Some patients respond favorably to a drug while others develop adverse reactions. Early investigations showed evidence of variation in genes that code for drug receptors, drug transporters, and drug metabolizing enzymes; and pharmacogenetics appeared as the science that studies the relationship between drug response and genetic variation. Thiazide diuretics are the recommended first-line monotherapy for hypertension (i.e. SBP>140 or DBP>90). Even so, diuretics are associated with adverse metabolic side effects, such as hyperglycemia, which increase the risk of developing type 2 diabetes. Published approaches testing variation in candidate genes (e.g. the renin-angiotensin-aldosteron system (RAAS) and salt–sensitivity genes) have met with only limited success. We conducted the first genome wide association study to identify genes influencing hyperglycemia as an adverse effect of thiazide diuretics in non-Hispanic White hypertensive patients participating in the Genetic Epidemiology of Responses to Antihypertensives (GERA) and Pharmacogenomic Evaluation of Antihypertensive Responses (PEAR) clinical trials. No SNP reached the a priori defined threshold of statistical significance (p<5x10-8). We detected 50 SNPs in 9 genomic regions with suggestive p-values (p<1x10-5). Two of them, rs6870564 (p-value=3.28 X 10-6) and rs7702121 (p-value=5.09 X 10-6), were located close to biologic candidate genes, MYO and MGAT1, and one SNP in a genomic region in chromosome 6, rs7762018 (p-value=4.59 X 10-6) has been previously related to Insulin-Dependent Diabetes Mellitus (IDDM8). I conclude that 1) there are unlikely to be common SNPs with large effects on the adverse metabolic effects to hydrochlorothiazide treatment and 2) larger sample sizes are needed for pharmacogenetic studies of inter-individual variation in response to commonly prescribed medication.

Disappearance of body fat in normal rats induced by adenovirus-mediated leptin gene therapy

Sustained hyperleptinemia of 8 ng/ml was induced for 28 days in normal Wistar rats by infusing a recombinant adenovirus containing the rat leptin cDNA (AdCMV-leptin). Hyperleptinemic rats exhibited a 30–50% reduction in food intake and gained only 22 g over the experimental period versus 115–132 g in control animals that received saline infusions or a recombinant virus containing the β-galactosidase gene (AdCMV-βGal). Body fat was absent in hyperleptinemic rats, whereas control rats pair-fed to the hyperleptinemic rats retained ≈50% body fat. Further, plasma triglycerides and insulin levels were significantly lower in hyperleptinemic versus pair-fed controls, while fatty acid and glucose levels were similar in the two groups, suggestive of enhanced insulin sensitivity in the hyperleptinemic animals. Thus, despite equivalent reductions in food intake and weight gain in hyperleptinemic and pair-fed animals, identifiable fat tissue was completely ablated only in the former group, raising the possibility of a specific lipoatrophic activity for leptin.

Correction of obesity and diabetes in genetically obese mice by leptin gene therapy

The ob/ob mouse is genetically deficient in leptin and exhibits both an obese and a mild non-insulin-dependent diabetic phenotype. To test the hypothesis that correction of the obese phenotype by leptin gene therapy will lead to the spontaneous correction of the diabetic phenotype, the ob/ob mouse was treated with a recombinant adenovirus expressing the mouse leptin cDNA. Treatment resulted in dramatic reductions in both food intake and body weight, as well as the normalization of serum insulin levels and glucose tolerance. The subsequent diminishment in serum leptin levels resulted in the rapid resumption of food intake and a gradual gain of body weight, which correlated with the gradual return of hyperinsulinemia and insulin resistance. These results not only demonstrated that the obese and diabetic phenotypes in the adult ob/ob mice are corrected by leptin gene treatment but also provide confirming evidence that body weight control may be critical in the long-term management of non-insulin-dependent diabetes mellitus in obese patients.

Viral mediated expression of insulin-like growth factor I blocks the aging-related loss of skeletal muscle function

During the aging process, mammals lose up to a third of their skeletal muscle mass and strength. Although the mechanisms underlying this loss are not entirely understood, we attempted to moderate the loss by increasing the regenerative capacity of muscle. This involved the injection of a recombinant adeno-associated virus directing overexpression of insulin-like growth factor I (IGF-I) in differentiated muscle fibers. We demonstrate that the IGF-I expression promotes an average increase of 15% in muscle mass and a 14% increase in strength in young adult mice, and remarkably, prevents aging-related muscle changes in old adult mice, resulting in a 27% increase in strength as compared with uninjected old muscles. Muscle mass and fiber type distributions were maintained at levels similar to those in young adults. We propose that these effects are primarily due to stimulation of muscle regeneration via the activation of satellite cells by IGF-I. This supports the hypothesis that the primary cause of aging-related impairment of muscle function is a cumulative failure to repair damage sustained during muscle utilization. Our results suggest that gene transfer of IGF-I into muscle could form the basis of a human gene therapy for preventing the loss of muscle function associated with aging and may be of benefit in diseases where the rate of damage to skeletal muscle is accelerated.

Insulin-secreting non-islet cells are resistant to autoimmune destruction.

Transgenic nonobese diabetic mice were created in which insulin expression was targeted to proopiomelanocortin-expressing pituitary cells. Proopiomelanocortin-expressing intermediate lobe pituitary cells efficiently secrete fully processed, mature insulin via a regulated secretory pathway, similar to islet beta cells. However, in contrast to the insulin-producing islet beta cells, the insulin-producing intermediate lobe pituitaries are not targeted or destroyed by cells of the immune system. Transplantation of the transgenic intermediate lobe tissues into diabetic nonobese diabetic mice resulted in the restoration of near-normoglycemia and the reversal of diabetic symptoms. The absence of autoimmunity in intermediate lobe pituitary cells engineered to secrete bona fide insulin raises the potential of these cell types for beta-cell replacement therapy for the treatment of insulin-dependent diabetes mellitus.

Non-response to antiviral therapy is associated with obesity and increased hepatic expression of suppressor of cytokine signalling 3 (SOCS-3) in patients with chronic hepatitis C, viral genotype 1

Background: Interferon alpha (IFN-alpha) activated cellular signalling is negatively regulated by inhibitory factors, including the suppressor of cytokine signalling (SOCS) family. The effects of host factors such as obesity on hepatic expression of these inhibitory factors in subjects with chronic hepatitis C virus (HCV) are unknown. Objectives: To assess the independent effects of obesity, insulin resistance, and steatosis on response to IFN-alpha therapy and to determine hepatic expression of factors inhibiting IFN-alpha signalling in obese and nonobese subjects with chronic HCV. Methods: A total of 145 subjects were analysed to determine host factors associated with non-response to antiviral therapy. Treatment comprised IFN-alpha or peginterferon alpha, either alone or in combination with ribavirin. In a separate cohort of 73 patients, real time-polymerase chain reaction was performed to analyse hepatic mRNA expression. Immunohistochemistry for SOCS-3 was performed on liver biopsy samples from 38 patients with viral genotype 1 who had received antiviral treatment. Results: Non-response (NR) to treatment occurred in 55% of patients with HCV genotypes 1 or 4 and 22% with genotypes 2 or 3. Factors independently associated with NR were viral genotype 1/4 (p < 0.001), cirrhosis on pretreatment biopsy (p = 0.025), and body mass index >= 30 kg/m(2) (p = 0.010). Obese subjects with viral genotype 1 had increased hepatic mRNA expression of phosphoenolpyruvate carboxy kinase (p = 0.01) and SOCS-3 (p = 0.047), in comparison with lean subjects. Following multivariate analysis, SOCS-3 mRNA expression remained independently associated with obesity (p = 0.023). SOCS-3 immunoreactivity was significantly increased in obesity (p = 0.013) and in non-responders compared with responders (p = 0.014). Conclusions: In patients with chronic HCV viral genotype 1, increased expression of factors that inhibit interferon signalling may be one mechanism by which obesity reduces the biological response to IFN-alpha.