The pathophysiology of diabetes involves a defective amplification of the late-phase insulin response to glucose by glucose-dependent insulinotropic polypeptide-regardless of etiology and phenotype.
The effect of the insulinotropic incretin hormone, glucagon-like peptide-1 (GLP-1), is preserved in typical middle-aged, obese, insulin-resistant type 2 diabetic patients, whereas a defective amplification of the so-called late-phase plasma insulin response (20-120 min) to glucose by the other incretin hormone, glucose-dependent insulinotropic polypeptide (GIP), is seen in these patients. The aim of the present investigation was to evaluate plasma insulin and C-peptide responses to GLP-1 and GIP in five groups of diabetic patients with etiology and phenotype distinct from the obese type 2 diabetic patients. We studied (six in each group): 1) patients with diabetes mellitus secondary to chronic pancreatitis; 2) lean type 2 diabetic patients (body mass index < 25 kg/m(2)); 3) patients with latent autoimmune diabetes in adults; 4) diabetic patients with mutations in the HNF-1alpha gene [maturity-onset diabetes of the young (MODY)3]; and 5) newly diagnosed type 1 diabetic patients. All participants underwent three hyperglycemic clamps (2 h, 15 mM) with continuous infusion of saline, 1 pmol GLP-1 (7-36)amide/kg body weight.min or 4 pmol GIP pmol/kg body weight.min. The early-phase (0-20 min) plasma insulin response tended to be enhanced by both GIP and GLP-1, compared with glucose alone, in all five groups. In contrast, the late-phase (20-120 min) plasma insulin response to GIP was attenuated, compared with the plasma insulin response to GLP-1, in all five groups. Significantly higher glucose infusion rates were required during the late phase of the GLP-1 stimulation, compared with the GIP stimulation. In conclusion, lack of GIP amplification of the late-phase plasma insulin response to glucose seems to be a consequence of diabetes mellitus, characterizing most, if not all, forms of diabetes.
Vilsbøll
T
T
Department of Internal Medicine F, Gentofte Hospital, DK-2900 Hellerup, Denmark. tivi@gentoftehosp.kbhamt.dk
Knop
F K
FK
Krarup
T
T
Johansen
A
A
Madsbad
S
S
Larsen
S
S
Hansen
T
T
Pedersen
O
O
Holst
J J
JJ
D000328:Adult; D000368:Aged; D001786:Blood Glucose / Q000378:metabolism*; D002096:C-Peptide / Q000097:blood; D002908:Chronic Disease; D004268:DNA-Binding Proteins; D003922:Diabetes Mellitus, Type 1 / Q000209:etiology / Q000235:genetics / Q000378:metabolism / Q000503:physiopathology*; D003924:Diabetes Mellitus, Type 2 / Q000209:etiology / Q000235:genetics / Q000378:metabolism / Q000503:physiopathology*; D005260:Female; D005749:Gastric Inhibitory Polypeptide / Q000008:administration & dosage / Q000097:blood; D005934:Glucagon / Q000097:blood*; D052216:Glucagon-Like Peptide 1; D004763:Glucagon-Like Peptides; D005947:Glucose / Q000008:administration & dosage; D051537:Hepatocyte Nuclear Factor 1; D051538:Hepatocyte Nuclear Factor 1-alpha; D051539:Hepatocyte Nuclear Factor 1-beta; D006801:Humans; D006943:Hyperglycemia / Q000235:genetics / Q000378:metabolism / Q000503:physiopathology; D007328:Insulin / Q000097:blood*; D007515:Islets of Langerhans / Q000187:drug effects / Q000378:metabolism; D008297:Male; D008875:Middle Aged; D018377:Neurotransmitter Agents / Q000008:administration & dosage / Q000097:blood; D009687:Nuclear Proteins; D010195:Pancreatitis / Q000150:complications; D010446:Peptide Fragments / Q000008:administration & dosage / Q000097:blood*; D010641:Phenotype; D011498:Protein Precursors / Q000097:blood*; D014157:Transcription Factors / Q000235:genetics
D001786:Blood Glucose; D002096:C-Peptide; D004268:DNA-Binding Proteins; C496487:HNF1A protein, human; C496495:HNF1B protein, human; D051538:Hepatocyte Nuclear Factor 1-alpha; D007328:Insulin; D018377:Neurotransmitter Agents; D009687:Nuclear Proteins; D010446:Peptide Fragments; D011498:Protein Precursors; D014157:Transcription Factors; C055453:glucagon-like peptide 1 (7-36)amide; D051537:Hepatocyte Nuclear Factor 1; D051539:Hepatocyte Nuclear Factor 1-beta; D005749:Gastric Inhibitory Polypeptide; D004763:Glucagon-Like Peptides; D052216:Glucagon-Like Peptide 1; D005934:Glucagon; D005947:Glucose