Enhanced glucose tolerance in pancreatic-derived factor (PANDER) knockout C57BL/6 mice.

Pancreatic-derived factor (PANDER; also known as FAM3B) is a uniquely structured protein strongly expressed within and secreted from the endocrine pancreas. PANDER has been hypothesized to regulate fasting and fed glucose homeostasis, hepatic lipogenesis and insulin signaling, and to serve a potential role in the onset or progression of type 2 diabetes (T2D). Despite having potentially pivotal pleiotropic roles in glycemic regulation and T2D, there has been limited generation of stable animal models for the investigation of PANDER function, and there are no models on well-established genetic murine backgrounds for T2D. Our aim was to generate an enhanced murine model to further elucidate the biological function of PANDER. Therefore, a pure-bred PANDER knockout C57BL/6 (PANKO-C57) model was created and phenotypically characterized with respect to glycemic regulation and hepatic insulin signaling. The PANKO-C57 model exhibited an enhanced metabolic phenotype, particularly with regard to enhanced glucose tolerance. Male PANKO-C57 mice displayed decreased fasting plasma insulin and C-peptide levels, whereas leptin levels were increased as compared with matched C57BL/6J wild-type mice. Despite similar peripheral insulin sensitivity between both groups, hepatic insulin signaling was significantly increased during fasting conditions, as demonstrated by increased phosphorylation of hepatic PKB/Akt and AMPK, along with mature SREBP-1 expression. Insulin stimulation of PANKO-C57 mice resulted in increased hepatic triglyceride and glycogen content as compared with wild-type C57BL/6 mice. In summary, the PANKO-C57 mouse represents a suitable model for the investigation of PANDER in multiple metabolic states and provides an additional tool to elucidate the biological function and potential role in T2D.

PANDER transgenic mice display fasting hyperglycemia and hepatic insulin resistance.

PANcreatic-DERived factor (PANDER, FAM3B) is a novel protein that is highly expressed within the endocrine pancreas and to a lesser degree in other tissues. Under glucose stimulation, PANDER is co-secreted with insulin from the ß-cell. Despite prior creation and characterization of acute hepatic PANDER animal models, the physiologic function remains to be elucidated from pancreas-secreted PANDER. To determine this, in this study, a transgenic mouse exclusively overexpressing PANDER from the endocrine pancreas was generated. PANDER was selectively expressed by the pancreatic-duodenal homeobox-1 (PDX1) promoter. The PANDER transgenic (PANTG) mice were metabolically and proteomically characterized to evaluate effects on glucose homeostasis, insulin sensitivity, and lipid metabolism. Fasting glucose, insulin and C-peptide levels were elevated in the PANTG compared with matched WT mice. Younger PANTG mice also displayed glucose intolerance in the absence of peripheral insulin sensitivity. Hyperinsulinemic-euglycemic clamp studies revealed that hepatic glucose production and insulin resistance were significantly increased in the PANTG with no difference in either glucose infusion rate or rate of disappearance. Fasting glucagon, corticosterones, resistin and leptin levels were also similar between PANTG and WT. Stable isotope labeling of amino acids in cell culture revealed increased gluconeogenic and lipogenic proteomic profiles within the liver of the PANTG with phosphoenol-pyruvate carboxykinase demonstrating a 3.5-fold increase in expression. This was matched with increased hepatic triglyceride content and decreased p-AMPK and p-acetyl coenzyme A carboxylase-1 signaling in the PANTG. Overall, our findings support a role of pancreatic ß-cell-secreted PANDER in the regulation of hepatic insulin and lipogenenic signaling with subsequent impact on overall glycemia.

Progressive central puberty in a toddler with partial androgen insensitivity.

A male infant was diagnosed with partial androgen insensitivity caused by a novel mutation in the androgen receptor. At 3.5 months of age, he received 100 mg of testosterone intramuscularly over the course of 3 months to increase phallic size. He developed pubic hair after 5 months and signs of progressive central precocious puberty when re-examined at 17.5 months, which subsequently was suppressed with depot leuprolide.