Separate impact of obesity and glucose tolerance on the incretin effect in normal subjects and type 2 diabetic patients.
OBJECTIVE
To quantitate the separate impact of obesity and hyperglycemia on the incretin effect (i.e., the gain in beta-cell function after oral glucose versus intravenous glucose).


METHODS
Isoglycemic oral (75 g) and intravenous glucose administration was performed in 51 subjects (24 with normal glucose tolerance [NGT], 17 with impaired glucose tolerance [IGT], and 10 with type 2 diabetes) with a wide range of BMI (20-61 kg/m(2)). C-peptide deconvolution was used to reconstruct insulin secretion rates, and beta-cell glucose sensitivity (slope of the insulin secretion/glucose concentration dose-response curve) was determined by mathematical modeling. The incretin effect was defined as the oral-to-intravenous ratio of responses. In 8 subjects with NGT and 10 with diabetes, oral glucose appearance was measured by the double-tracer technique.


RESULTS
The incretin effect on total insulin secretion and beta-cell glucose sensitivity and the GLP-1 response to oral glucose were significantly reduced in diabetes compared with NGT or IGT (P <or= 0.05). The results were similar when subjects were stratified by BMI tertile (P <or= 0.05). In the whole dataset, each manifestation of the incretin effect was inversely related to both glucose tolerance (2-h plasma glucose levels) and BMI (partial r = 0.27-0.59, P <or= 0.05) in an independent, additive manner. Oral glucose appearance did not differ between diabetes and NGT and was positively related to the GLP-1 response (r = 0.53, P < 0.01). Glucagon suppression during the oral glucose tolerance test was blunted in diabetic patients.


CONCLUSIONS
Potentiation of insulin secretion, glucose sensing, glucagon-like peptide-1 release, and glucagon suppression are physiological manifestations of the incretin effect. Glucose tolerance and obesity impair the incretin effect independently of one another.
Muscelli
Elza
E
Department of Internal Medicine, Consiglio Nazionale delle Ricerche (CNR), Institute of Clinical Physiology, University of Pisa, Italy.
Mari
Andrea
A
Casolaro
Arturo
A
Camastra
Stefania
S
Seghieri
Giuseppe
G
Gastaldelli
Amalia
A
Holst
Jens J
JJ
Ferrannini
Ele
E
D000328:Adult; D001786:Blood Glucose / Q000378:metabolism*; D015992:Body Mass Index; D003924:Diabetes Mellitus, Type 2 / Q000097:blood* / Q000150:complications / Q000188:drug therapy; D005260:Female; D005951:Glucose Tolerance Test; D006801:Humans; D007004:Hypoglycemic Agents / Q000627:therapeutic use; D007328:Insulin / Q000097:blood / Q000378:metabolism; D000078790:Insulin Secretion; D050417:Insulin-Secreting Cells / Q000502:physiology; D008297:Male; D008875:Middle Aged; D009765:Obesity / Q000150:complications / Q000503:physiopathology*; D012016:Reference Values
D001786:Blood Glucose; D007004:Hypoglycemic Agents; D007328:Insulin