The K cell is a specific sub-type of enteroendocrine cell located in the proximal small intestine that produces glucosedependent insulinotropic polypeptide (GIP), xenin, and potentially other unknown hormones. Because GIP promotes weight gain and insulin resistance, reducing hormone release from K cells could lead to weight loss and increased insulin sensitivity. However, the consequences of coordinately reducing circulating levels of all K cell-derived hormones are unknown. To reduce the number of functioning K cells, regulatory elements from the rat GIP promoter/gene were used to express an attenuated diphtheria toxin A chain in transgenic mice. K cell number, GIP transcripts, and plasma GIP levels were profoundly reduced in the GIP/DT transgenic mice. Other enteroendocrine cell types were not ablated. Food intake, body weight, and blood glucose levels in response to insulin or intraperitoneal glucose were similar in control and GIP/DT mice fed standard chow. In contrast to single or double incretin receptor knock-out mice, the incretin response was absent in GIP/DT animals suggesting K cells produce GIP plus an additional incretin hormone. Following high fat feeding for 21-35 weeks, the incretin response was partially restored in GIP/DT mice. Transgenic versus wildtype mice demonstrated significantly reduced body weight (25%), plasma leptin levels (77%), and daily food intake (16%) plus enhanced energy expenditure (10%) and insulin sensitivity. Regardless of diet, long term glucose homeostasis was not grossly perturbed in the transgenic animals. In conclusion, studies using GIP/DT mice demonstrate an important role for K cells in the regulation of body weight and insulin sensitivity. Enteroendocrine (EE)2 cells are a complex population of rare, diffusely distributed hormone-producing intestinal epithelial cells (1-3). Peptides and hormones secreted by EE cells play important roles in many aspects of gastrointestinal and whole animal physiology (4 -6). There are at least 16 different subtypes of EE cells based upon the major product(s) synthesized and secreted by individual cells (1). Several EE cell products, including GIP, glucagon-like peptide-1 (GLP-1), ghrelin, cholecystokinin, and peptide tyrosine, regulate food intake and/or degree of adiposity (7-11).GIP is produced almost exclusively by K cells located in the proximal small intestine and is secreted immediately after ingestion of a meal (4, 5, 12, 13). GIP release is regulated by nutrients in the intestinal lumen but not by those in the blood (4,6,13,14). Glucose (12,15,16), protein hydrolysates (17), specific amino acids (18), and fat (19) are major GIP secretagogues. Long term administration of a high fat diet increases intestinal GIP mRNA and peptide levels (12), as well as the circulating amount of plasma GIP (20, 21). There is a large body of biochemical and animal data suggesting that GIP signaling promotes the accumulation of fat (22-31). Obese humans also hyper-secrete GIP (32-36) suggesting that GIP may promote obesity in humans.Originally, G...

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The intestinal peptides GLP-1 and GIP potentiate glucosemediated insulin release. Agents that increase GLP-1 action are effective therapies in type 2 diabetes mellitus (T2DM). However, GIP action is blunted in T2DM, and GIP-based therapies have not been developed. Thus, it is important to increase our understanding of the mechanisms of GIP action. We developed mice lacking GIP-producing K cells. Like humans with T2DM, "GIP/DT" animals exhibited a normal insulin secretory response to exogenous GLP-1 but a blunted response to GIP. Pharmacologic doses of xenin-25, another peptide produced by K cells, restored the GIP-mediated insulin secretory response and reduced hyperglycemia in GIP/DT mice. Xenin-25 alone had no effect. Studies with islets, insulin-producing cell lines, and perfused pancreata indicated xenin-25 does not enhance GIP-mediated insulin release by acting directly on the ␤-cell. The in vivo effects of xenin-25 to potentiate insulin release were inhibited by atropine sulfate and atropine methyl bromide but not by hexamethonium. Consistent with this, carbachol potentiated GIP-mediated insulin release from in situ perfused pancreata of GIP/DT mice. In vivo, xenin-25 did not activate c-fos expression in the hind brain or paraventricular nucleus of the hypothalamus indicating that central nervous system activation is not required. These data suggest that xenin-25 potentiates GIP-mediated insulin release by activating non-ganglionic cholinergic neurons that innervate the islets, presumably part of an enteric-neuronal-pancreatic pathway. Xenin-25, or molecules that increase acetylcholine receptor signaling in ␤-cells, may represent a novel approach to overcome GIP resistance and therefore treat humans with T2DM.The entero-insulin axis is a physiologic system composed of peptides secreted from the gastrointestinal tract that play an important role in regulating insulin secretion from pancreatic islet ␤-cells (1, 2). To date, attention has focused on two intestinal peptides, glucagon-like peptide-1 (GLP-1) 2 and glucosedependent insulinotropic polypeptide (GIP). GIP is produced predominantly by intestinal K cells located in the proximal small intestine, whereas GLP-1 is produced primarily by intestinal L-cells present in the distal bowel (3-5). Release of GLP-1 and GIP is controlled by nutrient levels in the lumen of the gut rather than the bloodstream. Both hormones are released into the bloodstream immediately after ingestion of a meal and then potentiate glucose-stimulated insulin release. This increase in insulin secretion has been termed the incretin effect. Importantly, the incretin effect occurs only in the presence of elevated blood glucose and does not cause postprandial hypoglycemia.An increase in circulating GLP-1 activity has significant therapeutic benefit in patients with T2DM (1, 2, 6 -10). Two major classes of drugs that accomplish this goal have recently been introduced into the market with substantial success. Long acting analogs of GLP-1 potentiate glucose-stimulated insulin secretion leadin...

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Early response assessment with serum SCCA is a powerful prognostic tool. These findings suggest that escalation of therapy in patients with elevated or sustained serum SCCA and molecular targeting of SCCA1 should be considered.