Published online Jan 21, 2015. doi: 10.3748/wjg.v21.i3.836
Peer-review started: June 20, 2014
First decision: August 6, 2014
Revised: August 16, 2014
Accepted: September 29, 2014
Article in press: September 30, 2014
Published online: January 21, 2015
AIM: To characterize an alcohol and high fat diet induced chronic pancreatitis rat model that mimics poor human dietary choices.
METHODS: Experimental rats were fed a modified Lieber-DeCarli alcohol (6%) and high-fat (65%) diet (AHF) for 10 wk while control animals received a regular rodent chow diet. Weekly behavioral tests determined mechanical and heat sensitivity. In week 10 a fasting glucose tolerance test was performed, measuring blood glucose levels before and after a 2 g/kg bodyweight intraperitoneal (i.p.) injection of glucose. Post mortem histological analysis was performed by staining pancreas and liver tissue sections with hematoxylin and eosin. Pancreas sections were also stained with Sirius red and fast green to quantify collagen content. Insulin-expressing cells were identified immunohistochemically in separate sections. Tissue staining density was quantified using Image J software. After mechanical and heat sensitivity became stable (weeks 6-10) in the AHF-fed animals, three different drugs were tested for their efficacy in attenuating pancreatitis associated hypersensitivity: a Group II metabotropic glutamate receptor specific agonist (2R,4R)-4-Aminopyrrolidine-2,4-dicarboxylate (APDC, 3 mg/kg, ip; Tocris, Bristol, United Kingdom), nociceptin (20, 60, 200 nmol/kg, ip; Tocris), and morphine sulfate (3 mg/kg, μ-opioid receptor agonist; Baxter Healthcare, Deerfield, IL, United States).
RESULTS: Histological analysis of pancreas and liver determined that unlike control rats, AHF fed animals had pancreatic fibrosis, acinar and beta cell atrophy, with steatosis in both organs. Fat vacuolization was significantly increased in AHF fed rats (6.4% ± 1.1% in controls vs 23.8% ± 4.2%, P < 0.05). Rats fed the AHF diet had reduced fasting glucose tolerance in week 10 when peak blood glucose levels reached significantly higher concentrations than controls (127.4 ± 9.2 mg/dL in controls vs 161.0 ± 8.6 mg/dL, P < 0.05). This concurred with a 3.5 fold higher incidence of single and small 2-10 cell insulin-positive cell clusters (P < 0.05). Insulin expressing islet of Langerhans cells appeared hypertrophied while islet number and area measurements were not different from controls. Weekly behavioral tests determined that mechanical and heat sensitivities were significantly increased by 4 wk on AHF diet compared to controls. Hypersensitivity was attenuated with efficacy similar to morphine with single dose treatment of either metabotropic glutamate receptor 2/3 agonist APDC, or nociceptin, the endogenous ligand for opioid-receptor-like 1 receptor.
CONCLUSION: The AHF diet induces a chronic alcoholic pancreatitis in rats with measurable features resembling clinical patients with chronic pancreatitis and type 3c diabetes mellitus.
Core tip: Chronic pancreatitis is a progressive and potentially fatal disease caused by persistent unresolved inflammation and pancreatic fibrosis. It can be accompanied by intractable abdominal pain and progress to type 3c diabetes mellitus (T3cDM) and pancreatic cancer. Animal models of acute pancreatitis are typically chemically induced, invasive, of short duration, and have a high mortality rate. This study characterizes a diet-induced chronic rat model closely mimicking poor human dietary choices to investigate therapies for alcoholic chronic pancreatitis with developing T3cDM. The efficacy of acute opioid and non-opioid pharmacological interventions are compared to morphine in pain-related behavior tests.