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Regulation of Rat Pancreatic CCKB Receptor and Somatostatin Expression by Insulin Sophie Julien, Jean Laine, and Jean Morisset

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Regulation of Rat Pancreatic CCKB Receptor and Somatostatin Expression by Insulin Sophie Julien, Jean Laine, and Jean Morisset Regulation of Rat Pancreatic CCKB Receptor and Somatostatin Expression by Insulin Sophie Julien, Jean Laine, and Jean Morisset was targeted to the pancreas and stomach but not to the The cholecystokinin B receptor (CCKBR) is localized on pancreatic endocrine somatostatin ␦-cells. Pancreatic other somatostatin-producing tissues (15). somatostatin content was increased in diabetic rats. The role played by insulin in somatostatin release The mechanisms involved in this phenomenon are un- remains controversial. Indeed, insulin can stimulate soma- known, and we believe insulin is involved. In this study, tostatin release from perfused chicken pancreas-duode- four groups of rats were used: controls, streptozotocin- num (16); however, data from monolayer cultures of induced diabetic, streptozotocin-induced diabetic with neonatal rat pancreas (17) and isolated dog pancreas (18) insulin, and streptozotocin-induced diabetic with insu- clearly show that insulin fails to induce somatostatin lin and its cessation. Rats were killed after 7–28 days of release. In anesthetized normal and diabetic dogs, insulin treatment for diabetes, and somatostatin mRNA expres- infusion or injection was associated with an immediate sion and pancreatic somatostatin content, CCKBR mRNA and protein expression evaluation in total pan- reduction of the venous pancreaticoduodenal release of creas and purified islets, and the cellular localization of somatostatin (19). All of these differences could be ex- somatostatin and CCKBR in islets was measured. Data plained by the different models used to study somatostatin indicate that diabetes is established after 7 days, is release. controlled by insulin, and reappears after treatment Cholecystokinin (CCK), a duodenal hormone released cessation. Pancreatic somatostatin mRNA expression into the bloodstream after meal ingestion, is recognized as and somatostatin content were increased during diabe- the major hormonal factor involved in the regulation of tes, normalized during insulin treatment, and reaug- pancreatic exocrine secretion, gallbladder contraction, mented after treatment cessation. Gland and islet gastric emptying, and small bowel motility. CCK is also CCK R mRNA and protein almost disappeared during B involved in the regulation of the endocrine pancreas; diabetes; CCKB mRNA reappeared in response to insu- lin, but the protein did not. Confocal microscopy con- indeed, it can stimulate insulin secretion from an in vitro rat perfused pancreas (20) and in vivo in the rat (21), pig firmed data obtained on somatostatin and CCKBRas established biochemically in the course of the treat- (22), mouse (23), and human (24). In humans, the insuli- ments. In conclusion, these data strongly suggest that notropic effect of CCK was attenuated by the specific insulin can negatively control pancreatic somatostatin CCK-A receptor antagonist L-364718 (25). Finally, it was mRNA and hormone content and positively control recently observed (26,27) that a defect in the CCK-A CCKBR mRNA; the CCKBR protein appears to be de- receptor gene OLETF (Otsuka Long-Evans Tokushima layed. Diabetes 53:1526–1534, 2004 Fatty) rats led to obesity and diabetes. With regard to pancreatic somatostatin ␦-cells, we re- cently demonstrated (28,29) that these cells specifically bear the CCKB receptor (CCKBR) as established by RT- uring the 1970s, major changes were observed PCR, Western blotting, and confocal microscopy in rat, in the metabolism of pancreatic somatostatin mouse, dog, pig, horse, calf, and human. This new discov- during diabetes development in human and ery may indicate that the CCKBR could be involved in Dexperimental animals; these modifications in- somatostatin metabolism and/or control of ␦-cell growth. cluded increased secretion, tissue contents, and ␦-cell Therefore, knowing that diabetes causes modifications population (1–12). On the contrary, it was also reported in the pancreatic ␦-cell metabolism and that these cells (13,14) that in diabetic mice mutants (ob/ob and db/db), express the CCKBR, the objectives for this study are to pancreatic somatostatin content was decreased, along characterize the changes in somatostatin mRNA expres- with a reduction in somatostatin cells within the islet. It sion and contents along with those of the CCKBRin was later suggested that in streptozotocin (STZ)-induced normal and diabetic rats and to determine whether insulin diabetic rats, regulation of somatostatin gene transcription treatment can normalize the modifications observed dur- ing diabetes development. From the Gastroenterology Service, Department of Medicine, Faculty of Medicine, Universite´ de Sherbrooke, Sherbrooke, Quebec, Canada. RESEARCH DESIGN AND METHODS Address correspondence and reprint requests to Jean Morisset, Gastroen- Male Sprague-Dawley rats, purchased from Charles River Laboratories (St. terology Service, Department of Medicine, Faculty of Medicine, Universite´de Constant, Canada), were housed in a light- and humidity-controlled room and Sherbrooke, Sherbrooke, Quebec, Canada, J1H 5N4. E-mail: jean.morisset@ given free access to food and water. usherbrooke.ca. Received for publication 11 November 2003 and accepted in revised form 19 After an overnight fast, rats (200–220 g) were rendered diabetic (group March 2004. STZ-D, n ϭ 160) by a single intraperitoneal injection of 65 mg/kg body wt STZ CCK, cholecystokinin; CCKBR, CCK-B receptor; STZ, streptozotocin. (Sigma, St. Louis, MO) dissolved in 0.1 mol/l citrate buffer, pH 4.5. Controls © 2004 by the American Diabetes Association. received the same volume of citrate buffer alone (nondiabetic, group ND, n ϭ 1526 DIABETES, VOL. 53, JUNE 2004 S. JULIEN, J. LAINE, AND J. MORISSET 40). Animals were studied for 7 (group STZ-D7, n ϭ 20), 14 (group STZ-D14, TCAC, position 1516–1498, with a 478 bp cDNA fragment amplified. Reverse n ϭ 20), 21 (group STZ-D21, n ϭ 20), or 28 (group STZ-D28, n ϭ 20) days after transcription was performed for1hat50°C, and PCR amplifications were diabetes induction. Seven days after STZ injection, 80 diabetic rats received performed under the following conditions: somatostatin: 60 s 94°C, 45 s 60°C, twice daily subcutaneous injections of Novolin ge NPH insulin (Novo Nordisk, and 45 s 72°C (35 cycles); CCKBR: 30 s 94°C, 30 s 57°C, and 30 s 72°C (35 Bagsvaerd, Denmark; 3 units at 8:00 A.M., 5 units at 8:00 P.M.) (group STZ-I) and cycles); 18S: 60 s 94°C, 45 s 47°C, and 45 s 72°C (30 cycles). PCR samples were were killed 7 (group STZ-I7, n ϭ 20), 14 (group STZ-I14, n ϭ 20), or 21 (group electrophoresed on a 1% agarose gel, and DNA was visualized with ethidium STZ-I21, n ϭ 20) days after the initial insulin injection. Twenty other bromide. insulin-treated rats were denied insulin after 21 days and were killed 21 days Immunochemistry and image analysis by confocal microscopy. These later (group STZ-I21/D21). Before killing them, all animals were fasted except procedures were extensively described recently (29,39) with regard to the the group I rats. Under anesthesia, blood was collected from the inferior vena antibodies used, their dilution, and their specificity. Ϯ cava and the pancreas was excised. Plasma was separated by centrifugation at Statistical analysis. Results represent means SE. The statistical analysis Ͻ 4°C and stored at Ϫ20°C for measurement of glucose and triglycerides. These was done using a Student’s t test (two tailed). A P value of 0.05 was studies were performed according to our institutional animal care policies. considered significant. Tissue preparations. Once excised, pancreata were quickly frozen in liquid nitrogen and kept frozen at Ϫ80°C until they were processed for receptor RESULTS protein analysis by Western blotting or for total pancreas RNA extraction to determine CCK receptor and somatostatin expression by RT-PCR. Body weight, plasma glucose, triglycerides, and pan- Glycemia and lipidemia determinations. Plasma glucose and triglycerides creatic amylase. As shown in Fig. 1A, body weights of the were measured according to the Vitros GLU slide and Vitros TRIG slide test diabetic animals (STZ-D) exhibited significant early de- methodologies (Ortho-Clinical Diagnostics, Rochester, NY), respectively. Both creases of 18% at day 7, down to 29.6% at day 28 when analyses are based on enzymatic methods as described by Curme (30) and compared with their respective controls. Treatment of the Spayd (31). diabetic animals with insulin (STZ-I) immediately reversed Rat islet isolation. Islets were purified from diabetic and control rats according to the modified method of Lacy and Kosianovsky (32) as recently the losses in body weight; a 15% increase was observed described (33). Yields were ϳ350–400 islets from each diabetic pancreas and after 7 days, up to 28.4% after 3 weeks, thus indicating a ϳ650–800 islets from a normal pancreas. return to control values. Cessation of insulin for 21 days RIN-14B cells. The RIN-14B cells were obtained from American Type Culture caused a new drop of 14.2% in body weight when group Collection (ATCC). These cells are of a secondary clone derived from the STZ-I21/D21 is compared with group STZ-I21. RIN-m rat islet cell line (34), and they do not produce insulin. Cells were grown in RPMI 1640 medium according to ATCC specifications. The STZ-induced diabetic rats (STZ-D) presented severe Somatostatin and amylase content determinations. Tissue samples were hyperglycemia after 7 days (182%), up to 286% after 28 rapidly frozen in liquid nitrogen until used. For somatostatin determination, a days when compared with their respective controls (Fig. 10% homogenate was made in CH3COOH 2N, boiled for 15 min, and centri- 1B). Under insulin, a gradual recovery was observed and fuged for 20 min at 12,000g. The supernatants (3 ml) were extracted using glycemia reached control values after 14 days (ND-28 Waters Sep-Pak C18 cartridges (Waters Associates, Milford, MA) that were prewetted with 100% acetonitrile followed by 0.05% trifluoroacetic acid (15 versus STZ-I28). Cessation of insulin resulted in a signifi- ml).
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