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PubMed1992

The antidiabetic beta 3-adrenoceptor agonist BRL 26830A works by release of endogenous insulin.

A beta 3-adrenoceptor agonist, BRL 26830A, has been shown to have antiobesity and antidiabetic actions. However, the insulin-release mechanism of this agent is not well understood. Therefore, we tested the hypothesis that BRL 26830A promotes insulin release via beta 3 receptors on pancreatic-islet beta cells by using both in vivo and in vitro studies. In ICR mice fasted for 48 h, BRL 26830A significantly stimulated insulin release and markedly decreased the glucose level. Administration of a non-selective beta-receptor antagonist 30 min before BRL 26830A injection completely inhibited insulin release and the reduction of the glucose level. Neither beta 1- nor beta 2-selective antagonists produced the same effect. In the in vitro study with rat pancreatic-islet cell culture, BRL 26830A and its free acid BRL 28410 did not promote insulin secretion. The results of the in vivo studies support our hypothesis, but the results of the in vitro study showed some discrepancies.

Adrenergic beta-Agonists↗
PubMed2002

Rodent carcinogenicity with the thiazolidinedione antidiabetic agent troglitazone.

Carcinogenic potential of the thiazolidinedione antidiabetic troglitazone was assessed in 104-week studies in mice and rats. Mice were given 50, 400, or 800 mg/kg, male rats 100, 400, or 800 mg/kg, and female rats 25, 50, or 200 mg/kg. Vehicle and placebo controls were included. Survival was significantly decreased in both sexes of both species at high doses, but was adequate for valid evaluation of carcinogenicity. Hypertrophy and hyperplasia of brown adipose tissue was observed in both species at all doses, and fatty change and hypocellularity of bone marrow was noted in mice at all doses and in female rats at 50 and 200 mg/kg. Hepatocellular vacuolation was observed in mice at 400 and 800 mg/kg, and centrilobular hepatocellular hypertrophy occurred in rats at > or = 200 mg/kg. Ventricular dilatation, myocardial fibrosis, and atrial myocyte karyomegaly in male rats at 400 and 800 mg/kg and female rats at all doses were morphologically similar to spontaneous lesions, but incidence and severity were increased compared with controls. In mice, the incidence of hemangiosarcoma was increased in females at 400 mg/kg and in both sexes at 800 mg/kg. The incidence of hepatocellular carcinoma was increased in female mice at 800 mg/kg. Troglitazone exposure [AUC((0-24))] at the lowest dose associated with increased tumor incidence in mice was 16 times human therapeutic exposure at 400 mg daily. No tumors of any type were increased in rats at exposures up to 47 times therapeutic exposure.

Adipose Tissue, Brown↗
PubMed2002

Use of antidiabetes agents in pregnancy: current practice and controversy.

Prior to the discovery of insulin, the combination of diabetes and pregnancy was considered potentially lethal. Advances in the care of diabetes, combined with advances in antepartum fetal testing, have reduced maternal and perinatal mortality outcomes to levels expected in nondiabetic pregnancies. As new oral antidiabetes medications are introduced, the safety and efficacy of using them during pregnancy are under investigation. This article describes the oral medications currently available to treat diabetes, reviews the body of research available on these agents, and discusses current recommendations and controversies.

Administration, Oral↗
PubMed1996

Amelioration of hyperglycemia in streptozotocin-induced diabetic rats receiving a marginal mass of islet grafts by troglitazone, an oral antidiabetic agent.

Troglitazone, a novel oral antidiabetic agent, was evaluated to determine whether it could have hypoglycemic effects in streptozotocin (STZ)-induced diabetic rats when a marginal mass of islets was transplanted and hyperglycemia persisted after transplantation. Lewis rats (RT1(1)) were used as both donors and recipients. Five hundred fresh islets were transplanted beneath the kidney capsule of STZ-induced diabetic recipients. Troglitazone was administered orally (0.34 mmol/kg/day) for 7 days before and for 60 days after islet transplantation. Neither troglitazone treatment without islet transplantation (n = 8) nor islet transplantation alone (n = 7) could produce normoglycemia (< 11 mmol/L) in diabetic recipients by 60 days after transplantation. In marked contrast, seven of 10 rats receiving islet grafts and treated with troglitazone became normoglycemia at 26.9 +/- 16.4 days (mean +/- SD; n = 7) after transplantation. Removal of the kidney bearing the grafts promptly resulted in the normoglycemic recipients (n = 4) becoming diabetic again. Light and electron microscopically, the intact islets with well-granulated beta cells could be observed in the transplant site of the normoglycemic recipients. These findings clearly demonstrate that the hyperglycemia in STZ-induced diabetic rats receiving an insufficient number of islet grafts to reverse diabetes was ameliorated by troglitazone treatment.

Animals↗
PubMed1999

Allosteric inhibition of glycogen phosphorylase a by the potential antidiabetic drug 3-isopropyl 4-(2-chlorophenyl)-1,4-dihydro-1-ethyl-2-methyl-pyridine-3,5,6-tricarbo xylate.

The effect of the potential antidiabetic drug (-)(S)-3-isopropyl 4-(2-chlorophenyl)-1,4-dihydro-1-ethyl-2-methyl-pyridine-3,5,6-tricarbox ylate (W1807) on the catalytic and structural properties of glycogen phosphorylase a has been studied. Glycogen phosphorylase (GP) is an allosteric enzyme whose activity is primarily controlled by reversible phosphorylation of Ser14 of the dephosphorylated enzyme (GPb, less active, predominantly T-state) to form the phosphorylated enzyme (GPa, more active, predominantly R-state). Upon conversion of GPb to GPa, the N-terminal tail (residues 5-22), which carries the Ser14(P), changes its conformation into a distorted 3(10) helix and its contacts from intrasubunit to intersubunit. This alteration causes a series of tertiary and quaternary conformational changes that lead to activation of the enzyme through opening access to the catalytic site. As part of a screening process to identify compounds that might contribute to the regulation of glycogen metabolism in the noninsulin dependent diabetes diseased state, W1807 has been found as the most potent inhibitor of GPb (Ki = 1.6 nM) that binds at the allosteric site of T-state GPb and produces further conformational changes, characteristic of a T'-like state. Kinetics show W1807 is a potent competitive inhibitor of GPa (-AMP) (Ki = 10.8 nM) and of GPa (+1 mM AMP) (Ki = 19.4 microM) with respect to glucose 1-phosphate and acts in synergism with glucose. To elucidate the structural features that contribute to the binding, the structures of GPa in the T-state conformation in complex with glucose and in complex with both glucose and W1807 have been determined at 100 K to 2.0 A and 2.1 A resolution, and refined to crystallographic R-values of 0.179 (R(free) = 0.230) and 0.189 (R(free) = 0.263), respectively. W1807 binds tightly at the allosteric site and induces substantial conformational changes both in the vicinity of the allosteric site and the subunit interface. A disordering of the N-terminal tail occurs, while the loop of chain containing residues 192-196 and residues 43'-49' shift to accommodate the ligand. Structural comparisons show that the T-state GPa-glucose-W1807 structure is overall more similar to the T-state GPb-W1807 complex structure than to the GPa-glucose complex structure, indicating that W1807 is able to transform GPa to the T'-like state already observed with GPb. The structures provide a rational for the potency of the inhibitor and explain GPa allosteric inhibition of activity upon W1807 binding.

Allosteric Regulation↗
PubMed2006

Type 2 diabetes in China: partnerships in education and research to evaluate new antidiabetic treatments.

There are 40 million people with diabetes in China, and the projected increase in the rates of obesity and premature cardiovascular disease is alarming. Most patients prefer to combine traditional Chinese medicine with Western medicine, but there is little or no information about the risks and benefits of this approach. Traditional Chinese medicine identifies three patterns of 'depletion-thirst' syndrome and therapy is aimed at reversing the deficiency in yin and qi, using a combination of products tailored to the symptoms and clinical features of individual patients. In Western medicine a number of new oral and injectable antidiabetic therapies are likely to enter routine clinical practice over the next 5 years, for example long-acting GLP-1 analogues, DPP-IV inhibitors and dual PPAR-alpha, PPAR-gamma agonists. To make best use of these agents in China and to promote diabetes education and health service development, there is a need for improved communication and collaboration between universities and hospitals both inside and outside China; and Western pharmacologists and clinicians need a better understanding of traditional Chinese medicine. There are several examples of institutional cooperation that should further diabetes research in China, for example the Beijing Chaoyang Diabetes Hospital linked with Imperial College, London, and the University of Nottingham, which has a new campus in Ningbo, south of Shanghai.

Diabetes Mellitus, Type 2↗
PubMed2006

Trends in the use of oral antidiabetic drugs by outpatients in Taiwan: 1997-2003.

OBJECTIVE: To define the prescribing patterns of oral antidiabetic drugs (OADs) in Taiwan over a 7-year period (1997-2003) and to critically comment on changes observed. METHODS: A cross-sectional study design was implemented using data from Taiwan's National Health Insurance Research Database between January 1997 and December 2003. Outpatients who were 18 years or older and had at least an OAD claim during the study period were identified. The unit of analysis was each OAD prescription for diabetic outpatient visits. The prescribing trends were described in terms of annual changes in prescribing rates and patterns. RESULTS: The numbers of OAD prescriptions rose 1.23-fold. The sulfonylurea (SU) class was the most commonly used OAD, but the prescribing rates for this class declined over time. The biguanide (BG) class was the second most frequently prescribed OAD class and its prescribing rate initially increased, peaked in 2000, and then substantially decreased. The largest increase in prescribing was for acarbose use. The prescribing rates of two new classes of OAD, meglitinide (MG) and thiazolidinedione (TZD), also significantly increased within a short period of time. A trend towards combination therapy was observed away from monotherapy. The SU class was the most commonly prescribed as monotherapy. SU plus BG was the most commonly prescribed dual therapy. Triple oral therapy showed a significant ninefold increase. CONCLUSION: The prescribing rates of OADs are shifting from the older OADs (i.e. SUs) to newer OADs [i.e. alpha-glucosidase inhibitor (AGI), MGs, and TZDs]. The prescribing patterns of OADs are moving toward combination therapy, especially triple oral therapy.

Administration, Oral↗
PubMed2005

Antidiabetic effect of a new peptide from Squalus mitsukurii liver (S-8300) in alloxan-diabetes.

1. The purpose of the present study was to evaluate the antidiabetic effect of S-8300 in alloxan diabetic mice. 2. Diabetes was induced by single intravenous injection of alloxan (60 mg/kg bodyweight). 3. The effects of S-8300 on diabetic mice were investigated by observing changes in the glycometabolic index (fasting plasma glucose, glycosylated haemoglobin), the lipometabolic index (triglyceride, cholesterol, free fatty acids), anti-oxidant index (superoxide dismutase, malondialdehyde) and in the degree of injury of beta-cells in the pancreatic islets. 4. A significant decrease in fasting plasma glucose, glycosylated haemoglobin, triglycerides, cholesterol, free fatty acids in the plasma and malondialdehyde in the tissues, as well as a significant increase in the activity of superoxide dismutase, was observed in diabetic mice treated with 10, 3 and 1 mg/kg S-8300. 5. Treatment with S-8300 also attenuated the degree of injury of beta-cells. 6. A comparison was made between the action of S-8300 and 6 U/kg insulin. The effects of S-8300 were similar to those of insulin.

Alloxan↗
PubMed2007

Insulin glargine benefits patients with type 2 diabetes inadequately controlled on oral antidiabetic treatment: an observational study of everyday practice in 12,216 patients.

AIMS: This observational study aimed to investigate the long-term efficacy and safety of adding insulin glargine (LANTUS((R))) to support oral antidiabetic (OAD) treatment in patients with type 2 diabetes in everyday practice. METHODS: A 9-month, open-label, multicentre, observational study, with an optional 20-month extension phase, in which add-on insulin glargine therapy was initiated in 12,216 patients with type 2 diabetes inadequately controlled on OADs. The insulin glargine dose was adjusted at the physician's discretion, reflecting everyday practice. The main outcome measures were changes in HbA(1c), fasting blood glucose (FBG), insulin dose and body mass index (BMI). RESULTS: At baseline, mean (+/- s.d.) age was 63.9 +/- 11.3 years; disease duration was >5 years in 47% of patients, 1-5 years in 39% of patients and <1 year in 10% of patients, while 4% of patients were newly diagnosed. Addition of insulin glargine to OAD therapy led to reductions in mean HbA(1c) (-1.5% from 8.7%) and FBG (-69 mg/dl from 202 mg/dl) levels after 3 months, which were maintained after 9 months [HbA(1c): -1.7%; FBG: -71 mg/dl (-3.9 mmol/l)] without an increase in BMI. Similar glycaemic control was observed after 20 months in the 2721 patients in the extension study. Adverse drug reactions were documented in 26 patients (0.2%). Of 47 adverse events documented, 19 were due to hypoglycaemia. CONCLUSIONS: In everyday practice, patients with type 2 diabetes who are inadequately controlled on OADs benefit from add-on basal insulin treatment with insulin glargine as they demonstrate improved glycaemic control without weight gain.

Administration, Oral↗
PubMed1996

Photodegradation products of sulphonamide-derived oral antidiabetics and diuretics are not phototoxic in vitro.

The oral antidiabetics glibenclamide and glipizide, and the diuretics bendroflumethiazide and furosemide, all sulphonamide derived drugs, were investigated in vitro for phototoxic properties. Irradiation with broad-band UV induced phototoxic inhibition of colony forming ability in cell cultures. During irradiation, the substances lost one absorption maximum in the UVA region, demonstrated by UV spectroscopy. These findings correlate well with the UV applied, the action spectrum being in the UVA region. Photoproducts detected during and after irradiation showed a decomposition of the substances due to ionization and fragmentation. Incubation of these preirradiated drugs with the cell cultures revealed no phototoxic effects.

Bendroflumethiazide↗
PubMed1996

Photooxidation of troglitazone, a new antidiabetic drug.

Troglitazone (CS-045) is a new oral antidiabetic drug reported to be effective in insulin-resistant diabetes and to show antihypertensive effects. Photooxidation of troglitazone gave the quinone and quinone epoxide as the major final stable products. An intermediate observed by NMR spectroscopy was shown to be the hydroperoxydienone, which is moderately stable at room temperature. The rate constant of singlet oxygen quenching by troglitazone is 2.14 x 10(8) M(-1) s(-1) and the reaction rate constant in acetone-d6 is 8.64 X 10(6) M(-1) s(-1). Only the chroman ring of troglitazone reacts with and quenches singlet oxygen significantly, and its reactivity and products are analogous to those of alpha-tocopherol. The reactivity of CS-45 toward singlet oxygen is much larger than that of the related compounds lacking the chroman ring.

Chromans↗
PubMed1990

Antidiabetic and aldose reductase activities of biflavanones of Garcinia kola.

Kolaviron, a mixture of C-3/C-8 linked biflavonoids obtained from Garcinia kola produces significant hypoglycaemic effects when administered intraperitoneally to normal and alloxan diabetic rabbits at a dose of 100 mg kg-1. The fasting blood sugar in normoglycaemic rabbits was reduced from 115 mg/100 mL to 65 mg/100 mL after 4 h. In alloxan diabetic rabbits, the blood sugar was lowered from 506 mg/100 mL to 285 mg/100 mL at 12 h. The hypoglycaemic effects have been compared with those of tolbutamide. Kolaviron inhibited rat lens aldose reductase (RLAR) activity, with an IC50 value of 5.4 x 10(-6). The significance of these findings in the potential use of kolaviron as an antidiabetic agent is discussed.

Aldehyde Reductase↗
PubMed2003

PAT5A: a partial agonist of peroxisome proliferator-activated receptor gamma is a potent antidiabetic thiazolidinedione yet weakly adipogenic.

PAT5A [5-[4-[N-(2-pyridyl)-(2S)-pyrrolidine-2-methoxyl]phenylmethylene[thiazolidine-2,4-dione, malic acid salt]], a chemically distinct unsaturated thiazolidinedione, activates peroxisome proliferator-activated receptor gamma (PPARgamma) submaximally in vitro with the binding affinity approximately 10 times less than that of rosiglitazone, a highly potent thiazolidinedione. PAT5A reduces plasma glucose level and improves insulin sensitivity in insulin resistant db/db mice, similar to that of rosiglitazone, while exerting a relatively weak adipogenic effect. In contrast to rosiglitazone, PAT5A inhibits cholesterol and fatty acid biosynthesis suggesting that PAT5A possesses a unique receptor-independent non-PPAR related property. PAT5A induces qualitatively similar but quantitatively different protease digestion patterns and interacts with PPARgamma differently than rosiglitazone. PAT5A shows differential cofactor recruitment and gene activation than that of rosiglitazone. Thus, the partial agonism of PAT5A to PPARgamma together with its receptor independent effects may contribute to its antidiabetic potency similar to rosiglitazone in vivo despite reduced affinity for PPARgamma. These biological effects suggest that PAT5A is a PPARgamma modulator that activates some (insulin sensitization), but not all (adipogenesis), PPARgamma-signaling pathways.

3T3 Cells↗
PubMed2004

Antidiabetic thiazolidinediones inhibit invasiveness of pancreatic cancer cells via PPARgamma independent mechanisms.

BACKGROUND/AIMS: Thiazolidinediones (TZD) are a new class of oral antidiabetic drugs that have been shown to inhibit growth of some epithelial cancer cells. Although TZD were found to be ligands for peroxisome proliferators activated receptor gamma (PPARgamma) the mechanism by which TZD exert their anticancer effect is currently unclear. Furthermore, the effect of TZD on local motility and metastatic potential of cancer cells is unknown. The authors analysed the effects of two TZD, rosiglitazone and pioglitazone, on invasiveness of human pancreatic carcinoma cell lines in order to evaluate the potential therapeutic use of these drugs in pancreatic adenocarcinoma. METHODS: Expression of PPARgamma in human pancreatic adenocarcinomas and pancreatic carcinoma cell lines was measured by reverse transcription polymerase chain reaction and confirmed by western blot analysis. PPARgamma activity was evaluated by transient reporter gene assay. Invasion assay was performed in modified Boyden chambers. Gelatinolytic and fibrinolytic activity were evaluated by gel zymography. RESULTS: TZD inhibited pancreatic cancer cells' invasiveness, affecting gelatinolytic and fibrinolytic activity with a mechanism independent of PPARgamma activation and involving MMP-2 and PAI-1 expression. CONCLUSION: TZD treatment in pancreatic cancer cells has potent inhibitory effects on growth and invasiveness suggesting that these drugs may have application for prevention and treatment of pancreatic cancer in humans.

Adenocarcinoma↗
PubMed2002

Antidiabetic effect of nitobegiku in KK-Ay diabetic mice.

In the past, nitobegiku (the herb of Tithonia diversifolia (Hemsl) A. Gray) has been used as a medicinal plant for diabetes. Antidiabetic effect of the water extract of Nitobegiku (NG) was investigated in KK-Ay-mice--one of the animal models of type 2 diabetes. NG (1,500 mg/kg body weight) reduced the blood glucose of KK-Ay mice from 509 +/- 22 mg/dl to 340 +/- 14 mg/dl (p < 0.001) and also lowered the plasma insulin (p < 0.05) 7 hours after single oral administration. No change in blood glucose of NG-treated normal mice (ddY) was seen. These results support that NG improve glucose metabolism by reducing insulin resistance. Therefore, NG may be useful for treatment of type 2 diabetes.

Animals↗
PubMed1993

Antidiabetic agent pioglitazone enhances adipocyte differentiation of 3T3-F442A cells.

Adipocytes play an important role in normal physiology as a major site for systemic energy homeostasis. In disorders such as diabetes, adipocyte function is markedly altered. In this study, we investigated the effect of pioglitazone, a novel antidiabetic agent known to lower plasma glucose in animal models of diabetes mellitus, on cellular differentiation and expression of adipose-specific genes. Treatment of confluent 3T3-F442A preadipocyte cultures for 7 days with pioglitazone (Pio; 1 microM) and insulin (Ins; 0.17 microM) resulted in > 95% cell differentiation into lipid-accumulating adipocytes in comparison with 60-80% cell differentiation by treatment with either agent alone. Analysis of triglyceride accumulation showed increases of triglyceride content over time above untreated preadipocytes by treatment of the cells with Ins, Pio, and especially with Ins + Pio. Basal glucose transport, as measured by cellular uptake of 2-deoxy-D-[14C]glucose, was likewise enhanced in a time-dependent manner by treatment of preadipocytes with Ins, Pio, or Ins + Pio, such that a synergistic effect resulted from the combined treatment with both agents. It was further determined that RNA transcript abundance for genes encoding glucose transporters GLUT-1 and GLUT-4, as well as the adipose-specific genes encoding adipsin and aP2, were increased by the Ins, Pio, or Ins + Pio treatment. Taken together, these findings indicate that pioglitazone is a potent adipogenic agent. By promoting differentiation, this agent may move cells into a state active for glucose uptake, storage, and metabolism.

3T3 Cells↗
PubMed1998

Mechanisms of the antidiabetic effects of the beta 3-adrenergic agonist CL-316243 in obese Zucker-ZDF rats.

Previous studies have demonstrated that chronic cold exposure activates the sympathetic nervous system, increases energy expenditure, improves glucose uptake in peripheral tissues [brown and white adipose tissues (BAT and WAT) and muscles] of normal rats. The goal of the present studies was to test whether the selective beta 3-adrenergic agonist CL-316243 (CL) would mimic the beneficial beneficial effects of cold exposure in lean and obese ZDF/Gmi-fa male (ZDF) rats, a new model of type II diabetes. In obese ZDF rats, chronic infusion of CL (1 mg.kg-1.day-1 for 14 days) significantly decreased body weight gain, food intake, and WAT weight. It also increased total tissue cytochrome oxidase activity, not only in BAT (15 times), but also in WAT (2-4) times, suggesting that it progressively enhanced mitochondriogenesis in adipose tissues. CL treatment normalized hyperglycemia and reduced hyperinsulinemia and circulating free fatty acid (FFA) levels. It also improved glucose tolerance and reduced insulin response during an intravenous glucose tolerance test. In general, the beneficial effects of CL were more pronounced in obese than in lean rats. Hyperinsulinemic-euglycemic glucose clamps combined with the [2-3H]deoxyglucose method revealed that CL markedly improved insulin responsiveness in obese rats (3-4 times) and increased glucose uptake in BAT (21 times), WAT (3 times), skeletal muscles (2-3 times), and in the diaphragm (2.8 times), but not in the heart. It is concluded that chronic CL treatment improves glucose tolerance and insulin responsiveness in obese ZDF rats by a mechanism similar to that induced by chronic cold exposure, i.e., by stimulating facultative thermaogenesis, mitochondriogenesis, and glucose utilization in BAT and WAT. In addition to this mechanism, the reduction in plasma FFA levels induced by chronic CL treatment may further contribute to enhance glucose uptake in skeletal muscles (a tissue that does not express typical beta 3-adrenoceptors) via the "glucose-fatty acid" cycle. The antiobesity and antidiabetic properties of CL suggest that selective beta 3-adrenergic agonists may represent useful agents for the treatment of type II diabetes.

Adipose Tissue, Brown↗
PubMed2003

[Prevalence of diabetes treated with drugs in Andalucía. Evolution of the oral antidiabetics and insulin prescription between 1994 and 2000].

CONTEXT: [corrected] Diabetes is an important, complex, expensive, and increasingly frequent disease. The objective of this study was to investigate the diabetes mellitus prevalence and evolution in the Adalusian population between 1994 and 2000. METHODS: We used and indirect method for estimating the rate of prevalence of the disease based on antidiabetic drug consumption data at regional level, using the official billing data, and the annual population data. RESULTS: The prevalence estimated for diabetes mellitus in Andalusia was, 4.41%. This prevalence ranged from 2.47% in 1994 up to 4.41% in 2000. Oral antidiabetics/insulin use ratio was 2.31. The study shows an important variability of the prescription habits in diabetic patients in Andalucía. CONCLUSIONS: The prevalence observed in diabetes mellitus in Andalucía increased between 1994 and 2000. An important variability was observed among the different provinces.

Administration, Oral↗