Cholestyramine reverses hyperglycemia and enhances glucose-stimulated glucagon-like peptide 1 release in Zucker diabetic fatty rats.

Bile acid sequestrants (BAS) have shown antidiabetic effects in both humans and animals but the underlying mechanism is not clear. In the present study, we evaluated cholestyramine in Zucker diabetic fatty (ZDF) rats. Although control ZDF rats had continuous increases in blood glucose and hemoglobin A1c (HbA1c) and serum glucose and a decrease in serum insulin throughout a 5-week study, the cholestyramine-treated ZDF rats showed a dose-dependent decrease and normalization in serum glucose and HbA1c. An oral glucose tolerance test showed a significant increase in glucose-stimulated glucagon-like peptide 1 (GLP-1), peptide YY (PYY), and insulin release in rats treated with cholestyramine. Quantitative analysis of gene expression indicated that cholestyramine treatment decreased farnesoid X receptor (FXR) activity in the liver and the intestine without liver X receptor (LXR) activation in the liver. Moreover, a combination of an FXR agonist with cholestyramine did not reduce the antihyperglycemic effect over cholestyramine alone, suggesting that the FXR-small heterodimer partner-LXR pathway was not required for the glycemic effects of cholestyramine. In summary, our results demonstrated that cholestyramine could completely reverse hyperglycemia in ZDF rats through improvements in insulin sensitivity and pancreatic beta-cell function. Enhancement in GLP-1 and PYY secretion is an important mechanism for BAS-mediated antidiabetic efficacy.

It takes nine days to iron a shirt: the development of cognitive estimation skills in school age children.

Data are presented for 315 elementary school-aged children (K-11) who took the Biber Cognitive Estimation Test, a 20-item test with five estimation questions in each of four domains: quantity, time/duration, weight, and distance/length. Performance showed significant development yearly until around the age of nine years, with much slower development subsequently. No gender effects were found. Age and fund of knowledge correlated with overall test performance. Fund of information accounted for a large proportion of the variance in estimation skills for children 8 years and under, but not for children 9 years and older. Since estimation skills require retrieval and manipulation of relevant knowledge and inhibition of impulsive responding and are necessary in many everyday tasks, it was anticipated that this test may provide a useful measure of judgment and estimations and may correlate with other executive skills in school-aged children.

The Biber Cognitive Estimation Test.

Normative data from 113 participants, and cross-validation data from 49 additional participants, are presented for the Biber Cognitive Estimation Test (BCET), a 20-item test with five estimation questions in each of four categories: time/duration, quantity, weight, and distance. In Study 1, the range of normal answers is provided for each item, and a cut-off for impaired performance is suggested. Although very low IQ or education levels would be expected to invalidate this test as a measure of estimation skills, participants in the current sample made few errors. In Study 2, a cross-validation suggested a slightly more conservative cut-off score for abnormality. Study 3 examined cognitive estimation in demented (dementia of the Alzheimer's type and dementia syndrome of Parkinson's disease) versus intact elderly participants. Results indicated that the BCET was able to distinguish between demented and intact elderly participants.

Discovery of 6,7-dihydro-5H-pyrrolo[2,3-a]pyrimidines as orally available G protein-coupled receptor 119 agonists.

GPR119 is a 7-transmembrane receptor that is expressed in the enteroendocrine cells in the intestine and in the islets of Langerhans in the pancreas. Indolines and 6,7-dihydro-5H-pyrrolo[2,3-a]pyrimidines were discovered as G protein-coupled receptor 119 (GPR119) agonists, and lead optimization efforts led to the identification of 1-methylethyl 4-({7-[2-fluoro-4-(methylsulfonyl)phenyl]-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-4-yl}oxy)-1-piperidinecarboxylate (GSK1104252A) (3), a potent and selective GPR119 agonist. Compound 3 showed excellent pharmacokinetic properties and sufficient selectivity with in vivo studies supporting a role for GPR119 in glucose homeostasis in the rodent. Thus, 3 appeared to modulate the enteroinsular axis, improve glycemic control, and strengthen previous suggestions that GPR119 agonists may have utility in the treatment of type 2 diabetes.