Relationship between Insulin Secretion and Pancreas Morphology in Subjects with Chronic Pancreatitis

Glucagon-like peptide-1 (GLP-1) promotes insulin release; however, the relationship between the GLP-1 signal and chronic pancreatitis is not well understood. Here we focus on chemokine (C-C motif) ligand 2 (CCL2) and its receptor (CCR2) axis, which regulates various immune cells, including macrophages, to clarify the mechanism of GLP-1-mediated insulin secretion in chronic pancreatitis in mice. One and multiple series of repetitive cerulein administrations were used to induce acute and chronic cerulein pancreatitis, respectively. Acute cerulein-administered CCR2-knockout (KO) mice showed suppressed infiltration of CD11b+Gr-1low macrophages and pancreatic inflammation and significantly upregulated insulin secretion compared with paired wild-type (WT) mice. However, chronic cerulein-administered CCR2-KO mice showed significantly increased infiltration of CD11b+/Gr-1− and CD11b+/Gr-1high cells, but not CD11b+/Gr-1low cells, in pancreas with severe inflammation and significantly decreased insulin secretion compared with their WT counterparts. Furthermore, although serum GLP-1 levels in chronic cerulein-administered WT and CCR2-KO mice were comparably upregulated after cerulein administrations, GLP-1 receptor levels in pancreases of chronic cerulein-administered CCR2-KO mice were significantly lower than in paired WT mice. Nevertheless, a significantly higher hyperglycemia level in chronic cerulein-administered CCR2-KO mice was markedly restored by treatment with a GLP-1 analog to a level comparable to the paired WT mice. Collectively, the CCR2/CCL2 axis-mediated CD11b+-cell migration to the pancreas is critically involved in chronic pancreatitis-mediated hyperglycemia through the modulation of GLP-1 receptor expression and insulin secretion.

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Increased postprandial responses of GLP-1 and GIP in patients with chronic pancreatitis and steatorrhea following pancreatic enzyme substitution

AJP Endocrinology and Metabolism ◽

10.1152/ajpendo.00059.2006 ◽

2007 ◽

Vol 292 (1) ◽

pp. E324-E330 ◽

Cited By ~ 64

Author(s):

Filip K. Knop ◽

Tina Vilsbøll ◽

Steen Larsen ◽

Patricia V. Højberg ◽

Aage Vølund ◽

...

Keyword(s):

Insulin Secretion ◽

Chronic Pancreatitis ◽

Pancreatic Enzyme ◽

Control Group ◽

Β Cell ◽

Exocrine Insufficiency ◽

Liquid Meal ◽

Postprandial Plasma Glucose ◽

Glucagon Like Peptide 1 ◽

Pancreatic Enzyme Substitution

We aimed to investigate how assimilation of nutrients affects the postprandial responses of glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP) and to evaluate the effect of pancreatic enzyme substitution (PES) on insulin secretion in patients with chronic pancreatitis (CP) and pancreatic exocrine insufficiency (PEI). Eight male patients with CP and PEI were studied. Blood was sampled frequently on two separate days after ingestion of a liquid meal with and without PES, respectively. Eight healthy male subjects served as a control group. β-Cell responsiveness was estimated as changes in insulin secretion rates in response to changes in postprandial plasma glucose (PG). There was no difference in the PG incremental area under curve (AUC) for patients with and without PES [406 ± 100 vs. 425 ± 80 mM·4 h (mean ± SE), P = 0.8]. The response of total GLP-1 was higher after PES (AUC: 7.8 ± 1.2 vs. 5.3 ± 0.6 nM·4 h, P = 0.01), as was the response of total GIP (AUC: 32.7 ± 7.5 vs. 21.1 ± 8.3 nM·4 h, P = 0.01). Concurrently, both plasma insulin, plasma C-peptide, and total insulin secretion increased after PES (AUC: 17.7 ± 4.2 vs. 13.6 ± 2.9 nM·4 h, P = 0.02; 237 ± 31.4 vs. 200 ± 27.4 nM·4 h, P = 0.005; and 595 ± 82 vs. 497 ± 80 pmol·kg−1·4 h, P = 0.01, respectively). β-Cell responsiveness to glucose was not significantly different on the two study days for patients with CP. These results suggest that the secretion of GLP-1 and GIP is under influence of the digestion and absorption of nutrients in the small intestine and that PES increases insulin secretion.

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