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Glucagon is believed to be a pancreas-specific hormone, and hyperglucagonemia has been shown to contribute significantly to the hyperglycemic state of patients with diabetes. This hyperglucagonemia has been thought to arise from α-cell insensitivity to suppressive effects of glucose and insulin combined with reduced insulin secretion. We hypothesized that postabsorptive hyperglucagonemia represents a gut-dependent phenomenon and subjected 10 totally pancreatectomized patients and 10 healthy control subjects to a 75-g oral glucose tolerance test and a corresponding isoglycemic intravenous glucose infusion. We applied novel analytical methods of plasma glucagon (sandwich ELISA and mass spectrometry-based proteomics) and show that 29-amino acid glucagon circulates in patients without a pancreas and that glucose stimulation of the gastrointestinal tract elicits significant hyperglucagonemia in these patients. These findings emphasize the existence of extrapancreatic glucagon (perhaps originating from the gut) in man and suggest that it may play a role in diabetes secondary to total pancreatectomy. [ABSTRACT FROM AUTHOR]

The incretin effect is preserved in patients with chronic pancreatitis (CP) and normal glucose tolerance (NGT), but reduced in patients with CP and secondary diabetes mellitus (DM). In order to evaluate the pathophysiology of this deficiency we investigated the insulinotropic properties of the incretin hormones, glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP), in 8 patients with CP and NGT (fasting plasma glucose (FPG): 5.5 (4.5-6.0) mM (mean (range); HbA[sub 1c]: 5.8 (5.4-6.3) %; plasma glucose 120 min following 75-g oral glucose tolerance test: 5.9 (4.7-7.7) mM) and 8 patients with CP and secondary DM (FPG: 7.1 (6.0-8.8) mM; HbA[sub 1c]: 7.0(5.8-10.0) %). In a randomized and single-blinded design each patient underwent 3 (3 separate days) 2-hour 15 mM-hyperglycemic clamps with continuous infusion of saline, GLP-1 (1 pmol/kg body weight/min) or GIP (8 pmol/kg body weight/min). The initial (0-20 min) plasma insulin and C-peptide responses were enhanced significantly in both groups by GLP-1 and GIP, respectively, compared to saline (P < 0.05). In both groups GLP-1 infusion resulted in significantly greater insulin and C-peptide responses from 20-120 minutes compared with saline infusion (CP +NGT: 10.7 ± 2.5 and 3.4 ± 0.4 fold; CP+DM: 7.2±2.3 and 3.5 ± 0.4 fold). During GIP infusion the late-phase insulin response (20-120 min) was 3.1 ± 1.0 fold greater than during saline infusion in the group of patients with CP and NGT (P < 0.05) whereas the corresponding late-phase insulin responses in patients with CP and DM did not differ 1.3±0.2 (p = NS). In conclusion, the impaired GIP amplification of the late-phase insulin response to glucose as previously observed in patients with type 2 diabetes mellitus (T2DM) is developing along with diabetic glucose tolerance in patients with CP, suggesting it to be a consequence of the diabetic state and not a primary event leading to T2DM. [ABSTRACT FROM AUTHOR]