Profiles of Two Glycaemia Modifying Drugs on the Expression of Rat and Human Sulfotransferases.

AIMS: To study the effects of blood glucose regulating compounds on human and rat sulfotransferases (SULTs) expressions. BACKGROUND: Phase-II enzymes, sulfotransferases catalyze the sulfuryl-group-transfer to endogenous/exogenous compounds. The alteration of expressions of SULTs may have influence on the sulfation of its substrate and other biomolecules. OBJECTIVES: The influence of the altered biotransformation might alter different biochemical events, drug-drug interactions and bioaccumulation or excretion pattern of certain drug. METHODS: In this brief study, diabetes-inducing drug streptozotocin (STZ; 10 or 50 mg/kg to male Sprague Dawley rat for 2 weeks) or hyperglycemia controlling drug tolbutamide (TLB 0.1 or 10µM to human hepato-carcinoma cells, HepG2 for 10 days) was applied and the SULTs expressions were verified. Extensive protein-protein (STa, SULT2A1/DHEAST) interactions were studied by the STRING (Search-Tool-for-the-Retrieval-of-Interacting Genes/Proteins) Bioinformatics-software. RESULTS: Present result suggests that while STZ increased the STa (in rat) (dehydroepiandrosterone catalyzing SULT; DHEAST in human HepG2), tolbutamide decreased PPST (phenol catalyzing SULT) and DHEAST activity in human HepG2 cells. Moderate decreases of MPST (monoamine catalyzing SULT) and EST (estrogen catalyzing) activities are noticed in this case. STa/DHEAST was found to be highly interactive to SHBG/- sex-hormone-binding-globulin; PPARα/lipid-metabolism-regulator; FABP1/fatty-acid-binding-protein. CONCLUSION: Streptozotocin and tolbutamide, these two glycaemia-modifying drugs demonstrated regulation of rat and human SULTs activities. The reciprocal nature of these two drugs on SULTs expression may be associated with their contrasting abilities in influencing glucose-homeostasis. Possible association of certain SULT-isoform with hepatic fat-regulations may indicate an unfocused link between calorie-metabolism and the glycemic-state of an individual. Explorations of this work may uncover the role of sulfation metabolism of specific biomolecule on cellular glycemic regulation.

Physiologically Based Pharmacokinetic Modelling of Cytochrome P450 2C9-Related Tolbutamide Drug Interactions with Sulfaphenazole and Tasisulam.

BACKGROUND AND OBJECTIVES: Cytochrome P450 2C9 (CYP2C9) is involved in the biotransformation of many commonly used drugs, and significant drug interactions have been reported for CYP2C9 substrates. Previously published physiologically based pharmacokinetic (PBPK) models of tolbutamide are based on an assumption that its metabolic clearance is exclusively through CYP2C9; however, many studies indicate that CYP2C9 metabolism is only responsible for 80-90% of the total clearance. Therefore, these models are not useful for predicting the magnitude of CYP2C9 drug-drug interactions (DDIs). This paper describes the development and verification of SimCYP®-based PBPK models that accurately describe the human pharmacokinetics of tolbutamide when dosed alone or in combination with the CYP2C9 inhibitors sulfaphenazole and tasisulam. METHODS: A PBPK model was optimized in SimCYP® for tolbutamide as a CYP2C9 substrate, based on published in vitro and clinical data. This model was verified to replicate the magnitude of DDI reported with sulfaphenazole and was further applied to simulate the DDI with tasisulam, a small molecule investigated for the treatment of cancer. A clinical study (CT registration # NCT01185548) was conducted in patients with cancer to assess the pharmacokinetic interaction of tasisulum with tolbutamide. A PBPK model was built for tasisulam, and the clinical study design was replicated using the optimized tolbutamide model. RESULTS: The optimized tolbutamide model accurately predicted the magnitude of tolbutamide AUC increase (5.3-6.2-fold) reported for sulfaphenazole. Furthermore, the PBPK simulations in a healthy volunteer population adequately predicted the increase in plasma exposure of tolbutamide in patients with cancer (predicted AUC ratio = 4.7-5.4; measured mean AUC ratio = 5.7). CONCLUSIONS: This optimized tolbutamide PBPK model was verified with two strong CYP2C9 inhibitors and can be applied to the prediction of CYP2C9 interactions for novel inhibitors. Furthermore, this work highlights the utility of mechanistic models in navigating the challenges in conducting clinical pharmacology studies in cancer patients.

The Effect of Genetic Polymorphism on the Inhibition of Azole Antifungal Agents Against CYP2C9-Mediated Metabolism.

We investigated the effect of cytochrome P450 (CYP) 2C9 polymorphism on the inhibition of methylhydroxylation activity of tolbutamide, a typical CYP2C9 substrate, by triazole antifungal agents, fluconazole and voriconazole. Although the Michaelis constants (Km), maximal velocities (Vmax), and Vmax/Km values for CYP2C9.1 (wild type) and CYP2C9.2 (Arg144Cys) were similar and CYP2C9.3 (Ile359Leu) had a higher Km and a lower Vmax than CYP2C9.1 and CYP2C9.2, the inhibition constants of fluconazole and voriconazole against CYP2C9.2 were lower than that against CYP2C9.1 and CYP2C9.3. These results suggest that more careful administration of azole antifungals to patients with the CYP2C9*2 allele might be required because of the strong inhibitory effects.

La mortalidad entre las sulfonilureas / Mortality among the sulphonylureas

Fundamento: Las sulfonilureas (SU) son una opción terapéutica en segunda intención (cuando la metformina [MET] no se puede utilizar), o en el segundo nivel, en asociación con MET. Sin embargo, estos antidiabéticos orales (ADO) están asociados con un alto riesgo de eventos cardiovasculares (ECV) en comparación con otros ADO. La sensibilidad tisular y el riesgo de hipoglucemia son distintos según la SU, por ello esta revisión en forma de metaanálisis intenta evaluar si la mortalidad y el riesgo cardiovascular son diferentes según la molécula. Métodos: Para ello se buscó en Medline y en Embase, hasta el 11 de junio de 2014, estudios controlados que evaluaran el riesgo de muerte por cualquier causa (MCC), de muerte cardiovascular (MCV), o por infarto agudo de miocardio (IAM) entre al menos 2 SU. Se examinaron las diferencias entre el riesgo de ECV y SU utilizando modelos de efectos aleatorios con comparación directa por pares en una red de metaanálisis que incorporara datos directos e indirectos. Resultados: En 18 estudios evaluados, con un total de 167.327 pacientes, 14.970 murieron (9%); 841 (4%) de 19.334 que utilizaban gliclazida, 5.482 (11%) de 49.389 con glimepirida, 2.106 (15%) de 14.464 con glipizida; 5.296 (7%) de 77.169 con glibenclamida; 1.066 (17%) de 6.187 con tolbutamida y, por último, 179 (23%) de 784 con clorpropamida. Hubo una baja inconsistencia en la red de metaanálisis referente a la MCC y al riesgo relativo (RR) de muerte en relación con glibenclamida, que fue de 0,65 (IC 95% 0,53-0,79) para gliclazida, de 0,83 (IC 95% 0,68-1,00) para glimepirida, de 0,98 (IC 95% 0,80-1,19) para glipizida, de 1,13 (IC 95% 0,90-1·,42) para tolbutamida, y de 1,34 (IC 95% 0,98-1,86) para clorpropamida. Parecidas asociaciones se dieron en la MCV, de tal manera que el RR en comparación con glibenclamida fue de 0,60 (IC 95% 0,45-0,84) para gliclazida; de 0,79 (IC 95% 0,57-1,11) para glimepirida, de 1,01 (IC 95% 0,72-1,43) para glipizida, de 1,11 (IC 95%0,79-1,55) para tolbutamida, y de 1,45 (IC 95% 0,88-2,44) para clorpropamida. Conclusión: Concluyen que gliclazida y glimepirida se asociaron con un menor riesgo de MCC y MCV en comparación con glibenclamida. Con ello, se aconseja que los médicos consideren las diferencias en el riesgo de mortalidad entre las SU para seleccionar cuál deben prescribir (AU)

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Functional characterization of 32 CYP2C9 allelic variants.

Genetic variations in cytochrome P450 2C9 (CYP2C9) contribute to interindividual variability in the metabolism of clinically used drugs such as warfarin and tolbutamide. We functionally characterized 32 types of allelic variant CYP2C9 proteins. Recombinant CYP2C9 proteins generated using a heterologous expression system are useful for comparing functional changes in CYP2C9 variant proteins expressed from low-frequency alleles. Wild-type CYP2C9 and its 31 variants were found to be transiently expressed in COS-7 cells, and the enzymatic activity of the CYP2C9 variants was characterized using S-warfarin as a representative substrate. Among the 32 types of CYP2C9 allelic variants tested, CYP2C9.18, CYP2C9.21, CYP2C9.24, CYP2C9.26, CYP2C9.33 and CYP2C9.35 exhibited no enzyme activity, and 12 types showed significantly decreased enzyme activity. In vitro analysis of CYP2C9 variant proteins should be useful for predicting CYP2C9 phenotypes and for application to personalized drug therapy.

Antihyperglycemic and hypolipidemic effects of Hibiscus schizopetalus (Mast) Hook in alloxan-induced diabetic rats.

The antihyperglycemic and hypolipidemic activities of Hibiscus schizopetalus (Mast) Hook (Malvaceae) flower and leaves extracts were investigated in alloxan-induced diabetic rats. The hypoglycemic activity of both the extracts (100mg/kg, body weight) was tested in fasting normal rat, glucose loaded rats. Observation on body weight was also recorded. The extracts showed a significant (p<0.001) reduction in blood glucose level in normal fasting rats. In glucose tolerance test, significant (p<0.01) decreased observed in all glucose loaded animals. While in alloxan induced diabetic rats, the percent blood glucose reduction was 59.94% and 45.14% in extracts treated groups. The results obtained were compared with the reference standard drug Tolbutamide (100mg/kg, body weight). The diabetic rats showed sign of decreased in their body weight during the treatment period. Cholesterol and triglycerides levels were significantly decreased (p<0.001) by HFE. The results obtained demonstrated the potential hypoglycemic activity of methanolic extracts of H. schizopetalus. There is need of bioassay-directed assay of the active principles responsible for the anti-diabetic activity. The methanolic extracts showed the presence of carbohydrates, alkaloids, steroids, terpenes, saponins and glycosides.

Mortality outcomes of different sulphonylurea drugs: the results of a 14-year cohort study of type 2 diabetic patients.

OBJECTIVE: Available data about mortality of type 2 diabetic patients treated with different sulphonylureas are scarce and contradictory. DESIGN: We evaluated the associations between all-cause and cause-specific mortality and treatments with different sulphonylureas in a retrospective cohort of type 2 diabetic patients from a diabetes clinic. METHODS: All 1277 patients treated with sulphonylureas during 19961997 were enrolled: 159 patients were treated with tolbutamide, 977 glibenclamide and 141 gliclazide. The baseline data (centralised laboratory parameters, anthropometric data and presence of chronic complications) were abstracted from the clinical records. Information on vital status was collected from demographic files after 14-year follow-up. Adjusted hazard ratios (HR) were estimated with Cox (all-cause mortality) or Fine and Gray models (cause-specific mortality), including several potential confounders. RESULTS: Five hundred and fifty-six patients died during the follow-up: 262 from cardiovascular causes, 158 from cancer and 136 from other causes. When compared with the glibenclamide users, the gliclazide and tolbutamide users showed a significantly lower cancer mortality (HR=0.30; 95% CI 0.16-0.55, and HR=0.48; 95% CI 0.29-0.79 respectively). These results were strongly confirmed in the 555 patients on sulphonylurea monotherapy. None of the patients who were treated with gliclazide monotherapy died from cancer during the follow-up, and the patients on tolbutamide treatment exhibited a lower cancer mortality than the glibenclamide users (HR=0.40; 95% CI 0.22-0.71). Data did not change after stratification for the duration of sulphonylurea treatment from diabetes diagnosis to the study enrollment. CONCLUSIONS: Cancer mortality was markedly reduced in the patients on gliclazide and tolbutamide treatment. These results suggest additional benefits for these drugs beyond their blood glucose-lowering effect and strongly advocate for further investigation.

Genetic and pharmacological manipulations that alter metabolism suppress seizure-like activity in Drosophila.

There is increasing evidence that alterations in metabolism can affect seizure susceptibility in a wide range of organisms. In order to investigate the link between metabolism and seizures, we took advantage of a group of Drosophila mutants, the Bang-sensitive (BS) paralytics, which are 3-10 times more susceptible to seizure-like activity (SLA) than wild type flies following a variety of stimuli including mechanical shock. To alter metabolism, we introduced the atsugari (atu) mutation into three of the BS mutants, easily shocked (eas), bang senseless (bss), and technical knockout (tko). The atu mutants, which exhibit reduced expression of the Drosophila ortholog of dystroglycan gene, have previously been shown to have a higher metabolic rate than wild type flies. Following mechanical shock, all three BS;atu double mutants displayed a reduction in SLA and the eas;atu and tko;atu double mutants recovered from the shock quicker than the respective single mutant BS flies. In addition, the eas;atu and tko;atu flies displayed higher levels of metabolism as compared to the single mutant BS flies. To further study the correlation between metabolism and seizure susceptibility, the three BS strains were fed a sulfonylurea drug (tolbutamide) known to both increase heamolymph glucose concentrations and stimulate lipid metabolism in flies. Following mechanical shock, the eas and tko mutants fed tolbutamide displayed less SLA and recovered quicker than unfed flies. While the bss mutants fed tolbutamide did not display a reduction in SLA, they did recover quicker than unfed controls. These data indicate that the upregulation of metabolism can have a protective effect against seizure susceptibility, a result that suggests new avenues for possible drug development.

Comparable long-term mortality risk associated with individual sulfonylureas in diabetes patients with heart failure.

AIMS: The aim was to investigate the outcomes of individual sulfonylureas in patients with heart failure (HF). METHODS: All patients hospitalized with HF for the first time in 1997-2006, alive 30 days after discharge, and who received anti-diabetic monotherapy with glimepiride (n=1097), glibenclamide (glyburide) (n=1031), glipizide (n=557), gliclazide (n=251), or tolbutamide (n=541) were identified from nationwide registers. Risk of all-cause mortality was assessed by multivariable Cox regression models. RESULTS: Over the median observational time of 744 (Inter Quartile Range 268-1451) days, 2242 patients (64%) died. The analysis demonstrated similar hazard ratio (HR) for mortality for treatment with glimepiride (1.10 [95% confidence interval 0.92-1.33]), glibenclamide (1.12 [0.93-1.34]), glipizide (1.14 [0.93-1.38]), tolbutamide (1.04 [0.85-1.26]), and gliclazide (reference). Grouped according to pancreatic specificity, i.e., with tolbutamide, glipizide, and gliclazide as specific, and glibenclamide, and glimepiride as non-specific agents, no differential prognosis was found between the two groups (HR 1.04 [0.96-1.14], for non-specific, compared to pancreas specific agents). The prognosis was not dependent on prior acute myocardial infarction or ischemic heart disease (p for interactions >0.3). CONCLUSIONS: In current clinical practice, it is unlikely that there are considerable differences in risk of mortality associated with individual sulfonylureas in patients with heart failure.

Hypolipidaemic & hepatoprotective effects of Psidium guajava raw fruit peel in experimental diabetes.

BACKGROUND & OBJECTIVES: The study evaluated the hypolipidaemic and hepatoprotective effects of unripe Psidium guajava fruit peel aqueous extract in streptozotocin (STZ) induced severely diabetic rats by assaying their triglyceride (TG), total cholesterol (TC), high density lipoprotein (HDL) cholesterol, alkaline phosphatase (ALKP), asperate amino transeferase (AST), alanine amino transferase (ALT) and creatanine (CRTN) levels. METHOD: Severely diabetic albino Wister rats of same age group were treated orally once a day upto 3wk with a dose of 400 mg/kg bw of lyophilized extract. TG, TC, HDL, ALKP, AST, ALT and CRTN were estimated. LDL and VLDL cholesterol levels were calculated from the above measurements by using Friedwald formula. RESULTS: A significant decrease in TG (P<0.01), TC (P<0.01), HDL (P<0.001) VLDL (P<0.001) and LDL (P<0.01), ALKP (P<0.01), AST (P<0.05), ALT (P<0.05) and CRTN (P<0.001) levels were observed after 21 days treatment of aquous extract of raw fruit peel compared to pre treatment levels. INTERPRETATION & CONCLUSION: The extract showed significant hypolipidaemic activity in addition to its hypoglycaemic and antidiabetic activity. In view of its relative non-toxic nature P. guajava raw fruit peel may be a potential antidiabetic agent.

Hypoglycemic effect of methanolic extract of Anacardium occidentale leaves in alloxan-induced diabetic rats.

Anacardium occidentale Leave (Anacardiaceae), a plant natively grown in wastelands in Africa is used as a folk remedy for diabetes mellitus. Previous studies, reported the hypoglycemic effect of the aqueous leaf extract of A. occidentale in diabetic rats and its prophylactic activity against the diabetogenic action of streptozotocin This study evaluated the hypoglycemic effect of a methanolic extract of streptozotocin leaves and its fractions in Alloxan-induced diabetic rats in comparison to Tolbutamide, a reference drug. For moderately diabetic rat, A. occidentale caused a 79.2 % change over 4 hours and Tolbutamide caused a 63.1 % change over this same time period. When the rat were considered to be severely diabetic, the A. occidentale decreased the blood glucose levels by 20.8% change over four hours and the mean percent change over 4 hours for Tolbutamide was 47.63%. These values were not considered significant. So the same conclusion can be made about the efficacy of A. occidentale, when compared to the reference drug, Tolbutamide. These results that show that A. occidentale has a similar ability compared with Tolbutamide to lower blood glucose levels.

Trials review: cardiovascular outcome with intensive glycemic control and implications for patients with type 2 diabetes.

Hyperglycemia is associated with microvascular and macrovascular complications. Intensive glucose control has been shown to reduce microvascular complications. Nevertheless, cardiovascular disease remains the leading cause of death in patients with type 2 diabetes. A positive association exists between hemoglobin A1c level and cardiovascular events, but whether reducing blood glucose will reduce cardiovascular events is still not quite clear. The benefits of intensive glucose control also remain uncertain for the heterogenous group of older patients with type 2 diabetes. This article reviews results of earlier and recently published intervention trials of intensive glucose control and their outcomes and discusses relevant recommendations for adults with type 2 diabetes.

Hypoglycemic effect of Mucuna pruriens seed extract on normal and streptozotocin-diabetic rats.

The hypoglycemic effect of the aqueous extract of the seeds of Mucuna pruriens was investigated in normal, glucose load conditions and streptozotocin (STZ)-induced diabetic rats. In normal rats, the aqueous extract of the seeds of Mucuna pririens (100 and 200 mg/kg body weight) significantly (P<0.001) reduced the blood glucose levels after an oral glucose load from 127.5+/-3.2 to 75.6+/-4.8 mg% 2 h after oral administration of seed extract. It also significantly lowered the blood glucose in STZ diabetic rats from 240.5+/-7.2 to 90.6+/-5.6 mg% after 21 days of daily oral administration of the extract (P<0.001). Thus, this study shows that M. pruriens has an anti-hyperglycemic action and it could be a source of hypoglycemic compounds.

[Neonatal diabetes mellitus]. / Diabetes melito neonatal.

Neonatal diabetes is a rare condition characterized by hyperglycemia, requiring insulin treatment, diagnosed within the first months of life. The disorder may be either transient, resolving in infancy or early childhood with possible relapse later, or permanent in which case lifelong treatment is necessary. Both conditions are genetically heterogeneous; however, the majority of the cases of transient neonatal diabetes are due to abnormalities of an imprinted region of chromosome 6q24. For permanent neonatal diabetes, the most common causes are heterozygous activating mutations of KCNJ11, the gene encoding the Kir6.2 sub-unit of the ATP-sensitive potassium channel. In this article we discuss the clinical features of neonatal diabetes, the underlying genetic defects and the therapeutic implications.

Diabetes melito neonatal: [revisão] / Neonatal diabetes mellitus: [review]

O diabetes neonatal (DN) é uma condição rara caracterizada por hiperglicemia, que necessita de tratamento com insulina, diagnosticado nos primeiros meses de vida. Clinicamente pode ser classificado em DN transitório quando ocorre remissão da doença em poucos meses, podendo haver recorrência posterior; ou permanente quando, como o nome indica, não ocorre remissão. Ambas as condições são geneticamente heterogêneas; entretanto a maioria dos casos de DN transitório é decorrente de anormalidades da região de imprinted no cromossomo 6q24. Mutações ativadoras em heterozigose no gene KCNJ11, que codifica a subunidade Kir6.2 do canal de potássio ATP-sensível, são a causa mais comum de DN permanente. No presente artigo, discutimos as características clínicas do DN, os mecanismos moleculares envolvidos e suas implicações terapêuticas.

Neonatal diabetes is a rare condition characterized by hyperglycemia, requiring insulin treatment, diagnosed within the first months of life. The disorder may be either transient, resolving in infancy or early childhood with possible relapse later, or permanent in which case lifelong treatment is necessary. Both conditions are genetically heterogeneous; however, the majority of the cases of transient neonatal diabetes are due to abnormalities of an imprinted region of chromosome 6q24. For permanent neonatal diabetes, the most common causes are heterozygous activating mutations of KCNJ11, the gene encoding the Kir6.2 sub-unit of the ATP-sensitive potassium channel. In this article we discuss the clinical features of neonatal diabetes, the underlying genetic defects and the therapeutic implications.

Dioscorea as the principal herb of Die-Huang-Wan, a widely used herbal mixture in China, for improvement of insulin resistance in fructose-rich chow-fed rats.

The present study was designed to clarify the principal herb responsible for the improvement of insulin resistance produced by Die-Huang-Wan, a mixture of six herbs, in rats fed with fructose-rich chow for 4 weeks. A decrease in plasma glucose was observed in fructose-rich chow-fed rats received an oral administration of Die-Huang-Wan at 26 mg/kg for 60 min but it disappeared with the deletion of dioscorea (Dioscoreae rhizoma) while this action was not modified by the deletion of other five herbs. The decrease of plasma glucose in fructose-rich chow-fed rats produced by dioscorea was similar to that treated with Die-Huang-Wan at same dosing; while the other five herbs failed to produce same influence. Similar to the effect of Die-Huang-Wan, dioscorea improved the fructose-induced decrement of insulin-stimulated glucose disposal rate after 3 days of treatment. Also, oral administration of dioscorea at effective dose (4.2 mg/kg per administration, three times daily) into streptozotocin-induced diabetic rats for 10 days increased the response to exogenous insulin, approaching to that induced by Die-Huang-Wan in same treatment. However, these effects failed to induce in the dioscorea-deleted formula of Die-Huang-Wan or other five herbs of this mixture. These results suggest that dioscorea is the major herb for the improvement of insulin sensitivity produced by Die-Huang-Wan. This can be applied to use as an adjuvant for subjects who need to increase insulin sensitivity.

Antihyperglycemic effect of the fruit-pulp of Eugenia jambolana in experimental diabetes mellitus.

The oral antihyperglycemic effect of the water and ethanolic extracts of the fruit-pulp of Eugenia jambolana (EJ) was investigated in alloxan-induced diabetic with fasting blood glucose between 120 and 250 mg/dl as well as severely diabetic rabbits (fasting blood glucose above 250 mg/dl). Water extract was found to be more effective than the ethanolic extract in reducing fasting blood glucose and improving blood glucose in glucose tolerance test. Chromatographic purification of the water extract yielded not only two hypoglycaemic fractions (F-III more active than F-IV) but indicated the presence of hyperglycemic compounds (F-I and F-II) also in the water extract of Eugenia jambolana fruits. When administered as a single dose of 25 mg/kg of body weight; F-III could reduce fasting blood glucose from 174.0 +/- 4.6 to 137.3 +/- 5.4 mg/dl in diabetic (21% fall) and from 266.0 +/- 5.4 to 202.2 +/- 5.2 mg/dl in severely diabetic rabbits (24% fall). After treatment of diabetic and severely diabetic rabbits daily once with 25mg/kg, body weight with F-III for 7 and 15 days, respectively, there was fall in fasting blood glucose (38% diabetic; 48% severely diabetic) and improvement in blood glucose during glucose tolerance test (48%) in diabetic rabbits. Further, there was increase in the plasma insulin levels in both diabetic (24.4%) and severely diabetic rabbits (26.3%). The in vitro studies with pancreatic islets showed that the insulin release was nearly two and half times more than that in untreated diabetic rabbits. The mechanism of action of FIII fraction appears to be both pancreatic by stimulating release of insulin and extra pancreatic by directly acting on the tissues.

Antidiabetic and hypolipidaemic effects of a methanol/methylene-chloride extract of Laportea ovalifolia (Urticaceae), measured in rats with alloxan-induced diabetes.

A decoction of the leaves of Laportea ovalifolia is widely used in Cameroon for the treatment of several illnesses, including diabetes mellitus. The antidiabetic and hypolipidaemic effects of a methanol/methylene-chloride extract of the aerial parts of L. ovalifolia have now been investigated, in normal rats and rats with diabetes induced by the intraperitoneal injection of alloxan (at 150 mg/kg bodyweight). In the diabetic rats, 2 weeks of daily, intragastric treatment with the L. ovalifolia extract not only produced a significant reduction in the fasting serum glucose concentrations but also lowered the serum concentrations of total cholesterol, triglycerides, and low-density-lipoprotein cholesterol, lowered the ratio of total cholesterol to high-density-lipoprotein (HDL) cholesterol, and increased the serum concentration of HDL cholesterol. At least in rats with alloxan-induced diabetes, the methanol/methylene-chloride extract of L. ovalifolia therefore appears to possess antidiabetic and hypolipidaemic properties.

Increasing the decrement in insulin secretion improves glucagon responses to hypoglycemia in advanced type 2 diabetes.

OBJECTIVE: In advanced beta-cell failure, counterregulatory glucagon responses may be impaired due to a reduced decrement in insulin secretion during the development of hypoglycemia. The present studies were therefore undertaken to test the hypothesis that these may be improved by increasing this decrement in insulin secretion. RESEARCH DESIGN AND METHODS: Twelve subjects with type 2 diabetes who have been insulin requiring were studied as a model of advanced beta-cell failure. Glucagon responses were examined during a 90-min hypoglycemic clamp (approximately 2.8 mmol/l) on two separate occasions. On one occasion, tolbutamide was infused for 2 h before the clamp so that the decrement in insulin secretion during the induction of hypoglycemia would be increased. On the other occasion, normal saline was infused as a control. RESULTS: Before the hypoglycemic clamp, infusion of tolbutamide increased insulin secretion approximately 1.9-fold (P < 0.001). However, during hypoglycemia, insulin secretion decreased to similar rates on both occasions (P = 0.31) so that its decrement was approximately twofold greater following the tolbutamide infusion (1.63 +/- 0.20 vs. 0.81 +/- 0.17 pmol x kg(-1) x min(-1), P < 0.001). This was associated with more than twofold-greater glucagon responses (42 +/- 11 vs. 19 +/- 8 ng/l, P < 0.002) during the hypoglycemic clamp but unaltered glucagon responses to intravenous arginine immediately thereafter (449 +/- 50 vs. 453 +/- 50 ng/l, P = 0.78). CONCLUSIONS: Increasing the decrement in insulin secretion during the development of hypoglycemia improves counterregulatory glucagon responses in advanced beta-cell failure. These findings further support the concept that the impaired counterregulatory glucagon responses in advanced beta-cell failure may at least partially be due to a reduced decrement in insulin secretion.

Hypoglycemic effects of Murraya koenigii on normal and alloxan-diabetic rabbits.

In past there have been many medicinal plants, which have been used in traditional medicines for their antidiabetic properties without any scientific support and pharmacological evidence. The aqueous extract of Murraya koenigii leaves has been taken to evaluate the hypoglycemic activity in normal and alloxan induced diabetic rabbits. This plant is promising as it is widely and regularly used as a spice for food flavoring and as such it appears to be without any side effects and toxicity. Adequate characterization of hypoglycemic activity of aqueous extract has not been yet done, as no such reports are available in the literature though the activity is reported. The scientific evaluation of its hypoglycemic activity was, therefore, explored and also compared with the effect of a standard hypoglycemic drug, tolbutamide. A single oral administration of variable dose levels (200, 300 and 400 mg/kg) of aqueous extract led to lowering of blood glucose level in normal as well as in diabetic rabbits. The maximum fall of 14.68% in normal and 27.96% in mild diabetic was observed after 4 h of oral administration of 300 mg/kg. The same dose also showed a marked improvement in glucose tolerance of 46.25% in sub-diabetic (AR) and 38.5% in mild diabetic rabbits in glucose tolerance test after 2 h. The findings from this study suggest that the aqueous extract of these leaves may be prescribed as adjunct to dietary therapy and drug treatment for controlling diabetes mellitus.