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.

Both GH and IGF-I stimulate islet cell growth, inhibit cell apoptosis, and regulate insulin biosynthesis and secretion. GH receptor gene deficiency (GHR(-/-)) caused diminished pancreatic islet cell mass and serum insulin level and elevated insulin sensitivity. Because IGF-I gene expression was nearly abolished in these mice, we sought to determine whether that had caused the islet defects. To restore IGF-I level, we have generated transgenic mice that express rat IGF-I cDNA under the direction of rat insulin promoter 1 (RIP-IGF). Using RNase protection assay and immunohistochemistry, the IGF-I transgene expression was revealed specifically in pancreatic islets of the RIP-IGF mice, which exhibited normal growth and development and possess no abnormalities in glucose homeostasis, insulin production, and islet cell mass. GHR(-/-) mice exhibited 50% reduction in the ratio of islet cell mass to body weight and increased insulin sensitivity but impaired glucose tolerance. Compared with GHR(-/-) alone, IGF-I overexpression on a GHR(-/-) background caused no change in the diminished blood glucose and serum insulin levels, pancreatic insulin contents, and insulin tolerance but improved glucose tolerance and insulin secretion. Remarkably, islet-specific overexpression of IGF-I gene in GHR(-/-) mice restored islet cell mass, at least partially through cell hypertrophy. Interestingly, double-transgenic male mice demonstrated a transient rescue in growth rates vs. GHR(-/-) alone, at 2-3 months of age. Our results suggest that IGF-I deficiency is part of the underlying mechanism of diminished islet growth in GHR(-/-) mice and are consistent with the notion that IGF-I mediates GH-induced islet cell growth.

The prognosis for diabetic foot ulcers (DFUs) remains poor. Nutritional status has not been identified as one of the factors affecting the outcome of DFUs. Therefore, indicators correlated with nutritional status and outcome were analyzed to investigate their relationship. A total of 192 hospitalized patients with Wagner grade 1–5 ulcers and 60 patients with Wagner grade 0 ulcers (all had type 2 diabetes) were assessed by the following: subjective global assessment (SGA), anthropometric measurements, biochemical indicators and physical examinations to evaluate nutritional status, severity of infection and complications. Patient outcome was recorded as healing of the ulcer and the patients were followed up for 6 months or until the wound was healed. The percentage of malnutrition was 62.0% in the DFU patients. The SGA was closely correlated with infection (r=0.64), outcome (r=0.37) and BMI (r=−0.36), all P<0.001. The risk of poor outcome increased with malnutrition [odds ratio (OR), 10.6, P<0.001]. The nutritional status of the DFU patients was independently correlated with the severity of infection and outcome (both P<0.001) and Wagner grades and nutritional status (SGA) were independent risk factors for patient outcome (both P<0.001). Nutritional status deteriorated as the severity of the DFU increased, and malnutrition was a predictor of poor prognosis.

Moderately and severely reduced eGFR in patients with DFU were independent predictors for poor prognoses of both the limbs and the patients.