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Institut National de la Santé et de la Recherche Médicale, Unité 690, Hôpital Robert Debré (C.D., C.L.-M.), 75019 Paris, France; Pediatric Endocrinology and Diabetes Unit (N.T.-R.) and Service de Biochimie Hormonologie (D.C., O.R.), Hôpital Robert Debré, Assistance Publique-Hôpitaux de Paris, 75019 Paris, France; and Department of Pediatric Endocrinology, Diabetic Unit, Hôpital des Enfants-Malades (M.P.), 75015 Paris, France
Address all correspondence and requests for reprints to: Dr. Céline Druet, Institut National de la Santé et de la Recherche Médicale, Unité 690, Hôpital Robert Debré, 48 boulevard Sérurier, 75019 Paris, France. E-mail: drucel{at}yahoo.fr.
Abstract
Context: Type 2 diabetes (T2D) in obese children is an emerging problem, including in Europe. Its presentation at diagnosis very often differs from that in adults.
Objective: The objective of this study was to investigate the relative contributions of the two components of T2D, insulin resistance and insulin secretion, early in the history of the disease in adolescents.
Patients and Methods: Six obese adolescents with T2D were included 2 months to 4.3 yr after diagnosis (five girls and one boy; median age, 15.4 yr; median body mass index, 4.4 SD). Peripheral and hepatic insulin sensitivity was evaluated with euglycemic hyperinsulinemic (40 mU/m2·min) clamp. First-phase insulin release was evaluated after iv glucose stimulation. A graded iv glucose infusion and an arginine test were performed to measure insulin secretion.
Results: All patients showed decreased peripheral glucose uptake to the same extent. Five patients showed hepatic insulin resistance. First-phase insulin release was very low in two patients. Three patients showed an exaggerated insulin response under graded glucose infusion and preserved secretion under arginine stimulation. Three other patients, with elevated fasting plasma glucose levels, demonstrated a very low insulin response under glucose stimulation and a low insulin response under arginine stimulation.
Conclusions: These data emphasize that together with marked insulin resistance, the failure of ß-cell function is a major component in the course of T2D in childhood.
UNTIL RECENTLY, TYPE 2 diabetes (T2D) was considered as an adult disease entity. However, recent reports indicate an increasing prevalence of T2D in childhood around the world. This is particularly the case in the United States (1), but it has also been reported in Europe (2, 3, 4, 5). T2D is typically diagnosed in obese pubertal girls, with a family history of T2D, and in minority ethnic groups, at least in the United States (6, 7).
One among many differences between T2D in adults and children is the initial clinical presentation. In adults, diagnosis may be delayed because of the absence of symptoms early in the course of disease, whereas nearly all children are symptomatic at the time of diagnosis, one third of them presenting with ketoacidosis (8).
It has been suggested that both insulin resistance (IR) and failure of pancreatic ß-cells contribute to T2D. However, the respective role of either trait remains unclear in the development of the early steps of T2D, particularly in children. Studies of offspring of T2D parents have pointed to IR as the primary mechanism (9, 10), whereas others have implicated ß-cell dysfunction (11, 12).
The aim of the study was to evaluate the relative contributions of the two components of T2D: IR and insulin secretion (IS), early in the history of the disease in adolescents.
Patients and Methods
Study population
Six adolescents with T2D were included. Criteria for eligibility were the following: age 10–17 yr, overweight or obese according to the definition of overweight and obesity by the International Obesity Task Force (13), absence of ß-cell antibodies (tyrosine phosphatase-like protein, islet cell, and glutamate decarboxylase antibodies testing was performed at Institut National de la Santé et de la Recherche Médicale, Unité 457, laboratory 138 of the Immunology and Diabetes Workshop proficiency program, between diagnosis and 2 yr thereafter), an 8-wk or more delay from initial decompensation, and hemoglobin A1c levels below 7.5% at the time of the study. Antidiabetic drugs were discontinued at least 2 d before the study. Patients were not taking any other drugs known to affect glucose tolerance. Patients were hospitalized for 3 d. A 2-h euglycemic hyperinsulinemic clamp with measurement of hepatic glucose production (HGP) was performed on the first day; a graded iv glucose infusion, followed by an arginine test, were performed on the second day; and an iv glucose tolerance test was performed on the last day. Written informed consent from parents and written assent from children and adolescents were obtained. The study protocol was reviewed and approved by the ethical committee of Paris-St Louis University.
General examination
Information about the child and family histories was recorded from interviews with the parents and from the child’s individual health leaflet. Body weight was measured with a portable scale, height was measured with a wall-mounted stadiometer, and body mass index was calculated as weight in kilograms divided by the square of the height in meters. Pubertal development was assessed by physical examination according to Tanner staging (14, 15). Body composition was assessed by dual energy x-ray absorptiometry (GE Medical Systems, Prodigy, Lunar Radiation, Madison, WI).
Insulin sensitivity
Insulin sensitivity was determined with a 2-h euglycemic hyperinsulinemic clamp, as described by De Fronzo et al. (16). Primed doses of insulin were followed by a continuous infusion rate of 40 mU/m2·min. Plasma glucose was clamped at 5.5 mmol/liter with a variable rate of 20% glucose solution. The rate of glucose infusion was adjusted on the basis of plasma glucose measurements performed every 5 min. Peripheral insulin sensitivity was determined from the amount of glucose required to maintain euglycemia over the final 40 min at steady state.
HGP was measured with an infusion of [2H2]glucose administered as a bolus (5 mg/kg) starting 165 min before beginning insulin infusion, followed by a constant infusion (5 mg/kg·h) until the end of the clamp. Isotopic enrichment of glucose was determined at baseline and during insulin infusion at steady state. HGP was calculated using a tracer enrichment method (17). Hepatic insulin sensitivity was evaluated as the ability of insulin to suppress HGP.
Plasma free fatty acids (FFA) were measured at baseline and during insulin infusion at steady state. The insulin sensitivity of the adipose tissue was evaluated as the ability of insulin to suppress FFA production.
Intravenous glucose tolerance test (IVGTT)
The acute insulin response was determined by IVGTT. After obtaining baseline samples, an iv bolus of glucose was injected (0.5 g/kg body weight). Blood samples for glucose and insulin were obtained at 1, 3, 5, and 10 min after the glucose injection. First-phase insulin release (FPIR) was calculated as the sum of 1 and 3 min serum insulin values during the IVGTT.
Glucose disposition index (GDI)
GDI (micromoles per kilogram per minute) was calculated as the product of insulin sensitivity and FPIR, where insulin sensitivity was calculated by dividing peripheral insulin sensitivity by the steady-state plasma insulin concentration.
Graded iv glucose infusion
IS was calculated using a graded iv glucose stimulation. Glucose was infused over five 40-min periods at infusion rates of 2, 4, 6, 8, and 10 mg/kg·min, respectively. Blood samples were taken every 10 min to measure plasma glucose and at 30 and 40 min during each period to measure insulin and C peptide concentrations. The test was stopped if the plasma glucose concentration was above 22 mmol/liter. IS was estimated by deconvolution of C peptide rates.
Arginine test
Insulin response to a nonglucose stimulus was determined using intravenous arginine stimulation. At the end of the five periods of the graded iv glucose infusion, after a 20-min plasma glucose concentration stabilization, arginine hydrochloride (5 g) was injected iv over 1 min. Samples were taken at 0, 3, 5, 10, and 15 min to measure glucose, insulin, and C peptide concentrations.
Analytical methods
Plasma glucose concentrations were measured by the glucose oxidase method (Glucose Analyzer II, Beckman Coulter, Roissy, France). FFA concentrations were measured by an enzymatic colorimetric method (NEFA C, Wako Chemicals GmbH, Neuss, Germany). Serum insulin concentrations were measured using an immunoradiometric assay (Bi-Insulin IRMA, Cis Bio International, Gif-sur-Yvette, France). The cross-reactivity with proinsulin and 31,32 split proinsulin was less than 1%. The detection limit was 0.5 mU/liter, and the interassay coefficient of variation was less than 8%. Serum C peptide concentrations were measured using an immunoradiometric assay (IRMA-C-PEP, Cis Bio International). The detection limit was 0.05 nmol/liter, and the interassay coefficient of variation was less than 8%.
Results
Characteristics of subjects
As shown in Table 1
, six adolescents (five girls and one boy) were included 2 months to 4.3 yr after diagnosis, at a median age of 15.4 yr (range, 12.0–17.1 yr) and a median body mass index of 4.4 SD (2.5–7.2 SD). The median age of beginning obesity was 4.3 yr (range, 2–5.5 yr). The median hemoglobin A1c level was 6.0% (range, 5.1–7.4%), and three patients (no. 1, 4, and 5) had impaired fasting plasma glucose (
6.1 mmol/liter) (18) at the time of the study.
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The median peripheral glucose uptake was 3.1 mg/kg·min (range, 1.83–4.48 mg/kg·min). Using reference values of glucose uptake (8.4 ± 2.4 mg/kg·min for girls and 9.5 ± 2.4 mg/kg·min for boys) in adolescents (19), all six patients were insulin resistant.
The median rate of fasting HGP was 3.1 mg/kg·min (range, 1.59–6.42 mg/kg·min). All patients had an increased fasting HGP, using the reference value from a young adult population (1.2 ± 0.2 mg/kg/min; unpublished data from our group).
At the insulin infusion rate of 40 mU/m2·min, HGP was abolished in only one of six patients.
The median suppression of FFA production during insulin infusion was 73.8% (range, 68.3–93.5). Interestingly, FFA production suppression was inversely correlated to the peripheral glucose uptake (r = 0.76; P = 0.07), i.e. with insulin sensitivity.
IS
The median FPIR was 60.2 mU/liter (range, 3.9–124.6); two patients (no. 1 and 4) had FPIR below the fifth percentile for children and young adults reference values (20) (Table 1
).
IS under a graded glucose infusion identified two groups of patients. The first group (patients 2, 3, and 6) showed an exaggerated IS, whereas the second group (patients 1, 4, and 5) showed a very low response (Fig. 1).
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). Other patients (patients 2, 3, and 6) demonstrated a preserved insulin response under arginine stimulation.
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The median GDI was 9.8 µmol/kg·min (range, 0.8–51.2 µmol/kg·min; Table 1). Patients with low IS response (patients 1, 4, and 5) showed lower GDI than patients with exaggerated IS response (patients 2, 3, and 6) to glucose stimulation.
Discussion
The study was undertaken to understand the respective roles of IR and secretion at the onset of T2D in adolescents. Our data clearly show that IR is a consistent and severe feature, whereas IS is not as uniform. Six patients only were recruited over 2 yr, attesting that T2D in obese children has not reached an epidemic level in our country, similar to what has been reported in Europe (2, 22).
T2D seems to be predominant in girls (2, 4, 23), and this was the case in our study. Even if girls show more important IR than boys during puberty (19), this physiological IR does not explain all the contrasting sex ratio in T2D.
As expected, our patients showed marked IR. Indeed, they were all severely obese, and obesity is recognized as a major risk factor for IR, even in adolescents. In addition, all patients have been obese for a long time. Moreover, a recent American study (24) found that adolescents with T2D had approximately 50% lower insulin sensitivity than paired obese nondiabetic adolescents.
The pattern of IS under glucose stimulation separates two types of patients. One group (patients 2, 3, and 6) shows a preserved first-phase insulin response, a sustained and exaggerated response under graded glucose infusion. This is in agreement with what was described in adult insulin-resistant obese patients. The other group (patients 1, 4, and 5) shows a low first-phase insulin response and a very low response under graded glucose infusion even for very high plasma glucose values (20 mmol/liter), attesting for a severe defect in ß-cell function. Consequently, the first group shows higher GDI than the second group.
In the first group, the insulin response was also preserved under arginine stimulation. In the second group, two patients (no. 1 and 4) demonstrated a very low response under arginine, implying reduced insulin reserve. In patient 5, the response was intermediate. In this type of patients it is likely that glucotoxicity induced by elevated fasting plasma glucose does not favor the ß-cell response.
It is obvious that our study population is limited. However, no clear profile emerges from clinical data and medical history to characterize the patients with the worst IS. The most consistent patterns would be the duration of T2D and the lack of weight loss since the diagnosis of T2D. IS is inversely correlated with the duration of T2D, except in patient 2. This patient has a preserved IS, contrasting with the longest duration of T2D. This could be explained by a very significant weight loss since diagnosis inducing an improvement in insulin sensibility, which, in turn, would delay the impairment of ß-cell function. Interestingly, in the United States, where severe obesity and T2D are more frequent and pronounced than in Europe, the major contribution of ß-cell failure has been recently emphasized in the genesis of T2D in adolescents (24).
In adults, progression from normal glucose tolerance to impaired glucose tolerance and from impaired glucose tolerance to diabetes required continuous weight gain associated with deterioration of ß-cell function (25).
Our study contributes to a better understanding of T2D in obese adolescents, which is characterized by a marked IR compensated by an elevated IS able to maintain normal fasting plasma glucose levels, followed by a rapid and severe impairment of IS. Deterioration of ß-cell function could appear less than 4 yr after diagnosis.
Acknowledgments
We acknowledge the nursing and technical staffs of the Clinical Investigation Unit of Robert Debré Hospital for supervision of the patients.
Footnotes
This work was supported in part by fellowships from the Aide aux Jeunes Diabétiques (Paris, France; to C.D.) and the International Society for Pediatric and Adolescent Diabetes.
First Published Online November 15, 2005
Abbreviations: FFA, Free fatty acid; FPIR, first-phase insulin release; GDI, glucose disposition index; HGP, hepatic glucose production; IR, insulin resistance; IS, insulin secretion; IVGTT, iv glucose tolerance test; T2D, type 2 diabetes.
Received July 27, 2005.
Accepted November 3, 2005.
References
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  S. Wiegand, K. Raile, T. Reinehr, S. Hofer, A. Nake, W. Rabl, R. W Holl, and on behalf of the DPV-Wiss Study Group Daily insulin requirement of children and adolescents with type 1 diabetes: effect of age, gender, body mass index and mode of therapy. Eur. J. Endocrinol., April 1, 2008; 158(4): 543 - 549. [Abstract] [Full Text] [PDF]
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 A. D. Salbe, R. S. Lindsay, C. B. Collins, P. A. Tataranni, J. Krakoff, and J. C. Bunt Comparison of Plasma Insulin Levels after a Mixed-Meal Challenge in Children with and without Intrauterine Exposure to Diabetes J. Clin. Endocrinol. Metab., February 1, 2007; 92(2): 624 - 628. [Abstract] [Full Text] [PDF]
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