Permanent neonatal diabetes by a new mutation in KCNJ11: unsuccessful switch to sulfonylurea

Lau, Eva; Correia, Cecília; Freitas, Paula; Nogueira, Cláudia; Costa, Mário J.; Saavedra, Ana; Costa, Carla; Carvalho, Davide; Fontoura, Manuel

doi:10.1590/2359-3997000000076

Cited by 8 publications

(6 citation statements)

References 13 publications

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“…Age and prolonged poor glycemic control seem to be important predictors of responsiveness to sulphonylureas in neonatal diabetic patients. Effective transfer is less likely in elderly patients with poor glycemic control ( 64 - 66 ). Because insulin therapy does not improve the neurological symptoms of DEND syndrome, an early-stage diagnosis is critical, as it enables sulphonylurea therapy to be initiated as quickly as possible.…”

Section: Implications For Therapymentioning

confidence: 99%

K<sub>ATP</sub> Channel Mutations and Neonatal Diabetes

Shimomura

Maejima

2017

Intern. Med.

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Since the discovery of the KATP channel in 1983, numerous studies have revealed its physiological functions. The KATP channel is expressed in various organs, including the pancreas, brain and skeletal muscles. It functions as a “metabolic sensor” that converts the metabolic status to electrical activity. In pancreatic beta-cells, the KATP channel regulates the secretion of insulin by sensing a change in the blood glucose level and thus maintains glucose homeostasis. In 2004, heterozygous gain-of-function mutations in the KCNJ11 gene, which encodes the Kir6.2 subunit of the KATP channel, were found to cause neonatal diabetes. In some mutations, diabetes is accompanied by severe neurological symptoms [developmental delay, epilepsy, neonatal diabetes (DEND) syndrome]. This review focuses on mutations of Kir6.2, the pore-forming subunit and sulfonylurea receptor (SUR) 1, the regulatory subunit of the KATP channel, which cause neonatal diabetes/DEND syndrome and also discusses the findings of the pathological mechanisms that are associated with neonatal diabetes, and its neurological features.

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Section: Implications For Therapymentioning

confidence: 99%

K<sub>ATP</sub> Channel Mutations and Neonatal Diabetes

Shimomura

Maejima

2017

Intern. Med.

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“…The G334V mutation has been described in one previous case, a male, in whom complete transfer was also attempted, around 20 years post diagnosis [8]. Despite a rise in C-peptide concentration, insulin had to be recommenced after a 5-day trial of glibenclamide.…”

Section: Discussionmentioning

confidence: 92%

“…In those who have been unable to transfer completely to sulfonylureas, variable practice is observed with some reverting to insulin monotherapy, and others remaining on a combination of sulfonylureas and insulin or other agents [6][7][8]. The clinical benefits of remaining on combined insulin and sulfonylurea therapy have not been fully explored.…”

Section: Accepted Articlementioning

confidence: 99%

Permanent neonatal diabetes: combining sulfonylureas with insulin may be an effective treatment

et al. 2018

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What's new?• KCNJ11 mutations causing permanent neonatal diabetes are treated with sulfonylureas, but not all individuals are able to transfer completely from insulin to sulfonylureas.• Our data highlight that combining sulfonylurea treatment with insulin in those who are unable to fully transfer may still lead to clinically meaningful outcomes.• We demonstrate improvements in endogenous insulin production, HbA 1c , glycaemic variability and hypoglycaemia awareness.• These changes were not observed at initial doses of glibenclamide and improvements required higher sustained doses of glibenclamide.• Combining insulin and sulfonylureas should be considered in those with permanent neonatal diabetes who are not able to transfer to sulfonylurea therapy alone. AbstractBackground Permanent neonatal diabetes caused by mutations in the KCNJ11 gene may be

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“…Since patients with KCNJ11 mutations have KATP channels with decreased sensitivity to ATP inhibition, sulfonylureas, which close KATP channels by an ATP-independent mechanism thereby causing insulin secretion, are an excellent therapy for KATP mutations (8). There is 1 case report of a 20-yearold with a KCNJ11 mutation who developed diabetes at 3 months of age who was switched from insulin to glibenclamide and struggled with "rapid interchange between hypoglycemia and hyperglycemia," but hypoglycemia has not been a common reason for treatment failure (9). In their large trial of patients with KCNJ11 mutations, Pearson et al (8) found that 10% of patients failed transition from insulin to sulfonylureas but none had hypoglycemia.…”

Section: Discussionmentioning

confidence: 99%

KCNJ11 Mutation in One Family is Associated with Adult-Onset Rather than Neonatal-Onset Diabetes Mellitus

Breidbart

Golden

Gonzaga‐Jauregui

et al. 2018

AACE Clinical Case Reports

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Objective: To present a case of adult-onset familial diabetes mellitus in which a genetic etiology typical for neonatal diabetes was identified. Methods: We conducted whole-exome and Sanger sequencing, assessed clinical presentation and family history, and performed a literature review. Results: A 40-year-old, thin woman presented with a 10-year history of mildly elevated fasting glucose and A1C levels. Her mother had diabetes mellitus since her 40s and is on insulin, and her daughter presented with diabetes mellitus at age 21. The patient and her daughter underwent whole-exome sequencing and were found to have a mutation in the KCNJ11 gene, c.G685A, p.E229K. This mutation is known to be associated with neonatal presentation of diabetes mellitus, which neither of these family members had a history of. Given her known mutation and postpran-dial hyperglycemia, a trial of low-dose sulfonylurea was initiated in the daughter but failed due to hypoglycemia. She was found to have a CYP2C9 genotype associated with poor oral drug clearance. Conclusion: KCNJ11 mutation should be screened for in patients and families meeting criteria for maturity-onset diabetes of the young, even without evidence of neonatal onset in the family. Furthermore, even though sulfonylurea therapy is successful in the majority of patients with KCNJ11 mutations, there may be a role for other interacting environmental or genetic modifiers, such as CYP2C9 genotype, that affect sulfonylurea metabolism. Those patients who have delayed onset of disease and milder courses may be less ideal candidates for this treatment. (AACE Clinical Case Rep. 2018;4:e411-e414) Abbreviations: BMI = body mass index; KATP = ATP-sensitive potassium channel; MODY = maturity-onset diabetes of the young; NDM = neonatal diabetes mellitus

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Permanent neonatal diabetes by a new mutation in KCNJ11: unsuccessful switch to sulfonylurea

Cited by 8 publications

References 13 publications

K<sub>ATP</sub> Channel Mutations and Neonatal Diabetes

K<sub>ATP</sub> Channel Mutations and Neonatal Diabetes

Permanent neonatal diabetes: combining sulfonylureas with insulin may be an effective treatment

KCNJ11 Mutation in One Family is Associated with Adult-Onset Rather than Neonatal-Onset Diabetes Mellitus

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