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PubMed2003

Differential effects of YM440 a hypoglycemic agent on binding to a peroxisome proliferator-activated receptor gamma and its transactivation.

Peroxisome proliferator-activated receptor (PPAR) gamma is a ligand-inducible transcription factor mediating glucose and lipid metabolism. Prior studies showed that YM440 ameliorated hyperglycemia in diabetic mice without affecting body fat weight or PPARgamma transactivation. In this study we have examined further the effects of YM440 on PPARgamma binding, transactivation and conformational change. YM440, pioglitazone and rosiglitazone displaced [3H]rosiglitazone from PPARgamma with K(i) values of 4.0, 3.1, and 0.20 microM, indicating that YM440 was comparable to pioglitazone and 20-fold less potent than rosiglitazone. Although pioglitazone and rosiglitazone increased both PPARgamma transactivation in cells expressing human full-length PPARgamma2 or GAL4-PPARgamma and mRNA expression of PPARgamma responsive genes in 3T3-L1 cells, YM440 had weak effects on PPARgamma transactivation and mRNA expression being 550- to 790-fold and 36- to 110-fold less active than rosiglitazone, respectively. YM440 and rosiglitazone induced interaction between PPARgamma and the transcriptional cofactor, p300 or SRC-1, but YM440 was 151- and 1091-fold less potent than rosiglitazone, respectively. The weak transcriptional activity of YM440 was not due to poor cell permeability. Limited trypsin digestion of the full-length human PPARgamma2 with YM440 or rosiglitazone showed distinct patterns of digestion, suggesting a difference in the conformational change of PPARgamma. When db/db mice were treated with YM440 (100mg/kg) for 28 days, YM440 increased hepatic glucokinase expression but not adipose tissue FABP and UCP1 expression, indicating a tissue selective expression of PPARgamma-related genes. Unique properties regarding the binding-transactivation of PPARgamma by YM440 may lead to the hypoglycemic activity without affecting body fat weight in diabetic mice.

3T3 Cells↗
PubMed2000

Inhibitory effect of novel oral hypoglycemic agent nateglinide (AY4166) on peptide transporters PEPT1 and PEPT2.

The novel oral hypoglycemic agent nateglinide (AY4166) is a nonsulfonylurea insulin secretagogue, and its pharmacokinetic features include rapid absorption and elimination. As nateglinide is a dipeptide-like drug, we investigated the interaction of nateglinide with peptide transporters PEPT1 and PEPT2, which mediate the absorption of various peptide-like drugs. Nateglinide exhibited a potent inhibitory effect on [14C]glycylsarcosine uptake by the human colon adenocarcinoma cell line Caco-2 and rat PEPT-transfectants. Kinetic analysis revealed that these inhibitory effects were noncompetitive. Na(+)-coupled alanine or threonine uptake by Caco-2 cells was not inhibited by nateglinide, suggesting that the inhibitory effect of nateglinide on peptide transporters was not due to nonspecific interaction. There was little uptake of [14C]nateglinide by peptide transporters. Various sulfonylureas, such as glibenclamide, also inhibited [14C]glycylsarcosine uptake by rat PEPT-transfectants. In conclusion, nateglinide as well as sulfonylureas inhibit the transport activity of PEPT1 and PEPT2, although nateglinide itself is not transported by these transporters.

Administration, Oral↗
PubMed1998

Changes in the liver protein pattern of female Wistar rats treated with the hypoglycemic agent SDZ PGU 693.

SDZ PGU 693 acts as a hypoglycemic agent by stimulating glucose utilisation in insulin-sensitive peripheral tissues, such as skeletal muscle and fat. In a 28 day toxicity study the compound was found to induce hepatocellular hypertrophy in Wistar rats treated with 300 mg/kg/day. To gain insights into the pathomechanism of these alterations, aliquots of liver samples from control and treated female Wistar rats were separated by two-dimensional protein gel electrophoresis and the digitized images of the protein patterns were searched for protein abundance changes. Significant treatment-related quantitative changes (P < 0.001) were found in 29 liver proteins. Major increases were observed in several microsomal proteins, including NADPH cytochrome P-450 reductase, cytochrome b5 and serine protease inhibitor. The changes in the cytochrome related enzymes, both known co-factors of the P-450 enzyme system, strongly suggest that SDZ PGU 693 induces microsomal proliferation and induction of the P-450 enzyme system. Decreases were observed in a series of mitochondrial proteins, such as F1ATPase-delta subunit and ornithine aminotransferase precursor as well as in several cytosolic proteins such as the liver fatty acid binding protein, arylsulfotransferase and the senescence marker protein-30. The changes in F1ATPase-delta subunit and liver fatty acid binding protein together suggest a down-regulation of the mitochondrial liver fatty acid metabolism, likely reflecting the pharmacological action of the compound. These results show that SDZ PGU 693 produces a complex pattern of gene expression changes which give insights into the molecular mechanisms of both its pharmacological action and a toxic response.

Animals↗
PubMed1999

Natural products with hypoglycemic, hypotensive, hypocholesterolemic, antiatherosclerotic and antithrombotic activities.

This article reviews compounds of botanical origin which are capable of lowering plasma levels of glucose and cholesterol and blood pressure, as well as compounds inhibiting atherosclerosis and thrombosis. Hypoglycemic natural products comprise flavonoids, xanthones, triterpenoids, alkaloids, glycosides, alkyldisulfides, aminobutyric acid derivatives, guanidine, polysaccharides and peptides. Hypotensive compounds include flavonoids, diterpenes, alkaloids, glycosides, polysaccharides and proteins. Among natural products with hypocholesterolemic activity are beta-carotene, lycopene, cycloartenol, beta-sitosterol, sitostanol, saponin, soybean protein, indoles, dietary fiber, propionate, mevinolin (beta-hydroxy-beta-methylglutaryl coenzyme A reductase inhibitor) and polysaccharides. Heparins, flavonoids, tocotrienols, beta-hydroxy-beta-methylglutaryl coenzyme A reductase inhibitors (statins), garlic compounds and fungal proteases exert antithrombotic action. Statins and garlic compounds also possess antiatherosclerotic activity.

Animals↗
PubMed1988

Oral hypoglycemic agents.

The sulfonylureas remain the most important oral agents, although their chronic hypoglycemic actions are still unexplained and the evidence on their relative efficacy is inconclusive. Data on relative safety suggest that chlorpropamide is the most toxic sulfonylurea but glyburide causes dangerous hypoglycemia as often as chlorpropamide. For many patients, good blood glucose control will be achieved by taking tolbutamide or another sulfonylurea 30 minutes before breakfast and the main evening meal. The biguanide metformin, which is as safe as glyburide, is of use in treating overweight diabetic patients who do not have cardiovascular, hepatic, or renal dysfunction.

Administration, Oral↗
PubMed2000

JTT-501, a new oral hypoglycemic agent, reverses hypertriglyceridemia in Zucker fatty and ventromedial hypothalamus-lesioned obese rats.

JTT-501 is a new oral hypoglycemic agent that is reported to be effective in insulin-resistant diabetic animal models by improving insulin resistance. It also improves hypertriglyceridemia. We investigated the mechanism of the reversal of hypertriglyceridemia in two types of obese animals using JTT-501. In Zucker fatty obese rats, an animal model of genetic obesity, fasting plasma triglyceride and glucose significantly decreased after a single daily oral dose of JTT-501 (100 mg/kg) for 7 days. In ventromedial hypothalamus (VMH)-lesioned obese rats, an animal model of nongenetic obesity, fasting plasma triglycerides significantly decreased but fasting plasma glucose levels remained unchanged after treatment with this agent. In Sprague-Dawley (SD) rats, fasting plasma triglyceride and glucose levels remained unchanged. The JTT-501-treated Zucker fatty and VMH-lesioned obese rats showed a decrease in insulin, but it was not significant, while the treated SD rats showed a significant decrease in insulin. Postheparin plasma lipoprotein lipase (LPL) increased significantly in treated Zucker fatty obese and SD rats, but did not change in VMH-lesioned obese rats. The hepatic triglyceride secretion rate (TGSR) did not change in any species treated with JTT-501. There was a negative correlation between postheparin plasma LPL and plasma triglyceride levels in Zucker fatty obese rats, while no such correlation was observed in VMH-lesioned obese or SD rats. The fractional catabolic rate (FCR) for plasma triglyceride was increased significantly by JTT-501 in both Zucker fatty and VMH-lesioned obese rats. These results suggest that JTT-501 decreases plasma triglycerides mainly by increasing postheparin plasma LPL in Zucker fatty obese rats, while it ameliorates an impairment in the ability of adipose tissue to remove triglyceride from the circulation in VMH-lesioned obese rats.

Animals↗
PubMed1996

Somatostatin and insulin secretion due to common mechanisms by a new hypoglycemic agent, A-4166, in perfused rat pancreas.

N-[(trans-4-isopropylcyclohexyl)-carbonyl]-D-phenylalanine (A-4166) is a nonsulfonylurea hypoglycemic agent that decreases blood glucose levels in nondiabetic and diabetic animals. In the present study, we attempted to determine the effect of A-4166 on hormone secretion from the in vitro-perfused rat pancreas and to examine the underlying secretory mechanisms. In the presence of basal glucose (3 mmol/L), A-4166 markedly stimulated insulin and somatostatin release in a concentration-dependent manner over 0.03 to 3 mmol/L. A sulfonylurea, tolbutamide, also stimulated insulin and somatostatin release. A-4166 and tolbutamide elevated the level of glucagon release; however, the change lacked a clear concentration-dependent property. A-4166 at 0.3 mmol/L and tolbutamide at 3 mmol/L exhibited maximal stimulation of insulin release to a similar extent, indicating that A-4166 is one log-order more potent than and as effective as tolbutamide. By contrast, A-4166 stimulated somatostatin release to a threefold greater extent than tolbutamide. A-4166 evoked an increase in the cytosolic free-Ca2+ concentration ([Ca2+]i) in rat pancreatic beta cells. [Ca2+]i and insulin secretory responses to A-4166 were inhibited by nitrendipine (NTD), a blocker of the L-type Ca2+ channel, and by diazoxide (DAZ), an opener of the adenosine triphosphate (ATP)-sensitive K+ channel. Furthermore, A-4166-stimulated somatostatin release was also inhibited by NTD and by DAZ. The results indicate that A-4166 and tolbutamide stimulate the release of insulin and somatostatin, and that A-4166 is much more effective than tolbutamide in releasing somatostatin, a hormone that attenuates hyperglycemia under certain circumstances. It is concluded that A-4166-induced insulin release is mediated by an increase in [Ca2+]i in beta cells. An inhibition of ATP-sensitive K+ channels and a consequent activation of L-type Ca2+ channels appear to play a key role not only in insulin secretion from beta cells, but also in somatostatin secretion from delta cells in response to A-4166.

Adenosine Triphosphate↗
PubMed1983

Theoretical study on conformation-related activity of hypoglycemic sulfonylureas.

Theoretical conformational analysis has been carried out for different hypoglycemic sulfonylurea -Ca complexes. The formed complex has an hydrophobic external surface and a low amphiphilic character. Our results suggest that Calcium may effectively be transported across membranes of Langerhans B cells and that the different biological potencies of the drugs may be due in part to the shape of the different complexes.

Hypoglycemic Agents↗
PubMed1996

Effect of a novel hypoglycemic agent, KAD-1229 on glucose metabolism and fructose-2,6-bisphosphate content in isolated hepatocytes of normal rats.

The effects of a novel hypoglycemic agent, calcium(2s)-2-benzyl-3-(cis-hexahydro-2-isoindolinylcarbonyl) propionate dihydrate (KAD-1229), which is a benzyl succinate derivative, on liver metabolism were investigated using isolated hepatocytes from normal rats. In the presence of 10 mM glucose, KAD-1229 increased the L-lactate production (41.1 +/- 0.9 versus 60.9 +/- 2.6 mumol of lactate/g of cells/30 min; P < 0.05) and inhibited gluconeogenesis in hepatocytes (0.94 +/- 0.02 versus 0.70 +/- 0.03 mumol of [2-14C]-pyruvate converted to glucose/g of cells/20 min; P < 0.05). These effects by KAD-1229 were accompanied by an increase in the cellular content of fructose-2,6-bisphosphate (F-2,6-P2), which is one of the important regulators of hepatic glucose metabolism, in a dose-dependent manner (0.05-2.5 mM). KAD-1229 also stimulated the oxidation of [2-14C]-pyruvate and [6-14C]-glucose in the tricarboxylic acid cycle (+18 and +31%, respectively), indicating that stimulation of tricarboxylic acid cycle activity and/or enhancement of the glycolytic flux rate had occurred. Moreover, KAD-1229 did not modify the activities of 6-phosphofructo 2-kinase or fructose-2,6-bisphosphatase, but increased significantly the accumulation of fructose 6-phosphate in hepatocytes. These results suggest that KAD-1229 has extrapancreatic effects on hepatic glucose metabolism, that its actions are mediated through the inhibition of fructose-1,6-bisphosphatase and stimulation of both the 6-phosphofructo 1-kinase reaction and tricarboxylic acid cycle activity by increasing the F-2,6-P2 content in hepatocytes, and that these multiple effects may account in part for the ability of KAD-1229 to reduce blood glucose levels in vivo.

Analysis of Variance↗
PubMed1999

Hepatic amino- to urea-N clearance and forearm amino-N exchange during hypoglycemic and euglycemic hyperinsulinemia in normal man.

BACKGROUND/AIMS: Hypoglycemia has well-described effects on glucose metabolism, whereas the possible effects on hepatic amino nitrogen conversion in relation to muscle amino nitrogen flux are more uncertain. METHODS: We studied six healthy young male subjects three times, i.e. for 6 h in the basal state, during a 6-h euglycemic hyperinsulinemic (1.5 mU/kg/min) clamp and during a 6-h hypoglycemic (plasma glucose below 2.8 mmol/l) clamp. Alanine (2 mmol/kg body weight/h) was infused for 3 h to describe the relationship between blood amino nitrogen concentrations and hepatic ureagenesis estimated from urea urine excretion and accumulation in body water. The slope of this relationship is denoted functional hepatic nitrogen clearance (FHNC) and quantifies substrate-independent alterations in hepatic amino nitrogen degradation. In parallel, amino nitrogen balances across muscles were estimated by the forearm flux method. RESULTS: Euglycemia decreased circulating glucagon values (100+/-25 ng/l vs. 160+/-30 ng/l), whereas hypoglycemia doubled glucagon (350+/-45 ng/l, p<0.05). Hepatic nitrogen clearance (FHNC) decreased during hyperinsulinemic euglycemia (19.5+/-3.4 l/h vs. 30.6+/-5.7 l/h, p<0.01), whereas forearm net uptake of amino nitrogen increased (130+/-40 nmol/100 ml x min vs. control: -10+/-4 nmol/100 ml x min). During hypoglycemia there was a 3-fold increase in hepatic nitrogen clearance up to 83.0+/-16.8 l/h (p<0.01) and increased release of amino nitrogen from the forearm (-100+/-30 nmol/100 ml x min, p<0.01). CONCLUSION: Hypoglycemia in man induces a marked increase in hepatic amino- to urea-N clearance. This catabolic response to hypoglycemia in the liver may be of primary importance for muscle amino acid release. Our data are compatible with the notion that liver and muscle together are responsible for catabolism during hypoglycemia, and that glucagon may be the primary mediator via its effect on liver metabolism.

Adult↗
PubMed1995

NIDDM in the cat: treatment with the oral hypoglycemic medication, glipizide.

The oral hypoglycemic medication, glipizide, provides a viable therapeutic alternative to conventional insulin therapy with a positive therapeutic response in approximately 50% of diabetic cats with non-insulin-dependent disease. Response to glipizide therapy or lack thereof usually is evident within the first 4 to 6 weeks of treatment. Adverse side effects occurred in less than 10% of patients. The existence of residual beta cell function is necessary for response to glipizide therapy. Predictors of response to glipizide therapy were not found. Identification and correction or control of existing insulin antagonistic disease processes, as well as, discontinuation of diabetogenic medications that may be contributing to insulin resistance is also important.

Administration, Oral↗
PubMed2002

Effect of some hypoglycemic herbs on the activity of phase I and II drug-metabolizing enzymes in alloxan-induced diabetic rats.

Polycyclic aromatic hydrocarbons (PAHs) and N-nitrosamines (NNA) are mainly activated by cytochrome P450s, and their associated enzyme activities such as aryl hydrocarbon (benzo(a)pyrene) hydroxylase (AHH), N-nitrosdimethylamine N-demethylase I (NDMA-dI), NADPH-cytochrome C reductase, and detoxified by glutathione S-transferase (GST) and glutathione (GSH). The present study shows the influence of Cymbopogon proximus (Halfa barr), Zygophyllum coccineum L. (Kammun quaramany), Lupinus albus (Termis) as herbs capable of inducing hypoglycemia on the activity of the above mentioned enzymes in the liver of diabetic rats. Alloxan was administered as a single dose (120 mg/kg body weight) to induce diabetes and the herbs were administered to diabetic rats as repeated doses for 4 weeks. Alloxan-induced diabetes significantly increased the blood glucose level by 93% compared to the control level. On the other hand, repeated-dose treatments of diabetic rats with Cymbopogon proximus and Lupinus albus are more effective than Zygophyllum coccineum in restoring the elevated blood glucose level to the normal level. Alloxan treatment increased the hepatic activity of cytochrome P450, NADPH-cytochrome C reductase, AHH, NDMA-dI, GST and GSH by 112, 122, 82, 99, 64 and 26%, respectively. These herbs decreased the activity of above mentioned enzymes in the liver of diabetic rats compared to alloxan-treated rats. We conclude that alloxan increased the activity of cytochrome P450 system and that such herbs reduced these activities. The toxic effects of PAHs (e.g. benzo(a)pyrene) and NNA (e.g. N-nitrosdimethylamine) could be increased in the liver of diabetic rats through induction of their corresponding bioactivating enzymes. On the other hand, hypoglycemic herbs could alleviate the deleterious effects of these carcinogens in the liver of diabetic rats since these herbs reduced the hepatic content of cytochrome P450 and other associated enzyme activities compared to the diabetic group. Such alterations in the activity of phase I and II drug-metabolizing enzymes should be considered when therapeutic drugs are administered to diabetic patients since most of drugs are metabolized mainly by the cytochrome P450 system.

Animals↗
PubMed2003

Hypoglycemic effect of surfactant-coated insulin solubilized in a novel solid-in-oil-in-water (S/O/W) emulsion.

A novel solid-in-oil-in-water (S/O/W) emulsion for oral administration of insulin has been developed using surfactant-coated insulin. The S/O/W emulsion prepared by a shirasu porous glass (SPG) membrane provided a sharp size distribution and was stable. Leakage of insulin from the S/O/W emulsions was not observed for several days. The S/O/W emulsion showed the hypoglycemic activity for a long period after oral administration to rats.

Animals↗
PubMed2001

Hypoglycemic effects of aqueous extract of Rhizoma Polygonati Odorati in mice and rats.

Water soluble extract of Rhizoma Polygonati Odorati (RPO) was studied for its hypoglycemic effect in diabetic mice and rats. Results showed that RPO significantly lowered hyperglycemia caused by starch loading in both normal and diabetic mice. Four week's administration with RPO reduced fasting blood glucose, decreased glycosylated hemoglobin (GHb), and improved the glucose tolerance in diabetic mice. In diabetic rats complicated with hyperlipemia, RPO prevented and reduced both hyperglycemia and hypertriglyceridemia. The results support the view that RPO may influence glucose or carbohydrate metabolism of diabetic animals in many ways including inhibiting the activity of alpha-glucosidase in digestive canal, and improving the metabolism of glucose and triglyceride.

Animals↗
PubMed2002

Evaluation of anti-hyperglycemic and hypoglycemic effect of Trigonella foenum-graecum Linn, Ocimum sanctum Linn and Pterocarpus marsupium Linn in normal and alloxanized diabetic rats.

The hypoglycemic effect of the aqueous (Aq) extract of the bark of Pterocarpus marsupium (PM) and alcoholic (Alc) extract of seeds of Trigonella foenum-graecum (FG) and leaves of Ocimum sanctum (OS) was investigated in both normal and alloxan-induced diabetic rats. The Aq extract of PM (1 g/kg PO) significantly (P<0.001) reduced the blood sugar levels from 72.32+/-5.62 to 61.35+/-1.2 mg% 2 h after oral administration of the extract and also significantly lowered the blood glucose in alloxan diabetic rats from 202.91+/-5.44 to 85.22+/-11.28 mg% 21 days after daily oral administration of the extract (P<0.001). Similarly, reduction was seen with Alc extract of FG (74.33+/-4.77 to 60.56+/-1.9 in normal rats and 201.25+/-7.69 to 121.25+/-6.25 in diabetic rats) (P<0.001) and OS (204.48+/-11.0 to 131.43+/-7.86 in normal rats and 73.54+/-3.7 to 61.44+/-2.3 in diabetic rats) (P<0.001). In addition, the extract also showed a favorable effect on glucose disposition in glucose fed hyperglycemic rats.

Alloxan↗
PubMed2002

Hypoglycemic and antihyperglycemic activity of Murraya koenigii leaves in diabetic rats.

The commonly used spice curry patta (Murraya koenigii) is traditionally consumed by diabetics in southern part of India. Feeding of diet containing various doses of curry leaves (5, 10 and 15%) to normal rats for 7 days as well as mild diabetic (blood glucose levels >175 mg/dl induced by alloxan 35 mg/kg IP) and moderate diabetic rats (blood glucose levels >250 mg/dl induced by STZ 60 mg/kg IP) for 5 weeks showed varying hypoglycemic and anti-hyperglycemic effect. In normal rats, reduction in blood glucose was almost negligible (approximately 4% with 10 and 15% diet). In mild and moderate diabetic rats, feeding of 5, 10 and 15% diet caused a maximal reduction in blood sugar by 13.1, 16.3 and 21.4% (NS, P<0.05 and 0.005) and 3.2, 5.58, 8.21% (NS), respectively. The mechanism of action is further discussed in light of results of previous and the present study.

Animals↗
PubMed2002

Hypoglycemic effects of Potentilla fulgens L in normal and alloxan-induced diabetic mice.

Tap roots of Potentilla fulgens L. traditionally chewed along with betel nut (Areca catechu) and betel leaves (Piper betel), are commonly used by local practitioners for various types of ailments. The crude methanolic extract of the roots was tested for its effects in normoglycemic and alloxan-induced diabetic mice. Hypoglycemic activity was observed to be dose- and time- dependent. The extracts reduced blood glucose level 2 h following administration in both normal and alloxan-induced diabetic mice. In alloxan-induced diabetic mice blood glucose was markedly reduced by 63%, while in normal mice a 31% reduction was observed 24 h after the effective dose of extract was administered. Further, in the diabetic mice a prolonged anti-hyperglycemic action was observed where glucose levels was, found to be significantly low (79%) when compared with control even on the third day. Glucose tolerance was also improved in both normal and diabetic mice. The results were compared against those of insulin, glibenclamide, metformin, and the probable mechanism of action is discussed.

Alloxan↗