Mechanism of exocrine pancreatic insufficiency in streptozotocin-induced type 1 diabetes mellitus

Rekha Patel, Amil Shervington, Jose A. Pariente, Maria A. Martinez-Burgos, Gines M. Salido, Ernest Adeghate, Jaipaul Singh

Research output: Chapter in Book/Report/Conference proceedingConference contribution

41 Citations (Scopus)

Abstract

Diabetes mellitus (DM) is a major health problem at present affecting about 180 million people worldwide. DM is associated with many metabolic abnormalities in the body including the indigestion of carbohydrates leading to malnutrition and weight loss. In this article we investigate the cellular and molecular mechanisms of exocrine pancreatic insufficiency in streptozotocin (STZ, 60 mg kg-1, i.p.)-induced DM in male rats compared to healthy age-matched controls. Either electrical field stimulation (EFS) or cholecystokinin octapeptide (CCK-8, 10-8 M) can elicit large and significant (P < 0.05) increases in amylase output from pancreatic segments compared to basal secretion. Insulin (10-6 M) alone has no significant effect on amylase output compared to basal but it enhanced the secretory responses to either EFS or CCK-8. When rats were rendered diabetic with STZ, either EFS or CCK-8-evoked amylase output was significantly (P < 0.01) decreased compared to the responses obtained with either EFS or CCK-8 alone in healthy age-matched control pancreas. In addition, CCK-8 can elicit large dose-dependent release of amylase in age-matched control and diabetic acinar cells with significantly (P < 0.05) reduced responses in diabetic acinar cells. CCK-8 evoked a large rapid increase in peak cytosolic free calcium concentration ([Ca2+]c) followed by a decrease to a plateau phase in age-matched control fura-2-loaded pancreatic acinar cells. These responses were significantly (P < 0.05) decreased in STZ-induced diabetic acinar cells. In the presence of 10-6 Minsulin, CCK-8 evoked a much larger increase in the Ca2+ transient compared to the response obtained with CCK-8 alone. These effects were significantly (P < 0.01) inhibited in STZ-induced diabetic acinar cells. Similarly, in zero extracellular Ca2+ [Ca2+]ĉ, the CCK-8-evoked [Ca2+]c was significantly (P < 0.05) reduced in both diabetic and age-matched control acinar cells, but with more pronounced reduction in diabetic acinar cells. CCKA receptor mRNA levels remained unchanged in diabetic rat acinar cells compared to age-matched healthy control. In contrast, amylase mRNA was significantly (P < 0.05) reduced in diabetic acinar cells compared to control. The results indicate that reduced amylase secretion in response to either EFS or CCK-8 in the diabetic pancreas may be due to reduced [Ca2+]c and gene expression for amylase and not to the gene expression of CCKA receptor in pancreatic acinar cells.

Original languageEnglish
Title of host publicationDiabetes Mellitus and Its Complications
Subtitle of host publicationMolecular Mechanisms, Epidemiology, and Clinical Medicine
PublisherBlackwell Publishing Inc.
Pages71-88
Number of pages18
ISBN (Print)1573316350, 9781573316354
DOIs
Publication statusPublished - Nov 2006

Publication series

NameAnnals of the New York Academy of Sciences
Volume1084
ISSN (Print)0077-8923
ISSN (Electronic)1749-6632

Keywords

  • Amylase
  • Calcium
  • Cholecystokinin
  • Diabetes
  • Gene expression
  • Insulin

ASJC Scopus subject areas

  • General Neuroscience
  • General Biochemistry,Genetics and Molecular Biology
  • History and Philosophy of Science

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