Inhibition of dipeptidyl peptidase-4 reduces glycemia, sustains insulin levels, and reduces glucagon levels in type 2 diabetes.
The stimulation of insulin vs. inhibition of glucagon secretion in relation to the antidiabetic action of glucagon-like peptide-1 (GLP-1) is not established. Here, the influence of a 4-wk increase in circulating GLP-1 by inhibition of dipeptidyl peptidase-4 (DPP-4) on 24-h glucose and insulin and glucagon responses to breakfast was studied in subjects with dietary controlled diabetes [age: 65 +/- 8 yr (SD), body mass index: 27.3 +/- 3.3 kg/m(2), fasting plasma glucose: 9.0 +/- 1.3 mmol/liter]. Compared with placebo (n = 19), a specific DPP-4 inhibitor [(1-[[(3-hydroxy-1-adamantyl) amino] acetyl]-2-cyano-(S)-pyrrolidine) (LAF237); 100 mg daily, n = 18] reduced fasting glucose by 0.70 mmol/liter (P = 0.037), 4-h prandial glucose excursion by 1.45 mmol/liter (P < 0.001), and mean 24-h glucose by 0.93 mmol/liter (P < 0.001). Baseline and postprandial active GLP-1 were increased by LAF237. The glucagon response to breakfast was reduced by LAF237 (glucagon levels at 60 min were 88 +/- 8 pg/ml before treatment vs. 77 +/- 5 pg/ml after; P = 0.001). In contrast, the overall insulin levels were not altered. The 4-wk reduction in glucagon correlated with the reduction in 2-h glucose (r = 0.61; P = 0.008). No such association was observed for insulin. Thus, improved metabolic control by DPP-4 inhibition in type 2 diabetes is seen in association with reduced glucagon levels and, despite the lower glycemia, unaltered insulin levels.
Ahrén
Bo
B
Department of Medicine, Lund University B11 Biomedical Centre, SE-21184 Lund, Sweden.
Landin-Olsson
Mona
M
Jansson
Per-Anders
PA
Svensson
Maria
M
Holmes
David
D
Schweizer
Anja
A
D000218:Adamantane / Q000009:adverse effects / Q000031:analogs & derivatives / Q000627:therapeutic use*; D000368:Aged; D001786:Blood Glucose / Q000378:metabolism*; D001835:Body Weight / Q000187:drug effects; D002940:Circadian Rhythm; D003924:Diabetes Mellitus, Type 2 / Q000097:blood* / Q000188:drug therapy*; D018819:Dipeptidyl Peptidase 4 / Q000187:drug effects*; D004435:Eating; D004791:Enzyme Inhibitors / Q000009:adverse effects / Q000627:therapeutic use*; D005260:Female; D005934:Glucagon / Q000097:blood*; D006442:Glycated Hemoglobin / Q000378:metabolism; D006801:Humans; D007328:Insulin / Q000097:blood*; D008055:Lipids / Q000097:blood; D008297:Male; D008875:Middle Aged; D011759:Pyrrolidines / Q000009:adverse effects / Q000627:therapeutic use*
D000218:Adamantane; D001786:Blood Glucose; D018819:Dipeptidyl Peptidase 4; D004791:Enzyme Inhibitors; D005934:Glucagon; D006442:Glycated Hemoglobin; D007328:Insulin; D008055:Lipids; D011759:Pyrrolidines; C475520:1-(((3-hydroxy-1-adamantyl)amino)acetyl)-2-cyanopyrrolidine