Hypomagnesemia due to two novel TRPM6 mutations.

BACKGROUND: Although most hypocalcemia with hypomagenesemia in the neonatal period is due to transient neonatal hypoparathyroidism, magnesium channel defects should also be considered. CASE: We report a case of persistent hypomagnesemia in an 8-day-old Hispanic male who presented with generalized seizures. He was initially found to have hypomagnesemia, hypocalcemia, hyperphosphatemia and normal parathyroid hormone. Serum calcium normalized with administration of calcitriol and calcium carbonate. Serum magnesium improved with oral magnesium sulfate. However, 1 week after magnesium was discontinued, serum magnesium declined to 0.5 mg/dL. Magnesium supplementation was immediately restarted, and periodic seizure activity resolved after serum magnesium concentration was maintained above 0.9 mg/dL. The child was eventually weaned off oral calcium and calcitriol with persistent normocalemia. However, supraphysiologic oral magnesium doses were necessary to prevent seizures and maintain serum magnesium at the low limit of normal. METHODS AND RESULTS: As his clinical presentation suggested primary renal magnesium wastage, TRPM6 gene mutations were suspected; subsequent genetic testing revealed the child to be compound heterozygous for TRPM6 mutations. CONCLUSION: Two novel TRPM6 mutations are described with a new geographic and ethnic origin. This case highlights the importance of recognizing disorders of magnesium imbalance and describing new genetic mutations.

Changes in plasma FGF23 in growth hormone deficient children during rhGH therapy.

BACKGROUND: Children with growth hormone deficiency (GHD) have increased renal phosphorus reabsorption during rhGH therapy, Fibroblast growth factor 23 (FGF23) is a known regulator of serum phosphorus and may be responsible for this effect. METHODS: Prospective study in GHD children investigating changes in plasma C-terminal FGF23 (C-FGF23), markers of mineral metabolism, and insulin-like growth factor (IGF-1) in the first year of rhGH therapy. Normal stature children served as baseline controls. RESULTS: The two groups at baseline were similar, except GHD patients had lower baseline TmP/GFR vs. controls (p < 0.05). C-FGF23 in GHD patients trended upward at follow-up 1 (p = 0.058) and significantly increased at follow-up 2 (p = 0.0005) compared to baseline. TmP/GFR also rose at follow-up 1 (p = 0.002) and follow-up 2 (p = 0.027). The C-FGF23 rise persisted after adjusting for age, gender, sex, total calcium, and phosphorus (p < 0.01) but attenuated after adjusting for TmP/GFR or IGF-1. CONCLUSIONS: C-FGF23 rises during rhGH therapy in spite of increased Tmp/GFR, an unanticipated observation given the role of FGF23 as a phosphaturic factor. The C-FGF23 rise may be a secondary response during rhGH therapy.

Growth hormone-IGF-I axis and growth velocity in Chinese children with type 1 diabetes mellitus.

OBJECTIVE: To elucidate hormonal disturbances in patients with type 1 diabetes mellitus (DM1) with and without growth retardation. METHODS: Patients with DM1 were divided into two groups, group A consisted of 14 patients with poor growth, and group B consisted of 24 patients with normal growth. Serum IGF-I, IGFBP-3, basal and stimulated GH, and HbA1c were measured. RESULTS: Serum IGF-I and IGFBP-3 concentrations were significantly decreased in group A versus both groups B and controls in Tanner stages I-III; in addition, these measurements in group B were significantly lower compared to controls in Tanner stages II and III, but there was no significant difference in prepuberty. Both basal and peak serum GH were attenuated significantly in group A versus group B. Basal serum GH in group B (normal growth DM1) was significantly elevated versus the controls. There was an unambiguous negative linear regression between IGF-I and mean HbA1c in patients with DM1. CONCLUSIONS: Growth retardation in patients with DM1 is associated with an abnormal GH-IGF-I axis and poor glycemic control.

Evidence that the 11 beta-hydroxysteroid dehydrogenase (11 beta-HSD1) is regulated by pentose pathway flux. Studies in rat adipocytes and microsomes.

11 beta-hydroxysteroid dehydrogenase type 1 (11 beta-HSD1) catalyzes the interconversion of biologically inactive 11 keto derivatives (cortisone, 11-dehydrocorticosterone) to active glucocorticoids (cortisol, corticosterone) in fat, liver, and other tissues. It is located in the intraluminal compartment of the endoplasmic reticulum. Inasmuch as an oxo-reductase requires NADPH, we reasoned that 11 beta-HSD1 would be metabolically interconnected with the cytosolic pentose pathway because this pathway is the primary producer of reduced cellular pyridine nucleotides. To test this theory, 11 beta-HSD1 activity and pentose pathway were simultaneously measured in isolated intact rodent adipocytes. Established inhibitors of NAPDH production via the pentose pathway (dehydroandrostenedione or norepinephrine) inhibited 11 beta-HSD1 oxo-reductase while decreasing cellular NADPH content. Conversely these compounds slightly augmented the reverse, or dehydrogenase, reaction of 11 beta-HSD1. Importantly, using isolated intact microsomes, the inhibitors did not directly alter the tandem microsomal 11 beta-HSD1 and hexose-6-phosphate dehydrogenase enzyme unit. Metabolites of 11 beta-HSD1 (corticosterone or 11-dehydrocorticosterone) inhibited or increased pentose flux, respectively, demonstrating metabolic interconnectivity. Using isolated intact liver or fat microsomes, glucose-6 phosphate stimulated 11 beta-HSD1 oxo-reductase, and this effect was blocked by selective inhibitors of glucose-6-phosphate transport. In summary, we have demonstrated a metabolic interconnection between pentose pathway and 11 beta-HSD1 oxo-reductase activities that is dependent on cytosolic NADPH production. These observations link cytosolic carbohydrate flux with paracrine glucocorticoid formation. The clinical relevance of these findings may be germane to the regulation of paracrine glucocorticoid formation in disturbed nutritional states such as obesity.