Antidiabetic sulfonylureas act through receptors coupled to ATP-dependent potassium channels. Using the binding of [3Hjglibenclamide, a highly potent sulfonylurea, to rat brain membranes to follow the purification procedure, we extracted from ovine brain, purified, and partially characterized two peptides that are endogenous ligands for the central nervous system sulfonylurea receptors. These peptides, referred to as a and (3 endosulfme, differ by their isoelectric points, the (3 form being more basic. Each form of endosulfine is recognized equally by the sulfonylurea receptors from the central nervous system and from insulin-secreting m3 cells. In the same concentration range that is active on the receptors, 13 endosulfine releases insulin from a 13-cell line. Endosulfine is a good candidate for being implicated in the physiology of 13 cells and their disorders (e.g., type H diabetes) and in certain pathologies related to modifications of ion fluxes.The antidiabetic sulfonylureas (1) are widely used in the management of non-insulin-dependent diabetes mellitus (NIDDM), also referred to as type II diabetes (2). These drugs (3, 4) stimulate insulin secretion from the islets of Langerhans, which in diabetes display a decreased insulin content (5) and an impaired response to glucose (6). The sulfonylureas act at the cell surface of the 13 cell (7) through interaction with specific binding sites (or receptors) present in membranes from insulin-secreting cells or tissues (8-13). Receptors with similar characteristics were also observed in the central nervous system (CNS; refs. 10,14,and 15) and in the myocardial tissue (16). The sulfonylurea receptor is closely associated to ATP-dependent potassium channels (17-19), also involved in glucose-induced insulin secretion (20). The existence of such a receptor led us to suggest that it represents a recognition site for an endogenous ligand (14) that would regulate physiological processes through mechanisms triggered, in a pharmacological context, by the sulfonylureas. Such an approach for the binding sites for morphine led to the discovery of the endorphines (21). In the CNS, the potential endogenous ligand is likely to be present near the receptor. We have shown that such a ligand exists in the rat brain (22). We describe the presence in and the purification from ovine brain of two peptides, representing most likely two forms of the same entity, for which we propose the name "'endosulfine. " Endosulfine is present in the brain of rat and sheep at similar concentrations-i.e., ca 0.1 pmol of glibenclamide equivalent per g of tissue-and in the rat pancreas. Highly purified endosulfine is like sulfonylureas in that, at concentrations where it interacts with the receptors, it is able to induce insulin release from JTC cells in culture.MATERIALS AND METHODS Sulfonylureas. Glibenclamide was provided by the Guidotti laboratory.[3H]Glibenclamide (40)(41)(42)(43)(44)(45)(46)(47)(48)(49)(50) Ci/mmol; 1 Ci = 37 GBq) was purchased from Hoechst Pharmaceuticals or DuPont.Binding ...

We report a case of Becker muscular dystrophy in a 6-month-old, mixed-breed, castrated male pig detected with macroglossia at a meat inspection center. The pig presented a severely enlarged tongue extending outside its mouth. The tongue was firm and pale with discolored muscles. Histologically, there was severe fibrosis, fatty replacement, and myofiber necrosis, degeneration, and regeneration. Immunofluorescence showed focal and severely weak labeling for dystrophin at the sarcolemma of myocytes in the tongue. Analysis of dystrophin mRNA showed a 62 base pair insertion between exons 26 and 27. The insertion was derived from intron 26. Based on these findings, we diagnosed the case as Becker muscular dystrophy—the first known muscular dystrophy case induced by pseudoexon insertion in animals.

Hypochlorhydria is considered to be a risk factor for gastric cancer, both clinically and experimentally. In humans, the hypo‐acidic condition appears to be closely associated with the development of differentiated‐tyne gastric carcinomas. We investigated relationships between antral pH and histological types of gastric cancer using an animal model. A total of 7.65 g of N‐ethyl‐N′‐nitro‐N‐nitrosoguanidine (ENNG) was orally administered to male beagle dogs. Subsequently, the dogs were divided into four groups and underwent four surgical interventions designed to create various conditions in the antrum. Antral pM was recorded at the time of killing after an observation period ranging from 16 to 33 months. The number of gastrin‐secreting cells (G‐cells) was counted after immunohistochemical staining. Carcinomas were found in the antrum of 12 of the 21 dogs that had survived. Although limited doses of ENNG, such as those used in this study, have been reported to produce only undifferentiated adenocarcinomas, differentiated adenocarcinomas were found in seven of these 12 dogs. Antral pH and the number of G‐cells were significantly higher in these seven dogs than in the other five dogs, which had developed only undifferentiated adenocarcinomas. Bile inflow showed no significant effect on the development of differentiated adenocarcinomas. Neither atrophic gastritis nor intestinal metaplasia was seen in any of the dogs. These results suggest that the hypo‐acidic condition itself may play a role in the development of differentiated adenocarcinomas.

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