The role of adjunctive exenatide therapy in pediatric type 1 diabetes.

OBJECTIVE: Exenatide improves postprandial glycemic excursions in type 2 diabetes. Exenatide could benefit type 1 diabetes as well. We aimed to determine an effective and safe glucose-lowering adjuvant exenatide dose in adolescents with type 1 diabetes. RESEARCH DESIGN AND METHODS: Eight subjects completed a three-part double-blinded randomized controlled study of premeal exenatide. Two doses of exenatide (1.25 and 2.5 microg) were compared with insulin monotherapy. Prandial insulin dose was reduced by 20%. Gastric emptying and hormones were analyzed for 300 min postmeal. RESULTS: Treatment with both doses of exenatide versus insulin monotherapy significantly reduced glucose excursions over 300 min (P < 0.0001). Exenatide administration failed to suppress glucagon but delayed gastric emptying (P < 0.004). CONCLUSIONS: Adjunctive exenatide therapy reduces postprandial hyperglycemia in adolescents with type 1 diabetes. This reduction in glucose excursion occurs despite reduction in insulin dose. We suggest that exenatide has therapeutic potential as adjunctive therapy in type 1 diabetes.

Twenty-four-hour simultaneous subcutaneous Basal-bolus administration of insulin and amylin in adolescents with type 1 diabetes decreases postprandial hyperglycemia.

CONTEXT: The purpose of this study was to examine the effect of continuous sc replacement of amylin and insulin for a 24-h period on glucose homeostasis in adolescents with type 1diabetes. METHODS: Thirteen adolescents with type 1 diabetes on insulin pump therapy participated in a randomized, controlled, crossover design study comparing continuous sc insulin monotherapy (part A) vs. continuous sc insulin and pramlintide infusion (part B). In part A, basal and bolus insulin infusion was per prescribed home regimen. In part B, the basal insulin infusion was the same as part A, but prandial insulin boluses were reduced by 20%. Basal and prandial bolus pramlintide were administered simultaneously via another pump. All boluses were given as a dual wave. RESULTS: The study regimen resulted in a 26% reduction in postprandial hyperglycemia as compared to insulin monotherapy (area under the curve, 600 min, 2610 +/- 539 vs. 692 +/- 861 mg/liter . min) (P < 0.008). Glucagon concentrations were suppressed postprandially (P < 0.003) but not in the postabsorptive state, whereas plasma insulin concentrations were unchanged. CONCLUSIONS: Simultaneous continuous sc pramlintide and insulin infusion has the potential of improving glucose concentrations by way of physiological replacement.

Targeting blood glucose management in school improves glycemic control in children with poorly controlled type 1 diabetes mellitus.

We hypothesized that school nurse supervision of glucose and insulin-dose adjustment significantly improves the hemoglobinA(1c) (HbA(1c)) level in pediatric patients with poorly controlled type 1 diabetes mellitus (HbA(1c) > or = 9%). A total of 36 subjects were enrolled and 18 subjects were randomized to receive the 3-month intervention. Their average HbA(1c) was lowered by 1.6%, suggesting that this intervention helps this difficult group of patients.

Gastric emptying and postprandial glucose excursions in adolescents with type 1 diabetes.

Because amylin is co-secreted with insulin from beta cells, patients with type 1 diabetes (T1DM) are deficient in both insulin and amylin. Amylin delays gastric emptying and suppresses glucagon in the postprandial period. Hence, we hypothesized that children with complication-naive T1DM have accelerated gastric emptying in response to a mixed meal because of amylin deficiency. Amylin, glucagon, insulin, glucose, and gastric emptying were measured in seven T1DM and in eight control subjects without diabetes. Subjects with T1DM had markedly elevated glucose concentrations when compared with controls (p < 0.0001). Amylin concentrations as predicted were lower in T1DM compared with those in controls (p < 0.0001). Insulin did not peak in the immediate postprandial period in T1DM when compared with controls (p < 0.0001). Glucagon concentrations did not significantly differ between groups. Interestingly, gastric velocity was delayed in patients with T1DM compared with controls (p < 0.01). In conclusion, subjects with T1DM do have amylin deficiency but this is not associated with accelerated gastric emptying as we had hypothesized but rather with delayed gastric emptying. Factors other than amylin play a role in control of gastric motility in T1DM. Subcutaneous insulin delivery fails to reach adequate concentrations in the postprandial period to curtail peak glucose concentration in T1DM.

The role of prandial pramlintide in the treatment of adolescents with type 1 diabetes.

Pramlintide, a synthetic analog of amylin, improves postprandial hyperglycemia. We compared subcutaneous (s.c.) pramlintide injection with square wave pramlintide infusion in adolescents with type 1 diabetes (T1DM). Eight subjects with T1DM underwent two randomized studies. Subcutaneous pramlintide (dose = 5 microg/unit of insulin) bolus, was given one time and another time, the same dose was given as a 120-min s.c. infusion. Insulin dose was constant between studies. Gastric emptying was assessed with oral acetaminophen and [l-13C]glucose in meal. Plasma glucagon, pramlintide, and insulin concentrations were measured. Insulin concentrations (p < 0.99) between pramlintide injection versus infusion were similar; however, glucose concentrations were different (p < 0.0001), with the absence of hypoglycemia during pramlintide infusion [AUC (0-120 min) -0.07 +/- 0.2 versus 1.05 +/- 0.24 mg * h/dL (p < 0.0088)]. Insulin-only administration resulted in postprandial hyperglycemia and late postprandial hypoglycemia (p < 0.0001). Two subjects experienced hypoglycemia with pramlintide injection. Pramlintide bolus caused pronounced glucagon suppression (p < 0.0003) and delayed gastric emptying as ([13CO2] p < 0.0003 and acetaminophen p < 0.01) compared with infusion. We conclude that pramlintide bolus may result in an increase in risk of immediate postprandial hypoglycemia. Further modifications in pramlintide delivery are indicated before it can be safely used in children.

Serum 1,5-anhydroglucitol (Glycomark) levels in children with and without type 1 diabetes mellitus.

Postprandial hyperglycemia associated with diabetes is a risk factor for cardiovascular disease. Currently, glycated hemoglobin A(1c) (HgbA(1c)) and glycated protein fructosamine are not sensitive markers for acute and short-term hyperglycemia. 1,5-Anhydroglucitol (1,5-AG) (Glycomark; Tomen America, New York, NY, USA) is reported in adults with type 1 diabetes mellitus (T1DM) and type 2 diabetes mellitus (T2DM) as a marker for postmeal hyperglycemia. However, the reference ranges for 1,5-AG in normal children and children with T1DM are not known. We studied 1,5-AG levels in 10 control children (6 males and 4 females) and 10 children with T1DM (7 males and 3 females). The levels of 1,5-AG in the normal controls were higher than those in children with T1DM (24.60 +/- 3.99 microg/mL vs. 4.75 +/- 2.95 microg/mL; p < 0.0001). There were no gender differences noted. The 1,5-AG levels were negatively correlated with HgbA(1c) (r =-0.9366; p < 0.0001) and the peak postmeal plasma glucose concentrations (Pearson r =-7230; p = 0.0003). Our findings suggest that despite good glycemic control, postprandial glucose concentrations are elevated and that 1,5-AG showed a difference between controls and children with T1DM. The data are comparable with previous studies in normal adults and in those with T1DM and T2DM. They support the use of 1,5-AG concentrations, together with HgbA(1c), to evaluate therapy, especially to target postprandial hyperglycemia.