Mechanism of Exocrine Pancreatic Insufficiency in Streptozotocin‐Induced Type 1 Diabetes Mellitus

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) M insulin, 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. CCK(A) 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 CCK(A) receptor in pancreatic acinar cells.

Liver X Receptor Agonist TO901317 Prevents Diacylglycerols Accumulation in the Heart of Streptozotocin-Diabetic Rats

“…Streptozotocin is a chemical agent used to produce type 1 diabetes in animal model due to selective destruction of β-islet cells of the pancreas which leads to impaired insulin secretion [20]. In our study, 3 weeks after single injection of streptozotocin, rats showed hypoinsulinemia and hyperglycemia, as expected.…”

Gene Expression Profiles in Fetal and Neonatal Rat Offspring of Energy-Restricted Dams

“…A reduced secretion capacity of exocrine pancreas has been reported in diabetic humans [27] and adult rats with streptozotocin-induced diabetes [28] , but from the present results it is not possible to assess whether the rats subjected to fetal undernutrition in our study would have developed diabetes as they grew older, possibly secondary due to pancreatic dysfunction, though this is an intriguing possibility. This should be investigated further in a study where the experimental animals would be followed to an older age.…”

Animal models to test drugs with potential antidiabetic activity

“…As a result of STZ action, pancreatic ␤-cells are destroyed by necrosis (Mythili et al, 2004). In adult rats, 60 mg/kg is the most common dose of STZ to induce insulin dependent diabetes (Patel et al, 2006), but higher doses are also used. STZ is also efficacious after intraperitoneal administration of a similar or higher dose, but single doses below 40 mg/kg may be ineffective (Katsumata et al, 1992).…”