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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., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.)

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.

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., (Copyright © 2016 American Pharmacists Association®. Published by Elsevier Inc. All rights reserved.)

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.

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.

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.

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., (Copyright © 2012 Elsevier B.V. All rights reserved.)

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., (Copyright © 2011 Elsevier Ireland Ltd. All rights reserved.)

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.

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.

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.

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 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.

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.

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.

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.

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.

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.

In the UGDP study, published in the 1970s, a high incidence of cardiovascular mortality was found in patients treated with the sulfonylurea agent tolbutamide. Impaired ischaemic preconditioning is presumed to be the most important mechanism for the excess cardiovascular mortality observed. However, as tolbutamide has only a low affinity for cardiac sulfonylurea receptors, interference with ischaemic preconditioning seems unlikely to account for this excess mortality. Several smaller studies also failed to establish a definite link between sulfonylurea treatment before acute myocardial infarction and in-hospital mortality. However, when the myocardium becomes exposed to repeated or prolonged periods of ischaemia, ischaemic preconditioning may become clinically important. Myocardial ischaemia can also develop during emergency or elective angioplasty and during coronary bypass surgery. Therefore discontinuation of sulfonylurea treatment should be considered in these circumstances.

We performed a double blind randomised controlled trial in general practice to assess equivalence between tolbutamide and acarbose with respect to the effect on mean HbA(1c) in newly diagnosed patients with type 2 diabetes. Secondary objectives were to compare the effects of both treatments on fasting and post-load blood glucose and insulin levels, lipids, and adverse events. Patients were randomised to receive acarbose, titrated step-wise to a maximum of 100mg three times daily (n=48) or tolbutamide, similarly titrated to a maximum of 2000 mg in three doses (n=48). The two treatments were considered equivalent if the two-sided 90% confidence interval (CI) for the difference in mean HbA(1c) levels was within the range -0.4 to 0.4%. Results were analysed on an intention-to-treat, per-protocol and on worst-case basis. Both agents reduced the HbA(1c) percentage and fasting blood glucose levels. The difference in mean decrease of HbA(1c) was 0.6% in favour of tolbutamide (90% CI 0.3, 0.9; 95% CI 0.2, 1.0). A worst-case analysis, assuming no change in HbA(1c) for dropouts, yielded a difference in mean decrease of 0.9% (90% CI 0.6, 1.2) in favour of tolbutamide. The difference in mean decrease of fasting blood glucose was 1.0 mmol/l in favour of tolbutamide (95% CI 0.3, 1.7). There were no significant differences in post-load blood glucose, fasting and post-load insulin levels, or lipids. In the acarbose group significantly more patients (15 versus 3) discontinued therapy because of adverse effects, mostly of gastrointestinal origin. We conclude that the results of this study favour tolbutamide over acarbose as first treatment for patients with newly diagnosed type 2 diabetes.

Adverse drug reactions and ineffective drug treatment are responsible for a large health care burden. Considerable variability in drug response makes the prediction of the individual reaction difficult. Pharmacogenetics can help to individualize drug treatment in accordance with the genetic make-up of the patient. Drug response is best understood as a complex interplay between pharmacokinetics, pharmacodynamics, and other disease-associated factors. There are a large number of genetic variants in the enzymes of phase I and phase II drug metabolism, in drug transporters, and drug targets, all of which account for differences in drug response. The polymorphisms in the cytochrome P450 enzyme system have been investigated most extensively. Genotype-based dose adjustment which should ensure "bioequivalent" drug concentrations in all patients has been derived from pharmacokinetic parameters, but this approach will have to be verified in prospective studies. Drug transport has recently been recognized as a further crucial determinant in pharmacokinetics. The effect of genetics on disease susceptibility and drug treatment has been studied quite extensively; however, hardly any of this progress is at present reflected in routine health care. The integration of pharmacogenetic factors in clinical trials requires novel considerations for study design and data interpretation. It is to be hoped that the new science bioinformatics will (a) help us identify the contribution of genetics to disease and treatment response and will (b) create data-processing devices which help the physician in the face of the enormously expanding scientific knowledge in selecting the best individually adapted treatment for the patient.

Focused on interpreting data as statistical evidence, the evidential paradigm uses likelihood ratios to measure the strength of statistical evidence. Under this paradigm, re-examination of accumulating evidence is encouraged because (i) the likelihood ratio, unlike a p-value, is unaffected by the number of examinations and (ii) the probability of observing strong misleading evidence is naturally low, even for study designs that re-examine the data with each new observation. Further, the controllable probabilities of observing misleading and weak evidence provide assurance that the study design is reliable without affecting the strength of statistical evidence in the data. This paper illustrates the ideas and methods associated with using likelihood ratios to measure statistical evidence. It contains a comprehensive introduction to the evidential paradigm, including an overview of how to quantify the probability of observing misleading evidence for various study designs. The University Group Diabetes Program (UGDP), a classic and still controversial multi-centred clinical trial, is used as an illustrative example. Some of the original UGDP results, and subsequent re-analyses, are presented for comparison purposes., (Copyright 2002 John Wiley & Sons, Ltd.)

Triphenyltin (TPT) induces transient hyperglycemia and hypertriglyceridemia in rabbits and hamsters through inhibition of the insulin release stimulated by glucose. The disturbed site in TPT-diabetes is a result of signal transduction occurring before the voltage-dependent Ca2+ channel. The ATP-sensitive K channel (KATP channel) is located immediately at the upstream signal of voltage dependent Ca2+ channels on the signaling pathway of insulin secretion. KATP channel produces depolarization by a signal of ATP through glucose metabolism and by stimulation from sulfonylurea drugs (tolbutamide, glibenclamide). To clarify if the insulin secretion that a KATP channel mediates is inhibited in vivo, we studied the effects of tolbutamide (a sulfonylurea) on changes in plasma glucose, triglyceride and insulin in TPT-diabetic rabbits prepared by po administration of 100 mg TPT-chloride/kg bw. In TPT-diabetic rabbits, plasma glucose decreased to a minimum at about 50% and plasma triglyceride levels also decreased. Insulin release was detected after injecting = 10 mg tolbutamide/kg, and insulin was secreted much higher than in normal rabbits. These findings suggest that the insulin released by tolbutamide stimulus decreased the plasma glucose and triglyceride levels in the TPT-diabetic rabbits. Moreover, a possible mechanism to be considered is as follows: tolbutamide combines with sulfonylurea receptor; membrane depolarization is induced by a KATP channel with the signal of a sulfonylurea receptor; insulin is released. The inhibition of insulin secretion by TPT may be caused by a glucose metabolic disorder in beta cells before the occurrence of membrane depolarization due to closed KATP channels interacting directly with a sulfonylurea receptor.

This study was undertaken to compare the oral hypoglycaemic activity of an aqueous extract of the green leafy vegetable Ipomoea aquatica (dose equivalent to 3.3 g starting material /kg body weight) with that of the known oral hypoglycaemic drug tolbutamide (15 mg/kg body weight) in glucose challenged Wistar rats (3 g/kg body weight, administered 30 min after the administration of Ipomoea aquatica or tolbutamide). One and half hours after administration of glucose (equivalent to 2 h after administration of plant extract or tolbutamide), the mean blood glucose level of the Ipomoea aquatica treated group was 47.5% lower than that of the control group treated with distilled water. The tolbutamide treated group showed a mean blood glucose level which was only 33.8% lower than that of the control group. However, statistical analysis indicated that the blood glucose levels of the Ipomoea aquatica treated group were not significantly different from that of the tolbutamide treated group. Our results show that the aqueous extract of Ipomoea aquatica is as effectve as tolbutamide in reducing the blood glucose levels of glucose-challenged Wistar rats., (Copyright 2001 John Wiley & Sons, Ltd.)

Sulphonylurea drugs have been shown to protect against hypoxic damage in isolated proximal tubules of the kidney. In the present study we investigated whether these drugs can protect against hypoxic damage in a whole kidney preparation. Tolbutamide (200 microM) and glibenclamide (10 microM) were applied to the isolated perfused rat kidney prior to changing the gassing from oxygen to nitrogen for 30 min. Hypoxic perfusions resulted in an increased fractional excretion of glucose (FE % glucose 14.3+/-1.5 for hypoxic perfusions vs 4.9+/-1.6 for normoxic perfusions, mean +/- s.e. mean, P<0.05), which could be completely restored by 200 microM tolbutamide (5.7+/-0.4 for tolbutamide vs 14.3+/-1.5 for untreated hypoxic kidneys, P<0.01). Furthermore, tolbutamide reduced the total amount of LDH excreted in the urine (220+/-100 mU for tolbutamide vs. 1220+/-160 mU for untreated hypoxic kidneys, P<0.01). Comparable results were obtained with glibenclamide (10 microM). In agreement with the effect on functional parameters, ultrastructural analysis of proximal tubules showed increased brush border preservation in tolbutamide treated kidneys compared to untreated hypoxic kidneys. We conclude that glibenclamide and tolbutamide are both able to reduce hypoxic damage to proximal tubules in the isolated perfused rat kidney when applied in the appropriate concentrations.

Aims: To assess maternal and neonatal complications in pregnancies of diabetic women treated with oral hypoglycaemic agents during pregnancy., Methods: A cohort study including all consecutively registered, orally treated pregnant diabetic patients set in a diabetic obstetrical service at a university hospital: 50 women treated with metformin, 68 women treated with sulphonylurea during pregnancy and a reference group of 42 diabetic women treated with insulin during pregnancy., Results: The prevalence of pre-eclampsia was significantly increased in the group of women treated with metformin compared to women treated with sulphonylurea or insulin (32 vs. 7 vs. 10%, P < 0.001). No difference in neonatal morbidity was observed between the orally treated and insulin-treated group; no cases of severe hypoglycaemia or jaundice were seen in the orally treated groups. However, in the group of women treated with metformin in the third trimester, the perinatal mortality was significantly increased compared to women not treated with metformin (11.6 vs. 1.3%, P < 0.02)., Conclusion: Treatment with metformin during pregnancy was associated with increased prevalence of pre-eclampsia and a high perinatal mortality.

Type 2 diabetic patients are at increased risk to develop atherosclerotic vascular disease. These patients are often treated with sulphonylurea derivatives, and it has been suggested that this treatment might contribute to the increased atherosclerotic process. The aim of the present study was therefore to investigate whether tolbutamide influences lipid metabolism in such a way that the atherosclerotic process may be promoted. Addition of tolbutamide (5-500 mg/l) to isolated rat fat adipocytes inhibited the lipoprotein lipase (LPL) activity in a dose-dependent manner to levels about 50% of those registered in the absence of tolbutamide. This effect was due to inhibition of the activation of the enzyme in the tissue and not to interference with the interaction of enzyme with its substrate. Addition of tolbutamide (500 mg/l) also inhibited noradrenaline (100 nM) and isoprenaline (40 nM)-induced lipolysis by 48.1 +/- 7.4% (mean +/- S.E.M.) and 47.3 +/- 5.5%, respectively. The decreased lipolysis in tolbutamide preincubated adipocytes was shown to be the result of an inhibition of the phosphorylation of hormone sensitive lipase (HSL). Three months of tolbutamide treatment (0.5 g t.i.d.) in diet treated type 2 diabetic patients did not influence the plasma concentrations of cholesterol, triglycerides, LDL cholesterol, HDL cholesterol as well as HDL triglycerides and HDL phospholipids, and there were no differences compared to placebo treated patients. There was a tendency towards a decrement in the elimination rate of exogenous triglycerides in the tolbutamide group (P = 0.0801). No differences between the groups and no treatment effects were seen on LPL and hepatic lipase activities. In conclusion, our in vitro data show that tolbutamide has dual effects on lipid transport, with impairment of the LPL system, which would tend to decrease plasma lipoproteins by reducing hepatic production of lipoproteins. In vivo, these two effects seem to balance each other and plasma lipoprotein levels remain unaffected.

Secondary failure of plasma glucose control following initial successful response to diet therapy may be due to dietary indiscretion, or to progression of the intrinsic diabetic condition. We report a 10-year prospective natural history study of 432 newly diagnosed diabetic patients aged 40-69 years undertaken to assess the effect of intensive dietary management, where patients were transferred to insulin, or oral hypoglycaemic therapy (tolbutamide, metformin) by predetermined criteria of weight and plasma glucose. Secondary failure to diet therapy occurred in 41 patients in years 2-4, 67 patients in years 5-7, and 51 patients in years 8-10; 173 patients remained on diet alone until death or the end of the study. Continuation on diet alone was associated with a lower ongoing fasting plasma glucose, greater beta-cell function assessed by an oral glucose tolerance test at 6 months, and increasing age. The rate of rise of fasting plasma glucose was inversely related to the duration of successful dietary therapy, but mean weight remained constant in all groups while on diet alone. The ongoing fall in beta-cell function assessed by HOMA modelling closely mirrored the progressive rise in fasting plasma glucose: there was no change in mean insulin sensitivity in any of the groups.

This study presents the characteristics of 20 children (17 female) with NIDDM who required oral hypoglycemic agent (OHA) therapy. A family history of NIDDM was present in 55%. None had islet cell antibodies (ICA) or glutamic acid decarboxylase (GAD) antibodies. Tolbutamide was the drug of choice; glibenclamide was introduced if glycemic control was not obtained after 2 to 3 months of tolbutamide therapy. Seven of the patients eventually required insulin therapy.

Mortality according to glucose tolerance was studied to determine the prognosis of impaired glucose tolerance. Among 2500 persons tested in a community screening programme in 1962-1965 and followed-up for mortality to the end of 1987, age-sex-adjusted mortality rates were 37.9 +/- 1.9, 53.6 +/- 4.2, and 70.1 +/- 3.6 deaths per 1000 person-years (+/-SE) in those with normal glucose tolerance, impaired glucose tolerance, and diabetes by World Health Organization criteria at baseline. Age-sex-adjusted mortality rates due to ischaemic heart disease were 14.3 +/- 1.1, 16.3 +/- 2.4, and 25.8 +/- 2.0 deaths per 1000 person-years, respectively. Using criteria predating those of the World Health Organization 147 men with abnormal glucose tolerance were entered into a randomized clinical trial in which 49 were treated with tolbutamide for approximately 10 years. Those treated had lower mortality rates from all causes (mortality rate ratio = 0.66, 95% confidence interval = 0.39, 1.10) and from ischaemic heart disease (mortality rate ratio = 0.42, 95% confidence interval = 0.16, 1.12) than those not receiving tolbutamide. Thus mortality rates are increased in persons with impaired glucose tolerance and diabetes, and the small clinical trial suggests that tolbutamide may be beneficial in men with abnormal glucose tolerance.

We investigated how fasting or postprandial insulin levels were altered by treatment with acarbose or sulfonylureas. Plasma glucose and serum insulin, C-peptide, and proinsulin levels were measured before as well as 1 and 2 h after breakfast in 23 patients with non-insulin-dependent diabetes mellitus and 17 patients with impaired glucose tolerance. In the diabetic patients, 12 weeks of acarbose therapy decreased the postprandial levels of glucose (1 h: -60.0%; 2 h: -67.6%), insulin (1 h: -67.5%; 2 h: -72.2%) and proinsulin (1 h: -55.2%; 2 h: -46.7%), and proinsulin (1 h: -20.9%; 2 h: -57.5%). In contrast, sulfonylurea treatment increased postprandial insulin and proinsulin levels. Since increased in the serum insulin or proinsulin levels are associated with a higher risk of cardiovascular disease, the present findings suggest that the acarbose-induced reduction of the postprandial serum insulin or proinsulin responses to food intake might be useful for preventing vascular complications in patients with diabetes.

The classical sulphonylurea derivatives like glibenclamide and tolbutamide are widely prescribed in non-insulin dependent diabetes mellitus in order to stimulate insulin secretion. The insulinotropic effect of these agents is based on the closure of adenosine-5'-triphosphate (ATP)-sensitive potassium channels (KATP-channels) in the beta-cells of the pancreas. Interestingly, the cardiovascular system also shares these KATP-channels. The open state probability of these channels is regulated by the intracellular concentration of ATP. During ischaemia, the KATP-channels are thought to open by a fall in the cytosolic ATP concentration. The increase in the extracellular adenosine concentration, and the release of endothelium-derived hyperpolarizing factor (EDHF) during ischaemia may further contribute to the opening of cardiovascular KATP-channels. Sulphonylurea derivatives like glibenclamide and tolbutamide have been reported to block the opening of KATP-channels in several types of tissues including myocardial and vascular smooth muscle cells. Since the opening of KATP-channels is regarded as an endogenous cardioprotective mechanism, the blocking effect of sulphonylurea derivatives in the cardiovascular system may have deleterious effects. Human studies on this issue have just been initiated, and preliminary results point towards a significant interaction between glibenclamide and cardiovascular KATP-channels at clinically relevant concentrations. In this regard, the introduction of more pancreas specific sulphonylurea derivatives like glimepiride, which do not interact with cardiovascular KATP-channels, is a promising development.

Objective: To examine the usefulness of alpha-glucosidase inhibitors in glycemic control of patients with NIDDM. The involvement of carbohydrate ingestion in manifestation of the effects of alpha-glucosidase inhibitors was also investigated., Research Design and Methods: A total of 41 patients hospitalized with NIDDM (22 patients receiving sulfonylurea and 19 receiving insulin therapy) were given alpha-glucosidase inhibitors during the period when their blood glucose levels were well controlled. They were followed for 3 weeks as inpatients and for an additional 6 months as outpatients. They were retrospectively divided into two groups according to the percentage of carbohydrates in all sources of calories during outpatient management: the < 50% group and the > 50% group. Between these two groups, we compared circadian variation in blood glucose levels, HbA1c, and urine C-peptide., Results: Treatment with alpha-glucosidase inhibitors during the hospital stay markedly improved circadian variation in blood glucose levels and HbA1c and decreased urine C-peptide in both groups. While HbA1c returned to its pretreatment level at 6 months after the treatment in the < 50% group, HbA1c had further improved in the > 50% group at 6 months., Conclusions: alpha-Glucosidase inhibitors are useful for glycemic control in patients with NIDDM and the percentage of carbohydrate in all calorie sources is an important factor for the expression of their effects.

Long-term intervention studies have evaluated the effect of diet, exercise and pharmacological regimens on the conversion rate of impaired glucose tolerance (IGT) to non-insulin dependent diabetes mellitus (NIDDM). Two UK studies, the Bedford study (10 years) and the Whitehall study (5 years), found that a diet which restricts carbohydrate intake to less than 120 g/day had no effect on the development of NIDDM in subjects with IGT. In contrast, the Swedish Malmöhus study (10 years) found that the conversion rate was reduced from 29% in the control group to 13% in a group told to limit their intake of carbohydrates and lipids and to reduce weight when overweight. A further Swedish study, the Malmö study (6 years and ongoing) is investigating a combination of dietary intervention and a strenuous exercise programme. In this study the conversion rate decreased from 29% in the control group to 11% in the diet plus exercise group. The Bedford and Whitehall studies also investigated intervention with tolbutamide and phenformin, respectively. Neither drug was found to have an effect on the conversion rate in either study. In contrast, positive results for tolbutamide were obtained in the Malmöhus study. No subjects in the tolbutamide plus diet group developed NIDDM compared with 29% in the control group. This regimen was also found to have beneficial effects on blood pressure, serum lipids and on cardiovascular morbidity and mortality.

The effects of administration of an alpha-glucosidase inhibitor and a sulphonylurea compound on lipid profile were investigated in patients with non-insulin-dependent diabetes mellitus, (NIDDM) previously treated with sulphonylurea compounds alone, but in whom metabolic control was inadequate. A group of patients (n = 10) were treated with the alpha-glucosidase inhibitor at a dose of 0.2 mg, three times daily, for 4 weeks. Treatment significantly reduced the post-prandial glucose level and the serum total cholesterol level. In addition, there were non-significant reductions in the triglyceride and very low density lipoprotein levels. These preliminary results suggest that administration of alpha-glucosidase inhibitors might improve the lipid profile of patients with NIDDM.

Human drug interaction studies in vivo are conducted when in vitro and/or animal interactions suggest clinical relevance. Studies in vitro have indicated that the new, entirely synthetic 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitor fluvastatin affects the metabolism of the nonsteroidal anti-inflammatory drug diclofenac and the oral hypoglycemic tolbutamide. Diclofenac and tolbutamide are both model substrates of the CYP2C isozymes, suggesting that this enzyme could be involved in the underlying mechanism of interaction. The concomitant use of lipid-lowering drugs with oral hypoglycemic agents has been recommended in patients with non-insulin-dependent diabetes mellitus (NIDDM). Therefore, 2 studies were initiated to explore potential pharmacokinetic and pharmacodynamic interactions between fluvastatin, simvastatin, or placebo and the oral hypoglycemic agents tolbutamide (study I) and glyburide (study II), each in 16 healthy subjects. These compounds were selected because of a demonstrated in vitro interaction with tolbutamide and widespread clinical use of glyburide. A further study (study III) was conducted to investigate the potential pharmacokinetic and pharmacodynamic interactions between fluvastatin and glyburide under therapeutic conditions in 32 patients with NIDDM. Single and multiple coadministration of fluvastatin 40 mg or simvastatin 20 mg increased the mean maximum plasma concentration and area under the concentration-time curve of glyburide by about 20%. The pharmacokinetics of tolbutamide were influenced to only a minor extent. Fluvastatin concentration-time profiles were unaffected by tolbutamide or glyburide coadministration. However, the pharmacokinetic interactions between fluvastatin or simvastatin and tolbutamide and glyburide were not associated with clinically relevant changes in blood glucose and insulin concentrations and, therefore, are not considered to be relevant in therapeutic practice.(ABSTRACT TRUNCATED AT 250 WORDS)

Ten patients with non-insulin-dependent diabetes mellitus who were being treated with a sulphonylureal compound but whose glucose metabolism needed further improvement were given a combination of their usual sulphonylurea treatment and an alpha-glucosidase inhibitor. Treatment with the alpha-glucosidase inhibitor (0.6 mg/day), in addition to glibenclamide (7.5 mg/day in two patients; 5.0 mg/day in four; 2.5 mg/day in one) or tolbutamide (500 mg/day in three patients) for 4 weeks, improved hyperglycaemia after meals from 237-247 mg/dl to 192 mg/dl, and reduced glycosylated haemoglobin levels from 8.5-8.6% to 7.9% without causing hypoglycaemia.

We hypothesized that elevated hepatic glucose output (HGO) may occur in children with cystic fibrosis (CF) as an early sign of declining insulin secretion and that tolbutamide therapy would correct the defect. We studied eight glucose-tolerant CF patients (mean +/- SD, 9.1 +/- 1.9 y) and five healthy controls (9.0 +/- 1.6 y). Fasting glucose, insulin, and insulin-connecting peptide concentrations were not different in the CF and control subjects; however, meal stimulation tests in the CF patients suggested that insulin secretion was defective in the fed state. HGO (mg.kg-1 body weight.min-1) was 26% higher in the CF patients (4.2 +/- 0.7 versus 3.1 +/- 0.6 in HC) (p = 0.016). When normalized for fat-free mass (mg.kg fat-free mass-1.min-1), HGO was 27% higher in CF (4.9 +/- 0.8 versus 3.8 +/- 0.5) (p = 0.015). However, when expressed as a function of resting energy expenditure (mg.kcal-1), HGO was not significantly different in CF (121 +/- 22) versus healthy controls (116 +/- 30). In seven of the CF group, HGO was re-assessed after a 2-h glucose infusion at a rate of 0.90 +/- 0.02 mg.kg-1.min-1. HGO was suppressed (p < 0.05) by an amount equal to 103 +/- 18% of the glucose infusion rate. Finally, in five CF patients, HGO was re-measured after 2 wk of oral therapy with tolbutamide (750 mg/d). Tolbutamide did not affect HGO (fasting or during the glucose infusion). In conclusion, fasting HGO was elevated in the CF patients in proportion to energy expenditure.

Background: Acarbose delays release of glucose from complex carbohydrates and disaccharides by inhibiting intestinal alpha-glucosidases, thereby attenuating postprandial increments in blood glucose and insulin. This multicenter, double-blind, placebo-controlled study compared the efficacy and safety of diet alone, acarbose, tolbutamide, and acarbose-plus-tolbutamide in non-insulin-dependent diabetes mellitus (NIDDM) patients., Patients and Methods: A total of 290 patients with NIDDM and fasting plasma glucose levels of at least 140 mg/dL were randomized to receive treatment TID with acarbose 200 mg, tolbutamide 250 to 1,000 mg, a combination of both drugs, or placebo. A 6-week run-in period was followed by double-blind treatment for 24 weeks, then a 6-week follow-up period., Results: All active treatments were superior (P < 0.05) to placebo in reducing postprandial hyperglycemia and HbA1c levels. The ranking in order of efficacy was: acarbose-plus-tolbutamide, tolbutamide, acarbose, and placebo. The postprandial reductions in glucose were approximately 85 mg/dL for acarbose-plus-tolbutamide, 71 mg/dL for tolbutamide, 56 mg/dL for acarbose, and 13 mg/dL for placebo. Tolbutamide was associated with increases in body weight and postprandial insulin levels when taken alone, but these were ameliorated when tolbutamide was taken in combination with acarbose. Acarbose alone or in combination with tolbutamide caused significantly more gastrointestinal adverse events (mainly flatulence and soft stools or diarrhea) than tolbutamide or placebo, but these were generally well tolerated. Clinically significant elevations in hepatic transaminase levels occurred in 3 patients in the acarbose group and 2 in the acarbose-plus-tolbutamide group. Transaminase levels returned to normal when therapy was discontinued., Conclusions: Acarbose was effective and well tolerated in the treatment of NIDDM. Control of glycemia was significantly better with acarbose compared with diet alone. Acarbose-plus-tolbutamide was superior to tolbutamide alone.

Blood sugar levels of normal rats treated with D-400 showed significant reduction (P < 0.05) as compared to control groups. The fall was seen at one month and remained so uptill 3 months. Hyperglycemic response to adrenaline was significantly lowered (P < 0.05) following D-400 treatment. D-400 potentiated the hypoglycemia following tolbutamide treatment. Blood sugar remained persistently low in tolbutamide plus D-400 treated group after 3 and 4 hours (P < 0.05). In the alloxan-induced diabetic rats, a significant lowering of blood and urinary sugar was noticed on day 20, 30 and 40 following treatment with D-400 (P < 0.05). Liver glycogen depletion was significantly inhibited in the D-400 treated group (P < 0.025). D-400 has significantly potentiated (P < 0.05) the hypoglycemic action of insulin in alloxan-induced diabetic rats.

Present communication deals with the synthesis of complexes of [N-(p-tolylsulphonyl)-N'-n butyl-urea], with certain transition metals viz. Cu(II), Zn(II), Fe(II) and Cd(II). Structures of all the complexes have been established on the basis of their consistent elemental and spectral analysis. Also, it reports their in vivo hypoglycemic screening on albino rats. Out of all the complexes studied, Zn-Tolbutamide complex could be recommended as more potent hypoglycemic agent in lieu of tolbutamide alone.

This study examined parotid salivary flow rate and composition in three groups of differently treated diabetics and a control group of non-diabetics. The study population was composed of edentulous African-Americans at least 65 years of age. Group A was the control, Group B insulin-dependent (Regular Iletin, U-100 qd.), Group C controlled by oral medication (Tolbutamide, 500 mg qd.), and Group D was diet controlled. All diabetic patients had serum glucose values under 250 mg/dl. Salivary flow rates, secretory IgA, electrolytes (Na+, Cl-, K+, Ca++) and total protein concentrations were evaluated. The results showed no significant differences between groups with respect to salivary flow rates, electrolytes and IgA concentrations. Additionally, all diabetic groups demonstrated a significantly lower salivary total protein concentration when compared to the controls. There appears to be no evident decrease in salivary flow rate in these three differently controlled diabetic groups compared with healthy non-diabetics.

Objective: To ascertain whether the effect of sulfonylureas on glucose-mediated insulin release persists for years to decades in patients with maturity-onset diabetes of the young., Research Design and Methods: The effect of sulfonylurea treatment on glucose-induced insulin secretion was ascertained prospectively for up to 33 yr in 12 diabetic patients of the maturity-onset diabetes of the young RW pedigree, who are genetically homogeneous because they share DNA markers on chromosome 20q. In 7 of these patients, paired glucose tolerance tests, given while the patients were on and off sulfonylureas, were performed after 7-31 yr., Results: Glucose-induced insulin secretion showed an average increase of 68% in diabetic patients who remained responsive to chlorpropamide after having been on and off the drug for decades. In most patients, however, glucose-induced insulin secretion declines over time (1-4%/yr). Some patients become unresponsive to sulfonylureas after 3-25 yr and then have very small or no increases in glucose-induced insulin secretion and require treatment with insulin to normalize fasting hyperglycemia., Conclusions: Increase in glucose-induced insulin secretion remains the most important mechanism of the action of sulfonylureas during long-term administration.

The functional state of beta cells may influence the rate of their destruction in Type 1 (insulin-dependent) diabetes mellitus. We examined the effect of diazoxide, which inhibits insulin secretion, or tolbutamide, which stimulates insulin secretion, upon the incidence of diabetes in the non-obese-diabetic (NOD) mouse. Female mice were treated from 3-30 weeks of age with diet containing diazoxide 250 mg.kg-1 or tolbutamide 125 mg.kg-1. The cumulative incidence of diabetes at 35 weeks was similar in the diazoxide (16 of 24) and control (18 of 24) groups, but reduced in the tolbutamide group (10 of 23, p < 0.04 vs control group). In a second experiment, treatment was started from 9 weeks of age, by which time insulitis is already present. The cumulative incidence of diabetes at 35 weeks was 16 of 24 in controls, 15 of 24 on diazoxide and 11 of 24 on tolbutamide (p = NS vs control). A third experiment compared the effect of treatment from 3 weeks with control diet or diet containing tolbutamide 125 mg.kg-1 or 500 mg.kg-1. Diabetes was reduced by tolbutamide treatment, with a cumulative incidence of 25 of 31 in controls, 18 of 30 on tolbutamide 125 mg.kg-1 (p < 0.04) and 14 of 32 on 500 mg.kg-1 (p < 0.002), although the difference between the two treatment groups failed to reach statistical significance. A fourth experiment showed that treatment from 3-12 weeks with diazoxide 1000 mg.kg-1 increased the extent of insulitis compared with controls and animals treated with tolbutamide 500 mg.kg-1.(ABSTRACT TRUNCATED AT 250 WORDS)

We have evaluated the effects of repaglinide, a new non-sulphonylurea oral hypoglycaemic agent that has a stimulatory effect on insulin secretion. Forty-four patients with NIDDM, already treated with a sulphonylurea, took part in an open, randomised, group comparison study of 12 weeks duration, during which they received either repaglinide or glibenclamide twice daily. While glibenclamide had a greater effect on fasting blood glucose (10.4 to 8.6 mmol.l-1), repaglinide significantly lowered postprandial blood glucose (13.8 to 12.2 mmol.l-1). Glycosylated haemoglobin remained unchanged in both groups, and serum fructosamine showed a tendency to fall. With both treatments total cholesterol was significantly decreased after 12 weeks, while HDL-cholesterol and triglycerides did not change. Fasting plasma insulin in the repaglinide group decreased from 80 (median value) to 67 pmol.l-1; it did not change in the glibenclamide group. Two patients in the repaglinide group did not complete the study, one for personal reasons, and one because of a rise in blood glucose. No abnormal findings attributable to repaglinide were observed in clinical and laboratory examinations, and no hypoglycaemic symptoms caused by it were observed.

The effect of tolbutamide on improving burn hypermetabolism was studied prospectively in 31 burn adults with total body surface area burned > 40 per cent and 18 burned rabbits immediately after burn injury to postburn day 10. The results showed that burn hypermetabolism could be reduced using tolbutamide, which may be the result of the correction of relative insulin insufficiency, tissue insulin resistance and improving glucose utilization.