Congenital hyperinsulinism:Role of fluorine-18L-3, 4 hydroxyphenylalanine positron emission tomography scanning

Congenital hyperinsulinism(CHI) is a rare but complex heterogeneous disorder caused by unregulated secre-tion of insulin from the β-cells of the pancreas leading to severe hypoglycaemia and neuroglycopaenia. Swift diagnosis and institution of appropriate management is crucial to prevent or minimise adverse neurodevel-opmental outcome in children with CHI. Histologically there are two major subtypes of CHI, diffuse and focal disease and the management approach will significantly differ depending on the type of the lesion. Patients with medically unresponsive diffuse disease require a near total pancreatectomy, which then leads on to the de-velopment of iatrogenic diabetes mellitus and pancre-atic exocrine insufficiency. However patients with focaldisease only require a limited pancreatectomy to re-move only the focal lesion thus providing complete cure to the patient. Hence the preoperative differentiation of the histological subtypes of CHI becomes paramount in the management of CHI. Fluorine-18L-3, 4-hydroxy-phenylalanine positron emission tomography(18F-DOPA-PET) is now the gold standard for pre-operative differentiation of focal from diffuse disease and locali-sation of the focal lesion. The aim of this review article is to give a clinical overview of CHI, then review the role of dopamine in β-cell physiology and finally discuss the role of 18F-DOPA-PET imaging in the management of CHI.

Neonatal hyperinsulinism with an ABCC8 mutation:A case report

BACKGROUND Neonatal hyperinsulinism can result from perinatal stress,genetic disorders,or syndromes,which can lead to persistent or intractable hypoglycemia in newborns.Mutations in the ABCC8 gene result in abnormal functioning of potassium channel proteins in pancreaticβ-cells,leading to an overproduction of insulin and congenital hyperinsulinemia.CASE SUMMARY We report a case of a high-birth-weight infant with postnatal hypoglycemia and hyperinsulinemia,whose mother had pregestational diabetes mellitus with poor glycemic control and whose sister had a similar history at birth.Whole-exome sequencing revealed a new mutation in the ABCC8 gene in exon 8(c.1257T>G),which also occurred in his sister and mother;thus,the patient was diagnosed with neonatal hyperinsulinism with an ABCC8 mutation.With oral diazoxide treatment,the child’s blood glucose returned to normal,and the pediatrician gradually discontinued treatment because of the child’s good growth and development.CONCLUSION We report a new mutation locus in the ABCC8 gene.This mutation locus warrants attention for genetic disorders and long-term prognoses of hypoglycemic children.

Efficacy and safety of octreotide treatment for diazoxide-unresponsive congenital hyperinsulinism in China

Importance: Octreotide is an off-label medicine for congenital hyperinsulinism (CHI), but is currently widely used for treatment of patients with CHI. Thus far, variable efficacy and adverse effects have been reported for octreotide.Objective: The present study evaluated the efficacy and safety of a subcutaneous octreotide injection for treatment of diazoxide-unresponsive CHI in China.Methods: This study was a retrospective review of children with diazoxide-unresponsive CHI who were treated with a subcutaneous octreotide injection. The efficacy and side effects of the treatment were assessed.Results: Twenty-five Chinese children (15 boys) were involved in the study. Their median age at diagnosis was 8 weeks (range, 1-24 weeks) and median age at the final follow-up was 1.8 years (range, 0.3-3.3 years). Octreotide therapy effectively increased blood glucose levels in all patients. The intravenous glucose infusion rate was reduced in all patients. Twenty-one patients gradually discontinued the intravenous glucose infusion while receiving octreotide combined with frequent carbohydrate/glucose-rich feeding. Among patients with a monoallelic ATP-sensitive potassium (KATP) channel mutation, 50.0% showed gradual remission during follow up, indicating that the octreotide treatment may be a feasible alternative to surgery, especially for patients with monoallelic KATP-channel mutations. Transient elevation of liver enzymes occurred in 20.0% of patients, while asymptomatic gallbladder pathology occurred in one patient. The growth rates of these patients were normal (height standard deviation score was 0.3 ± 1.5 at the final follow-up).Interpretation: Octreotide was a well-tolerated, effective therapy for most children with diazoxide-unresponsive CHI.

Molecular mechanisms of protein induced hyperinsulinaemic hypoglycaemia

The interplay between glucose metabolism and that of the two other primary nutrient classes, amino acids and fatty acids is critical for regulated insulin secretion. Mitochondrial metabolism of glucose, amino acid and fatty acids generates metabolic coupling factors(such as ATP, NADPH, glutamate, long chain acyl-CoA and diacylglycerol) which trigger insulin secretion. The observation of protein induced hypoglycaemia in patients with mutations in GLUD1 gene, encoding the enzyme glutamate dehydrogenase(GDH) and HADH gene, encoding for the enzyme short-chain 3-hydroxyacyl-CoA dehydrogenase has provided new mechanistic insights into the regulation of insulin secretion by amino acid and fatty acid metabolism. Metabolic signals arising from amino acid and fatty acid metabolism converge on the enzyme GDH which integrates both signals from both pathways and controls insulin secretion. Hence GDH seems to play a pivotal role in regulating both amino acid and fatty acid metabolism.

Concomitant dysregulation of androgen secretion and dysfunction of adipose tissue induced insulin resistance

Hyperandrogenism and hyperinsulinemia have resulted from dysfunction of the theca cell of the ovary and adipose tissue and each one potentiates the other in patients with androgen excess disorders e.g.,polycystic ovary disease and idiopathic hirsutism.Possible external and/or internal triggers can produce such cellular dysfunction.There is evidence that sodium valproate acts as a trigger of cellular dysfunction and produces both hyperinsulinemia and hyperandrogenism.Therefore,the elimination of these triggers can help the patients to recover from hyperinsulinemia,insulin resistance and hyperandrogenism.

Endocrine and metabolic effects of metformin in combination with compound cyproterone acetate in women with polycystic ovarian syndrome

Objective:To study the endocrinologic and metabolic effects of metformin in combi-nation with compound cyproterone acetate (CPA) on patients with polycystic ovariansyndrome (PCOS).Methods: A prospective study involved total 65 patients, 45 PCOS patients as group Aand 20 non-PCOS infertility patients as control (group B). Complete baseline work-up inclu-ding body mass index (BMI), waist/hip ratio(WHR), Ferriman-Gallwey score(FGS), gona-dotrophin, testosterone(T), sex hormone-binding globulin (SHBG), dehydroepiandrosteronesulfate (DHEAS), and fasting lipid, glucose (FG) , insulin (FI) and oral glucose tolerancetest (OGTT), were performed in all patients. Patients in group A were treated with CPA a-lone (group A1), metformin alone (group A2) or combination of CPA with metformin (groupA3) , respectively by randomizatior. At the end of the 12-week therapy, subjects were re-evaluated and above parameters were measured.Results: Women in group A had significant increases in BMI, WHR, FGS, LH, T,FI, insulin resistance (IR), triglycerides(TG), and significant decrease in HDL-C com-paring with the control group (P＜0.01). No significant difference among A1, A2 andA3 were found at baseline. LH, T, FT (free testosterone) were significant decreasedfrom (13.9±5.9)IU/L, (2. 1±0. 8)nmol/L and (2.8±2.3)nmol/L respectively to(5.8±2.2)IU/L, (1.2±0. 4)nmol/L and (0. 8±0.5)nmol/L respectively and SHBGwas significant increased from (99 ± 42) nmol/L to (187±64)nmol/L in group A3,when compared with LH,T and FT from (13.8±7.6)IU/L, (2.2±1.1) nmol/L and(2. 5±1.9) nmol/L respectively to (11.8±6.5)IU/L, (1.8±0.8) nmol/L and (1.7±1.0) nmol/L respectively and SHBG from (99±40) nmol/L to (120±51) nmol/L ingroup A2 (P＜0.05,P＜0. 001). HDL-C was significant increased from (1.5±0.3)mmol/L to (1.8±0.3) mmol/L in group A3 comparing with HDL-C from (1.5±0.4)mmol/L to (1.6±0.4) mmol/L in groupA1(P＜0.001).Conclusions: The PCOS patients treated with metformin in combination with compoundcyproterone acetate may be more effective in inhibiting hyperandrogen and hypersecretion ofLH than metfrornin alone and more obvious in improving lipid profiles than CPA alone.

Age-dependent changes in the exocytotic efficacy in Kir6.2 ablated mouse pancreatic β-cells

In this study, we aimed to examine the electrophysio- logical properties of β-cells in Kir6.2-/- mice using fresh pancreatic tissue slice preparation. This prepa-ration is advantageous since it preserves socio-cellular context of the β-cells. Using this novel approach we revisited basic morphology and used whole-cell patch-clamp to study electrical excitability as well as to assess the modulation of the late steps of the exocy-totic activity of β-cells by cytosolic [Ca2+] changes in control and Kir6.2-/- mice. We found that young Kir6.2-/- mice (2 - 4 weeks old) were hypoglycaemic while aged Kir6.2-/- mice (5 - 60 weeks old) were normo- or even hyper- glycaemic. Membrane ca-pacitance measurements show- ed more efficient Ca2+-secretion coupling in young Kir6.2-/- mice, but this coupling is significantly reduced in older Kir6.2-/- mice. We have found increased exo- cytotic efficacy induced by repetitive trains of depo- larization pulses which may result from higher cyto- solic [Ca2+] due to hyperexcitability in Kir6.2-/- mice. This condition in turn resulted in the reduced β-cell number and func-tion in the following weeks. Detailed assessment of the efficacy of Ca2+ dependent exocyto- sis in β-cell from Kir6.2-/- mice may contribute to our understanding of the pathophysiology of persistent hyperinsulinemia hypoglycemia of infancy (PHHI) and suggest potential alternative therapeutic approaches for PHHI patients.