Antihyperglycaemic activity of 2,4:3,5-dibenzylidene-D-xylose-diethyl dithioacetal in diabetic mice (original) (raw)
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Metabolism-clinical and Experimental, 2009
Insulin resistance is central to the pathogenesis of type 2 diabetes mellitus. Previous studies have demonstrated that compounds that cause adipogenesis and improve glucose uptake in 3T3-L1 cells are potential insulin sensitizers. Therefore, we evaluated one such compound, 18F9, for (1) adipogenesis in human subcutaneous preadipocyte (SQ) cells, (2) glucose uptake in human skeletal muscle myotubes and SQ cells, and (3) antidiabetic activity in db/db mice. We also investigated its effect on ex vivo glucose uptake in soleus muscle isolated from continuously treated db/db mice. Gene expression profiling in soleus muscle and epididymal fat of db/db mice was performed to understand its effect on glucose metabolism, lipid metabolism, and thermogenesis. 18F9 enhanced adipogenesis in SQ cells and increased glucose uptake in SQ and human skeletal muscle myotubes cells. In db/db mice, 18F9 exhibited dose-dependent reduction in plasma glucose and insulin level. Interestingly, 18F9 was as efficacious as rosiglitazone but did not cause body weight gain and hepatic adverse effects. In addition, 18F9 demonstrated no change in plasma volume in Wistar rats. Furthermore, it enhanced ex vivo glucose uptake in soleus muscles in these mice, which substantiates our in vitro findings. Human peroxisome proliferator activated receptor-γ transactivation assay revealed a weak peroxisome proliferator activated receptor-γ transactivation potential (44% of rosiglitazone at 10 μmol/L) of 18F9. Gene expression profiling indicated that 18F9 increased insulin sensitivity mainly through a phosphoinositide 3-kinase-dependent mechanism. 18F9 also up-regulated genes involved in lipid transport and synthesis at par with rosiglitazone. Unlike rosiglitazone, 18F9 elevated the expression of Pdk4. In addition, 18F9 elevated the expression of glycogen synthase and adiponectin significantly higher than rosiglitazone. Taken together, these observations suggest that 18F9 is a safer and potent insulin sensitizer that demonstrates promising antidiabetic activity and is worth further development.
A Small Insulinomimetic Molecule Also Improves Insulin Sensitivity in Diabetic Mice
PLOS ONE, 2017
Dramatic increase of diabetes over the globe is in tandem with the increase in insulin requirement. This is because destruction and dysfunction of pancreatic β-cells are of common occurrence in both Type1 diabetes and Type2 diabetes, and insulin injection becomes a compulsion. Because of several problems associated with insulin injection, orally active insulin mimetic compounds would be ideal substitute. Here we report a small molecule, a peroxyvanadate compound i.e. DmpzH[VO(O 2) 2 (dmpz)], henceforth referred as dmp, which specifically binds to insulin receptor with considerable affinity (KD-1.17μM) thus activating insulin receptor tyrosine kinase and its downstream signaling molecules resulting increased uptake of [ 14 C] 2 Deoxy-glucose. Oral administration of dmp to streptozotocin treated BALB/ c mice lowers blood glucose level and markedly stimulates glucose and fatty acid uptake by skeletal muscle and adipose tissue respectively. In db/db mice, it greatly improves insulin sensitivity through excess expression of PPARγ and its target genes i.e. adiponectin, CD36 and aP2. Study on the underlying mechanism demonstrated that excess expression of Wnt3a decreased PPARγ whereas dmp suppression of Wnt3a gene increased PPARγ expression which subsequently augmented adiponectin. Increased production of adiponectin in db/db mice due to dmp effected lowering of circulatory TG and FFA levels, activates AMPK in skeletal muscle and this stimulates mitochondrial biogenesis and bioenergetics. Decrease of lipid load along with increased mitochondrial activity greatly improves energy homeostasis which has been found to be correlated with the increased insulin sensitivity. The results obtained with dmp, therefore, strongly indicate that dmp could be a potential candidate for insulin replacement therapy.
Diabetes, 2001
with 5-aminoimidazole-4-carboxamide-1--D-ribofuranoside (AICAR) increases glucose transport in skeletal muscle via an insulin-independent pathway. To examine the effects of AMPK activation on skeletal muscle glucose transport activity and whole-body carbohydrate and lipid metabolism in an insulin-resistant rat model, awake obese Zucker fa/fa rats (n ؍ 26) and their lean (n ؍ 23) littermates were infused for 90 min with AICAR, insulin, or saline. The insulin infusion rate (4 mU ⅐ kg ؊1 ⅐ min ؊1 ) was selected to match the glucose requirements during AICAR (bolus, 100 mg/kg; constant, 10 mg ⅐ kg ؊1 ⅐ min ؊1 ) isoglycemic clamps in the lean rats. The effects of these identical AICAR and insulin infusion rates were then examined in the obese Zucker rats. AICAR infusion increased muscle AMPK activity more than fivefold (P < 0.01 vs. control and insulin) in both lean and obese rats. Plasma triglycerides, fatty acid concentrations, and glycerol turnover, as assessed by [2-13 C]glycerol, were all decreased in both lean and obese rats infused with AICAR (P < 0.05 vs. basal), whereas insulin had no effect on these parameters in the obese rats. Endogenous glucose production rates, measured by [U-13 C]glucose, were suppressed by >50% during AICAR and insulin infusions in both lean and obese rats (P < 0.05 vs. basal). In lean rats, rates of whole-body glucose disposal increased by more than twofold (P < 0.05 vs. basal) during both AICAR and insulin infusion; [ 3 H]2-deoxy-D-glucose transport activity increased to a similar extent, by >2.2-fold (both P < 0.05 vs. control), in both soleus and red gastrocnemius muscles of lean rats infused with either AICAR or insulin. In the obese Zucker rats, neither AICAR nor insulin stimulated whole-body glucose disposal or soleus muscle glucose transport activity. However, AICAR increased glucose transport activity by ϳ2.4-fold (P < 0.05 vs. control) in the red gastrocnemius from obese rats, whereas insulin had no effect. In summary, acute infusion of AICAR in an insulin-resistant rat model activates skeletal muscle AMPK and increases glucose transport activity in red gastrocnemius muscle while suppressing endogenous glucose production and lipolysis. Because type 2 diabetes is characterized by diminished rates of insulin-stimulated glucose uptake as well as increased basal rates of endogenous glucose production and lipolysis, these results suggest that AICAR-related compounds may represent a new class of antidiabetic agents.
General Physiology and Biophysics
The effects of the oral administration of a non-sulfonylurea hypoglycemic agent, the phenylalanine derivative A-4166, on serum insulin and glucose levels and glucose metabolism in isolated rat adipocytes and slices of muscle tissues were studied. An increase in serum insulin and a decrease in glucose levels were observed 30 minutes after A-4166 administration to rats fed basal or high fat diet. No changes in basal glucose transport in isolated fat cells were observed after the administration of A-4166. The effect of in vitro added insulin was, however, stronger in rats fed basal diet and treated with A-4166. An elevation of the membrane glucose transporter GLUT 4 was observed in rats treated with A-4166. An increase of basal lipogenesis, measured by incorporation of radiocarbon labeled glucose into lipids, was noted in adipocytes from rats fed high fat diet. The addition of insulin was followed by stimulation of lipogenesis in rats fed basal diet, however, this hormone had no effect...
American journal of physiology. Endocrinology and metabolism, 2015
Docosahexaenoic acid (DHA 22:6n-3) and salicylate (acetylsalicylic acid) are both known to exert anti-inflammatory effects. This study investigated the effects of a novel bifunctional drug compound consisting of DHA and salicylate linked together by a small molecule that is stable in plasma but hydrolyzed in the cytoplasm. The components of the bifunctional compound acted synergistically to reduce inflammation mediated via nuclear factor kappa B (NFκB) in cultured macrophages. Notably, oral administration of the bifunctional compound acted in two distinct ways to mitigate hyperglycemia in high-fat diet (HFD)-induced insulin resistance. In mice with diet-induced obesity, the compound lowered blood glucose by reducing hepatic insulin resistance. It also had an immediate glucose-lowering effect that was secondary to enhanced glucagon-like peptide-1 (GLP-1) secretion and abrogated by the administration of Exendin(9-39), a GLP-1 receptor antagonist. These results suggest that the bifunct...
Therapeutic Advances in Endocrinology and Metabolism, 2011
Objective: The management of diabetes with insulin and synthetic oral hypoglycemic drugs (OHDs) can produce serious side effects and in addition fails to prevent diabetes-related complications in many patients. A new diabetes management strategy is needed that is more effective and has fewer side effects. Methods: This paper analyzes the dose-and time-dependent effect of three phytochemicals: berberine, arecoline and vanillic acid, and two antidiabetic drugs: 2,4-thiazolidinedione (TZD) and metformin, on the uptake of 2-deoxyglucose (2DG) by 3T3-L1 adipocytes. The interactions of the phytochemicals with the OHDs were analyzed with isobolograms and the combination index.
Frontiers in Pharmacology, 2016
We had previously demonstrated the anti-diabetic potential and pancreatic protection of two thiazolidin-4-one derivatives containing nicotinamide moiety (NAT-1 and NAT-2) in STZ-induced diabetic mice. However, due to the limitations of the STZ model, we decided to undertake a detailed evaluation of anti-diabetic potential of the molecules on a high sucrose diet (HSD) fed diabetic mouse model. Further, in vitro mechanistic studies on the phosphorylation of AMPK, Akt and p38 MAP kinase in L6 myotubes and anti-inflammatory studies in RAW264.7 mouse monocyte macrophage cells were performed. 15 months of HSD induced fasting hyperglycaemia and impaired glucose tolerance in mice. Treatment with NAT-1 and NAT-2 (100 mg/kg) for 45 days significantly improved the glucose tolerance and lowered fasting blood glucose levels compared to untreated control. An improvement in the elevated triglycerides and total cholesterol levels, and favorable rise in HDL cholesterol were also observed with test drug treatment. Also, no major changes were observed in the liver (albumin, AST and ALT) and kidney (creatinine and urea) parameters. This was further confirmed in their respective histology profiles which revealed no gross morphological changes. In L6 cells, significant phosphorylation of Akt and p38 MAP kinase proteins were observed with 100 μM of NAT-1 and NAT-2 with no significant changes in phosphorylation of AMPK. The molecules failed to exhibit anti-inflammatory activity as observed by their effect on the generation of ROS and nitrite, and nuclear levels of NF-κB in LPS-stimulated RAW264.7 cells. In summary, the molecules activated Akt and p38 MAP kinase which could have partly contributed to their anti-hyperglycaemic and hypolipidemic activities in vivo.
Journal of Biological Chemistry, 2010
The triterpenoid 2-Cyano-3,12-dioxooleana-1,9-dien-28-oicacid (CDDO) and its methyl ester (CDDO-Me) are undergoing clinical trials in cancer and leukemia therapy. Here we report that CDDO-Me ameliorates diabetes in high fat diet-fed type 2 diabetic mice and in Lepr db/db mice. CDDO-Me reduces proinflammatory cytokine expression in these animals. Oral CDDO-Me administration reduces total body fat, plasma triglyceride, and free fatty acid levels. It also improves glucose tolerance and insulin tolerance tests. Its potent glucose-lowering activity results from enhanced insulin action. Hyperinsulinemic-euglycemic clamp reveals an increased glucose infusion rate required to maintain euglycemia and showed a significant increase in muscle-specific insulin-stimulated glucose uptake (71% soleus, 58% gastrocnemius) and peripheral glucose clearance as documented by a 48% increase in glucose disposal rate. CDDO-Me activates AMP-activated protein kinase (AMPK) and via LKB1 activation in muscle and liver in vivo. Treatment of isolated hepatocytes with CDDO-Me directly stimulates AMPK activity and LKB1 phosphorylation and decreases acetyl-coA carboxylase activity; it also down-regulates lipogenic gene expression, suppresses gluconeogenesis, and increases glucose uptake. Inhibition of AMPK phosphorylation using compound C and lentiviral-mediated knockdown of AMPK completely blocks the CDDO-Me-induced effect on hepatocytes as well as C 2 C 12 cells. We conclude that the triterpenoid CDDO-Me has potent anti-diabetic action in diabetic mouse models that is mediated at least in part through AMPK activation. The in vivo antidiabetogenic effects occur at a dose substantially lower than that used for anti-leukemia therapy. We suggest that CDDO-Me holds promise as a potential anti-diabetic agent. . The abbreviations used are: CDDO, 2-cyano-3,12-dioxooleana-1,9-dien-28oic-acid; CDDO-Me, CDDO methyl ester; AMPK, AMP-activated protein kinase; ACC, acetyl-coA carboxylase; FFA, free fatty acid; GTT, glucose tolerance test; ITT, insulin tolerance test; IR, insulin receptor; AICAR, 5amino-imidazole carboxamide riboside; WAT, white adipose tissue; FAS, fatty acid synthase; SREBP, sterol response element-binding protein; Comp C, Compound C; PEPCK, phosphoenolpyruvate carboxykinase; TG, triglyceride; T2DM, type 2 diabetes mellitus.