help button home button Endocrine Society JCEM JCEM Call for Nominations for EIC
HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS
This Article
Right arrow Abstract Freely available
Right arrow Full Text (PDF)
Right arrow Submit a related Letter to the Editor
Right arrow Purchase Article
Right arrow View Shopping Cart
Right arrow Alert me when this article is cited
Right arrow Alert me when eLetters are posted
Right arrow Alert me if a correction is posted
Right arrow Citation Map
Services
Right arrow Email this article to a friend
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Right arrow Request Copyright Permission
Citing Articles
Right arrow Citing Articles via HighWire
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Umpaichitra, V.
Right arrow Articles by Castells, S.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Umpaichitra, V.
Right arrow Articles by Castells, S.
The Journal of Clinical Endocrinology & Metabolism Vol. 86, No. 4 1605-1609
Copyright © 2001 by The Endocrine Society

Original Studies

C-peptide and Glucagon Profiles in Minority Children with Type 2 Diabetes Mellitus

Vatcharapan Umpaichitra, William Bastian, Doris Taha, Mary A. Banerji, Theodore W. AvRuskin and Salvador Castells

Departments of Pediatrics (V.U., W.B., D.T., S.C.) and Internal Medicine (M.A.B.), State University of New York Health Science Center, Children’s Medical Center of Brooklyn (V.U., W.B., D.T., T.W.A., S.C.), and The Brookdale University Hospital and Medical Center (V.U., T.W.A.), Brooklyn, New York 11203

Address all correspondence and requests for reprints to: Salvador Castells, M.D., Department of Pediatrics, Box 49, State University of New York, 450 Clarkson Avenue, Brooklyn, New York 11203. E-mail: umpaiv07{at}hscbklyn.edu


   Abstract
Top
 Abstract
Introduction
 Subjects and Methods
 Results
 Discussion
 References
 
The present study was conducted to determine the extent of insulin deficiency and glucagon excess in the hyperglycemia of type 2 diabetes in children. The incidence of type 2 diabetes mellitus in children and adolescents has increased substantially over the past several years. Because insulin and glucagon action both regulate blood glucose concentration, we studied their responses to mixed meals in children with type 2 diabetes. Subjects were 24 patients with type 2 diabetes compared with 24 controls, aged 9–20 yr (predominantly African-Americans), matched for body mass index and sexual maturation. All of those with diabetes were negative for antibodies to glutamic acid decarboxylase. Plasma glucose, glucagon, and serum C-peptide concentrations were measured at 0, 30, 60, 90, and 120 min after a mixed liquid meal (Sustacal) ingestion (7 mL/kg body weight; maximum, 360 mL). The area under the curve (AUC) was calculated by trapezoidal estimation. The incremental C-peptide ({Delta}CP) in response to the mixed meal was calculated (peak - fasting C-peptide). The plasma glucose AUC was significantly greater in patients than in controls (mean ± SEM, 1231 ± 138 vs. 591 ± 13 mmol/L·min; P < 0.001). The {Delta}CP was significantly lower in those with diabetes than in controls (1168 ± 162 vs. 1814 ± 222 pmol/L; P < 0.02). Glucagon responses did not differ between the two groups. Hyperglycemia is known to inhibit glucagon secretion. Therefore, our patients with substantial hyperglycemia would be expected to have decreased glucagon responses compared with controls and are thus relatively hyperglucagonemic. Patients were divided into poorly and well controlled subgroups (glycosylated hemoglobin A1c, >=7.2% and <7.2%, respectively). There were no significant differences in the {Delta}CP and glucagon responses between these two subgroups. We next analyzed the data in terms of duration of diabetes (long term, >=1 yr; short term, <1 yr). The {Delta}CP was significantly lower in long- vs. short-term patients (768 ± 232 vs. 1407 ± 199 pmol/L; P < 0.05). The plasma glucagon AUC was significantly higher in the long- vs. short-term patients (9029 ± 976 vs. 6074 ± 291 ng/L·min; P < 0.001). Hemoglobin A1c did not differ between long- vs. short-term patients. Our results indicate that relative hypoinsulinemia and hyperglucagonemia represent the pancreatic ß- and {alpha}-cell dysfunctions in children with type 2 diabetes. The severity of both ß- and {alpha}-cell dysfunctions appears to be determined by the duration of diabetes.


   Introduction
Top
 Abstract
 Introduction
Subjects and Methods
 Results
 Discussion
 References
 
DIABETES MELLITUS (DM) is classified into two major types, type 1 or insulin-dependent DM and type 2 or noninsulin-dependent DM. Type 1 diabetes occurs predominantly in children, whereas type 2 does so in adults. It has been reported that the frequency of type 2 diabetes has markedly increased recently in children and adolescents (1, 2, 3, 4, 5). Its occurrence has increased from 3–10% to 33% of new-onset diabetes patients, aged 10–19 yr, between 1992 and 1994 in one study (1). In type 2 DM, the causes of hyperglycemia are heterogeneous, including insulin resistance and absolute or relative insulin deficiency (6, 7, 8, 9, 10, 11). Type 1 diabetes results from permanent insulin deficiency due to an autoimmune destruction of the pancreatic ß-cells; such a condition does not occur in type 2 DM (8). In addition to the deficiency of insulin action, studies have shown that an excess of glucagon contributes to the metabolic disturbance in both type 1 and type 2 diabetes. Adults and children with diabetic ketoacidosis (12, 13), adults with hyperosmolar coma (14), obese and nonobese adults with type 2 diabetes (15), and those with maturity-onset diabetes of youth (16) all have hyperglucagonemia. The mechanisms of hyperglucagonemia in type 2 diabetes are unclear and different from those in type 1 diabetes (17, 18, 19). To test the hypothesis that insulin deficiency and glucagon excess play a role in the hyperglycemia of type 2 diabetes in children as they do in adults and to determine the extent, we measured plasma glucose, serum C-peptide, and plasma glucagon concentrations before and after a Sustacal stimulation test in 24 type 2 DM patients and in 24 controls matched for body mass index (BMI) and sexual maturation.


   Subjects and Methods
Top
 Abstract
 Introduction
 Subjects and Methods
Results
 Discussion
 References
 
Subjects

Subjects were selected by the inclusion criteria shown in Table 1Go. Type 2 DM patients were from our pediatric endocrinology clinic. Controls were identified to match BMI and sexual maturation with the patients. Eleven were from satellite pediatric clinics of our hospital, 7 were from private pediatric clinics, 4 were from our clinic, and 2 were siblings of 1 of the patients. The study was approved by the institutional review board of State University of New York Health Science Center (Brooklyn, NY). Each subject and his or her legal guardian gave consent to participate after the possible risks had been explained. All patients had been previously diagnosed using the criteria of the American Diabetes Association, 1997 (8). Clinical characteristics are shown in Table 2Go. A BMI (kilograms of body weight ÷ height in meters squared) of 27 or greater was used to define obesity (22).


View this table:
[in this window]
[in a new window]
  		Table 1. Inclusion criteria

 

View this table:
[in this window]
[in a new window]
  		Table 2. Clinical characteristics of study groups

 
Methods

After overnight fasting (at least 8 h) and withholding of insulin injection or oral agents (at least 12 h), the subjects ingested 7 mL/kg body weight (maximum, 360 mL) of Sustacal (Mead Johnson Nutritionals, Evansville, IN) over a period of less than 5 min. Venous blood samples were obtained at 0, 30, 60, 90, and 120 min after the ingestion for plasma glucose, serum C-peptide, and plasma glucagon determinations. Plasma glucose was measured by a glucose oxidase method (Glucose Analyzer 2, Beckman Coulter, Inc., Brea, CA). All samples for C-peptide and glucagon measurements were centrifuged at 4 C. Two milliliters of blood for glucagon were preserved by ethylenediamine tetraacetate-Trasylol (0.1 mL/1.0 mL blood). The sera (for C-peptide) and plasma (for glucagon) were frozen and stored at -20 C until assayed. Serum C-peptide determinations were performed in duplicate by double antibody RIA (C- peptide 125I RIA kit from DiaSorin, Inc., Stillwater, MN), with a lower limit of detection of 232 pmol/L. Plasma glucagon was determined in duplicate by double antibody RIA (Double Antibody Glucagon 125I RIA kit from Diagnostic Products, Los Angeles, CA), with a lower limit of detectability of 25 ng/L. C-peptide assays were performed by one technician, as were glucagon assays. The DM patients had an immunological marker determination, antibodies to glutamic acid decarboxylase (GAD65), which were measured by RIA with recombinant human GAD (Joslin Diabetes Clinic, Boston, MA). Glycosylated hemoglobin A1c (HgbA1c) was measured by high performance liquid chromatography.

Sustacal stimulation test

Sustacal, a mixed liquid meal containing approximately 14 g/dL carbohydrate, 6.1 g/dL protein, and 2.2 g/dL fat and providing 1 Cal/mL, was used to evaluate insulin and glucagon secretion because it is a more physiological stimulation than an oral glucose tolerance test (23).

Statistical analysis

The frequency of clinical characteristic is presented as a percentage. Age, BMI, duration of type 2 diabetes, and metabolic parameters (HgbA1c, glucose, C-peptide, and glucagon) are expressed as the mean ± SEM. Differences in age, BMI, and HgbA1c between the DM and control groups were examined by independent sample t tests, whereas differences in sexual maturation (Tanner stage) were determined by Fisher’s exact test because the Tanner stages are measured on an ordinal scale (24). Differences in changes in the levels of the metabolic parameters between the two groups were examined by repeated measures ANOVA (25, 26). Because there were unequal representations of ages between the two groups, analysis of covariance (27) was also performed. The result of a maximum serum C-peptide level subtracted by a basal level was termed an incremental C-peptide response ({Delta}CP). The area under the curve (AUC) was calculated by trapezoidal estimation integrating from 0–120 min. The {Delta}CP and AUC between two groups were compared by t tests. A relationship between two measures was reported as a correlation coefficient (r). The DM group was further divided into two subgroups by HgbA1c 7.2% or greater or less than 7.2% (28, 29, 30), indicating poor (10.3 ± 0.7%; n = 16) vs. good (6.1 ± 0.3%; n = 8) glycemic control, and by duration of the disease separating long-term (>=1 yr; 2.68 ± 0.33 yr; n = 9) from short-term (<1 yr; 0.23 ± 0.06 yr; n = 15) duration. Comparison between subgroups was also performed using the same statistical methods. P < 0.05 was considered statistically significant. Statistical analyses were performed with the Statistical Package for Social Sciences for Windows, version 9.0.1 (SPSS, Inc., Chicago, IL).


   Results
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
Discussion
 References
 
All DM patients had negative studies for antibodies to GAD65. As shown in Table 2Go, mean BMI and Tanner staging were not significantly different in patients vs. controls. Although we recruited all subjects in the age range 9–20 yr, the mean age of the DM group was significantly higher than that of the control group (14.08 ± 0.52 vs. 12.46 ± 0.60 yr; P < 0.05). However, when the data were analyzed using analysis of covariance, we found no effect of age on any of the metabolic parameters in the two groups. The fasting and Sustacal-stimulated glucose levels were significantly greater in patients than in controls (AUC, 1231 ± 138 vs. 591 ± 13 mmol/L·min; P < 0.001; Fig. 1AGo). The mean fasting C-peptide level was not different in the two groups. After Sustacal ingestion, the absolute serum C-peptide responses were not different (Fig. 1BGo). The {Delta}CP was significantly lower in the patients than in the controls (1168 ± 162 vs. 1814 ± 222 pmol/L; P < 0.02). The difference in glucagon responses within the two groups was nonsignificant (AUC, 7182 ± 495 vs. 7811 ± 482 ng/L·min; P < 0.37; Fig. 1CGo).



View larger version (20K):
[in this window]
[in a new window]
  		Figure 1. A–C, Plasma glucose (A), serum C-peptide (B), and plasma glucagon (C) during the Sustacal tests in diabetes patients and control subjects; mean ± SEM.

 
We further evaluated poorly vs. well controlled DM subgroups. We found a high positive correlation between HgbA1c and plasma glucose concentration at all five time points (r = 0.68–0.73; P < 0.001). Plasma glucose concentrations were significantly higher in the poorly controlled than in the well controlled subgroup (AUC, 1401 ± 188 vs. 890 ± 104 mmol/L·min; P < 0.03). No such differences were found in either serum C-peptide or plasma glucagon concentrations.

When long- and short-term subgroups were examined, a significant difference was noted in the {Delta}CP (768 ± 232 vs. 1407 ± 199 pmol/L; P < 0.05). Negative correlation between duration of diabetes and {Delta}CP was observed in the DM group (r = - 0.48; P < 0.02). The duration of diabetes was negatively correlated with C-peptide at 60 and 120 min (r = -0.42; P < 0.04 and r = -0.45; P < 0.03), but was positively correlated with glucagon at 30, 60, and 90 min (r = 0.53; P < 0.008, r = 0.41; P < 0.04, and r = 0.48; P < 0.02). Moreover, glucagon responses were significantly higher in long-term than short-term diabetes (AUC, 9029 ± 976 vs. 6074 ± 291 ng/L·min; P < 0.001; Fig. 2Go). Interestingly, no such difference was found in glucose responses. There was no significant difference in HgbA1c between the long- and short-term subgroups or in the duration of diabetes between the poorly and well controlled subgroups.



View larger version (19K):
[in this window]
[in a new window]
  		Figure 2. Plasma glucagon levels in patients with long-term and short-term diabetes during the Sustacal tests; mean ± SEM.

 
When the patients with short-term diabetes were separately compared to age-, BMI-, and sexual maturation-matched controls, the absolute C-peptide levels and {Delta}CP were not different ({Delta}CP, 1407 ± 199 vs. 1814 ± 222 pmol/L; P < 0.18). The glucagon responses were significantly lower in those with short-term diabetes than in the controls (AUC, 6074 ± 291 vs. 7811 ± 482 ng/L·min; P < 0.004). The plasma glucose concentrations were significantly higher in those with short-term diabetes than in the controls (AUC, 1108 ± 129 vs. 591 ± 13 mmol/L·min; P < 0.001).


   Discussion
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
 Discussion
References
 
The national rise of obesity in adolescents is thought to be associated with the increased incidence of type 2 DM among adolescents (1, 2, 3). The relationship between BMI and insulin/C-peptide levels has been well established (31, 32, 33). Our diabetes and control groups had a comparable mean BMI. Because insulin resistance occurs during pubertal development (34, 35), we also controlled for Tanner stages, which were comparable between the groups. Both groups were also matched for ethnicity. Sixty-seven percent of our DM patients were obese, 91.7% had a family history of type 2 DM, and 25% had acanthosis nigricans (AN), papillomatosis and hyperkeratosis of the skin (36). It was reported that up to 92% of children with type 2 DM are obese (1), 72–87% have positive family history of type 2 diabetes, and 60–90% have AN (1, 3, 37). The figures in adults are 51–59% (38), 66% (4), and 41% (36), respectively. All of these characteristics are risk factors for type 2 diabetes (1, 2, 3, 36). A nonstandardized method for the diagnosis of AN most likely was responsible for the different figures in our group (36). Moreover, it was observed that AN disappears in patients whose insulin secretion decreases as they progress to overt diabetes (39).

Fifty percent of our DM patients have been treated with oral agents or diet. The other 50% were started on insulin at the time of diagnosis (25% of these insulin-treated patients subsequently were able to maintain glycemic control with lower insulin dosage and oral agents); however, they had normal or higher than normal basal C-peptide levels. Our diabetes group had mean C-peptide levels comparable to those of Mexican-American children with type 2 DM (4). None of our patients had antibodies to GAD65. RIA for GAD65 autoantibodies has been reported to have diagnostic specificity as high as 90–99% (40, 41) and prevalence as high as 80–88% in new-onset type 1 DM in the 10–19 yr age group (42, 43). Compared with other autoantibodies in type 1 DM, GAD65 autoantibodies are present persistently years after diagnosis (40, 42). Therefore, we were convinced that our DM patients who have been treated with insulin were type 2.

We measured C-peptide because it is an excellent parameter for evaluating pancreatic ß-cell function (10), and half of our patients were receiving insulin therapy. It has equimolar secretion with insulin, longer half-life, and negligible hepatic clearance (10, 21). Some researchers prefer C-peptide concentrations to insulin concentrations in detecting changes in the ß-cell secretion of insulin. In our study, the impaired pancreatic ß-cell function was best characterized by the {Delta}CP. The contribution of insulin resistance to hyperglycemia in this study is difficult to analyze, because the mean C-peptide levels in DM patients were not different from those in controls, and the mean BMI of patients and controls were in the obesity range. Our data demonstrate that the DM patients were not able to secrete sufficient insulin to overcome their insulin resistance, whereas the controls were able to do so. It is possible that different genetic factors and life styles contribute to these different outcomes. However, the mean fasting C-peptide level in patients with diabetes was relatively higher than that in controls, suggesting relatively greater insulin resistance than in comparably obese controls. Our patients with short-term diabetes had similar C-peptide responses and {Delta}CP despite substantial hyperglycemia compared with the controls. This finding suggests that the short-term patients had an impairment in ß-cell function to secrete additional insulin to restore euglycemia (44). If first phase insulin release were measured, this impairment would be evident.

There was no suppression of glucagon secretion in our study, which is seen after glucose ingestion (45). It was previously found and suggested that the increase in plasma glucagon balances the potential of insulin-induced hypoglycemia, which may occur after the ingestion of a meal containing scant carbohydrate (46), and more reasonably, it is due to the protein component (46), a stimulus of glucagon secretion (17, 19, 45). With significant hyperglycemia in our diabetes patients, they should have secreted less glucagon to lower the plasma glucose concentration. In contrast, they had normal glucagon levels pre- and post-Sustacal ingestion. This condition has been referred to as relative hyperglucagonemia (45). This inappropriate glucagon secretion in our patients with type 2 DM may be explained by decreased sensitivity of the pancreatic {alpha}-cells to glucose from prolonged hyperglycemia [in a similar manner as glucose toxicity occurs in the ß-cells (10, 47)] or by decreased sensitivity of the {alpha}-cells to insulin [unlike type 1 diabetes, where absolute insulin deficiency leads to lack of inhibition of glucagon secretion (9, 17, 18, 19, 45, 48)]. The glucagon responses in our short-term patients were lower than those in the controls. This could be interpreted to indicate that {alpha}-cell function in the short-term patients remained intact. However, further investigation is needed to determine whether there is indeed normal {alpha}-cell function in the short-term patients.

Our study indicates that both pancreatic ß- and {alpha}-cell dysfunctions are present in children with type 2 diabetes and appear to be relative. Disease duration is an important determinant of the severity of the dysfunction. On the other hand, HgbA1c, an indicator of glycemic control, is related to the degree of Sustacal-stimulated glucose concentrations, not ß- and {alpha}-cell functions. Our results correspond to at least two recent studies in adults with type 2 DM. One showed that the ß-cell function is already 50% decreased at the time of the diagnosis and decreases progressively despite intensive therapy (49). The other study showed that the progressive deterioration of ß-cells occurs over time at the same rate in adults with 10-yr duration of DM and 13-yr duration of DM (secondary failure to oral hypoglycemic agents) independently of metabolic balance (50). The similarity between our data and those reported by the United Kingdom Prospective Diabetes Study Group (49) and Prando et al. (50) suggests a slowly progressing pathological process may be the etiology of type 2 diabetes.


   Acknowledgments
 
Dr. R. Jackson (Joslin Diabetes Clinic, Boston, MA) is gratefully acknowledged for measurement of GAD65 antibodies. Mr. I. Forson (Division of Endocrinology and Metabolism, Internal Medicine, State University of New York, Brooklyn, NY) and Ms. C. S. Juan (Division of Pediatric Endocrinology and Metabolism, Pediatrics, The Brookdale University Hospital and Medical Center, Brooklyn, NY) kindly performed the C-peptide and glucagon double antibody RIAs, respectively. We also are indebted to the clinic staff and patients of our pediatric endocrinology clinic, University Hospital of Brooklyn (Brooklyn, NY).

Received August 2, 2000.

Revised October 20, 2000.

Revised December 8, 2000.

Accepted December 13, 2000.


   References
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
 Discussion
 References
 

  1. Pinhas-Hamiel O, Dolan LM, Daniels SR, Standiford D, Khoury PR, Zeitler P. 1996 Increased incidence of non-insulin dependent diabetes mellitus among adolescents. J Pediatr. 128:608–615.[CrossRef][Medline]
  2. Rosenbloom AL, Young RS, Joe JR, Winter WE. 1999 Emerging epidemic of type 2 diabetes in youth. Diabetes Care. 22:345–354.[Abstract/Free Full Text]
  3. Glaser NS. 1997 Non-insulin-dependent diabetes mellitus in childhood and adolescence. Pediatr Clin North Am. 44:307–337.[CrossRef][Medline]
  4. Glaser NS, Jones KL. 1998 Non-insulin dependent diabetes mellitus in Mexican-American children. West J Med. 168:11–16.[Medline]
  5. Glaser NS, Araya A, McFeely ME, Jones KL. 1995 Non-insulin dependent diabetes mellitus in childhood. J Invest Med. 43(Suppl 1):134.A.
  6. Saad M, Pettitt DJ, Mott DM, Knowler WC, Nelson RG, Bennett PH. 1989 Sequential changes in serum insulin concentration during development of non-insulin-dependent diabetes. Lancet. 17:1356–1359.
  7. Banerji MA, Lebovitz HE. 1989 Insulin-sensitive and insulin-resistant variants in NIDDM. Diabetes. 38:784–792.[Abstract]
  8. Expert Committee on the Diagnosis and Classification of Diabetes Mellitus. 1997 Report of the expert committee on the diagnosis and classification of diabetes mellitus. Diabetes Care. 20:1183–1197.[Medline]
  9. Gerich JE. 1988 Abnormal glucagon secretion in type 2 (noninsulin-dependent) diabetes mellitus: Causes and consequences. In: Creutzfeldt W, Lefebvre PJ, eds. Diabetes mellitus: pathophysiology and therapy. Berlin: Springer-Verlag; 127–133.
  10. Polonsky KS. 1995 The ß-cell in diabetes. Diabetes. 44:705–717.[Abstract]
  11. Reaven GM. 1995 The fourth musketeer–from Alexandre Dumas to Claude Bernard. Diabetologia. 38:3–13.[Medline]
  12. Muller WA, Faloona GR, Unger RH. 1973 Hyperglucagonemia in diabetic ketoacidosis: its prevalence and significance. Am J Med. 54:52–57.[CrossRef][Medline]
  13. Onur K, Lala V, Juan CS, AvRuskin TW. 1979 Glucagon suppression with low-dose intramuscular insulin therapy in diabetic ketoacidosis. J Pediatr. 94:307–311.[CrossRef][Medline]
  14. Lindsey CA, Faloona GR, Unger RH. 1974 Plasma glucagon in nonketotic hyperosmolar coma. JAMA. 229:1771–1773.[CrossRef][Medline]
  15. Reaven GM, Chen Y-DI, Golay A, Swislocki ALM, Jaspan JB. 1987 Documentation of hyperglucagonemia throughout the day in nonobese and obese patients with noninsulin-dependent diabetes mellitus. J Clin Endocrinol Metab. 64:106–110.[Abstract]
  16. AvRuskin TW, Obilessetty V, Jabbar M, et al. 1994 Both glucagon excess and insulin deficiency characterize maturity-onset diabetes mellitus of youth (MODY). J Pediatr Endocrinol Metab. 7:335–341.
  17. Lefebvre PJ. 1995 Glucagon and its family revisited. Diabetes Care. 18:715–730.[Medline]
  18. Unger RH. 1985 Glucagon physiology and pathophysiology in the light of new advances. Diabetologia. 28:574–578.[Medline]
  19. Unger RH. 1978 Role of glucagon in the pathogenesis of diabetes: the status of the controversy. Metabolism. 27:1691–1709.[CrossRef][Medline]
  20. Diabetes Control and Complications Trial. 1986 Design and methodologic considerations for the feasibility phase. Diabetes. 35:530–545.[Abstract]
  21. Gjessing HJ. 1992 C-Peptide used in the estimation of islet ß-cell function in diabetes. Dan Med Bull. 39:438–452.[Medline]
  22. National Center for Health Statistics. Najjar M, Rowland M. 1987 NCHS. Anthropometric reference data and prevalence of overweight: United States. Vital and Health Statistics, series 11, no. 238. Washington DC: U.S. Government Printing Office. DHHS Publication (PHS) 87–1688.
  23. Marena S, Montegrosso G, Michieli FD, Pisu E, Pagano G. 1992 Comparison of the metabolic affects of mixed meal and standard oral glucose tolerance test on glucose, insulin and C-peptide response in healthy, impaired glucose tolerance, mild and severe non-insulin-dependent diabetic subjects. Acta Diabetol. 29:29–33.[CrossRef][Medline]
  24. Munro BH. 1997 Statistical methods for health care research, ed 3. Philadelphia: Lippincott-Raven; 105–106.
  25. Munro BH. 1997 Repeated measures analysis of variance. In: Zuccarini M, Cotlier E, Metzger G, eds. Statistical methods for health care research, ed 3. Philadelphia: Lippincott-Raven; 202–223.
  26. Godfrey K. 1985 Statistics in practice: comparing the means of several groups. N Engl J Med. 313:1450–1456.[Abstract]
  27. Munro BH. 1997 Analysis of covarience. In: Zuccarini M, Cotlier E, Metzger G, eds. Statistical methods for health care research, ed 3. Philadelphia: Lippincott-Raven; 188–201.
  28. American Diabetes Association. 2000 Implications of the diabetes control and complications trial. Diabetes Care. 23:S24–S26.
  29. American Diabetes Association. 2000 Standards of medical care for patients with diabetes mellitus. Diabetes Care. 23:S32–S42.
  30. Diabetes Control and Complications Trial Research Group. 1993 The effect of intensive treatment of diabetes on the development and progression of long-term complications in insulin-dependent diabetes mellitus. N Engl J Med. 329:977–986.[Abstract/Free Full Text]
  31. Bagdade JD, Bierman EL, Porte D. 1967 The significant of basal insulin levels in the evaluation of the insulin response to glucose in diabetic and nondiabetic subjects. J Clin Invest. 46:1549–1557.
  32. Relimpio F, Losada F, Pumar A, et al. 1997 Relationships of C-peptide levels and the C-peptide/bloodsugar ratio with clinical/biochemical variables associated with insulin resistance in orally-treated, well-controlled type 2 diabetic patients. Diabetes Res Clin Pract. 36:173–180.[CrossRef][Medline]
  33. Park SW, Ihm SH, Yoo HJ, Park JY, Lee KU. 1997 Differential effects of ambient blood glucose level and degree of obesity on basal serum C-peptide level and the C-peptide response to glucose and glucagon in non-insulin-dependent diabetes mellitus. Diabetes Res Clin Pract. 37:165–171.[CrossRef][Medline]
  34. Caprio S, Plewe G, Diamond MP, et al. 1989 Increased insulin secretion in puberty: a compensatory response to reductions in insulin sensitivity. J Pediatr. 114:963–967.[CrossRef][Medline]
  35. Polau N, Ilanez L, Rique S, Carrascosa A. 1997 Pubertal changes in insulin secretion and peripheral insulin sensitivity. Horm Res. 48:219–226.[Medline]
  36. Burke JP, Hale DE, Hazuda HP, Stern MP. 1999 A quantitative scale of acanthosis nigicans. Diabetes Care. 22:1655–1659.[Abstract/Free Full Text]
  37. American Diabetes Association. 2000 Type 2 diabetes in children and adolescents. Diabetes Care. 23:381–389.[Medline]
  38. Bray GA. 1992 Obesity increases risk for diabetes. Int J Obesity. 16(Suppl 4):S13–S17.
  39. Stuart CA, Gilkison CR, Smith MM, Bosma AM, Keenan BS, Nagamani M. 1998 Acanthosis nigricans as a risk factor for non-insulin dependent diabetes mellitus. Clin Pediatr. 37:73–80.
  40. Leslie RDG, Atkinson MA, Notkins AL. 1999 Autoantigens IA-2 and GAD in type 1 (insulin-dependent) diabetes. Diabetologia. 42:3–14.[CrossRef][Medline]
  41. Verge CF, Stenger D, Bonifacio E, et al. 1998 Combined use of autoantibodies (IA-2 autoantibody, GAD autoantibody, insulin autoantibody, cytoplasmic islet cell antibodies) in type 1 diabetes. Diabetes. 47:1857–1866.[Abstract]
  42. Vandewalle CL, Falorni A, Svanholm S, et al. 1995 High diagnostic sensitivity of glutamate decarboxylase autoantibodies in insulin-dependent diabetes mellitus with clinical onset between age 20 and 40 years. J Clin Endocrinol Metab. 80:846–581.[Abstract]
  43. Gorus FK, Goubert P, Semakula C, et al. 1997 IA-2-autoantibodies complement GAD65-autoantibodies in new-onset IDDM patients and help predict impending diabetes in their siblings. Diabetologia. 40:95–99.[CrossRef][Medline]
  44. Porte D. 1991 ß-Cells in type II diabetes mellitus. Diabetes. 40:166–180.[Abstract]
  45. Muller WA, Faloona GR, Aguilar-Parada E, Unger RH. 1970 Abnormal {alpha}-cell function in diabetes: response to carbohydrate and protein ingestion. N Engl J Med. 283:109–115.
  46. Mackes K, Rizza R, Gerich J. 1981 Effect of intermittent physiologic hyperglucagonemia on postprandial plasma glucose levels in normal man. Metab Clin Exp. 30:1042–1044.
  47. Gjessing HJ, Reinhold B, Pederson O. 1992 The effect of chronic hyperglycemia on the islet B-cell responsiveness in newly diagnosed type 2 diabetes. Diabetic Med. 9:601–604.[Medline]
  48. Lefebvre P, Paolisso G, Scheen A. 1991 The role of glucagon in non-insulin-dependent (type 2) diabetes mellitus. In: Sakamoto N, Angel A, Hotta N, eds. New directions in research and clinical works for obesity and diabetes mellitus, Amsterdam: Elsevier; 25–29.
  49. U.K. Prospective Diabetes Study Group. 1995 Perspective in diabetes: U.K. Prospective Diabetes Study 16–overview of 6 years’ therapy of type II diabetes. Diabetes. 44:1249–1258.[Abstract]
  50. Prando R, Odetti P, Melga P, Giusti R, Ciuchi E, Cheli V. 1996 Progressive deterioration of ß-cell function in nonobese type 2 diabetic subjects. Diabetes Metab. 22:185–191.[Medline]



This article has been cited by other articles:


Home page
 J. Clin. Endocrinol. Metab.Home page
D. A. Elder, R. L. Prigeon, R. P. Wadwa, L. M. Dolan, and D. A. D'Alessio
{beta}-Cell Function, Insulin Sensitivity, and Glucose Tolerance in Obese Diabetic and Nondiabetic Adolescents and Young Adults
J. Clin. Endocrinol. Metab., January 1, 2006; 91(1): 185 - 191.
[Abstract] [Full Text] [PDF]

Home page
 Diabetes CareHome page
N. Gungor, F. Bacha, R. Saad, J. Janosky, and S. Arslanian
Youth Type 2 Diabetes: Insulin resistance, {beta}-cell failure, or both?
Diabetes Care, March 1, 2005; 28(3): 638 - 644.
[Abstract] [Full Text] [PDF]

This Article
Right arrow Abstract Freely available
Right arrow Full Text (PDF)
Right arrow Submit a related Letter to the Editor
Right arrow Purchase Article
Right arrow View Shopping Cart
Right arrow Alert me when this article is cited
Right arrow Alert me when eLetters are posted
Right arrow Alert me if a correction is posted
Right arrow Citation Map
Services
Right arrow Email this article to a friend
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Right arrow Request Copyright Permission
Citing Articles
Right arrow Citing Articles via HighWire
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Umpaichitra, V.
Right arrow Articles by Castells, S.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Umpaichitra, V.
Right arrow Articles by Castells, S.

HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS
Endocrinology Endocrine Reviews J. Clin. End. & Metab.
Molecular Endocrinology Recent Prog. Horm. Res. All Endocrine Journals