Metabolic Effects of Growth Hormone Treatment in Short Prepubertal Children: A Double-Blinded Randomized Clinical Trial.

INTRODUCTION: Growth hormone (GH) is a central hormone for regulating linear growth during childhood and also highly involved in the metabolism of lipids, carbohydrates, and protein. However, few studies report on how treatment with GH during childhood influences metabolic parameters. Our aim was to investigate metabolic effects of different doses of GH in short children with GH peak levels in the low to normal range. DESIGN: Thirty-five prepubertal short children (<-2.5 SDS), aged 7-10 years, with peak levels of GH between 7 and 14 µg/L during an arginine-insulin tolerance test, were randomized to 3 different doses (11/33/100 µg/kg/day) of GH treatment for 2 years. Auxological and metabolic investigations were performed. These included metabolites in blood and interstitial microdialysis fluid, dual-energy X-ray absorptiometry, frequently sampled intravenous glucose tolerance test (FSIVGTT), and stable isotope examinations of rates of glucose production and lipolysis. RESULTS: At 24 months, the high-dose group (HD) had higher fasting insulin compared with the standard-dose (SD) and low-dose (LD) groups (HD: 111.7 vs. SD: 61.2 and LD: 46.0 pmol/L [p < 0.001]) and showed signs of insulin resistance (HOMA-IR, HD: 4.20 vs. SD: 2.17 and LD: 1.71 (LD) [p < 0.001]). The FSIVGTT also demonstrated higher acute insulin response (p < 0.05). Few other metabolic differences were found at 24 months, but a decreased insulin sensitivity index (Si) could already be seen at 12 months for both SD and HD compared with the LD group (p < 0.05). CONCLUSION: Treatment with GH resulted in a dose-dependent decrease in insulin sensitivity, demonstrated by higher levels of fasting insulin and signs of insulin resistance in both HOMA indices and FSIVGTT examinations.

18F-DOPA PET/CT and 68Ga-DOTANOC PET/CT scans as diagnostic tools in focal congenital hyperinsulinism: a blinded evaluation.

PURPOSE: Focal congenital hyperinsulinism (CHI) is curable by surgery, which is why identification of the focal lesion is crucial. We aimed to determine the use of 18F-fluoro-dihydroxyphenylalanine (18F-DOPA) PET/CT vs. 68Ga-1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic-acid-1-Nal3-octreotide (68Ga-DOTANOC) PET/CT as diagnostic tools in focal CHI. METHODS: PET/CT scans of children with CHI admitted to Odense University Hospital between August 2005 and June 2016 were retrospectively evaluated visually and by their maximal standardized uptake values (SUVmax) by two independent examiners, blinded for clinical, surgical and pathological data. Pancreatic histology was used as the gold standard. For patients without surgery, the genetic profile served as the gold standard. RESULTS: Fifty-five CHI patients were examined by PET/CT (18F-DOPA n = 53, 68Ga-DOTANOC n = 18). Surgery was performed in 34 patients, no surgery in 21 patients. Fifty-one patients had a classifiable outcome, either by histology (n = 33, 22 focal lesions, 11 non-focal) or by genetics (n = 18, all non-focal). The predictive performance of 18F-DOPA PET/CT to identify focal CHI was identical by visual- and cut-off-based evaluation: sensitivity (95% CI) of 1 (0.85-1); specificity of 0.96 (0.82-0.99). The optimal 18F-DOPA PET SUVmax ratio cut-off was 1.44 and the optimal 68Ga-DOTANOC PET SUVmax cut-off was 6.77 g/ml. The area under the receiver operating curve was 0.98 (0.93-1) for 18F-DOPA PET vs. 0.71 (0.43-0.95) for 68Ga-DOTANOC PET (p < 0.03). In patients subjected to surgery, localization of the focal lesion was correct in 91%, and 100%, by 18F-DOPA PET/CT and 68Ga-DOTANOC PET/CT, respectively. CONCLUSION: 18F-DOPA PET/CT was excellent in predicting focal CHI and superior compared to 68Ga-DOTANOC PET/CT. Further use of 68GA-DOTANOC PET/CT in predicting focal CHI is discouraged.

Metabolic differences between short children with GH peak levels in the lower normal range and healthy children of normal height.

OBJECTIVE: Severe growth hormone deficiency (GHD) leads to several metabolic effects in the body ranging from abnormal body composition to biochemical disturbances. However, less is known regarding these parameters in short children with GH peak levels in the lower normal range during provocation tests. Our aim was to study the metabolic profile of this group and compare it with that of healthy children of normal height. DESIGN: Thirty-five pre-pubertal short children (<-2.5 SDS) aged between 7 and 10years, with peak levels of GH between 7 and 14µg/L in an arginine insulin tolerance test (AITT), were compared with twelve age- and sex-matched children of normal height. The metabolic profile of the subjects was analysed by blood samples, DEXA, frequently sampled intravenous glucose tolerance test, microdialysis and stable isotope examinations of rates of glucose production and lipolysis. RESULTS: There were no overall significant metabolic differences between the groups. However, in the subgroup analysis, the short children with GH peaks <10µg/L had significantly lower fasting insulin levels which also correlated to other metabolic parameters. CONCLUSION: The short pre-pubertal children with GH peak levels between 7 and 14µg/L did not differ significantly from healthy children of normal height but subpopulations within this group show significant metabolic differences.

Tissue IGF-I Measured by Microdialysis Reflects Body Glucose Utilization After rhIGF-I Injection in Type 1 Diabetes.

CONTEXT: Type 1 diabetes is associated with portal insulin deficiency and disturbances in the GH-IGF axis including low circulating IGF-I and GH hypersecretion. Whether peripheral hyperinsulinemia and GH hypersecretion, which are relevant to the development of vascular complications, result in elevated tissue IGF-I remains unknown. OBJECTIVE: The purpose of this study was to determine the relationship between whole-body glucose uptake and tissue IGF-I measured by microdialysis. DESIGN: This was a single-blind placebo-controlled crossover study. SETTING: The setting was a tertiary pediatric endocrine referral center. PARTICIPANTS: The participants were seven young male adults with type 1 diabetes. INTERVENTION: After an overnight fast, a 6-h lasting euglycemic clamp was performed (constant insulin infusion at 0.5 mU/kg × minute and variable glucose infusion rate [GIR]) and a subcutaneous injection of recombinant human (rh) IGF-I (120 µg/kg) or saline was given after 2 hours. In parallel, tissue IGF-I levels were determined by microdialysis (md-IGF-I). MAIN OUTCOME MEASURES: md-IGF-I levels in muscle and subcutaneous fat, and GIR were determined. RESULTS: md-IGF-I levels were detectable but unchanged after saline. After rhIGF-I, muscle and subcutaneous fat md-IGF-I increased during the second and third hour and then reached a plateau up to 10-fold higher than baseline (P < .001). GIR was unchanged after saline, whereas it increased 2.5-fold concomitantly with the increase in md-IGF-I (P < .0001). In contrast, serum IGF-I was increased already at 30 minutes after rhIGF-I and reached a plateau 2-fold above baseline (P < .0001). CONCLUSION: We demonstrate that md-IGF-I measurements are valid and physiologically relevant by reflecting rhIGF-I-induced glucose uptake. Future studies should be conducted to elucidate the role of local tissue IGF-I in diabetic vascular complications.

Insulin-like growth factor-I and insulin-like growth factor binding protein-3 cotreatment versus insulin-like growth factor-I alone in two brothers with growth hormone insensitivity syndrome: effects on insulin sensitivity, body composition and linear growth.

BACKGROUND/AIMS: Growth hormone insensitivity syndrome (GHIS) is caused by a defective growth hormone receptor (GHR) and is associated with insulin-like growth factor-I (IGF-I) deficiency, severely short stature and, from adolescence, fasting hyperglycemia and obesity. We studied the effects of treatment with IGF-I in either a 1:1 molar complex with IGFBP-3 (IGF-I/BP-3-Tx) or with IGF-I alone (IGF-I-Tx) on metabolism and linear growth. METHODS: Two brothers, compound heterozygous for a GHR gene defect, were studied. After 8 months without treatment, we examined the short- and long-term effects of IGF-I/BP-3-Tx and, subsequently, IGF-I-Tx on 12-hour overnight levels of IGF-I, GH, insulin, IGFBP-1, insulin sensitivity by hyperinsulinemic euglycemic clamp, body composition by dual-energy X-ray absorptiometry and linear growth. RESULTS: Mean overnight levels of insulin decreased and IGFBP-1, a measure of hepatic insulin sensitivity, increased on both regimens, but was more pronounced on IGF-I-Tx. Insulin sensitivity by clamp showed no consistent changes. Lean body mass increased and abdominal fat mass decreased in both subjects on IGF-I-Tx. However, the changes were inconsistent during IGF-I/BP-3-Tx. Height velocity was low without treatment, increased slightly on IGF-I/BP-3-Tx and doubled on IGF-I-Tx. CONCLUSION: Both modalities of IGF-I improved determinants of hepatic insulin sensitivity, body composition and linear growth rate; however, IGF-I alone seemed to be more efficient.

Normalization of the IGF-IGFBP axis by sustained nightly insulinization in type 1 diabetes.

OBJECTIVE: We sought to test the hypothesis that start of insulin glargine with sustained nightly insulin action results in changes in circulating concentrations of IGF-I and IGF binding proteins (IGFBPs) in adolescents with type 1 diabetes-changes that may support improvement of A1C. RESEARCH DESIGN AND METHODS: Twelve pubertal adolescents with type 1 diabetes and initially on NPH insulin were studied during 12 weeks of intensified treatment with glargine. RESULTS: Subnormal IGF-I SD scores on NPH (-1.8 +/- 0.4) rapidly increased and remained 54 +/- 9% elevated (P < 0.001) after 12 weeks on glargine. A1C decreased from 8.3 +/- 0.6% to a nadir of 6.9 +/- 0.3% (P = 0.002) at 6 weeks and correlated with changes in IGF-I (r = -0.64, P < 0.05). The increase in IGF-I did not suppress the mean overnight growth hormone (GH) secretion at 6 weeks. The mean overnight IGFBP-1 levels decreased (P = 0.035), supporting the hypothesis that the nightly hepatic insulin action was increased. Circulating IGF-I increased in the absence of changes in both GH secretion and GH receptor numbers (assessed by growth hormone binding protein), indicating that postreceptor mechanisms are involved. IGFBP-3 proteolysis was decreased. CONCLUSIONS: Increased hepatic insulin action after start of glargine was evident from a decrease in night time IGFBP-1 concentrations. This may improve GH postreceptor signaling, resulting in increased circulating IGF-I. We suggest that even in the absence of changes in GH, increased IGF-I and decreased IGFBP-1 support the improvement of metabolic control.

Noninvasive diagnosis of focal hyperinsulinism of infancy with [18F]-DOPA positron emission tomography.

Congenital hyperinsulinism of infancy (CHI) is characterized by severe hypoglycemia due to dysregulated insulin secretion, associated with either focal or diffuse pathology of the endocrine pancreas. The focal condition is caused by a paternally inherited mutation in one of the genes encoding the subunits of the beta-cell ATP-sensitive potassium channel (SUR1/ABCC8 or Kir6.2/KCNJ11) and somatic loss of maternal 11p15 alleles within the affected area. Until now, preoperative diagnostics have relied on technically demanding and invasive catheterization techniques. We evaluated the utility of fluorine-18 l-3,4-dihydroxyphenylalanine ([(18)F]-DOPA) positron emission tomography (PET) to identify focal pancreatic lesions in 14 CHI patients, 11 of which carried mutations in the ABCC8 gene (age 1-42 months). To reduce bias in PET image interpretation, quantitative means for evaluation of pancreatic [(18)F]-DOPA uptake were established. Five patients had a visually apparent focal accumulation of [(18)F]-DOPA and standardized uptake value (SUV) >50% higher (mean 1.8-fold) than the maximum SUV of the unaffected part of the pancreas. When these patients were operated on, a focus of 4-5 x 5-8 mm matching with the PET scan was found, and all were normoglycemic after resection of the focus. The remaining nine patients had diffuse accumulation of [(18)F]-DOPA in the pancreas (SUV ratio <1.5). Diffuse histology was verified in four of these, and pancreatic catheterization was consistent with diffuse pathology in four cases. In conclusion, [(18)F]-DOPA PET is a promising noninvasive method for the identification and localization of the focal form of CHI.