Monogenic diabetes (DM) with beta-cell dysfunction β (MDBD), grouped under the term MODY (maturity-onset diabetes of the young), comprises a heterogeneous group of diseases associated with genetic mutations that lead to pancreatic β cell dysfunction.
The diagnostic criteria for MDBD include hyperglycemia, usually before 25 years of age; autosomal dominant inheritance with transmission in at least three generations; similar disease phenotypes among family members; and C-peptide levels maintained within reference ranges for years.
The MODY subtypes differ among each other in terms of prevalence, clinical manifestations and therapeutic requirements.
The prevalence of MODY is not known, though it is estimated that approximately 1-2% of all cases of diabetes could be classified as MODY. The most commonly mutated genes are hepatocyte nuclear factor 1α (HNF1A) and glucokinase (GCK), which cause MODY3 and MODY2, respectively - representing up to 90% of all cases of MODY1.
We describe a case of MODY12, caused by a mutation in the ABCC8 gene.
The ABCC8 (ATP-Binding Cassette subfamily C member 8) gene, located on chromosome 11, encodes the expression of ATP-sensitive potassium channels (KATP channels) of sulfonylurea receptor 1 (SUR 1) in the pancreatic β cells. Closure of the ATP-sensitive potassium channels is known to be necessary for insulin secretion from glucose-stimulated β cells, while the opening of these channels inhibits insulin secretion.
Gain-of-function mutations in ABCC8 in humans are associated to MODY, type 2 diabetes mellitus (DM) and gestational diabetes. Some ABCC8 mutations cause hyperinsulinemia in neonates, while others have been found in cases of neonatal diabetes2,3.
The patient was a 35-year-old woman from Mexico, living in Spain for about 8 years, and a student of Business Administration and Management. She was a former smoker, with no other toxic habits. No surgical history.
The patient was diagnosed with type 1 DM at 28 years of age in Guadalajara (Spain), where insulin therapy was started and was discontinued after four years due to problems with her residence permit. Subsequently, 10 months before reporting to our clinic, insulin therapy was restarted with a basal-bolus regimen (glargine 37 IU at 08:00 h and glulisine 8 IU with breakfast, 12 IU with lunch, and 6 IU with dinner). During insulin treatment, she reported frequent hypoglycemia episodes (levels as low as 26 mg/dl, capillary blood measurement), which sometimes proved asymptomatic. As microangiopathic complications, she presented moderate non-proliferative diabetic retinopathy. There have been no known macroangiopathic complications to date.
Her medical history moreover included arterial hypertension treated with an angiotensin II antagonist (irbesartan 75 mg) and hypercholesterolemia treated with a statin (atorvastatin 20 mg).
With regard to the family history, her father had suffered diabetes and died in a traffic accident. In addition, she had three siblings with diabetes who died of the disease (she was unable to specify the immediate cause of death). Her mother had no known diabetes, and died at 54 years of age due to acute myocardial infarction. The patient was the youngest of 8 siblings: the three older siblings died of diabetic nephropathy at around 50 years of age; her middle sister, also diabetic, has two daughters diagnosed with type 1 DM (aged 20 and 23 years). All are living in Mexico. The patient has no children, and has had no pregnancies.
She was referred from primary care to our endocrinology outpatient clinic. In view of the high familial burden, a study of monogenic diabetes was requested, resulting in the identification of a pathogenic variant in heterozygosis in exon 13 of the ABCC8 gene, consisting of a change from guanine in position 1819 to adenine (c.1819 G > A), which implies substitution in the protein of valine 607 protein for methionine (p.Val607Met).
Given these findings, scheduled hospital admission was decided for the start of treatment with sulfonylureas.
During admission, basal insulin was discontinued, treatment was started with gliclazide 60 mg4 with breakfast, lunch and dinner, and the use of rapid insulin was gradually reduced, maintaining only a bolus of insulin glulisine 6 IU at discharge, with good blood glucose control. The HbA1c concentration decreased from 8.3% to 7.2%, and the C-peptide levels improved: basal upon admission 0.52 ng/ml; post-breakfast upon admission 2.53 ng/ml; basal after starting sulfonylureas 2.86 ng/ml; post-breakfast after starting sulfonylureas (2 days after start) 4.97 ng/dl.
Two months after hospital discharge, the patient was evaluated in the endocrinology outpatient clinic. The patient reported home capillary blood glucose controls with basal values of 110-162 mg/dl; pre-lunch 86-112 mg/dl; post-lunch 132-213 mg/dl; and pre-dinner 95-161 mg/dl. We decided a gliclazide dose increase to 60 mg with breakfast and lunch, and 90 mg with dinner, and insulin was suspended entirely.
The present case illustrates the clinical characteristics associated to the mutation in the ABCC8 gene encoding SUR1 (MODY subtype 12). The disease was initially erroneously classified as type 1 DM despite negative pancreatic autoimmune test results.
Consideration of the case as corresponding to MODY was supported by the fact that, after diagnosis, the patient remained without insulin treatment for about three years, with no severe acute complications such as ketoacidosis, and also by the presence in her family of diabetes in at least three consecutive generations.
The genetic study revealed a heterozygous mutation in exon 13 of the ABCC8 gene. Identification of the MODY subtype is crucial for establishing appropriate treatment. In our patient, diagnostic confirmation allowed the discontinuation of insulin therapy, and thanks to the introduction of sulfonylureas, she improved her metabolic control with no hypoglycemia episodes, increased C-peptide, and decreased glycosylated hemoglobin levels.
Treatment with sulfonylureas in diabetes related to mutations in the ABCC8 gene is clearly beneficial for both patient quality of life and blood glucose control. A personalized diagnosis of non-classical forms of diabetes is essential for adequate management.
We thank the patient for placing her trust in us and for allowing us to make our experience with her case known.
Please cite this article as: Lanes Iglesias S, Ares Blanco J, Bellido Castañeda V, Sánchez-Ragnarsson C, Menéndez-Torre E. Efectividad del tratamiento con sulfonilureas en paciente con mutación en el gen ABCC8 (MODY12). Endocrinol Diabetes Nutr. 2020;67:682–683.
