Impaired beta-cell and alpha-cell function in African-American children with type 2 diabetes mellitus--"Flatbush diabetes".

UNLABELLED: The incidence of type 2 diabetes mellitus (T2DM) in children and adolescents has substantially increased over the past decade. This is attributed to obesity, insulin resistance and deficient beta-cell function. In children a pubertal increase in insulin resistance and an inability to mount an adequate beta-cell insulin response results in hyperglycemia. Adults with T2DM have a diminished first phase response to intravenous glucose and a delayed early insulin response to oral glucose. Long-term studies show progressive loss of beta-cell function in T2DM in adults; however, such long-term studies are not available in children. To characterize beta- and alpha-cell function in African-American adolescents with established T2DM, we used mixed meal, intravenous glucagon and oral glucose tolerance testing and compared them to obese non-diabetic controls. T2DM was defined as fasting C-peptide >0.232 nmol/l and absent autoimmune markers. BETA-CELL FUNCTION: Meal testing in 24 children and adolescents with T2DM, mean age 14 years, BMI 30 kg/m2, Tanner stage II-V, HbA1c 8.9%, were compared with BMI- and age-matched controls. Forty percent presented with DKA. Half were treated with insulin and half with diet/oral anti-diabetic agents. Although absolute C-peptide response in both groups was similar, the incremental rise in C-peptide relative to plasma glucose in the patients with T2DM compared to controls was 40% and 35% lower 30 and 60 min after the meal, p <0.007 and p <0.026. Glucagon testing in 20 pediatric patients with T2DM compared with 15 matched controls showed significantly lower 6 min stimulated C-peptide relative to the ambient plasma glucose in patients with T2DM compared to controls (0.039 +/- 0.026 vs 0.062 +/- 0.033, p <0.05). The clinical utility is that 78% of patients with a 6 min C-peptide <1.4 nmol required insulin, while 81% of those >1.4 nmol required oral anti-diabetic agents, p <0.0001. Furthermore, the duration of T2DM up to 5 years after diagnosis was associated with lower fasting and glucagon-stimulated C-peptide levels, implying worsening beta-cell function over time, even in children and adolescents. ALPHA-CELL FUNCTION: During meal testing, children and adolescents with T2DM had less suppression of plasma glucagon than non-diabetic controls; this was more severe with longer duration of T2DM and poorer glycemic control. BETA-CELL RECOVERY: In African-American and Hispanic adults, intensive treatment of blood glucose may achieve beta-cell recovery with 35-40% of newly diagnosed patients going into remission after 6 months treatment. They remain off anti-diabetic pharmacological agents in remission for a median of over 3 years with normal HbA1c levels. We hypothesize this to be due to removal of a critical component of glucose or lipotoxicity at the level of the beta-cell and/or peripheral tissue. Four of 20 African-American children presenting with mean glucose 650 mg/dl maintained normal HbA1c levels on small doses of metformin after initial treatment with multiple insulin injections with or without metformin. This suggests a marked recovery of beta-cell function, similar to that in adults.

SUMMARY: T2DM in children, as in adults, is characterized by insulin deficiency relative to insulin resistance. Plasma C-peptide levels may be clinically useful in guiding therapeutic choices, since patients with lower levels required insulin treatment; beta-cell function is also diminished with longer duration of T2DM. The possibility exists that in children, as in adults, intensive glycemic regulation may allow for beta-cell recovery and preservation. Thus, optimum beta- and alpha-cell function are central to the prevention of DM and maintenance of good glycemic control in African-American and Hispanic children and adolescents with T2DM.