Glucose Intolerance and Diabetes Are Observed in the Long-Term Follow-Up of Nonpancreatectomized Patients With Persistent Hyperinsulinemic Hypoglycemia of Infancy Due to Mutations in the ABCC8 Gene Free

We studied three nonpancreatectomized male PHHI patients unresponsive to diazoxide and with ABCC8 gene mutations whom we followed up from the neonatal period. Diagnosis in the neonatal period was based on the following: 1) hypoglycemic episodes; 2) high carbohydrate requirements (>15 mg · kg⁻¹ · min⁻¹) to maintain normoglycemia; 3) low plasma free fatty acid (<1.5 mmol/l), low ketone body values (<2 mmol/l), and unsuppressed insulin levels (glucose-to-insulin ratio <3) during hypoglycemia; 4) glucagon (0.1 mg/kg) response of hypoglycemic episodes (glycemia >50 mg/dl); and 5) nonresponse to diazoxide (15 mg · kg⁻¹ · day⁻¹ [failure to maintain glycemia >50 mg/dl with carbohydrate intake >15 mg · kg⁻¹ · min⁻¹]) (3).

ABCC8 gene study (39 exons and intron-exon boundaries) showed the following: patient 1, 2800C>T (R934X; exon 23) and 3992-9G>A (intron 32), parents not evaluated; patient 2, 3576delG (L1191LfsX1207; exon 29, paternal) and 3751C>T (R1251X; exon 30, maternal); and patient 3, 3443T>G (L1148R; exon 28, maternal) and 3751C>T (R1251X; exon 30, paternal) (4).

Patients received continuous enteral nutrition during the neonatal period and the first 3 months of life, including the carbohydrate intake necessary to maintain glycemic values >50 mg/dl. From then until 6 months of age, intervals between daytime feeds were prolonged progressively up to every 3 h and nighttime continuous enteral nutrition was maintained until the age of 4–6 years, when a six times daily intake was established and maintained thereafter.

Oral glucose tolerance test (OGTT) (5) and venous 24-h glucose insulin profile (GIP) with samples drawn every 2 h over a 24-h period were performed. Glucose, insulin (immunochemoluminescence), homeostasis model assessment (HOMA), quantitative insulin sensitivity check index (QUICKI) (6), A1C (normal values 4.7–6.6%; evaluated with high–molecular weight chromatography), anti-GAD65 autoantibodies (radioimmunoassay), islet cell antibodies (indirect immunofluorescence), anti–insulinoma-associated protein 2 antibodies (radioimmunoassay), and BMI values (7) were evaluated.

Patients 1 and 2 had diabetic responses, and patient 3 had intolerant responses to the OGTT, with insulin values at 120 min <27 mIU/l. In the 36 determinations (12 per patient) of the GIP evaluation, 12 hyperglycemic episodes (glucose >120 mg/dl) with relatively low insulin values and 3 hypoglycemic episodes (glucose <45 mg/dl) were detected. Patients 1 and 2 had impaired fasting glucose (IFG) (Table 1) (5). Hyperglycemia in the GIP evaluation was observed after fasting (0800 h) and between meals (1600 h and 1800 h) in patients 1 and 2 and between meals (1200 h) in patient 3.

Patient 1 is now 31 years of age. At the age of 22 years, IFG, hyperglycemic episodes, and diabetic OGTT response were detected together with hypoglycemic episodes (Table 1). Between the ages of 23 and 25 years, hypoglycemic episodes disappeared. At the age of 25 years, hyperglycemia was permanently observed and insulin therapy (0.7 IU · kg⁻¹ · day⁻¹) was started and maintained thereafter.

Patient 2 is now 17 years of age. From the age of 10 years, OGTT and 24-h GIP and A1C tests were performed annually (n = 6). Since then, IFG, diabetic OGTT response, and hyperglycemic and hypoglycemic episodes have been observed with normal A1C values (Table 1).

Patient 3 is now 24 years of age. From the age of 16 years, OGTT and 24-h GIP and A1C tests were performed annually (n = 7). Since then, intolerant OGGT response and hyperglycemic episodes have been observed with normal A1C values (Table 1).

HOMA and QUICKI values were within normal range (6) in patients 1 and 3. In patient 2, at the age of 10 years, HOMA was 3.8 and QUICKI was 0.31, but these values were not confirmed thereafter (HOMA <2, QUICKI >0.4; n = 5). Anti-GAD, anti–insulinoma-associated protein 2, and islet cell antibodies were negative, and BMI was normal in all patients.

A progressive improvement with age in severity and number of hypoglycemic episodes was observed. From the ages of 4 to 6 years, hypoglycemia was occasionally observed and capillary controls showed sporadic postprandial hyperglycemia (data not shown). The number and intensity of hyperglycemic episodes increased with age, and glucose metabolism impairment appeared with different progression among the patients. Patient 1 needed insulin at the age of 25 years and patient 2, now 17 years old, may need insulin by the same age. However, in patient 3, now 24 years old, only glucose intolerance has been observed. This evolution from a hyperinsulinemic state at birth to decreased insulin secretion later in life has also been reported in patients with ABCC8 (8,9) and maturity-onset diabetes of the young–associated hepatocyte nuclear factor-4A HNF4A gene mutations (10).

Type 1 diabetes–related autoantibodies were negative in our patients, suggesting that β-cell autoimmunity could be ruled out. HOMA and QUICKI within normal range (except the first evaluation of patient 2, not confirmed thereafter) and relatively low insulin values at 120 min suggested that insulin resistance may also be ruled out. BMI was also normal.

A higher rate of β-cell apoptosis than of proliferation was observed in the pancreas of PHHI patients (11). Furthermore, loss of insulin response to tolbutamide and blunted insulin response to intravenous dextrose were reported in PHHI nondiazoxide-responder patients treated medically or partially pancreatectomized, suggesting that lack of ATP-sensitive K⁺ channel activity may contribute to the late development of diabetes (12). Additional studies including larger numbers of nonpancreatectomized patients are required to establish the natural history of this disease. In summary, glucose metabolism impairment ranging from glucose intolerance to insulin-dependent diabetes is reported in three nonpancreatectomized PHHI patients, aged 17, 24, and 31 years, with mutations in the ABCC8 gene.