The presence of somatostatin receptors has been demonstrated in various endocrine tumors as well as in normal tissues. We recently have cloned five human somatostatin receptor subtypes (SSTRI-SSTR5). These mRNAs are expressed in a tissue-specific manner. In this study, we have determined the somatostatin receptor subtypes expressed in various endocrine tumors using a reverse transcriptase polymerase chain reaction method. In two cases of glucagonoma and its metastatic lymph nodes in one case, all the SSTR subtype mRNAs except SSTR5 mRNA were expressed. In four cases of insulinoma, SSTR1 and SSTR4 mRNAs were detected, but SSTR2 mRNA was not detected in one case and SSTR3 mRNA was not detected in two cases, indicating a heterogeneous expression of SSTR subtypes in insulinomas. Interestingly, SSTR3 mRNA, which is highly expressed in rat pancreatic islets, is not expressed in normal human pancreatic islets, while SSTR1, SSTR2, and SSTR4 mRNAs are expressed. In three cases of pheochromocytoma, SSTR1 and SSTR2 mRNAs were detected, showing an expression pattern identical to that of normal adrenal gland. In a carcinoid, SSTRI and SSTR4 mRNAs were detected. We have also found that human SSTR2 shows a high affinity for SMS 201-995, which has been used clinically for the treatment of endocrine tumors. Since SMS 201-995 was effective in the treatment of a patient with glucagonoma in which SSTR2 mRNA was present, but had no effect in a patient with carcinoid in which SSTR2 mRNA was not detected, this study suggests that the efficacy of SMS 201-995 may depend, at least in part, on the expression of SSTR2 in tumors. (J. Clin.

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We previously reported the cloning of two distinct somatostatin receptor (SSTR) subtypes, SSTR1 and SSTR2. Although both SSTR1 and SSTR2 bound somatostatin specifically and with high affinity, neither was coupled to adenylyl cyclase, a major cellular effector of somatostatin's actions. Here we report the cloning and functional characterization of a third member of the SSTR family. Human SSTR3 is a protein of 418 amino acids and has 45% and 46% identity with human SSTR1 and SSTR2, respectively. RNA blotting studies showed that SSTR3 mRNA could be readily detected in brain and pancreatic islets. The pharmacological properties of human SSTR3 were characterized by transiently expressing the human SSTR3 gene in COS-1 cells. Membranes from cells expressing human SSTR3 bound the somatostatin agonist [125I]CGP 23996 specifically and with high affinity, with a rank order of potency of somatostatin-28 = CGP 23996 > somatostatin-14 > SMS-201-995. Studies using cells transiently coexpressing the human dopamine D1 receptor and human SSTR3 showed that somatostatin was able to inhibit dopamine-stimulated cAMP formation in a dose-dependent manner, indicating that SSTR3 was functionally coupled to adenylyl cyclase. These results indicate that the diverse biological effects of somatostatin are mediated by a family of receptor with distinct, but overlapping, tissue distributions, unique pharmacological properties, and potentially different functions.

Cytosolic Ca(2+) elevations are known to be involved in triggering apoptosis in many tissues, but the effect of sustained enhancement of Ca(2+) influx on apoptosis in beta cells remains unknown. We have found that the viability of RINm5F cells is decreased dose-dependently by continuous exposure to glibenclamide at concentrations from 10(-7) to 10(-4) M, and that this effect is partially ameliorated by pretreatment with cycloheximide. Electrophoresis of the cells exposed to glibenclamide revealed ladder-like fragmentation characteristic of apoptosis, and which also is suppressed by cycloheximide pretreatment. By using terminal deoxynucleotidyl transferase-mediated dUTP nick end-labeling (TUNEL) staining, we detected increased DNA fragmentation in the nuclei of the cells exposed to glibenclamide, and staining with Hoechst 33342 and propidium iodide showed a dose-dependent increase in the number of cells with the chromatin condensation and fragmentation in their nuclei that is characteristic of apoptosis. The effects of glibenclamide on cell viability and apoptotic cell death were partially inhibited by treatment with Ca(2+) channel blocker, and by reducing the extracellular Ca(2+) concentration during glibenclamide exposure, suggesting that they may be derived from increased Ca(2+) influx. Furthermore, only the percentage of apoptotic cells, and not that of necrotic cells, increased with the increasing intracellular Ca(2+) concentration during glibenclamide exposure. In conclusion, we have demonstrated that the sustained enhancement of Ca(2+) influx caused by glibenclamide exposure can induce apoptotic cell death in a pure beta cell line.

Aim:The effect of pitavastatin on high-sensitivity C-reactive protein (hs-CRP) has not been reported, yet, in humans. We, therefore, investigated the effects of pitavastatin on lipid profiles and hs-CRP in Japanese subjects with hypercholesterolemia. Methods: The subjects were 178 Japanese with hypercholesterolemia, including 103 (58%) with type 2 diabetes. Pitavastatin (1 − 2 mg/day) was administered for 12 months. Serum low-density lipoprotein cholesterol (LDL-C), high-density lipoprotein cholesterol (HDL-C), remnant-like particle cholesterol (RLP-C), triglycerides (TG) and hs-CRP levels were measured for 12 months. Results: Serum LDL-C and RLP-C levels were significantly decreased by 30.3% and 22.8%, respectively. Serum TG levels were decreased by 15.9% in subjects with basal TG levels above 150 mg/dl. Serum HDL-C levels were significantly increased. The administration of pitavastatin reduced serum hs-CRP levels by 34.8%. No serious adverse events were observed, including changes in glycosylated hemoglobin levels of diabetic patients. Conclusion: These results suggest that pitavastatin significantly improves lipid profiles and reduces proinflammatory responses, without adverse effects, in Japanese subjects with hypercholesterolemia, including those with diabetes mellitus.