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At least 793 records · Page 44Linked to original sources
PubMed2002

Antidiabetic action of a liver x receptor agonist mediated by inhibition of hepatic gluconeogenesis.

The oxysterol receptors LXR (liver X receptor)-alpha and LXRbeta are nuclear receptors that play a key role in regulation of cholesterol and fatty acid metabolism. We found that LXRs also play a significant role in glucose metabolism. Treatment of diabetic rodents with the LXR agonist, T0901317, resulted in dramatic reduction of plasma glucose. In insulin-resistant Zucker (fa/fa) rats, T0901317 significantly improved insulin sensitivity. Activation of LXR did not induce robust adipogenesis but rather inhibited the expression of several genes involved in hepatic gluconeogenesis, including phosphoenolpyruvate carboxykinase (PEPCK). Hepatic glucose output was dramatically reduced as a result of this regulation. Nuclear run-on studies indicated that transcriptional repression was primarily responsible for the inhibition of PEPCK by the LXR agonist. In addition, we show that the regulation of the liver gluconeogenic pathway by LXR agonists was a direct effect on hepatocytes. These data not only suggest that LXRs are novel targets for diabetes but also reveal an unanticipated role for these receptors, further linking lipid and glucose metabolism.

Animals↗
PubMed1993

Combination of oral antidiabetic drugs and insulin in the treatment of non-insulin-dependent diabetes.

Non-insulin-dependent diabetes mellitus (NIDDM) appears to be an heterogeneous disorder characterized by both relative insulin deficiency and impaired insulin action. The initial management of NIDDM should include patient education, dietary counselling and individualized programs of physical activity. It is only when such measures fail that drug therapy should be considered. Oral drug therapies include sulphonylurea derivatives, biguanides, among which metformin remains the only one commercialized in our country, and alpha-glucosidase inhibitors such as acarbose. However, insulin therapy may be required to achieve adequate glycaemic control in some patients, the so-called secondary failures to oral treatment. The rationale for combining insulin and oral drug therapy derives from a better understanding of the pathophysiology of NIDDM and of the mechanisms of action of the oral drugs available: 1) type 2 diabetic patients are both insulin-deficient and insulin-resistant, thus requiring quite high doses of exogenous insulin; 2) peripheral insulin delivery leads to hyperinsulinaemia which could play a role in the pathogenesis of late diabetic complications; 3) sulphonylureas stimulate insulin release directly into the portal vein and could also potentiate peripheral insulin action; and 4) metformin (by improving glucose metabolism and insulin sensitivity) and alpha-glucosidase inhibitors (by slowing down the digestion of complex carbohydrates and sucrose) are able to reduce the amounts of insulin needed to control postprandial hyperglycaemia. Numerous studies have shown that a combination of insulin and sulphonylurea is more effective than insulin alone in the treatment of patients with NIDDM after secondary failure to oral drugs, leading to better glucose profiles and/or decreased insulin needs. The available data suggest that combination therapy is most beneficial in the diabetic patient who still has residual insulin secretory capacity and that the best scheme comprises an evening injection of lente insulin and the administration of sulphonylureas before meals. Preliminary results suggested that insulin-metformin (when obesity is present) or insulin-acarbose (when post-prandial hyperglycaemia occurs) combinations might offer some favourable features for the treatment of NIDDM patients although these therapeutical approaches still require adequate evaluation in further controlled studies. The additional cost of such combined therapy should be weighed against the potential advantages of better metabolic control.

Biguanides↗
PubMed2000

Association of the antidiabetic effects of bromocriptine with a shift in the daily rhythm of monoamine metabolism within the suprachiasmatic nuclei of the Syrian hamster.

Bromocriptine, a dopamine D2 agonist, inhibits seasonal fattening and improves seasonal insulin resistance in Syrian hamsters. Alterations in daily rhythms of neuroendocrine activities are involved in the regulation of seasonal metabolic changes. Changes in circadian neuroendocrine activities that regulate metabolism are believed to be modulated by central circadian oscillators within the hypothalamic suprachiasmatic nuclei (SCN) of seasonal animals. We examined the association of metabolic responses to bromocriptine with its effects on the daily rhythms of metabolic hormones and daily monoamine profiles within the SCN, a primary circadian pacemaker known to regulate metabolism, in Syrian hamsters. Obese glucose-intolerant male Syrian hamsters (body weight [BW] 185 +/- 10 g) held on 14h daily photoperiods were treated at light onset with bromocriptine (800 microg/animal/day, ip) or vehicle for 2 weeks. Animals were then subjected to a glucose tolerance test (GTT) (3 g/kg BW, ip). Different subsets of animals (n = 6) from each treatment group were sacrificed at 0h/24h, 5h, 10h, 15h, or 20h after light onset for analyses of SCN monoamines, plasma insulin, prolactin, cortisol, thyroxin (T4), triiodothyronine (T3), glucose, and free fatty acids (FFAs). Compared with control values, bromocriptine treatment significantly reduced weight gain (14.9 vs. -2.9 g, p < .01) and the areas under the GTT glucose and insulin curves by 29% and 48%, respectively (p < .05). Basal plasma insulin concentration was markedly reduced throughout the day in bromocriptine-treated animals without influencing plasma glucose levels. Bromocriptine reduced the daily peak in FFA by 26% during the late light span (p < .05). Bromocriptine significantly shifted the daily plasma cortisol peak from the early dark to the light period of the day, reduced the plasma prolactin (mean 1.8 vs. 39.4 ng/dL) and T4 throughout the day (mean 1.6 vs. 3.8 microg/dL), and selectively reduced T3 during the dark period of the day (p < .01). Concurrently, bromocriptine treatment significantly reduced SCN dopamine turnover during the light period and shifted daily peaks of SCN serotonin and 5-hydroxy-indoleacetic acid (5-HIAA) content by 12h from the light to the dark period of the day (p < .05). This was confirmed by a further in vivo microdialysis study in which bromocriptine increased SCN extracellular 5-HIAA of glucose-intolerant hamsters during the dark phase (47% increase, p < .05) toward levels observed in normal glucose-tolerant hamsters. Thus, bromocriptine-induced resetting of daily patterns of SCN neurotransmitter metabolism is associated with the effects of bromocriptine on attenuation of the obese insulin-resistant and glucose-intolerant condition. A large body of corroborating evidence suggests that such bromocriptine-induced changes in SCN monoamine metabolism may be functional in its effects on metabolism.

Animals↗
PubMed2004

Antidiabetic effect of Boerhavia diffusa: effect on serum and tissue lipids in experimental diabetes.

The present study was designed to investigate the antihyperlipidemic activity of an aqueous extract of Boerhavia diffusa leaves in alloxan diabetic rats. Hyperlipidemia is an associated complication of diabetes mellitus. Many herbs and spices are known to be antihyperglycemic. Oral administration of B. diffusa leaf extract (BLEt) at 200 mg/kg of body weight for 4 weeks resulted in significant reduction in serum and tissue cholesterol, free fatty acids, phospholipids, and triglycerides. Moreover, BLEt supplementation was found to be more effective than glibenclamide in the treatment of diabetic rats.

Administration, Oral↗
PubMed2006

Phytochemical and antimicrobial study of an antidiabetic plant: Scoparia dulcis L.

The antimicrobial and antifungal effects of different concentrations of chloroform/methanol fractions of Scoparia dulcis were investigated. The isolated fractions were tested against different bacteria like Salmonella typhii, Staphylococcus aureus, Escherichia coli, Bacillus subtilis, Pseudomonas aeruginosa, and Proteus vulgaris and fungal strains such as Alternaria macrospora, Candida albicans, Aspergillus niger, and Fusarium oxysporum. The isolated fractions exhibited significant antimicrobial and antifungal activity against all the tested organisms compared with respective reference drugs. The isolated fractions of S. dulcis showed properties like antimicrobial and antifungal activities that will enable researchers in turn to look for application-oriented principles.

Alternaria↗
PubMed1998

Troglitazone: an antidiabetic agent.

The pharmacology, pharmacokinetics, clinical efficacy, adverse effects, and dosage and administration of troglitazone are reviewed. Troglitazone is the first oral thiazolidinedione approved for use in treating non-insulin-dependent diabetes mellitus (NIDDM). The drug's mechanism of action has not been fully elucidated. Troglitazone acts as an insulin sensitizer. Cell-line and animal models indicate that troglitazone may decrease hepatic glucose output by decreasing the rate of gluconeogenesis in the liver or by increasing glycolysis. Troglitazone is rapidly absorbed after oral administration, with peak concentration occurring in two to three hours. Food increases absorption by 30-85%. The drug is extensively metabolized in the liver. Troglitazone has been shown to be efficacious in treating NIDDM, both as monotherapy and in combination with oral sulfonylureas. Patients who are obese or who have high fasting plasma insulin levels may derive the greatest benefit. Patients with impaired glucose tolerance, syndrome X, polycystic ovary syndrome, gestational diabetes, or Werner's syndrome may also benefit from troglitazone. Adverse effects, including hematologic abnormalities, liver toxicity, and hypoglycemia, have been rare in published trials; no life-threatening effects have been reported thus far. The recommended initial dosage is 200 mg once daily with meals, with an increase to 400 mg daily if satisfactory glycemic control is not achieved after two to four weeks. The average wholesale price is $348 for 100 200-mg tablets and $534 for 100 400-mg tablets. Troglitazone may be an effective agent for treating NIDDM, especially in patients who are obese or who have high fasting plasma insulin levels.

Adult↗
PubMed1999

Troglitazone, an euglycemic antidiabetic drug.

Troglitazone (or 5-{4-[(6-hydroxy-2,5,7,8-tetramethyl-chroman-2-yl) methoxy]benzyl}thiazolidine-2,4-dione, C24H27NO5S) is the first euglycemic drug. The molecules are held together in the lattice by intermolecular hydrogen bonds between the hydroxy O atom of the chroman moiety, and the ketone O and ring N atom of the thiazolidine-2,4-dione moiety.

Chromans↗
PubMed2005

Crystallographic studies on acyl ureas, a new class of glycogen phosphorylase inhibitors, as potential antidiabetic drugs.

Acyl ureas were discovered as a novel class of inhibitors for glycogen phosphorylase, a molecular target to control hyperglycemia in type 2 diabetics. This series is exemplified by 6-{2,6-Dichloro- 4-[3-(2-chloro-benzoyl)-ureido]-phenoxy}-hexanoic acid, which inhibits human liver glycogen phosphorylase a with an IC(50) of 2.0 microM. Here we analyze four crystal structures of acyl urea derivatives in complex with rabbit muscle glycogen phosphorylase b to elucidate the mechanism of inhibition of these inhibitors. The structures were determined and refined to 2.26 Angstroms resolution and demonstrate that the inhibitors bind at the allosteric activator site, where the physiological activator AMP binds. Acyl ureas induce conformational changes in the vicinity of the allosteric site. Our findings suggest that acyl ureas inhibit glycogen phosphorylase by direct inhibition of AMP binding and by indirect inhibition of substrate binding through stabilization of the T' state.

Adenosine Monophosphate↗