Reduction in insulin sensitivity and inadequate \u3b2-cell capacity to counteract the increase in insulin resistance in children with idiopathic growth hormone deficiency during 12 months of growth hormone treatment

Purpose: To evaluate the performance of various indexes of insulin sensitivity and secretion and to identify the most useful indicator of deterioration of glucose metabolism in a cohort of children with growth hormone (GH) deficiency (GHD) during GH treatment. Methods: In 73 GHD children (55 M, 18 F; mean age 10.5 years) at baseline and after 12 months of treatment, we evaluated a number of surrogate indexes of insulin secretion and sensitivity. In a subgroup of 11 children we also performed an euglycemic hyperinsulinemic clamp. Results: After 12 months, a significant increase in fasting glucose (p < 0.001) and HbA1c levels (p < 0.001) was documented, despite all children remained with a normal glucose tolerance. With regard the insulin secretion, Homa-\u3b2 did not show any significant change (p = 0.073), while oral disposition index (DIo) showed a significant decrease (p = 0.031). With regard the insulin sensitivity, Homa-IR significantly increased (p < 0.001) with a concomitant decrease in QUICKI (p < 0.001). ISI Matsuda showed a decrease, although not statistically significant (p = 0.069). In the subgroup of 11 children, the M value derived from clamp showed a significant decrease (p = 0.011) and a significant positive correlation was found between M value and ISI Matsuda both at baseline (\u3c1 0.950; p = 0.001) and after 12 months (\u3c1 0.980; p = 0.001) but not with Homa-IR and QUICKI. Conclusions: 12 months of GH treatment lead to a decrease in insulin sensitivity and impairment in insulin secretion relative to insulin sensitivity even without evident changes in glucose tolerance. DIo has proven to be the most useful indicator of deterioration of glucose metabolism even in cases in which the overt glucose abnormalities have not yet appeared

Corneal thickness in children with growth hormone deficiency: The effect of GH treatment.

Abstract OBJECTIVE: The eye represents a target site for GH action, although few data are available in patients with GH deficiency (GHD). Our aim was to evaluate central corneal thickness (CCT) and intraocular pressure (IOP) values in GHD children to assess the role played by GHD or GH treatment on these parameters. DESIGN: In 74 prepubertal GHD children (51M, 23F, aged 10.4\ub12.4years) we measured CCT and IOP before and after 12months of treatment. A baseline evaluation was also made in 50 healthy children matched for age, gender and body mass index. The study outcome considered CCT and IOP during treatment and their correlations with biochemical and auxological data. RESULTS: No difference in CCT and IOP between GHD children at baseline and controls was found (all p>0.005). GHD children after 12months of therapy showed greater CCT (564.7\ub113.1\u3bcm) than both baseline values (535.7\ub117\u3bcm; p<0.001) and control subjects (536.2\ub112.5\u3bcm; p<0.001), with a concomitantly higher corrected mean IOP (15.6\ub10.7mmHg; p<0.001) than both baseline (12.5\ub10.8mmHg; p<0.001) and controls (12.3\ub10.5mmHg; p<0.001), without correlation with auxological and biochemical parameters. CONCLUSIONS: 12months of GH treatment in children with GHD, regardless of auxological and biochemical data, affect CCT and IOP. Our findings suggest careful ocular evaluation in these patients to prevent undesirable side effects during the follow-up

Pasireotide versus pituitary surgery: a retrospective analysis of 12 months of treatment in patients with Cushing's disease

Pituitary surgery represents the first-line treatment for most patients with Cushing\u2019s disease (CD). In the case of surgery failure, additional treatment options are required. Pasireotide has shown favourable results in the first-line treatment of patients with CD, who are not candidates for surgery or in the second-line when surgery has failed. The aim of the current study is to compare the effects of surgery and pasireotide treatment in a cohort of patients with CD, and to evaluate the differences in response rate in terms of hormonal and clinical control, and improvement of metabolic complication

More favorable metabolic impact of three-times-weekly versus daily growth hormone (GH) treatment in na\uefve GH-deficient children

OBJECTIVE: Growth hormone treatment (GHT) is commonly administered daily, although pulsatile GH secretion is unlikely to be achieved. The auxological effect of a three-injections-per-week (TIW) regimen is controversial, while the metabolic effects have been never evaluated in children. The objective was to evaluate whether two different regimens of weekly injections could lead to similar auxological and metabolic effects in children with GH deficiency (GHD). DESIGN: 32 GHD children (25 males, mean age 10.5 \ub1 2.2 yr) were randomly assigned to receive daily (group A, No 16) or TIW (group B, No 16) GHT for 12 months. METHODS: Auxological parameters, insulin-like growth factor-I (IGF-I), glucose and insulin during OGTT, glycosylated hemoglobin (HbA1c), lipid profile, the oral disposition index (DIo), the homeostasis model assessment estimate of insulin resistance (Homa-IR) and the insulin sensitivity index (ISI). RESULTS: After 12 months, both groups showed a significant and comparable improvement in height (p<0.001) and IGF-I (p<0.001). As regards the metabolic parameters, in both groups we found a significant increase in fasting insulin (p<0.001 and p=0.026) and Homa-IR (p<0.001 and p=0.019). A significant increase in fasting glucose (p=0.001) and a decrease in ISI (p<0.001) and DIo (p=0.002) were only found in group A. CONCLUSIONS: The TIW regimen is effective and comparable with the daily regimen in improving auxological parameters and has a more favorable metabolic impact in GHD children (www.ClinicalTrials.gov. NCT03033121)

Janus kinase (JAK) 2 V617F mutation as the cause of primary thrombocythemia in acromegaly with severe visceromegaly and divergence between growth hormone and insulin-like growth factor-1 concentrations during the follow-up: causal or casual association?

OBJECTIVE: An increased prevalence of hematological abnormalities is reported in acromegaly, but to date no reports about the presence of the Janus Kinase (JAK) 2 mutation in acromegalic patients have been described. DESIGN: We report the complex clinical presentation of the unique case, never described, of acromegaly due to GH-secreting pituitary adenoma associated with JAK2 V617F mutation. RESULTS: The patient shows primary thrombocythemia and myelofibrosis, due to JAK2 V617F mutation, severe visceromegaly and a peculiar clinical course of the disease characterized by discrepant values of GH and IGF-1 during somatostatin analog (SA) treatment despite a significant reduction in pituitary adenoma size and therapeutic resistance both to SA and pegvisomant. CONCLUSIONS: The presence of JAK2 V617F mutation is a cause of primary thrombocythemia and myelofibrosis in acromegaly. In this patient, a peculiar clinical course of acromegaly was observed, with the difficulty in controlling the disease. More data, on a larger cohort of patients, could clarify whether JAK2 V617F mutation has a serious impact on the clinical features and course of acromegaly.OBJECTIVE: An increased prevalence of hematological abnormalities is reported in acromegaly, but to date no reports about the presence of the Janus Kinase (JAK) 2 mutation in acromegalic patients have been described. DESIGN: We report the complex clinical presentation of the unique case, never described, of acromegaly due to GH-secreting pituitary adenoma associated with JAK2 V617F mutation. RESULTS: The patient shows primary thrombocythemia and myelofibrosis, due to JAK2 V617F mutation, severe visceromegaly and a peculiar clinical course of the disease characterized by discrepant values of GH and IGF-1 during somatostatin analog (SA) treatment despite a significant reduction in pituitary adenoma size and therapeutic resistance both to SA and pegvisomant. CONCLUSIONS: The presence of JAK2 V617F mutation is a cause of primary thrombocythemia and myelofibrosis in acromegaly. In this patient, a peculiar clinical course of acromegaly was observed, with the difficulty in controlling the disease. More data, on a larger cohort of patients, could clarify whether JAK2 V617F mutation has a serious impact on the clinical features and course of acromegaly

Is diabetes in Cushing's syndrome only a consequence of hypercortisolism?

OBJECTIVE: Diabetes mellitus (DM) is one of the most frequent complications of Cushing's syndrome (CS). The aim of this study was to define the changes in insulin sensitivity and/or secretion in relation to glucose tolerance categories in newly diagnosed CS patients. DESIGN: Cross-sectional study on 140 patients with CS. METHODS: A total of 113 women (80 with pituitary disease and 33 with adrenal disease, aged 41.7±15.7 years) and 27 men (19 with pituitary disease and eight with adrenal disease, aged 38.1±20.01 years) at diagnosis were divided according to glucose tolerance into normal glucose tolerance (CS/NGT), impaired fasting glucose and/or impaired glucose tolerance (CS/prediabetes), and diabetes (CS/DM) groups. RESULTS: Seventy-one patients had CS/NGT (49.3%), 26 (18.5%) had CS/prediabetes and 43 (30.8%) had CS/DM. Significant increasing trends in the prevalence of family history of diabetes (P&lt;0.001), metabolic syndrome (P&lt;0.001), age (P&lt;0.001) and waist circumference (P=0.043) and decreasing trends in HOMA-β (P&lt;0.001) and oral disposition index (DIo) (P&lt;0.002) were observed among the groups. No significant trends in fasting insulin levels, area under the curve for insulin (AUCINS), Matsuda index of insulin sensitivity (ISI-Matsuda) and visceral adiposity index were detected. CONCLUSIONS: Impairment of glucose tolerance is characterized by the inability of β-cells to adequately compensate for insulin resistance through increased insulin secretion. Age, genetic predisposition and lifestyle, in combination with the duration and degree of hypercortisolism, strongly contribute to the impairment of glucose tolerance in patients with a natural history of CS. A careful phenotypic evaluation of glucose tolerance defects in patients with CS proves useful for the identification of those at a high risk of metabolic complications