SAR exploration at the C-3 position of tetrahydro-ß-carboline sstr3 antagonists.

MK-4256, a tetrahydro-ß-carboline sstr3 antagonist, was discontinued due to a cardiovascular (CV) adverse effect observed in dogs. Additional investigations revealed that the CV liability (QTc prolongation) was caused by the hERG off-target activity of MK-4256 and was not due to sstr3 antagonism. In this Letter, we describe our extensive SAR effort at the C3 position of the tetrahydro-ß-carboline structure. This effort resulted in identification of 5-fluoro-pyridin-2-yl as the optimal substituent on the imidazole ring to balance sstr3 activity and the hERG off-target liability.

Discovery of substituted (4-phenyl-1H-imidazol-2-yl)methanamine as potent somatostatin receptor 3 agonists.

We report SAR studies on a novel non-peptidic somatostatin receptor 3 (SSTR3) agonist lead series derived from (4-phenyl-1H-imidazol-2-yl)methanamine. This effort led to the discovery of a highly potent low molecular weight SSTR3 agonist 5c (EC50=5.2 nM, MW=359). The results from molecular overlays of 5c onto the L-129 structure indicate good alignment, and two main differences of the proposed overlays of the antagonist MK-4256 onto the conformation of 5c lead to inversion of antagonism to agonism.

Integrative analysis of a cross-loci regulation network identifies App as a gene regulating insulin secretion from pancreatic islets.

Complex diseases result from molecular changes induced by multiple genetic factors and the environment. To derive a systems view of how genetic loci interact in the context of tissue-specific molecular networks, we constructed an F2 intercross comprised of >500 mice from diabetes-resistant (B6) and diabetes-susceptible (BTBR) mouse strains made genetically obese by the Leptin(ob/ob) mutation (Lep(ob)). High-density genotypes, diabetes-related clinical traits, and whole-transcriptome expression profiling in five tissues (white adipose, liver, pancreatic islets, hypothalamus, and gastrocnemius muscle) were determined for all mice. We performed an integrative analysis to investigate the inter-relationship among genetic factors, expression traits, and plasma insulin, a hallmark diabetes trait. Among five tissues under study, there are extensive protein-protein interactions between genes responding to different loci in adipose and pancreatic islets that potentially jointly participated in the regulation of plasma insulin. We developed a novel ranking scheme based on cross-loci protein-protein network topology and gene expression to assess each gene's potential to regulate plasma insulin. Unique candidate genes were identified in adipose tissue and islets. In islets, the Alzheimer's gene App was identified as a top candidate regulator. Islets from 17-week-old, but not 10-week-old, App knockout mice showed increased insulin secretion in response to glucose or a membrane-permeant cAMP analog, in agreement with the predictions of the network model. Our result provides a novel hypothesis on the mechanism for the connection between two aging-related diseases: Alzheimer's disease and type 2 diabetes.

The role of voltage-gated potassium channels Kv2.1 and Kv2.2 in the regulation of insulin and somatostatin release from pancreatic islets.

The voltage-gated potassium channels Kv2.1 and Kv2.2 are highly expressed in pancreatic islets, yet their contribution to islet hormone secretion is not fully understood. Here we investigate the role of Kv2 channels in pancreatic islets using a combination of genetic and pharmacologic approaches. Pancreatic ß-cells from Kv2.1(-/-) mice possess reduced Kv current and display greater glucose-stimulated insulin secretion (GSIS) relative to WT ß-cells. Inhibition of Kv2.x channels with selective peptidyl [guangxitoxin-1E (GxTX-1E)] or small molecule (RY796) inhibitors enhances GSIS in isolated wild-type (WT) mouse and human islets, but not in islets from Kv2.1(-/-) mice. However, in WT mice neither inhibitor improved glucose tolerance in vivo. GxTX-1E and RY796 enhanced somatostatin release in isolated human and mouse islets and in situ perfused pancreata from WT and Kv2.1(-/-) mice. Kv2.2 silencing in mouse islets by adenovirus-small hairpin RNA (shRNA) specifically enhanced islet somatostatin, but not insulin, secretion. In mice lacking somatostatin receptor 5, GxTX-1E stimulated insulin secretion and improved glucose tolerance. Collectively, these data show that Kv2.1 regulates insulin secretion in ß-cells and Kv2.2 modulates somatostatin release in δ-cells. Development of selective Kv2.1 inhibitors without cross inhibition of Kv2.2 may provide new avenues to promote GSIS for the treatment of type 2 diabetes.

Hepatic safety of the antifungal triazole agent posaconazole: characterization of adverse event reports in a manufacturer's safety database.

BACKGROUND: Second generation triazoles including posaconazole are efficacious for prophylaxis and salvage treatment of life-threatening invasive fungal diseases but have been associated with hepatic adverse events (AEs). This report evaluated hepatic AEs in posaconazole-treated patients. RESEARCH DESIGN AND METHODS: Hepatobiliary AEs occurring after posaconazole exposure in the company's global safety database were analyzed to characterize underlying medical conditions and concomitant drug exposure. RESULTS: As of October 2019, 516 cases (168 from clinical trials, 348 from postmarketing use) containing 618 hepatobiliary AEs were reported regardless of causality. Frequently reported terms were hyperbilirubinemia, hepatic failure, and hepatic function abnormal (clinical trial reports) and hepatotoxicity, hepatocellular injury, and hepatic function abnormal (postmarketing reports). Cases reporting concurrent medications associated with drug-induced liver injury (DILI) included 8% with verified severe DILI (vMost-DILI) concern, 24% with verified mild to moderate DILI (vLess-DILI) concern, and 37% received both vMost-DILI and vLess-DILI-concern medications in the DILIrank data set. CONCLUSIONS: Use of concomitant medications with known risks for hepatic injury appears to be an important contributor for the development of hepatotoxicity in patients treated with posaconazole.

Identification of novel and selective Kv2 channel inhibitors.

Identification of selective ion channel inhibitors represents a critical step for understanding the physiological role that these proteins play in native systems. In particular, voltage-gated potassium (K(V)2) channels are widely expressed in tissues such as central nervous system, pancreas, and smooth muscle, but their particular contributions to cell function are not well understood. Although potent and selective peptide inhibitors of K(V)2 channels have been characterized, selective small molecule K(V)2 inhibitors have not been reported. For this purpose, high-throughput automated electrophysiology (IonWorks Quattro; Molecular Devices, Sunnyvale, CA) was used to screen a 200,000-compound mixture (10 compounds per sample) library for inhibitors of K(V)2.1 channels. After deconvolution of 190 active samples, two compounds (A1 and B1) were identified that potently inhibit K(V)2.1 and the other member of the K(V)2 family, K(V)2.2 (IC(50), 0.1-0.2 µM), and that possess good selectivity over K(V)1.2 (IC(50) >10 µM). Modeling studies suggest that these compounds possess a similar three-dimensional conformation. Compounds A1 and B1 are >10-fold selective over Na(V) channels and other K(V) channels and display weak activity (5-9 µM) on Ca(V) channels. The biological activity of compound A1 on native K(V)2 channels was confirmed in electrophysiological recordings of rat insulinoma cells, which are known to express K(V)2 channels. Medicinal chemistry efforts revealed a defined structure-activity relationship and led to the identification of two compounds (RY785 and RY796) without significant Ca(V) channel activity. Taken together, these newly identified channel inhibitors represent important tools for the study of K(V)2 channels in biological systems.

Trends in Blood Lead Levels in the U.S. From 1999 to 2016.

INTRODUCTION: Trends in blood lead levels in the same birth cohort (generation) are necessary to identify the lead load in the population. This analysis uses a nationally representative sample to investigate the trends in blood lead levels from 1999 to 2016 by birth cohort and to revisit the association between blood lead levels and age. METHODS: Data from the 1996 to 2016 National Health and Nutrition Examination Surveys were used to describe the distribution of blood lead levels. Trends in blood lead levels were analyzed using joinpoint regression models. Association of blood lead levels with age was conducted with both cross-sectional and birth cohort analysis. Analyses were conducted in 2020. RESULTS: In total, 68,877 participants were included (weighted mean age=38.4 years, 50.6% female). From 1999 to 2016, the geometric mean of blood lead levels decreased from 1.68 µg/dL (95% CI=1.63, 1.74) to 0.82 µg/dL (95% CI=0.77, 0.87). The annual percentage change estimated by the joinpoint model was -4.26% (p<0.05). The associations between blood lead levels and age were "U"-shaped by cross-sectional analysis, with higher risks for the lowest and highest ages. However, by birth cohort analysis the blood lead levels declined monotonically with age. The joinpoint analysis indicated the inflection point of age 13-17 years and statistically significant differences in decline slopes before and after this age. CONCLUSIONS: In this nationally representative study of the U.S. population, estimates of blood lead levels showed an overall decrease from 1999 to 2016. Blood lead levels are highest in childhood.

Discovery of 5-aryloxy-2,4-thiazolidinediones as potent GPR40 agonists.

Systematic structure-activity relationship (SAR) studies of a screening lead led to the discovery of a series of thiazolidinediones (TZDs) as potent GPR40 agonists. Among them, compound C demonstrated an acute mechanism-based glucose-lowering in an intraperitoneal glucose tolerance test (IPGTT) in lean mice, while no effects were observed in GPR40 knock-out mice.

Obesity and genetics regulate microRNAs in islets, liver, and adipose of diabetic mice.

Type 2 diabetes results from severe insulin resistance coupled with a failure of b cells to compensate by secreting sufficient insulin. Multiple genetic loci are involved in the development of diabetes, although the effect of each gene on diabetes susceptibility is thought to be small. MicroRNAs (miRNAs) are noncoding 19-22-nucleotide RNA molecules that potentially regulate the expression of thousands of genes. To understand the relationship between miRNA regulation and obesity-induced diabetes, we quantitatively profiled approximately 220 miRNAs in pancreatic islets, adipose tissue, and liver from diabetes-resistant (B6) and diabetes-susceptible (BTBR) mice. More than half of the miRNAs profiled were expressed in all three tissues, with many miRNAs in each tissue showing significant changes in response to genetic obesity. Furthermore, several miRNAs in each tissue were differentially responsive to obesity in B6 versus BTBR mice, suggesting that they may be involved in the pathogenesis of diabetes. In liver there were approximately 40 miRNAs that were downregulated in response to obesity in B6 but not BTBR mice, indicating that genetic differences between the mouse strains play a critical role in miRNA regulation. In order to elucidate the genetic architecture of hepatic miRNA expression, we measured the expression of miRNAs in genetically obese F2 mice. Approximately 10% of the miRNAs measured showed significant linkage (miR-eQTLs), identifying loci that control miRNA abundance. Understanding the influence that obesity and genetics exert on the regulation of miRNA expression will reveal the role miRNAs play in the context of obesity-induced type 2 diabetes.

Evaluation of Neural Tube Defects (NTDs) After Exposure to Raltegravir During Pregnancy.

OBJECTIVE: To evaluate the risk of neural tube defects (NTDs) after exposure to raltegravir during pregnancy. METHODS: Exposures to raltegravir during pregnancy reported cumulatively through May 31, 2018, to the company safety database were reviewed to identify cases of NTDs. This database includes all reports of pregnancy from Merck-sponsored clinical trials, spontaneous postmarketing reports, and non-interventional data sources, including the Antiretroviral Pregnancy Registry (APR). Reports were classified as prospective (before knowledge of pregnancy outcome) or retrospective (after knowledge of pregnancy outcome). We also reviewed data from 2 ongoing pregnancy cohorts. RESULTS: A total of 2426 pregnancies with reported outcomes were identified among women exposed to raltegravir: 1238 from the Merck database and 1188 from United Kingdom/Ireland and French pregnancy cohorts. Among all 2426 reports, 1991 were prospective. No cases of NTDs were identified among the prospective pregnancy reports, of which 767 were first trimester, including 456 in the periconception period (at or within 28 days after conception). Among the 435 retrospective reports, 3 NTD cases per APR criteria were identified (anencephaly, and 2 meningomyelocele), of which only one (meningomyelocele) was among exposures in the periconception period. Given the inherent limitations and bias of retrospective reports, it is not appropriate to calculate an incidence rate. CONCLUSIONS: Prospectively collected pregnancy outcome data do not suggest an association between raltegravir exposure in the periconception period and NTDs. The current data support the updated DHHS and EACS treatment guidelines for use of raltegravir as a preferred integrase inhibitor in all stages of pregnancy.

The aromatic amino acid sensor GPR142 controls metabolism through balanced regulation of pancreatic and gut hormones.

OBJECTIVES: GPR142, which is highly expressed in pancreatic islets, has recently been deorphanized as a receptor for aromatic amino acids; however, its physiological role and pharmacological potential is unclear. METHODS AND RESULTS: We find that GPR142 is expressed not only in ß- but also in α-cells of the islets as well as in enteroendocrine cells, and we confirm that GPR142 is a highly selective sensor of essential aromatic amino acids, in particular Trp and oligopeptides with N-terminal Trp. GPR142 knock-out mice displayed a very limited metabolic phenotype but demonstrated that L-Trp induced secretion of pancreatic and gut hormones is mediated through GPR142 but that the receptor is not required for protein-induced hormone secretion. A synthetic GPR142 agonist stimulated insulin and glucagon as well as GIP, CCK, and GLP-1 secretion. In particular, GIP secretion was sensitive to oral administration of the GPR142 agonist an effect which in contrast to the other hormones was blocked by protein load. Oral administration of the GPR142 agonist increased [3H]-2-deoxyglucose uptake in muscle and fat depots mediated through insulin action while it lowered liver glycogen conceivably mediated through glucagon, and, consequently, it did not lower total blood glucose. Nevertheless, acute administration of the GPR142 agonist strongly improved oral glucose tolerance in both lean and obese mice as well as Zucker fatty rat. Six weeks in-feed chronic treatment with the GPR142 agonist did not affect body weight in DIO mice, but increased energy expenditure and carbohydrate utilization, lowered basal glucose, and improved insulin sensitivity. CONCLUSIONS: GPR142 functions as a sensor of aromatic amino acids, controlling GIP but also CCK and GLP-1 as well as insulin and glucagon in the pancreas. GPR142 agonists could have novel interesting potential in modifying metabolism through a balanced action of gut hormones as well as both insulin and glucagon.

Identification of glucose-dependant insulin secretion targets in pancreatic beta cells by combining defined-mechanism compound library screening and siRNA gene silencing.

Identification and validation of novel drug targets continues to be a major bottleneck in drug development, particularly for polygenic complex diseases such as type 2 diabetes. Here, the authors describe an approach that allows researchers to rapidly identify and validate potential drug targets by combining chemical tools and RNA interference technology. As a proof-of-concept study, the known mechanism Sigma LOPAC library was used to screen for glucose-dependent insulin secretion (GDIS) in INS-1 832/13 cells. In addition to several mechanisms that are known to regulate GDIS (such as cyclic adenosine monophosphate-specific phosphodiesterases, adrenoceptors, and Ca(2+) channels), the authors find that several of the dopamine receptor (DRD) antagonists significantly enhance GDIS, whereas DRD agonists profoundly inhibit GDIS. Subsequent siRNA studies in the same cell line indicate that knockdown of DRD2 enhanced GDIS. Furthermore, selective DRD2 antagonists and agonists also enhance or suppress, respectively, GDIS in isolated rat islets. The data support that the approach described here offers a rapid and effective way for target identification and validation.

Discovery and Pharmacology of a Novel Somatostatin Subtype 5 (SSTR5) Antagonist: Synergy with DPP-4 Inhibition.

We report new SSTR5 antagonists with enhanced potency, subtype selectivity, and minimal off-target activities as compared to previously reported compounds. Starting from the reported SSTR5 antagonist 1, we systematically surveyed changes in the central core and head piece while maintaining the diphenyl tail group constant. From this study the azaspirodecanone 10 emerged as a new highly potent and selective SSTR5 antagonist. Compound 10 lowered glucose excursion by 94% in an oral glucose tolerance test (OGTT) in mice following a 3 mg/kg oral dose. The compound increased both total and active circulating incretin hormone GLP-1 levels in mice at a dose of 10 mg/kg. A synergistic effect was also demonstrated when compound 10 was coadministered with a DPP-4 inhibitor, substantially increasing circulating active GLP-1[7-36] amide and insulin in response to a glucose challenge.

Chronic inhibition of dipeptidyl peptidase-4 with a sitagliptin analog preserves pancreatic beta-cell mass and function in a rodent model of type 2 diabetes.

Inhibitors of dipeptidyl peptidase-4 (DPP-4), a key regulator of the actions of incretin hormones, exert antihyperglycemic effects in type 2 diabetic patients. A major unanswered question concerns the potential ability of DPP-4 inhibition to have beneficial disease-modifying effects, specifically to attenuate loss of pancreatic beta-cell mass and function. Here, we investigated the effects of a potent and selective DPP-4 inhibitor, an analog of sitagliptin (des-fluoro-sitagliptin), on glycemic control and pancreatic beta-cell mass and function in a mouse model with defects in insulin sensitivity and secretion, namely high-fat diet (HFD) streptozotocin (STZ)-induced diabetic mice. Significant and dose-dependent correction of postprandial and fasting hyperglycemia, HbA(1c), and plasma triglyceride and free fatty acid levels were observed in HFD/STZ mice following 2-3 months of chronic therapy. Treatment with des-fluoro-sitagliptin dose dependently increased the number of insulin-positive beta-cells in islets, leading to the normalization of beta-cell mass and beta-cell-to-alpha-cell ratio. In addition, treatment of mice with des-fluoro-sitagliptin, but not glipizide, significantly increased islet insulin content and improved glucose-stimulated insulin secretion in isolated islets. These findings suggest that DPP-4 inhibitors may offer long-lasting efficacy in the treatment of type 2 diabetes by modifying the courses of the disease.

Blockers of the delayed-rectifier potassium current in pancreatic beta-cells enhance glucose-dependent insulin secretion.

Delayed-rectifier K+ currents (I(DR)) in pancreatic beta-cells are thought to contribute to action potential repolarization and thereby modulate insulin secretion. The voltage-gated K+ channel, K(V)2.1, is expressed in beta-cells, and the biophysical characteristics of heterologously expressed channels are similar to those of I(DR) in rodent beta-cells. A novel peptidyl inhibitor of K(V)2.1/K(V)2.2 channels, guangxitoxin (GxTX)-1 (half-maximal concentration approximately 1 nmol/l), has been purified, characterized, and used to probe the contribution of these channels to beta-cell physiology. In mouse beta-cells, GxTX-1 inhibits 90% of I(DR) and, as for K(V)2.1, shifts the voltage dependence of channel activation to more depolarized potentials, a characteristic of gating-modifier peptides. GxTX-1 broadens the beta-cell action potential, enhances glucose-stimulated intracellular calcium oscillations, and enhances insulin secretion from mouse pancreatic islets in a glucose-dependent manner. These data point to a mechanism for specific enhancement of glucose-dependent insulin secretion by applying blockers of the beta-cell I(DR), which may provide advantages over currently used therapies for the treatment of type 2 diabetes.

Fibrolipomatous hamartoma of the median nerve: a case report and literature review / Hamartoma fibrolipomatoso del nervio mediano: reporte de un caso y revisión de la literatura

Abstract Fibrolipomatous hamartoma (FLH) of the nerve, also known as lipomatosis of the nerve, neurofibrillary lipomatous lesion, or intraneural lipoma, is a rare benign soft tissue tumor which mainly occurs in the nerves of the upper limb, especially in the median nerve. In April 2021, a 30-year-old male patient was secondly admitted to our hospital and underwent his third surgery, due to the recurrence of a mass and pain in the right palm, noticeable swelling and numbness of the right index and ring fingers, and limited flexion and extension activities of the right ring finger. He first visited our hospital in December 2017 due to a mass and pain in the right palm and swelling and numbness of the right index and ring fingers. When the clinician asked for the patient medical history, his parents stated that his right middle finger was swollen after birth. When the patient was ten years old; he was diagnosed with "macrodactyly" at the local county hospital, not in our hospital, and subsequently, the middle finger was amputated at the metacarpophalangeal joint level at the local county hospital. The postoperative pathological examination was not performed at that time, which was the first surgery the patient received. FLH is clinically rare, and its exact epidemiology and etiology are poorly understood. FLH is highly suspected in cases where a painless mass is present in the wrist, combined with macrodactyly. Magnetic resonance imaging and pathological examination are helpful in clarifying the diagnosis. Although FLH is a benign tumor, an individual treatment plan is the best choice according to the severity of the patient's symptoms. Therefore, further exploration and understanding of this disease by clinicians radiologists, and pathologists is necessary.

Resumen El hamartoma fibrolipomatoso (FLH) del nervio, también conocido como lipomatosis del nervio, lesión neurofibrilar lipomatosa, o lipointraneural, es un tumor benigno de tejido blando poco frecuente, que se presenta principalmente en los nervios del miembro superior, especialmente en el nervio mediano. En abril de 2021, un paciente masculino de 30 años fue ingresado por segunda vez en nuestro hospital y sometido a su tercera cirugía debido a la recurrencia de una masa y dolor en la palma derecha, evidente hinchazón y entumecimiento de los dedos índice y anular derecho y limitadas actividades de flexión y extensión del dedo anular derecho. En diciembre de 2017, visitó por primera vez nuestro hospital debido a una masa y dolor en la palma derecha, y a la hinchazón y entumecimiento de los dedos índice y anular derecho. Cuando el clínico preguntó la historia clínica del paciente, sus padres declararon que su dedo medio derecho estaba hinchado después del nacimiento, y cuando el paciente tenía 10 años, fue diagnosticado con "macrodactilia" en el hospital local del condado, no en nuestro hospital Posteriormente, el dedo medio fue amputado a nivel de la articulación metacarpofalángica en el hospital comarcal local, pero no se realizó la patología postoperatoria en ese momento, siendo ésta la primera cirugía a la cual se sometió el paciente. La FLH es clínicamente rara, y su epidemiología y etiología exactas no se entienden bien. En los casos que presentan una masa indolora en la muñeca, combinada con macrodactilia, se sospecha de FLH. La resonancia magnética y la patología son útiles para aclarar el diagnóstico. Aunque la FLH es un tumor benigno, el plan de tratamiento individual es la mejor opción de acuerdo con la gravedad de los síntomas del paciente. Por lo tanto, es necesaria una mayor exploración y comprensión de esta enfermedad por parte de médicos, radiólogos y patólogos.

Matrix metalloproteinases contribute to insulin insufficiency in Zucker diabetic fatty rats.

To assess the molecular changes associated with pancreatic beta-cell dysfunction occurring during the onset of type 2 diabetes, we profiled pancreatic islet mRNAs from diabetic male and high-fat-fed female Zucker diabetic fatty (ZDF) rats and their nondiabetic lean counterparts on custom islet-specific oligonucleotide arrays. The most prominent changes in both the male and female models of type 2 diabetes were increases in the mRNAs encoding proteases and extracellular matrix components that are associated with tissue remodeling and fibrosis. The mRNAs for metalloproteinase (MMP)-2, -12, and -14 were sharply increased with the onset of islet dysfunction and diabetes. Zymography of islet extracts revealed a concurrent, >10-fold increase in MMP-2 protease activity in islets from 9-week-old male ZDF rats. Treatment of female ZDF rats receiving a diabetogenic diet with PD166793, a broad-spectrum MMP inhibitor, substantially prevented diabetes. The effect of this compound was due in part to marked beta-cell expansion. These studies indicate that MMPs contribute to islet fibrosis and insulin insufficiency in ZDF rats. Class-targeted protease inhibitors should be explored for their potential therapeutic utility in preservation of beta-cell mass in type 2 diabetes.

Antidiabetic effects of Panax ginseng berry extract and the identification of an effective component.

We evaluated antihyperglycemic and anti-obese effects of Panax ginseng berry extract and its major constituent, ginsenoside Re, in obese diabetic C57BL/6J ob/ ob mice and their lean littermates. Animals received daily intraperitoneal injections of Panax ginseng berry extract for 12 days. On day 12, 150 mg/kg extract-treated ob/ob mice became normoglycemic (137 +/- 6.7 mg/dl) and had significantly improved glucose tolerance. The overall glucose excursion during the 2-h intraperitoneal glucose tolerance test decreased by 46% (P < 0.01) compared with vehicle-treated ob/ob mice. The improvement in blood glucose levels in the extract-treated ob/ ob mice was associated with a significant reduction in serum insulin levels in fed and fasting mice. A hyperinsulinemic-euglycemic clamp study revealed a more than twofold increase in the rate of insulin-stimulated glucose disposal in treated ob/ ob mice (112 +/- 19.1 vs. 52 +/- 11.8 micromol x kg(-1) x min(-1) for the vehicle group, P < 0.01). In addition, the extract-treated ob/ob mice lost a significant amount of weight (from 51.7 +/- 1.9 g on day 0 to 45.7 +/- 1.2 on day 12, P < 0.01 vs. vehicle-treated ob/ob mice), associated with a significant reduction in food intake (P < 0.05) and a very significant increase in energy expenditure (P < 0.01) and body temperature (P < 0.01). Treatment with the extract also significantly reduced plasma cholesterol levels in ob/ob mice. Additional studies demonstrated that ginsenoside Re plays a significant role in antihyperglycemic action. This antidiabetic effect of ginsenoside Re was not associated with body weight changes, suggesting that other constituents in the extract have distinct pharmacological mechanisms on energy metabolism.

Induction of miR-132 and miR-212 Expression by Glucagon-Like Peptide 1 (GLP-1) in Rodent and Human Pancreatic ß-Cells.

Better understanding how glucagon-like peptide 1 (GLP-1) promotes pancreatic ß-cell function and/or mass may uncover new treatment for type 2 diabetes. In this study, we investigated the potential involvement of microRNAs (miRNAs) in the effect of GLP-1 on glucose-stimulated insulin secretion. miRNA levels in INS-1 cells and isolated rodent and human islets treated with GLP-1 in vitro and in vivo (with osmotic pumps) were measured by real-time quantitative PCR. The role of miRNAs on insulin secretion was studied by transfecting INS-1 cells with either precursors or antisense inhibitors of miRNAs. Among the 250 miRNAs surveyed, miR-132 and miR-212 were significantly up-regulated by GLP-1 by greater than 2-fold in INS-1 832/3 cells, which were subsequently reproduced in freshly isolated rat, mouse, and human islets, as well as the islets from GLP-1 infusion in vivo in mice. The inductions of miR-132 and miR-212 by GLP-1 were correlated with cAMP production and were blocked by the protein kinase A inhibitor H-89 but not affected by the exchange protein activated by cAMP activator 8-pCPT-2'-O-Me-cAMP-AM. GLP-1 failed to increase miR-132 or miR-212 expression levels in the 832/13 line of INS-1 cells, which lacks robust cAMP and insulin responses to GLP-1 treatment. Overexpression of miR-132 or miR-212 significantly enhanced glucose-stimulated insulin secretion in both 832/3 and 832/13 cells, and restored insulin responses to GLP-1 in INS-1 832/13 cells. GLP-1 increases the expression of miRNAs 132 and 212 via a cAMP/protein kinase A-dependent pathway in pancreatic ß-cells. Overexpression of miR-132 or miR-212 enhances glucose and GLP-1-stimulated insulin secretion.

Discovery of MK-1421, a Potent, Selective sstr3 Antagonist, as a Development Candidate for Type 2 Diabetes.

The imidazolyl-tetrahydro-ß-carboline class of sstr3 antagonists have demonstrated efficacy in a murine model of glucose excursion and may have potential as a treatment for type 2 diabetes. The first candidate in this class caused unacceptable QTc interval prolongation in oral, telemetrized cardiovascular (CV) dogs. Herein, we describe our efforts to identify an acceptable candidate without CV effects. These efforts resulted in the identification of (1R,3R)-3-(4-(5-fluoropyridin-2-yl)-1H-imidazol-2-yl)-1-(1-ethyl-pyrazol-4-yl)-1-(3-methyl-1,3,4-oxadiazol-3H-2-one-5-yl)-2,3,4,9-tetrahydro-1H-ß-carboline (17e, MK-1421).