Neonatal diabetes is defined as diabetes that develops in the first 6 months of life. It is highly associated with monogenic etiology. ATP-sensitive potassium (KATP) channels in the β-cell of the pancreas modulate insulin secretion and blood glucose homeostasis. KCNJ11 codes for the Kir6.2 subunit of the KATP channel. Heterozygous activating mutations in this gene are the most common cause of permanent neonatal diabetes (1). Sulfonylurea (SU) therapy often results in long-term optimal glycemic control in this cohort (2).

We report the case of a 32-year-old woman who presented at 4 weeks old with dehydration, hyperglycemia, ketonuria, and acidosis. She was later diagnosed with a KCNJ11 mutation (R201H, c.601C>A). She commenced insulin treatment at diagnosis of diabetes and continued this throughout early childhood. At age 16 years, she was hospitalized to facilitate transition from insulin at a total daily dose of 36 units (24 units isophane insulin and 11–13 units insulin aspart) to glibenclamide therapy dose of 0.5 mg/kg/day. Despite titration of glibenclamide to 1 mg/kg/day, problematic postprandial hyperglycemia warranted insulin therapy. SU treatment was not continued, and she returned to exclusive insulin treatment at age 18 due to suboptimal glycemic control, large glibenclamide dose requirements, and patient preference. She has a history of background retinopathy diagnosed at age 19 years without other end-organ complications.

We previously reported her successful transfer to SU agents on a second attempt at age 24 with resultant optimization of glycemic control (HbA1c 6.2%, 44 mmol/mol), improved quality of life, and reduced hypoglycemia burden (3). She switched from a daily dose of 50 units insulin to a glibenclamide dose of 0.44 mg/kg/day.

After 7 years of SU therapy, glibenclamide dose requirements increased to 40 mg twice daily (1.3 mg/kg/day) and HbA1c was 8.6% (71 mmol/mol). Nonfasting lipid profile included total cholesterol 5.1 mmol/L, LDL 2.9 mmol/L, and triglycerides 1.18 mmol/L. Prandial insulin aspart 4 units was reintroduced at age 30. HbA1c remained 8.4% (68 mmol/mol). This was in the context of a busy job with shift work and stable weight with a negligible 0.6-kg weight increase over the duration of SU treatment. Liraglutide was commenced at age 31, and the initial dose of 0.3 mg daily was increased to 0.6 mg. Glibenclamide was concurrently reduced to 45 mg/day or 0.7 mg/kg/day due to nocturnal hypoglycemia. Reduced prandial insulin doses of 2 units were required intermittently, and weight remained stable, as shown in Fig. 1A. She switched to semaglutide 0.25 mg uptitrated to 0.5 mg for convenient weekly administration, and insulin therapy was discontinued. Nocturnal hypoglycemia postexertion required further dose reduction of glibenclamide to 35 mg/day (0.6 mg/kg/day). Continuous glucose monitoring (CGM) data (Fig. 1B) for 14 days before and after show reduced postprandial glucose excursion. C-peptide postprandially was 641 pmol/L on glibenclamide monotherapy and 715 pmol/L following addition of semaglutide. HbA1c reduced from 8.4% (68 mmol/mol) to 6.2% (44 mmol/mol) at 6 months and 6.5% (47 mmol/mol) at 12 months of follow-up, as shown in Fig. 1. Her weight has reduced from 64.2 kg to 58 kg and BMI from 26.7 kg/m2 to 24.2 kg/m2 following more than 1 year of treatment. Nonfasting lipids improved; total cholesterol is 4.1 mmol/L, LDL 2.4 mmol/L, and triglycerides 0.49 mmol/L. Given limited clinical experience of glucagon-like peptide 1 receptor agonist (GLP-1RA) in KCNJ11 diabetes, a GLP-1RA at a lower initial dose and with shorter half-life was chosen. HbA1c was reduced with low-dose therapy; however, withdrawal of prandial insulin and weight reduction were only seen with semaglutide at relatively higher dose.

Figure 1

HbA1c and weight changes and CGM profiles for a young adult with permanent neonatal diabetes. A: HbA1c and weight changes following GLP-1RA introduction. B: CGM profiles for 14 days prior to (i) and after (ii) GLP-1RA introduction.

Figure 1

HbA1c and weight changes and CGM profiles for a young adult with permanent neonatal diabetes. A: HbA1c and weight changes following GLP-1RA introduction. B: CGM profiles for 14 days prior to (i) and after (ii) GLP-1RA introduction.

Close modal

SU agents work downstream of the SUR receptor and activate the KATP channel through a route independent of ATP to stimulate insulin release. The therapeutic efficacy of SU has been shown in a long-term follow-up clinical trial (4). At 10 years of follow-up, 7% of patients in a cohort required additional therapy with insulin, although most of these patients were peripubertal or had suboptimal compliance with SU.

GLP-1RAs bypass the SU receptor in triggering insulin release. The insulinotropic effects of GLP-1RAs are dependent on cAMP; sufficient levels of cAMP are only achieved in Kir 6.2 diabetes with SU agents (2). Glucose-dependent insulin release results in improved glycemic control and is particularly effective in reducing postprandial hyperglycemia. One previous case report has described successful use of combined SU and GLP-1RA therapy in KCNJ11 diabetes (5). Concomitant GLP-1RA treatment appears to augment the glucose lowering effect of SU in individuals with KCNJ11 R201H mutation. The efficacy of GLP-1RA in KCNJ11 neonatal diabetes is dependent on coadministration with SU due to the inherent pathophysiology.

Duality of Interest. M.M.B. sat on an advisory board for and has received a speaker honorarium from Novo Nordisk, and she has received an institutional research grant and support for attending international conferences from Novo Nordisk. No other potential conflicts of interest relevant to this article were reported.

Author Contributions. M.T.C. and M.M.B. researched the background and wrote the first draft of the manuscript. A.T.H. researched the background and reviewed and edited the manuscript. S.R. was involved in conception and review of the manuscript. H.O.’S. is a nurse specialist involved in the patient’s care who reviewed and edited the manuscript. M.M.B. is the guarantor of this work and, as such, had full access to all the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis.

Prior Presentation. An abstract describing this case was presented at the Joint Irish-UK Endocrine Meeting, Belfast, Ireland, 14–15 October 2024.

Handling Editors. The journal editors responsible for overseeing the review of the manuscript were John B. Buse and Kristina M. Utzschneider.

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