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The dogma that IGF-I stimulates pancreatic islet growth has been challenged by combinational targeting of IGF or IGF-IR (IGF receptor) genes as well as ␤-cell-specific IGF-IR gene deficiency, which caused no defect in islet cell growth. To assess the physiological role of locally produced IGF-I, we have developed pancreaticspecific IGF-I gene deficiency (PID) by crossing Pdx1-Cre and IGF-I/loxP mice. PID mice are normal except for decreased blood glucose level and a 2.3-fold enlarged islet cell mass. When challenged with low doses of streptozotocin, control mice developed hyperglycemia after 6 days that was maintained at high levels for at least 2 months. In contrast, PID mice only exhibited marginal hyperglycemia after 12 days, maintained throughout the experiment. Fifteen days after streptozotocin, PID mice demonstrated significantly higher levels of insulin production. Furthermore, streptozotocin-induced ␤-cell apoptosis (transferase-mediated dUTP nick-end labeling [TUNEL] assay) was significantly prevented in PID mice. Finally, PID mice exhibited a delayed onset of type 2 diabetes induced by a high-fat diet, accompanied by super enlarged pancreatic islets, increased insulin mRNA levels, and preserved sensitivity to insulin. Our results suggest that locally produced IGF-I within the pancreas inhibits islet cell growth; its deficiency provides a protective environment to the ␤-cells and potential in combating diabetes.

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Summary Histochemical methods specific for carbohydrate constituents distinguish a number of widely different entities in several types of gastric epithelial cells in the dog. The surface gastric epithelium reveals basophilia, indicating mucosubstances rich in both carboxyl groups (presumably sialic acid) and sulfate esters. The carboxyl‐type basophilia predominates in the superficial convolutions, and that attributed to sulfate is found in the foveolar walls. The strong reactivity with both the periodic acid‐Schiff (PAS) and the periodic acid‐para diamine (PAD) methods for vicinal‐hydroxyls indicates presence of hexose‐ or deoxyhexose‐rich mucosubstances in both of these areas. Susceptibility of basophilia to blockage by initial periodate‐meta diamine treatment points to presence of vicinal‐glycols in proximity of the acid groups in surface epithelium mucin. The surface epithelium in the pylorus differs slightly in that its secretion is less strongly basophilic. The mucous neck cells secrete an apparently neutral mucosubstance which differs from the surface epithelium in its lack of both PAD reactivity and basophilia. The parietal cells also form a diastase‐resistant, neutral, carbohydrate‐rich substance. The zymogen cells are abundant, deep in the glands of the cardiac portion and the body of the stomach, but less numerous in the intermediate zone. They contain apical granular secretion apparently rich in sulfated mucosubstances. Lack of reactivity toward vic‐glycol methods, resistance of alcianophilia or azurophilia to a previous periodate‐meta diamine sequence, and resistance of mixed diamine staining to previous periodate oxidation indicate absence of residues with unsubstituted adjacent hydroxyls (e.g., hexose or deoxyhexose), in this acid mucosubstance. The pyloric glands resemble mucous neck cells in their strong PAS staining and lack of PAD reactivity, but differ in that they show a weak staining indicative of sulfomucin.