Youth type 2 diabetes: insulin resistance, beta-cell failure, or both?
OBJECTIVE
This study evaluates insulin sensitivity, pancreatic beta-cell function (BCF), and the balance between the two in youth with type 2 diabetes and assesses the relationship of diabetes duration and HbA(1c) to insulin sensitivity and BCF.


METHODS
The subjects were 14 adolescents with type 2 diabetes and 20 obese control subjects of comparable age, BMI, body composition, and puberty. Insulin sensitivity was evaluated with a 3-h hyperinsulinemic (80 mU . m(-2) . min(-1)) euglycemic clamp. First-phase insulin secretion (FPIS) and second-phase insulin secretion (SPIS) were evaluated with a 2-h hyperglycemic (12.5 mmol/l) clamp. Fasting glucose rate of appearance was determined with the use of [6,6-(2)H(2)]glucose.


RESULTS
Fasting glucose rate of appearance was higher in type 2 diabetic patients than in obese control subjects (16.5 +/- 1.1 vs. 12.3 +/- 0.5 micromol . kg(-1) . min(-1); P = 0.002). Insulin sensitivity was lower in type 2 diabetic patients than in obese control subjects (1.0 +/- 0.1 vs. 2.0 +/- 0.2 micromol . kg(-1) . min(-1) per pmol/l; P = 0.001). Fasting insulin was higher in type 2 diabetic patients than in obese control subjects (289.8 +/- 24.6 vs. 220.2 +/- 18.0 pmol/l; P = 0.007), and FPIS and SPIS were lower (FPIS: 357.6 +/- 42.0 vs. 1,365.0 +/- 111.0 pmol/l; SPIS: 652.2 +/- 88.8 vs. 1,376.4 +/- 88.8 pmol/l; P < 0.001 for both). The glucose disposition index (GDI = insulin sensitivity x FPIS) was approximately 86% lower in type 2 diabetic patients than in obese control subjects. HbA(1c) correlated with FPIS (r = -0.61, P = 0.025) with no relationship to insulin sensitivity.


CONCLUSIONS
Despite the impairment in both insulin sensitivity and BCF in youth with type 2 diabetes, the magnitude of the derangement is greater in BCF than insulin sensitivity when compared with that in obese control subjects. The inverse relationship between BCF and HbA(1c) may either reflect the impact of deteriorating BCF on glycemic control or be a manifestation of a glucotoxic phenomenon on BCF. Future studies in youth type 2 diabetes should target the natural course of beta-cell failure and means of retarding and/or preventing it.
Gungor
Neslihan
N
Division of Pediatric Endocrinology, Children's Hospital of Pittsburgh, 3705 Fifth Ave. at DeSoto St., Pittsburgh, PA 15213, USA.
Bacha
Fida
F
Saad
Rola
R
Janosky
Janine
J
Arslanian
Silva
S
D052242:Adiponectin; D000293:Adolescent; D001786:Blood Glucose / Q000378:metabolism; D001823:Body Composition; D015992:Body Mass Index; D003924:Diabetes Mellitus, Type 2 / Q000097:blood / Q000503:physiopathology*; D005260:Female; D006801:Humans; D007333:Insulin Resistance; D036341:Intercellular Signaling Peptides and Proteins / Q000097:blood; D007515:Islets of Langerhans / Q000503:physiopathology*; D008297:Male; D009765:Obesity / Q000097:blood / Q000503:physiopathology*
D052242:Adiponectin; D001786:Blood Glucose; D036341:Intercellular Signaling Peptides and Proteins
Diabetes Care. 2000 Mar;23(3):381-9
10868870
J Pediatr. 2001 Jan;138(1):38-44
11148510
J Clin Endocrinol Metab. 2001 Jan;86(1):66-71
11231980
J Clin Endocrinol Metab. 2001 Apr;86(4):1605-9
11297591
J Clin Endocrinol Metab. 2001 May;86(5):1930-5
11344187
J Clin Endocrinol Metab. 2001 Sep;86(9):4047-58
11549624
J Clin Endocrinol Metab. 2003 Jun;88(6):2534-40
12788850
J Pediatr. 2004 Jan;144(1):47-55
14722518
Diabetes Care. 2004 Feb;27(2):547-52
14747242
J Pediatr. 2004 May;144(5):656-9
15127006
Nutr Rev. 1981 Feb;39(2):43-55
7010232
Diabetes. 1990 Mar;39(3):283-8
2407581
Am J Med. 1991 Feb;90(2):229-35
1996593
Diabetes Care. 1992 Oct;15(10):1295-302
1425092
N Engl J Med. 1993 Dec 30;329(27):1988-92
8247074
Am J Physiol. 1997 Apr;272(4 Pt 1):E523-9
9142870
Diabet Med. 1998 Apr;15(4):290-6
9585393
Diabet Med. 1998 Apr;15(4):297-303
9585394
Diabetes Res Clin Pract. 1998 Jul;40 Suppl:S21-5
9740498
Diabetes Care. 1999 Apr;22(4):609-14
10189540
Diabetes Care. 1999 Aug;22(8):1325-9
10480778
J Clin Invest. 1999 Sep;104(6):787-94
10491414
Metabolism. 2000 Feb;49(2):186-91
10690942
Arterioscler Thromb Vasc Biol. 2000 Jun;20(6):1595-9
10845877
Diabetes. 2000 Jun;49(6):975-80
10866050