Luisa M. Rodriguez

A 12-Week Aerobic Exercise Program Reduces Hepatic Fat Accumulation and Insulin Resistance in Obese, Hispanic Adolescents

The rise in obesity‐related morbidity in children and adolescents requires urgent prevention and treatment strategies. Currently, only limited data are available on the effects of exercise programs on insulin resistance, and visceral, hepatic, and intramyocellular fat accumulation. We hypothesized that a 12‐week controlled aerobic exercise program without weight loss reduces visceral, hepatic, and intramyocellular fat content and decreases insulin resistance in sedentary Hispanic adolescents. Twenty‐nine postpubertal (Tanner stage IV and V), Hispanic adolescents, 15 obese (7 boys, 8 girls; 15.6 ± 0.4 years; 33.7 ± 1.1 kg/m2; 38.3 ± 1.5% body fat) and 14 lean (10 boys, 4 girls; 15.1 ± 0.3 years; 20.6 ± 0.8 kg/m2; 18.9 ± 1.5% body fat), completed a 12‐week aerobic exercise program (4 × 30 min/week at ≥70% of peak oxygen consumption (VO2peak)). Measurements of cardiovascular fitness, visceral, hepatic, and intramyocellular fat content (magnetic resonance imaging (MRI)/magnetic resonance spectroscopy (MRS)), and insulin resistance were obtained at baseline and postexercise. In both groups, fitness increased (obese: 13 ± 2%, lean: 16 ± 4%; both P < 0.01). In obese participants, intramyocellular fat remained unchanged, whereas hepatic fat content decreased from 8.9 ± 3.2 to 5.6 ± 1.8%; P < 0.05 and visceral fat content from 54.7 ± 6.0 to 49.6 ± 5.5 cm2; P < 0.05. Insulin resistance decreased indicated by decreased fasting insulin (21.8 ± 2.7 to 18.2 ± 2.4 µU/ml; P < 0.01) and homeostasis model assessment of insulin resistance (HOMAIR) (4.9 ± 0.7 to 4.1 ± 0.6; P < 0.01). The decrease in visceral fat correlated with the decrease in fasting insulin (R2 = 0.40; P < 0.05). No significant changes were observed in any parameter in lean participants except a small increase in lean body mass (LBM). Thus, a controlled aerobic exercise program, without weight loss, reduced hepatic and visceral fat accumulation, and decreased insulin resistance in obese adolescents.

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 μg) 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.

A Randomized, Controlled Trial Comparing Twice-a- Day Insulin Glargine Mixed With Rapid-Acting Insulin Analogs Versus Standard Neutral Protamine Hagedorn (NPH) Therapy in Newly Diagnosed Type 1 Diabetes

OBJECTIVE. Insulin glargine is difficult to use for children due to the number of injections required because it is claimed to be immiscible with rapid-acting insulin analogs. For this study, we hypothesized that treating new-onset type 1 diabetes with twice-daily insulin glargine plus a rapid-acting insulin analog mixed in the same syringe would result in better glycosylated hemoglobin than twice-daily neutral protamine Hagedorn with a rapid-acting insulin analog (standard treatment). METHODS. Forty-two patients with new-onset type 1 diabetes were started on standard treatment. Three months after diagnosis, if patients were found compliant and had a glycosylated hemoglobin level of ≤9%, then they were randomly assigned either to receive insulin glargine twice daily mixed with a rapid-acting insulin analog or to continue on standard treatment for 3 more months. Additional lunchtime rapid-acting insulin analog injections were given for the insulin glargine group as necessary. RESULTS. Nineteen patients in the insulin glargine group and 17 in the neutral protamine Hagedorn group completed the study. The glycosylated hemoglobin level at baseline was 6.8% ± 1% vs 6.9% ± 1% and at poststudy was 6.7% ± 1.3% vs 7.6% ± 1% in the insulin glargine versus neutral protamine Hagedorn group, respectively. Two patients in the insulin glargine group required lunch rapid-acting insulin analog in the last month of the study. Although both groups were encouraged to contact the principal investigator with all queries, more in the insulin glargine arm opted to do so. CONCLUSIONS. Glycemic control with insulin glargine mixed with a rapid-acting insulin analog given twice daily seems significantly more effective than the standard therapy in newly diagnosed type 1 diabetes. Furthermore, it decreases pain and burden of injections for children with diabetes by allowing patients to mix glargine with rapid-acting insulin analog.

Effects of Mixing Glargine and Short-Acting Insulin Analogs on Glucose Control

Intensive insulin management improves glycemic control and lowers the risks of long-term microvascular complications (1). Several new insulin analogs (2) are in use to improve glycemic control in type 1 diabetes. Glargine in particular is a “basal insulin” (3) and found to be relatively peakless. Glargine is thought to provide glucose profiles similar to insulin pumps (4). Although some clinical studies suggest that glargine lasts 24 h in children with diabetes (5), to date there have been no formal pharmacokinetic and pharmacodynamic data to make that claim in the pediatric population. In fact, clinical observations in pediatric type 1 diabetes suggest that glargine action may be <24 h. This would entail twice-daily glargine dosing and short-acting insulin analogs (SAIs), such as lispro and aspart, given separately three to four times per day, resulting in improved glycemic control but compromising compliance and increasing complexity of management (6). In this study, we tested the hypothesis that mixing glargine with SAIs and dividing the dose of glargine into twice- versus once-daily dosing would not adversely affect glycemic control as assessed by a continuous glucose monitoring system (CGMS). The protocol was approved by the institutional review board of the Baylor College of Medicine, and consent was obtained before each study. Subjects were recruited from Texas Children’s Hospital Diabetes Care Center, Houston, Texas. Subjects had type 1 diabetes for at least 1 year with no other chronic illness and were on …

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 μg/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.

Beta cell function and BMI in ethnically diverse children with newly diagnosed autoimmune type 1 diabetes

To examine the relationship between BMI and beta‐cell function at diagnosis of autoimmune type 1 diabetes (T1D) in a large group of ethnically diverse children.

Serum adiposity-induced biomarkers in obese and lean children with recently diagnosed autoimmune type 1 diabetes

Obesity increases the risk of cardiovascular disease and diabetic complications in type 1 diabetes. Adipokines, which regulate obesity‐induced inflammation, may contribute to this association. We compared serum adipokines and inflammatory cytokines in obese and lean children with new‐onset autoimmune 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.

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

Abstract:  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.

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

Abstract:  Postprandial hyperglycemia associated with diabetes is a risk factor for cardiovascular disease. Currently, glycated hemoglobin A1c (HgbA1c) 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 μg/mL vs. 4.75 ± 2.95 μg/mL; p < 0.0001). There were no gender differences noted. The 1,5‐AG levels were negatively correlated with HgbA1c (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 HgbA1c, to evaluate therapy, especially to target postprandial hyperglycemia.