Chromosome 6q24-related transient neonatal diabetes (6q24-TND) is a rare form of diabetes caused by an overexpression of PLAGL1 and HYMAI (1). After remitting in infancy, diabetes recurs in most patients later in life. While the best treatment remains unknown, many patients are managed with insulin (1). We sought to characterize β-cell function and glucose homeostasis in patients with 6q24-TND and assess their response to sulfonylurea (SU) therapy.

Adults with 6q24-TND and recurrence of hyperglycemia requiring insulin therapy later in life were identified through The University of Chicago Monogenic Diabetes Registry (http://monogenicdiabetes.uchicago.edu/registry) and invited to participate in a trial of SU therapy. Four patients with insulin doses of 0.41–0.76 units/kg/day attempted the trial. Three were available for a mixed-meal test (MMT) and arginine stimulation test (AST) on day one and day five of SU treatment. All insulin products were withheld on the morning of day one. Subjects ingested 7 mL/kg (maximal 360 mL) of BOOST High Protein (http://www.boost.com) within 5 min. Glucose and C-peptide were obtained at 0, 5, 10, 15, 20, 30, 40, 50, 60, 75, 90, 120, 150, and 180 min. At 185 min, 5 g of arginine hydrochloride was infused over 30 s, with samples collected at 184, 187, 188, 189, 190, 192, and 195 min. Glyburide was then initiated and increased daily, while insulin was steadily withdrawn as tolerated to maintain euglycemia using a modified published protocol used for those with mutations affecting the ATP-sensitive potassium channel (2).

Subjects were discharged on glyburide monotherapy with supplemental insulin only if required. Additional oral agents were subsequently added if needed to achieve complete insulin independence. Repeated-measures ANOVA was used to identify differences in metabolic variables between treatment conditions. When comparing MMT and AST before SU with those after a 5-day course of SU, there was no difference in the serum glucose, but C-peptide values were significantly higher in subjects following a course of SU (P < 0.05) (Table 1).

Table 1

Subjects’ clinical details

UC90AUC153AUC277AUC702A
Genetic defect UPD6 UPD6 UPD6 UPD6 
Sex Female Male Female Female 
Gestational age (weeks) 33 34 40 38 
Birth weight (g) 1,280 2,470 2,240 1,810 
Age at initial diabetes diagnosis (days) 
Age at diabetes remission (months) 
Age at diabetes recurrence (years) 13 12 27 12 
Age at cessation of insulin (years) 20 23 29 28 
BMI at cessation of insulin (kg/m226.28 31.38 21.66 29.44 
Insulin dose at transition (units/kg) 0.59 0.73 0.41 0.76 
MMT C-peptide AUC (nmol/L)     
 Day 1 83.1 87.9 188.5 — 
 Day 5 128.9 141.6 307.4 — 
AST C-peptide AUC (nmol/L)     
 Day 1 8.1 6.1 12.2 — 
 Day 5 9.6 9.8 23.4 — 
Medications at reassessment     
 Glyburide (mg/kg) 0.59 0.53 0.13 0.23 
 Sitagliptin (mg) 100 100 — — 
 Metformin (g) — 1.5 
HbA1c at cessation of insulin (%) 8.2 7.8 7.2 9.9 
HbA1c at reassessment (%) 7.1 6.6 7.3 7.5 
 Months off insulin therapy 17 
UC90AUC153AUC277AUC702A
Genetic defect UPD6 UPD6 UPD6 UPD6 
Sex Female Male Female Female 
Gestational age (weeks) 33 34 40 38 
Birth weight (g) 1,280 2,470 2,240 1,810 
Age at initial diabetes diagnosis (days) 
Age at diabetes remission (months) 
Age at diabetes recurrence (years) 13 12 27 12 
Age at cessation of insulin (years) 20 23 29 28 
BMI at cessation of insulin (kg/m226.28 31.38 21.66 29.44 
Insulin dose at transition (units/kg) 0.59 0.73 0.41 0.76 
MMT C-peptide AUC (nmol/L)     
 Day 1 83.1 87.9 188.5 — 
 Day 5 128.9 141.6 307.4 — 
AST C-peptide AUC (nmol/L)     
 Day 1 8.1 6.1 12.2 — 
 Day 5 9.6 9.8 23.4 — 
Medications at reassessment     
 Glyburide (mg/kg) 0.59 0.53 0.13 0.23 
 Sitagliptin (mg) 100 100 — — 
 Metformin (g) — 1.5 
HbA1c at cessation of insulin (%) 8.2 7.8 7.2 9.9 
HbA1c at reassessment (%) 7.1 6.6 7.3 7.5 
 Months off insulin therapy 17 

AUC, area under the curve (calculated by trapezoidal rule); UPD6, uniparental disomy of chromosome 6.

All four subjects remained on SU and off insulin therapy with good glycemic control at reevaluation at least 5 months after transition. One subject also required metformin, while two subjects required a combination of metformin and sitagliptin (Table 1).

SU therapy has been used safely and effectively in other forms of diabetes for decades (e.g., type 2, KCNJ11, and HNF1A diabetes). SU therapy in type 2 diabetes has raised concerns in terms of hastening of β-cell failure (3); however, our data and other reports (4,5) would suggest that insulin therapy may not be required for many years after relapse of diabetes in these patients. We, for the first time, demonstrate that insulin secretion in subjects with 6q24-TND improves in response to SU and provide further evidence that noninsulin-based therapies should be considered for the treatment of 6q24-TND.

Any history of neonatal hyperglycemia is important to note when assessing patients with diabetes as it may suggest an underlying genetic cause and can have a significant impact on clinical management and therapeutic strategies.

Acknowledgments. The authors thank Jacqueline Imperial and other members of the staff of the Clinical Research Center at The University of Chicago for expert care of the subjects who participated in these studies. The authors thank Kristen Wroblewski (Department of Health Studies, The University of Chicago) for providing statistical support and are grateful to all of the patients and families who participated in these studies.

Funding. This work was supported by National Institutes of Health grants from the National Institute of Diabetes and Digestive and Kidney Diseaseshttp://dx.doi.org/10.13039/100000062 for The University of Chicago Diabetes Research and Training Center (DK020595) and for a K23 Award (DK094866, to S.A.W.G.), the National Center for Advancing Translational Sciences (UL1TR000430), the American Diabetes Associationhttp://dx.doi.org/10.13039/100000041 (1-11-CT-41), and gifts from the Kovler Family Foundation and Lewis-Sebring Foundation. D.J.G.M. and I.K.T. are supported by Diabetes UK for research into 6q24-TND.

Duality of Interest. No potential conflicts of interest relevant to this article were reported.

Author Contributions. D.C. drafted the initial manuscript, coordinated and supervised data collection, analyzed data, and interpreted results. F.A.B., C.D.B., and J.L.H. assisted in writing the manuscript, helped with data analysis, coordinated and supervised data collection, and interpreted results. J.T.D. and N.A.D. coordinated data collection. D.J.G.M. and I.K.T. carried out the genetic analysis analyses and interpretation of results. L.R.H., R.N.N., and L.H.P. helped with the study design and interpretation of results. S.A.W.G. wrote the manuscript, conceptualized and designed the study, coordinated and supervised data collection, provided support and funding, and supervised the study. All authors reviewed and revised the manuscript and approved the final manuscript as submitted. S.A.W.G. 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.

1.
Temple
IK
,
Shield
JPH
.
6q24 transient neonatal diabetes
.
Rev Endocr Metab Disord
2010
;
11
:
199
204
2.
Pearson
ER
,
Flechtner
I
,
Njølstad
PR
, et al.;
Neonatal Diabetes International Collaborative Group
.
Switching from insulin to oral sulfonylureas in patients with diabetes due to Kir6.2 mutations
.
N Engl J Med
2006
;
355
:
467
477
3.
Kahn
SE
,
Haffner
SM
,
Heise
MA
, et al.;
ADOPT Study Group
.
Glycemic durability of rosiglitazone, metformin, or glyburide monotherapy
.
N Engl J Med
2006
;
355
:
2427
2443
4.
Søvik
O
,
Aagenaes
O
,
Eide
, et al
.
Familial occurrence of neonatal diabetes with duplications in chromosome 6q24: treatment with sulfonylurea and 40-yr follow-up
.
Pediatr Diabetes
2012
;
13
:
155
162
5.
Yorifuji
T
,
Hashimoto
Y
,
Kawakita
R
, et al
.
Relapsing 6q24-related transient neonatal diabetes mellitus successfully treated with a dipeptidyl peptidase-4 inhibitor: a case report
.
Pediatr Diabetes
2014
;
15
:
606
610