Efficacy and Safety of Insulin Glargine 300 Units/mL (Gla-300) Versus Insulin Glargine 100 Units/mL (Gla-100) in Children and Adolescents (6-17 years) With Type 1 Diabetes: Results of the EDITION JUNIOR Randomized Controlled Trial.

OBJECTIVE: To compare efficacy and safety of insulin glargine 300 units/mL (Gla-300) and 100 units/mL (Gla-100) in children and adolescents (6-17 years old) with type 1 diabetes. RESEARCH DESIGN AND METHODS: EDITION JUNIOR was a noninferiority, international, open-label, two-arm, parallel-group, phase 3b trial. Participants were randomized 1:1 to Gla-300 or Gla-100, titrated to achieve fasting self-monitored plasma glucose levels of 90-130 mg/dL (5.0-7.2 mmol/L), with continuation of prior prandial insulin. The primary end point was change in HbA1c from baseline to week 26. Other assessments included change in fasting plasma glucose (FPG), hypoglycemia, hyperglycemia with ketosis, and adverse events. RESULTS: In 463 randomized participants (Gla-300, n = 233; Gla-100, n = 230), comparable least squares (LS) mean (SE) reductions in HbA1c were observed from baseline to week 26 (-0.40% [0.06%] for both groups), with LS mean between-group difference of 0.004% (95% CI -0.17 to 0.18), confirming noninferiority at the prespecified 0.3% (3.3 mmol/mol) margin. Mean FPG change from baseline to week 26 was also similar between groups. During the 6-month treatment period, incidence and event rates of severe or documented (≤70 mg/dL [≤3.9 mmol/L]) hypoglycemia were similar between groups. Incidence of severe hypoglycemia was 6.0% with Gla-300 and 8.8% with Gla-100 (relative risk 0.68 [95% CI 0.35-1.30]). Incidence of any hyperglycemia with ketosis was 6.4% with Gla-300 and 11.8% with Gla-100. CONCLUSIONS: Gla-300 provided similar glycemic control and safety profiles to Gla-100 in children and adolescents with type 1 diabetes, indicating that Gla-300 is a suitable therapeutic option in this population.

Investigation of Pump Compatibility of Fast-Acting Insulin Aspart in Subjects With Type 1 Diabetes.

BACKGROUND: Ultra-fast-acting insulins, such as fast-acting insulin aspart (faster aspart), have pharmacokinetic properties that may be advantageous for patients using continuous subcutaneous insulin infusion (CSII), provided that they are compatible with and safe to use in CSII. METHODS: Randomized, double-blind, parallel-group, actively controlled trial evaluating compatibility, efficacy, and safety of faster aspart in adults with type 1 diabetes using their own MiniMed Paradigm pump with Quick-Set or Silhouette infusion sets. Following run-in, subjects were randomized (2:1) to faster aspart (n = 25) or insulin aspart (n = 12) for 6 weeks. Primary endpoint was the number of microscopically confirmed episodes of infusion-set occlusions. RESULTS: No microscopically confirmed episodes of infusion-set occlusions were observed in either arm. Seven possible infusion-set occlusions were reported by five subjects (all faster aspart); none were prompted by a plug observed by the subject (prompted by unexplained hyperglycemia [n = 6] or leakage [n = 1]) and none were confirmed. Macroscopic and microscopic evaluation showed no color change or particle/crystal formation in the infusion sets. Premature infusion-set changes were reported in 44% and 16.7% of subjects in the faster aspart and insulin aspart groups, respectively. A nonsignificant trend toward better efficacy was observed with faster aspart (estimated treatment difference [ETD] [95% CI] in HbA1c change: -0.14% [-0.40, 0.11]). No new safety issues were found in either treatment group. CONCLUSIONS: Over 6 weeks of treatment, no microscopically confirmed infusion-set occlusions were observed for faster aspart or insulin aspart, indicating similar compatibility with CSII use.

Adding fast-acting insulin aspart to basal insulin significantly improved glycaemic control in patients with type 2 diabetes: A randomized, 18-week, open-label, phase 3 trial (onset 3).

AIM: To confirm glycaemic control superiority of mealtime fast-acting insulin aspart (faster aspart) in a basal-bolus (BB) regimen vs basal-only insulin. MATERIALS AND METHODS: In this open-label, randomized, 18-week trial (51 sites; 6 countries), adults (n = 236) with inadequately controlled type 2 diabetes (T2D; mean glycosylated haemoglobin [HbA1c] ± SD: 7.9% ± 0.7% [63.1 ± 7.5 mmol/mol]) receiving basal insulin and oral antidiabetic drugs underwent 8-week optimization of prior once-daily basal insulin followed by randomization 1:1 to either a BB regimen with faster aspart (n = 116) or continuation of once-daily basal insulin (n = 120), both with metformin. Primary endpoint was HbA1c change from baseline after 18 weeks of treatment. Secondary endpoints included: postprandial plasma glucose (PPG) change and overall PPG increment (all meals); weight; treatment-emergent adverse events; hypoglycaemic episodes. RESULTS: HbA1c decreased from 7.9% (63.2 mmol/mol) to 6.8% (50.7 mmol/mol; BB group) and from 7.9% (63.2 mmol/mol) to 7.7% (60.7 mmol/mol; basal-only group); estimated treatment difference [95% confidence interval] -0.94% [-1.17; -0.72]; -10.3 mmol/mol [-12.8; -7.8]; P < .0001. Reductions from baseline in overall mean 2-hour PPG and overall PPG increment for all meals (self-measured plasma glucose profiles) were statistically significant in favour of BB treatment ( P < .0001). Severe/blood glucose confirmed hypoglycaemia rate (12.8 vs 2.0 episodes per patient-years of exposure), total daily insulin (1.2 vs 0.6 U/kg) and weight gain (1.8 vs 0.2 kg) were greater with BB than with basal-only treatment. CONCLUSIONS: In T2D, faster aspart in a BB regimen provided superior glycaemic control as compared with basal-only insulin, but with an increase in the frequency of hypoglycaemia and modest weight gain.

Improved Postprandial Glycemic Control with Faster-Acting Insulin Aspart in Patients with Type 1 Diabetes Using Continuous Subcutaneous Insulin Infusion.

BACKGROUND: Faster aspart is insulin aspart (IAsp) in a new formulation, which in continuous subcutaneous insulin infusion (CSII) in subjects with type 1 diabetes has shown a faster onset and offset of glucose-lowering effect than IAsp. METHODS: This double-blind, randomized, crossover active-controlled trial compared 2-h postprandial plasma glucose (PPG) response, following 2 weeks of CSII with faster aspart or IAsp. Primary endpoint: mean change in PPG 2 h after a standardized meal test (ΔPGav,0-2h). Subjects (n = 43) had masked continuous glucose monitoring (CGM) throughout. RESULTS: Faster aspart provided a statistically significantly greater glucose-lowering effect following the meal versus IAsp: ΔPGav,0-2h: 3.03 mmol/L versus 4.02 mmol/L (54.68 mg/dL vs. 72.52 mg/dL); estimated treatment difference (ETD) [95% CI]: -0.99 mmol/L [-1.95; -0.03] (-17.84 mg/dL [-35.21; -0.46]; P = 0.044). One hour postmeal, PG levels were -1.64 mmol/L (-29.47 mg/dL) lower with faster aspart versus IAsp (P = 0.006). Interstitial glucose (IG) profiles supported these findings; the largest differences were observed at breakfast: 9.08 versus 9.56 mmol/L (163.57 vs. 172.19 mg/dL; ETD [95% CI]: -0.48 mmol/L [-0.97; 0.01]; -8.62 mg/dL [-17.49; 0.24]; P = 0.057). Duration of low IG levels (≤3.9 mmol/L [70 mg/dL] per 24 h) was statistically significantly shorter for faster aspart versus IAsp (2.03 h vs. 2.45 h; ETD [95% CI]: -0.42 [-0.72; -0.11]; P = 0.008). No unexpected safety findings were observed. CONCLUSIONS: CSII delivery of faster aspart had a greater glucose-lowering effect than IAsp after a meal test. CGM results recorded throughout all meals supported this finding, with less time spent with low IG levels.

PPAR-gamma2 Pro12Ala polymorphism in the population of obese and non-obese men of the city of Wroclaw.

INTRODUCTION: The aim of this study was to examine the association of Pro12Ala PPARgamma2 polymorphism with anthropometric and biochemical parameters defining the risk for the development of metabolic syndrome in a healthy population of men. MATERIAL AND METHODS: The study group consisted of 176 healthy men, aged 25-65 years (average 54.16 years). Polymorphisms of the PPAR-g gene (Pro12Ala, Ala12Ala, Pro12Pro) were explored using the PCR-RFLP method. Plasma glucose, insulin, total cholesterol, LDL, HDL and TG were measured using commercially available kits. RESULTS: The genotypic distribution of the Pro12Ala polymorphism was as follows: Pro/Ala 69.8% (n = 123), Ala/Ala 28.4% (n = 50) and Pro/Pro 1.8% (n = 3). The Pro12Ala and Ala12Ala subjects did not differ in any of the measured variables. The non-obese (BMI < 30 kg/m(2), n = 117) and obese subpopulations (BMI > 30 kg/m(2), n = 56) did not significantly differ in the distribution of the genotypes. In the nonobese subpopulation, the homozygous Ala12 carriers (n = 38, 32.4%) had higher systolic blood pressure, plasma triglycerides, insulin levels and HOMA-IR. CONCLUSIONS: We conclude that despite the high frequency of the Ala allele at the PPAR-gamma2 gene in our population of Polish men, the Ala12 allele does not appear to improve insulin sensitivity or have an influence on the occurrence of obesity. It remains to be explained by larger studies if this polymorphism carries any risk of the development of metabolic abnormalities in non-obese men.

Plasma cytokines in obese women with polycystic ovary syndrome, before and after metformin treatment.

OBJECTIVES: Most research confirms that metformin therapy has a positive influence on cardiovascular risk factors (CVRF) such as dyslipidemia, insulin resistance and hyperandrogenism in polycystic ovary syndrome (PCOS). The aims of the present study were to establish other CVRF, such as plasma adiponectin, tumor necrosis factor-alpha (TNFalpha), interleukin-6 (IL-6) and C-reactive protein (CRP) levels, in obese premenopausal women with PCOS and to investigate the effect of metformin treatment on these factors. MATERIALS AND METHODS: The study group consisted of 29 PCOS woman with body mass index (BMI) >25 kg/m(2). They were treated over 6 months with 500 mg metformin twice daily. Twenty-nine healthy individuals matched for age and BMI were controls. Adiponectin, TNFalpha, IL-6 and CRP levels were examined in all PCOS (before and after treatment) and control women. RESULTS: In the PCOS group significantly lower plasma adiponectin and TNFalpha levels were observed, whereas there were no differences in plasma IL-6 and CRP levels between PCOS and control groups. Plasma adiponectin increased significantly after metformin treatment, but levels of inflammatory factors did not change.

Transient prenatal androgen exposure produces metabolic syndrome in adult female rats.

Androgen exposure during intrauterine life in nonhuman primates and in sheep results in a phenocopy of the reproductive and metabolic features of polycystic ovary syndrome (PCOS). Such exposure also results in reproductive features of PCOS in rodents. We investigated whether transient prenatal androgen treatment produced metabolic abnormalities in adult female rats and the mechanisms of these changes. Pregnant dams received free testosterone or vehicle injections during late gestation, and their female offspring were fed regular or high-fat diet (HFD). At 60 days of age, prenatally androgenized (PA) rats exhibited significantly increased body weight; parametrial and subcutaneous fat; serum insulin, cholesterol and triglyceride levels; and hepatic triglyceride content (all P < 0.0125). There were no significant differences in insulin sensitivity by intraperitoneal insulin tolerance test or insulin signaling in liver or skeletal muscle. HFD had similar effects to PA on body weight and composition as well as on circulating triglyceride levels. HFD further increased hepatic triglyceride content to a similar extent in both PA and control rats. In PA rats, HFD did not further increase circulating insulin, triglyceride, or cholesterol levels. In control rats, HFD increased insulin levels, but to a lesser extent than PA alone ( approximately 2.5- vs. approximately 12-fold, respectively). We conclude that transient prenatal androgen exposure produces features of the metabolic syndrome in adult female rats. Dyslipidemia and hepatic steatosis appear to be mediated by PA-induced increases in adiposity, whereas hyperinsulinemia appears to be a direct result of PA.

Familial hypopituitarism associated with mosaic form of Turner syndrome.

We present herein an unusual coincidence of familial hypopituitarism associated with a mosaic form of Turner syndrome in two adult sisters (51 and 43 years old). Both patients had hypopituitarism diagnosed in childhood. They have never been administered growth hormone, and remained short in stature. They were not given long-term estrogen-progestin treatment, despite lack of menstruation. Early in childhood both received thyroid hormone substitution. Pituitary imaging revealed pituitary hypoplasia with partial empty sella in one sister, and pituitary hypoplasia in the other. Very recently, during endocrinological evaluation, they were diagnosed with a mosaic form of Turner syndrome, additionally to their hypopituitarism. In this paper, we place special emphasis on the results of hormonal analyses and discuss the differential diagnosis.

Serum adiponectin concentration and cardiovascular risk factors in climacteric women.

OBJECTIVE: Adiponectin plays a significant role in the modulation of glucose tolerance and insulin sensitivity. We attempted to evaluate the relationship between adiponectin level and parameters of the menopausal metabolic syndrome: body mass index, waist-to-hip ratio, lipid profile and insulin resistance indices. SUBJECTS AND METHODS: Thirty-two women and ten men aged 40-63 years were included. The percentage of body fat and of abdominal fat deposits were measured with dual-energy X-ray absorptiometry. Serum adiponectin, tumour necrosis factor-a (TNFalpha) and leptin were measured with commercially available radioimmunoassay kits. To exclude the influence of nutritional factors on adiponectin secretion, diet content was analysed in the preceding three days. RESULTS: Postmenopausal non-obese women had a non-significantly lower level of adiponectin compared with premenopausal women of corresponding body mass. Serum adiponectin level was significantly lower in postmenopausal obese women than in non-obese women (p = 0.0023). Men with similar age and body mass to the women had the lowest level of adiponectin (p = 0.06). Three months of estrogen replacement therapy in women with surgical menopause did not significantly change the serum level of adiponectin. We found a negative correlation of adiponectin with leptin, insulin resistance index and total cholesterol, and a positive correlation with high-density lipoprotein cholesterol. Adiponectin level was negatively correlated with free testosterone, but we did not find such a relationship with estradiol. There was no correlation of adiponectin level with TNFalpha; however, serum TNFalpha correlated positively with leptin. The dietary analysis showed no differences between the diets of obese and non-obese women over the preceding three days. Moreover, mean diastolic and systolic blood pressures were noted to be significantly lower in premenopausal women than in postmenopausal non-obese women (p = 0.05). CONCLUSIONS: Our results suggest that adiponectin could be a marker of risk for developing menopausal metabolic syndrome. Moreover, it is possible that sex steroids have an influence on adiponectin secretion.

[Leptin level and the PPARgamma2 Pro12Ala and Pro115Gln polymorphisms in women with functional hyperandrogenism. Preliminary report]. / Poziom leptyny i wystepowanie polimorfizmu Pro12Ala i Pro115Gln genu PPARgamma2 u kobiet z czynnosciowym hiperandrogenizmem. Raport wstepny.

UNLABELLED: Hyperandrogenism is a multifactoral chronic disease, characterised by an androgen excess, often connected with obesity, hirsutism, polycystic ovaries, hyperinsulinemia, insulin resistance and hyperleptynemia. Peroxisome proliferator activated receptors (PPARgamma) are one of the factors influencing insulin sensitivity. As a transcriptional factor it plays a crucial role in the regulation of genes involved in insulin action. The aim of this study was to evaluate the frequency of PPARgamma Pro12Ala and Pro115Gln polymorphisms in hyperandrogenic women. The additional aim was to investigate differences in leptin levels in healthy and FOH (functional ovarian hyperandrogenism) women (non-obese and obese). MATERIAL AND METHODS: we investigated 90 women: 72 healthy women (37 nonobese and 35 obese)--control group, and 18 women with FOH (9 nonobese and 9 obese)--FOH group. We performed anthropological examination: BMI, WHR and total-body densytomery, biochemical and hormonal estimations in the whole group. PPARgamma polymorphism was studied using PCR and RFLP. RESULTS: in the control group Pro12Pro ("wild" type) was observed in 45 women (26 obese and 19 nonobese) - 62.5% of the group. Heterozygosity Pro12Ala was observed in 15 women (20.8%): 4 obese and 11 with BMI < 30 kg/m2, homozygosity Ala12Ala was seen in 12 women (16.6%): 5 obese i 7 nonobese. In FOH group "wild" type was discovered in 9 women (4 obese and 5 nonobese) - 50% of FOH group, heterozygosity Pro12Ala was seen in 5 women (27.7%): 2 obese and 3 with BMI < 30 kg/m2, homozygosityAla12Ala was observed in 4 women (22.2%): 3 obese and in 1 non-obese. Ala allel frequency in control group was 28%. (37% in non-obese and 20% in obese). In FOH group Ala allel frequency was 36% (nonobese - 28%, obese - 44%). In the studied group we did not find Pro115Gln polymorphism. Leptin level in control group was 19.92 +/- 14.3 ng/ml, and in FOH group - 23.41 +/- 19.47 ng/ml. Depending on BMI leptin level in non-obese healthy group was 7.45 +/- 3.76 ng/ml, in non-obese FOH women - 18.33 +/- 16.54 ng/ml, p < 0.005. In obese controls leptin level was 43.6 +/- 17.28 ng/ml, and in obese FOH women - 45.72 +/- 14.89 ng/ml. CONCLUSIONS: Leptin level in non-obese FOH women is significantly higher than in lean healthy controls. This difference was not observed in obese women. However the Pro12Ala polymorphism is quite common; it does not seem to be directly related to the obesity connected with hyperandrogenism. Higher frequency of Ala allele In FOH women compared to healthy controls (36% vs 28%) may at least partially explain the beneficial effect of tiazolidinediones in the treatment of hyperandrogenism.

Expression and differential effects of the activation of glucocorticoid receptors in mouse gonadotropin-releasing hormone neurons.

Prenatal exposure of rodents to glucocorticoids (Gc) affects the sexual development of the offspring, possibly interfering with the differentiation of the hypothalamic-pituitary-gonadal axis. Glucocorticoid receptors (GR) are present on gonadotropin-releasing hormone (GnRH) neurons in the rat hypothalamus, suggesting a direct effect of Gc in the control of the synthesis and/or release of the hormone. In this study, we demonstrate the colocalization of immunoreactive GR with GnRH in a subpopulation of mouse hypothalamic GnRH neurons, confirming the possible involvement of Gc in mouse GnRH neuronal physiology. Receptor-binding assay, RT-PCR, immunocytochemistry, and immunoblotting experiments carried out in GN11 immortalized GnRH neurons show the presence of GR even in the more immature mouse GnRH neurons and confirm the expression of GR in GT1-7 mature GnRH cells. In GN11 cells, the activation of GR with dexamethasone produces nuclear translocation, but does not lead to the inhibition of GnRH gene expression already reported in GT1-7 cells. Long-term exposure of GN11 cells to dexamethasone induces an epithelial-like phenotype with a reorganization of F-actin in stress fibers. Finally, we found that Gc treatment significantly decreases the migratory activity in vitro and the levels of phosphorylated focal adhesion kinase of GN11 immature neurons. In conclusion, these data indicate that GR are expressed in mouse hypothalamic GnRH neurons in vivo as well as in the immature GN11 GnRH neurons in vitro. Moreover, the effects of the GR activation in GN11 and in GT1-7 cells may be related to the neuronal maturational stage of the two cell lines, suggesting a differential role of Gc in neuronal development.

[Is obesity associated with a polymorphism Pro12Ala and Pro115Gln in PPARgamma gene?]. / Czy istnieje zwiazek miedzy otyloscia a polimorfizmem Pro12Ala i Pro115Gln genu PPARgamma?

UNLABELLED: Gene PPARgamma is one of the pivotal factors that influence adipocyte differentiation. It is transcriptional factor that plays a crucial role in the regulation of genes involved in lipid utilisation and storage as well as insulin action. The aim of this study was to evaluate whether PPARgamma Pro12Ala and Pro115Gln polymorphisms are connected with obesity and its anthropological parameters. MATERIAL AND METHODS: we investigated 93 subjects: 72 women (37 non-obese and 35 obese) and 21 men (8 non-obese and 13 obese). We performed anthropological examination: BMI, WHR and total-body densitometry in the whole group. PPARg polymorphism was studied using PCR and RFLP. RESULTS: Pro12Pro ("wild" type) variant was present in 57 subjects (32 obese and 25 non-obese): 45 women (26 obese and 19 non-obese) and 12 men (6 obese and 6 non-obese). Heterozygosity Pro12Ala was observed in 20 subjects (8 obese and 12 controls): 15 women (4 obese and 11 lean) and 5 men (4 obese). Homozygosity Ala12Ala was discovered in 16 subjects (8 obese and 8 controls): 12 women (5 obese and 7 non-obese) and 4 men (3 obese). Pro115Gln variant was not found in any of the studied subjects. CONCLUSIONS: The frequency Ala allele (pro12Ala and Ala12Ala variant) was 28% in the whole group and 25% in the obese subjects. However the Pro12Ala polymorphism is quite common, it does not seem to be directly connected with onset of obesity. But it is interesting that the Ala allele is more frequent in non-obese women comparing to obese women (33 vs 20%). Reverse tendency was seen in men. Pro12Ala and/or Ala12Ala polymorphism is twice more frequent in obese subjects comparing to non-obese ones (38 vs 19%).

[Is obesity associated with a polymorphism Pro12Ala and Pro115Gln in the PPARgamma gene?]. / Czy istnieje zwiazek miedzy otyloscia a polimorfizmem Pro12Ala i Pro115Gln genu PPARgamma?

UNLABELLED: PPARgamma is one of the pivotal factors that influence adipocyte differentiation. It is transcriptional factor that plays a crucial role in the regulation of genes involved in lipid utilisation and storage as well as insulin action. The objective of this study was to evaluate whether PPARgamma Pro12Ala and Pro115Gln polymorphisms are connected with obesity and its anthropological parameters. MATERIAL AND METHODS: We investigated 93 subjects: 72 women (37 non-obese and 35 obese) and 21 men (8 non-obese and 13 obese). We performed anthropological examination: body mass index (BMI), waist to hip ratio (WHR) and total-body densitometry in the whole group. PPARgamma polymorphism was studied using polymerase chain reaction (PCR) and restriction fragment length polymorphism (RFLP) analysis. RESULTS: Pro12Pro ("wild" type) variant was present in 57 subjects (32 obese and 25 non-obese): 45 women (26 obese and 19 non-obese) and 12 men (6 obese and 6 non-obese). Heterozygosity Pro12Ala was observed in 20 subjects (8 obese and 12 controls): 15 women (4 obese and 11 lean) and 5 men (4 obese). Homozygosity Ala12Ala was discovered in 16 subjects (8 obese and 8 controls): 12 women (5 obese and 7 non-obese) and 4 men (3 obese). Pro115Gln variant was not found in any of the studied subjects. CONCLUSIONS: The frequency Ala allele (pro12Ala and Ala12Ala variant) was 28% in the whole group and 25% in the obese subjects. However the Pro12Ala polymorphism is quite common, it does not seem to be directly connected with onset of obesity. But it is interesting that the Ala allele is more frequent in non-obese women comparing to obese women (33 vs 20%). Reverse tendency was seen in men. Pro12Ala and/or Ala12Ala polymorphism is twice more frequent in obese subjects comparing to non-obese ones (38 vs 19%).