Impaired incretin-induced amplification of insulin secretion after glucose homeostatic dysregulation in healthy subjects.
OBJECTIVE
The insulinotropic effect of the incretin hormones, glucose-dependent insulinotropic polypeptide (GIP), and glucagon-like peptide-1 (GLP-1) is impaired in patients with type 2 diabetes. It remains unclear whether this impairment is a primary pathophysiological trait or a consequence of developing diabetes. Therefore, we aimed to investigate the insulinotropic effect of GIP and GLP-1 compared with placebo before and after 12 d of glucose homeostatic dysregulation in healthy subjects.


METHODS
The insulinotropic effect was measured using hyperglycemic clamps and infusion of physiological doses of GIP, GLP-1, or saline in 10 healthy Caucasian males before and after intervention using a high-calorie diet, sedentary lifestyle, and administration of prednisolone (37.5 mg once daily) for 12 d.


RESULTS
The intervention resulted in increased insulin resistance according to the homeostatic model assessment (1.2 ± 0.2 vs. 2.6 ± 0.5, P = 0.01), and glucose tolerance deteriorated as assessed by the area under curve for plasma glucose during a 75-g oral glucose tolerance test (730 ± 30 vs. 846 ± 57 mm for 2 h, P = 0.021). The subjects compensated for the change in insulin resistance by significantly increasing their postintervention insulin responses during saline infusion by 2.9 ± 0.5-fold (P = 0.001) but were unable to do so in response to incretin hormones (which caused insignificant increases of only 1.78 ± 0.3 and 1.38 ± 0.3-fold, P value not significant).


CONCLUSIONS
These data show that impairment of the insulinotropic effect of both GIP and GLP-1 can be induced in healthy male subjects without risk factors for type 2 diabetes, indicating that the reduced insulinotropic effect of the incretin hormones observed in type 2 diabetes most likely is a consequence of insulin resistance and glucose intolerance rather than a primary event causing the disease.
Department of Clinical Physiology, Glostrup Hospital, University of Copenhagen, Nordre Ringvej 57, DK-2600 Glostrup, Denmark. kbaggehansen@dadlnet.dk
Katrine B
KB
Hansen
Tina
T
Vilsbøll
Jonatan I
JI
Bagger
Jens J
JJ
Holst
Filip K
FK
Knop
D000328:Adult; D001786:Blood Glucose / Q000032:analysis; D002096:C-Peptide / Q000097:blood; D005749:Gastric Inhibitory Polypeptide / Q000008:administration & dosage / Q000097:blood / Q000378:metabolism*; D005934:Glucagon / Q000097:blood; D052216:Glucagon-Like Peptide 1 / Q000008:administration & dosage / Q000097:blood / Q000378:metabolism*; D015309:Glucose Clamp Technique; D018149:Glucose Intolerance / Q000097:blood / Q000378:metabolism* / Q000503:physiopathology; D005951:Glucose Tolerance Test; D006801:Humans; D054795:Incretins / Q000008:administration & dosage / Q000097:blood / Q000378:metabolism*; D007262:Infusions, Intravenous; D007328:Insulin / Q000097:blood / Q000378:metabolism*; D007333:Insulin Resistance; D000078790:Insulin Secretion; D050417:Insulin-Secreting Cells / Q000378:metabolism; D007700:Kinetics; D008297:Male; D012720:Severity of Illness Index; D055815:Young Adult
D001786:Blood Glucose; D002096:C-Peptide; D054795:Incretins; D007328:Insulin; D005749:Gastric Inhibitory Polypeptide; D052216:Glucagon-Like Peptide 1; D005934:Glucagon