The Role of ATP Sensitive Channels in Insulin Secretion and The Implications in Persistent Hyperinsulinemic Hypoglycaemia of Infancy (PHHI)

Shah, Janaki; Maguire, David; Brown, David; Cotterill, Andrew

doi:10.1007/978-0-387-71764-7_18

Cited by 6 publications

(3 citation statements)

References 24 publications

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“…Mutation testing of ABCC8/KCNJ11 is now possible with a rapid turnaround time of !10 days; therefore, rapid genetic analysis of the K ATP channel genes has the potential to be important for several aspects of CHI therapy, from genetic counselling to the differential diagnosis of focal and diffuse disease and the likelihood of remission (3,6,8). The profiles of K ATP channel gene mutations have been reported in some cohorts, especially in relation to medical and surgical treatment (9)(10)(11)(12), but the utility of rapid genetic analysis on the clinical outcomes at follow-up in children with CHI remains to be defined. There is a need to understand the relevance of rapid K ATP channel gene mutation analysis at diagnosis and whether they inform the probability of various clinical outcomes in children with CHI.…”

Section: Introductionmentioning

confidence: 99%

The contribution of rapid KATP channel gene mutation analysis to the clinical management of children with congenital hyperinsulinism

Banerjee

Skae

Flanagan

et al. 2011

European Journal of Endocrinology

100

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Objective: In children with congenital hyperinsulinism (CHI), K ATP channel genes (ABCC8 and KCNJ11) can be screened rapidly for potential pathogenic mutations. We aimed to assess the contribution of rapid genetic testing to the clinical management of CHI. Design: Follow-up observational study at two CHI referral hospitals. Methods: Clinical outcomes such as subtotal pancreatectomy, 18 F-Dopa positron emission tomography-computed tomography (PET-CT) scanning, stability on medical treatment and remission were assessed in a cohort of 101 children with CHI. Results: In total, 32 (32%) children had pathogenic mutations in K ATP channel genes (27 in ABCC8 and five in KCNJ11), of which 11 (34%) were novel. In those negative at initial screening, other mutations (GLUD1, GCK, and HNF4A) were identified in three children. Those with homozygous/compound heterozygous ABCC8/KCNJ11 mutations were more likely to require a subtotal pancreatectomy CHI (7/10, 70%). Those with paternal heterozygous mutations were investigated with 18 F-Dopa PET-CT scanning and 7/13 (54%) had a focal lesionectomy, whereas four (31%) required subtotal pancreatectomy for diffuse CHI. Those with maternal heterozygous mutations were most likely to achieve remission (5/5, 100%). In 66 with no identified mutation, 43 (65%) achieved remission, 22 (33%) were stable on medical treatment and only one child required a subtotal pancreatectomy. Conclusions: Rapid genetic analysis is important in the management pathway of CHI; it provides aetiological confirmation of the diagnosis, indicates the likely need for a subtotal pancreatectomy and identifies those who require 18 F-Dopa PET-CT scanning. In the absence of a mutation, reassurance of a favourable outcome can be given early in the course of CHI.

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Section: Introductionmentioning

confidence: 99%

The contribution of rapid KATP channel gene mutation analysis to the clinical management of children with congenital hyperinsulinism

Banerjee

Skae

Flanagan

et al. 2011

European Journal of Endocrinology

100

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“…Rarer forms of CHI have been described as caused by defects in HADH (encoding short-chain L-3-hydroxyacyl-CoA dehydrogenase), GLUD1 (encoding glutamate dehydrogenase), GCK (encoding glucokinase), HNF4A (encoding hepatocyte nuclear factor 4 α ), HNF1A (encoding hepatocyte nuclear factor 1 α ), SLC16A1 (encoding monocarboxylate transporter, MCT1), UCP2 (encoding mitochondrial uncoupling protein 2), HK1 (hexokinase 1), PGM1 (phosphoglucomutase 1), and CACNA1D ( l -type calcium channel α -subunit) ( 1–7 ). However, there remains a high proportion of patients with persistent CHI [ e.g., >60% of CHI patients in Australia ( 8 ) and China ( 9 ) who have an unknown genetic cause of disease]. Among this cohort are patients with CHI who have been designated with atypical disease (CHI-A) ( 10, 11 ).…”

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confidence: 99%

Atypical Forms of Congenital Hyperinsulinism in Infancy Are Associated With Mosaic Patterns of Immature Islet Cells

Han

Mohamed

Estebanez

et al. 2017

The Journal of Clinical Endocrinology &Amp; Metabolism

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Objectives:We aimed to characterize mosaic populations of pancreatic islet cells from patients with atypical congenital hyperinsulinism in infancy (CHI-A) and the expression profile of NKX2.2, a key transcription factor expressed in β-cells but suppressed in δ-cells in the mature pancreas.Patients/Methods:Tissue was isolated from three patients with CHI-A following subtotal pancreatectomy. CHI-A was diagnosed on the basis of islet mosaicism and the absence of histopathological hallmarks of focal and diffuse CHI (CHI-D). Immunohistochemistry was used to identify and quantify the proportions of insulin-secreting β-cells and somatostatin-secreting δ-cells in atypical islets, and results were compared with CHI-D (n = 3) and age-matched control tissues (n = 3).Results:In CHI-A tissue, islets had a heterogeneous profile. In resting/quiescent islets, identified by a condensed cytoplasm and nuclear crowding, β-cells were reduced to <50% of the total cell numbers in n = 65/70 islets, whereas δ-cell numbers were increased with 85% of islets (n = 49/57) containing >20% δ-cells. In comparison, all islets in control tissue (n = 72) and 99% of CHI-D islets (n = 72) were composed of >50% β-cells, and >20% δ-cells were found only in 12% of CHI-D (n = 8/66) and 5% of control islets (n = 3/60). Active islets in CHI-A tissue contained proportions of β-cells and δ-cells similar to those of control and CHI-D islets. Finally, when compared with active islets, quiescent islets had a twofold higher prevalence of somatostatin/NKX2.2+ coexpressed cells.Conclusions:Marked increases in NKX2.2 expression combined with increased numbers of δ-cells strongly imply that an immature δ-cell profile contributed to the pathobiology of CHI-A.

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“… 1-3 The hypoglycemia can be unresponsive to diazoxide, somatostatin analogues, and other medications, necessitating partial or near-total pancreatectomy. 1‐3 Defects in several genes are identifiable causes of CHI, 4‐6 but for many cohorts of patients with persistent disease, the genetic basis of disease is unknown, 7‐11 ranging from 18% in Saudi Arabia 12 to greater than 60% in Australia 13 and China. 14 The most common origins of drug-unresponsive disease are due to inactivating mutations in either the ABCC8 or KCNJ11 genes.…”

mentioning

confidence: 99%

Enhanced Islet Cell Nucleomegaly Defines Diffuse Congenital Hyperinsulinism in Infancy but Not Other Forms of the Disease

Han

Newbould²,

Batra³

et al. 2016

Am J Clin Pathol

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Objectives: To quantify islet cell nucleomegaly in controls and tissues obtained from patients with congenital hyperinsulinism in infancy (CHI) and to examine the association of nucleomegaly with proliferation.Methods: High-content analysis of histologic sections and serial block-face scanning electron microscopy were used to quantify nucleomegaly.Results: Enlarged islet cell nuclear areas were 4.3-fold larger than unaffected nuclei, and the mean nuclear volume increased to approximately threefold. Nucleomegaly was a normal feature of pediatric islets and detected in the normal regions of the pancreas from patients with focal CHI. The incidence of nucleomegaly was highest in diffuse CHI (CHI-D), with more than 45% of islets containing two or more affected cells. While in CHI-D nucleomegaly was negatively correlated with cell proliferation, in all other cases, there was a positive correlation.Conclusions: Increased incidence of nucleomegaly is pathognomonic for CHI-D, but these cells are nonproliferative, suggesting a novel role in the pathobiology of this condition.

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The Role of ATP Sensitive Channels in Insulin Secretion and The Implications in Persistent Hyperinsulinemic Hypoglycaemia of Infancy (PHHI)

Cited by 6 publications

References 24 publications

The contribution of rapid KATP channel gene mutation analysis to the clinical management of children with congenital hyperinsulinism

The contribution of rapid KATP channel gene mutation analysis to the clinical management of children with congenital hyperinsulinism

Atypical Forms of Congenital Hyperinsulinism in Infancy Are Associated With Mosaic Patterns of Immature Islet Cells

Enhanced Islet Cell Nucleomegaly Defines Diffuse Congenital Hyperinsulinism in Infancy but Not Other Forms of the Disease

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