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A series of benzofuran-based chromenochalcones (16–35) were synthesized and evaluated for in vitroand in vivoantidiabetic activities in L-6 skeletal muscle cells and streptozotocin (STZ)-induced diabetic rat models, respectively, and further in vivodyslipidemia activity of the compounds was evaluated in a Triton-induced hyperlipidemic hamster model. Among them, compounds 16, 18, 21, 22, 24, 31, and 35showed significant glucose uptake stimulatory effects in skeletal muscle cells and were further evaluated for in vivoefficacy. Compounds 21, 22, and 24showed a significant reduction in blood glucose levels in STZ-induced diabetic rats. Compounds 16, 20, 21, 24, 28, 29, 34, 35, and 36were found active in antidyslipidemic studies. Furthermore, compound 24effectively improved the postprandial and fasting blood glucose levels, oral glucose tolerance, serum lipid profile, serum insulin level, and the HOMA-index of db/db mice, following 15 days of successive treatment.

Insulin resistance is a major predictor and leading cause of type 2 diabetes (1). Intricate links between metabolic and immune responses underlie the disease development (2) and a chronic, low-level [...], OBJECTIVE--Insulin resistance associates with chronic inflammation, and participatory elements of the immune system are emerging. We hypothesized that bacterial elements acting on distinct intracellular pattern recognition receptors of the innate immune system, such as bacterial peptidoglycan (PGN) acting on nucleotide oligomerization domain (NOD) proteins, contribute to insulin resistance. RESEARCH DESIGN AND METHODS--Metabolic and inflammatory properties were assessed in wild-type (WT) and [NOD1/2.sup.-/-] double knockout mice fed a high-fat diet (HFD) for 16 weeks. Insulin resistance was measured by hyperinsulinemic euglycemic clamps in mice injected with mimetics of mesodiaminopimelic acid-containing PGN or the minimal bioactive PGN motif, which activate NOD1 and NOD2, respectively. Systemic and tissue-specific inflammation was assessed using enzyme-linked inmmnosorbent assays in NOD ligand-injected mice. Cytokine secretion, glucose uptake, and insulin signaling were assessed in adipocytes and primary hepatocytes exposed to NOD ligands in vitro. RESULTS--[NOD1/2.sup.-/-] mice were protected from HFD-induced inflammation, lipid accumulation, and peripheral insulin intolerance. Conversely, direct activation of NOD1 protein caused insulin resistance. NOD1 ligands induced peripheral and hepatic insulin resistance within 6 h in WT, but not [NOD1.sup.-/-], mice. NOD2 ligands only modestly reduced peripheral glucose disposal. NOD1 ligand elicited minor changes in circulating proinflammatory mediators, yet caused adipose tissue inflammation and insulin resistance of muscle AS160 and liver FOXO1. Ex vivo, NOD1 ligand caused proinflammatory cytokine secretion and impaired insulin-stimulated glucose uptake directly in adipocytes. NOD1 ligand also caused inflammation and insulin resistance directly in primary hepatocytes from WT, but not [NOD1.sup.-/-], mice. CONCLUSIONS--We identify NOD proteins as innate immune components that are involved in diet-induced inflammation and insulin intolerance. Acute activation of NOD proteins by mimetics of bacterial PGNs causes whole-body insulin resistance, bolstering the concept that innate immune responses to distinctive bacterial cues directly lead to insulin resistance. Hence, NOD1 is a plausible, new link between innate immunity and metabolism. Diabetes 60:2206-2215, 2011

Purpose: Innate immune components participate in obesity-induced inflammation, which can contribute to endocrine dysfunction during metabolic diseases. However, the chronological activation of specific immune proteins such as Nucleotide-binding oligomerization domain-containing protein 1 (NOD1) and relevance to cellular crosstalk during the progression of obesity-associated insulin resistance (IR) is not known. Methods: The NOD1 signaling in various insulin-sensitive metabolic tissues during the progression of diet-insulin resistance was assessed in C57BL/6J mice fed with 60% high-fat diet (HFD) for 4, 8, 12, and 16 weeks. Intestinal permeability was measured using FITC-dextran. NOD1 activating potential was analyzed using HEK-Blue mNOD1 cells. Results: HFD-fed mice showed progressive induction of glucose intolerance and impairment of insulin signaling in key metabolic tissues. We found a time-dependent increase in intestinal permeability coupled with transport and accumulation of NOD1 activating ligand in the serum of HFD-fed mice. We also observed a progressive accumulation of γ-D-glutamyl-meso-diaminopimelic acid (DAP), a microbial peptidoglycan ligand known to activate NOD1, in serum samples of the HFD-fed mice. There was also a progressive increase in transcripts levels of NOD1 in bone marrow-derived macrophages during HFD-feeding. In addition, skeletal muscle, adipose and liver, the key insulin sensitive metabolic tissues also had a time-dependent increase in transcripts of NOD1 and Rip2 and a corresponding activation of pro-inflammatory responses in these tissues. Conclusion: These data highlight the correlation of inflammation and insulin resistance to NOD1 activation in the bone marrow derived macrophages and insulin responsive metabolic tissues during high fat diet feeding in mice.

ABSTRACTIntroduction: The sodium-glucose co-transporter 2 (SGLT2) is ascribed to target renal tubular glucose re-absorption, and its inhibition has been proved to induce glucosuria which improves the glycemic index. Accordingly, SGLT2 inhibitors have found to be the promising class of antidiabetic agents for the management of type 2 diabetes mellitus. A large number of SGLT2 inhibitors have developed through structural modification and investigated for their ability to selectivity inhibit SGLT2 transporters with better bioavailability.Areas covered: This review comprises a summary of patent applications (2013–2018) of SGLT2 inhibitors with focus on chemical structural advancement and therapeutic potentials in the management of diabetes and related disorders.Expert opinion: SGLT2 inhibitors exert multiple metabolic benefits, including reduced glycated hemoglobin (HbA1c), improved glycemic control (fasting and postprandial), reduced body weight, reduced systolic and diastolic blood pressure and improved HDL cholesterol. Due to the virtue of no interference with insulin action and secretion, their efficacy remains the same even in presence of progressive β cell failure in type 2 diabetes. Additionally, few members of this class have been reported to exhibit cardioprotective, renoprotective, and anticancer activity. However, more study on the long-term outcomes in patients taking SGLT2 inhibitors is warranted.

In the quest for the discovery of antidiabetic compounds, a series of 27 1,4-dihydropyridine–indole derivatives were synthesized using a diversity approach. These compounds were systematically evaluated for their antidiabetic activity, starting with an in vitro assessment for GLUT4 translocation stimulation in L6-GLUT4mycmyotubes, followed by in vivo antihyperglycemic activity evaluation in a streptozotocin (STZ)-induced diabetic rat model. Among the synthesized compounds, 12, 14, 15, 16, 19, 27, and 35demonstrated significant potential to stimulate GLUT4 translocation in skeletal muscle cells. Compound 19exhibited the highest potency and was selected for in vivo evaluation. A notable reduction of 21.6% (p< 0.01) in blood glucose levels was observed after 5 h of treatment with compound 19in STZ-induced diabetic rats. Furthermore, pharmacokinetic studies affirmed that compound 19was favorable to oral exposure with suitable pharmacological parameters. Overall, compound 19emerged as a promising lead compound for further structural modification and optimization.

This study identified koenidine (4) as a metabolically stable antidiabetic compound, when evaluated in a rodent type 2 model (leptin receptor-deficient db/dbmice), and showed a considerable reduction in the postprandial blood glucose profile with an improvement in insulin sensitivity. Biological studies were directed from the preliminary in vitro evaluation of the effects of isolated carbazole alkaloids (1–6) on glucose uptake and GLUT4 translocation in L6-GLUT4mycmyotubes, followed by an investigation of their activity (2–5) in streptozotocin-induced diabetic rats. The effect of koenidine (4) on GLUT4 translocation was mediated by the AKT-dependent signaling pathway in L6-GLUT4mycmyotubes. Moreover, in vivo pharmacokinetic studies of compounds 2and 4clearly showed that compound 4was 2.7 times more bioavailable than compound 2, resulting in a superior in vivo efficacy. Therefore, these studies suggested that koenidine (4) may serve as a promising lead natural scaffold for managing insulin resistance and diabetes.

A total of 8 out of 11 deep ground water samples collected from different villages in Central India were found contaminated with Vibrio choleraenon O1, non O139. In a multiplex PCR, isolates were found positive for ompWgene but negative for ctxABand rfbO1 genes. However, isolates from two places were positive for tcpand zotgenes, indicating their intestinal colonization and toxigenic potential. Antibiotic susceptibility studies revealed that all isolates were multidrug resistant. Although, none of the isolates was found PCR positive for the mobile genetic elements, class 1 integrons and SXT constins. The results of this study corroborated that deep ground water can also be an important reservoir of V. choleraein plane endemic areas, suggesting a continuous monitoring of water samples for timely prevention of the disease.

The serial chromatographic separation of chloroform and n-butanol fractions of Ammannia multifloraresulted in the isolation and characterization of 4-hydroxy-α-tetralone (1) and 3,3′-(2R,5R)-tetrahydrofuran-2,5-diyldiphenol (ammaniol, 2). Compound 1was chemically modified into six semi-synthetic acyl and aryl derivatives (1A- 1F). The isolated compounds 1and 2along with semi-synthetic derivatives 1A- 1Fwere evaluated for in vitroantihyperglycemic activity employing 2-deoxyglucose uptake by L-6 rat muscle cell lines. The results indicated that both the isolates, as well as derivatives (1A- 1F), have the property to stimulate glucose uptake. Ammaniol (2) increased glucose uptake significantly (64.8%), while one of the aryl derivatives of 1, 4-O-(3,4,5-trimethoxybenzoyl)-α-tetralone (1D), showed potent antihyperglycemic activity and increased glucose uptake by 94.6%, even more than rosiglitazone (88.8%). Further, since 1Dpossesses better antihyperglycemic activity than rosiglitazone (standard), this might be a new safer antidiabetic drug of herbal origin.

ChemInform is a weekly Abstracting Service, delivering concise information at a glance that was extracted from about 200 leading journals. To access a ChemInform Abstract of an article which was published elsewhere, please select a “Full Text” option. The original article is trackable via the “References” option.

ChemInform is a weekly Abstracting Service, delivering concise information at a glance that was extracted from about 200 leading journals. To access a ChemInform Abstract of an article which was published elsewhere, please select a “Full Text” option. The original article is trackable via the “References” option.

ChemInform is a weekly Abstracting Service, delivering concise information at a glance that was extracted from about 200 leading journals. To access a ChemInform Abstract, please click on HTML or PDF.