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PubMedDate not supplied

Long-term antidiabetic activity of vanadyl after treatment withdrawal: restoration of insulin secretion?

In its vanadate (V5+) or vanadyl (V4+) forms, vanadium has been demonstrated to possess antidiabetic activity. Oral treatment of streptozotocin (STZ)-diabetic animals with either form is associated with correction of hyperglycemia, and prevention of diabetes-induced complications, although weight gain is unaffected. Vanadium treatment of non-diabetic animals lowers plasma insulin levels by reducing insulin demand, as these animals remain normoglycemic. These results suggest that vanadium has in vivo insulin-mimetic or insulin-enhancing effects, in agreement with several in vitro observations. Chronic treatment with vanadium has also been shown to result in sustained antidiabetic effects in STZ-diabetic animals long after treatment has ceased. Thus, at 13 weeks after withdrawal from treatment, corrected animals had normalized glucose and weight gain, and improved basal insulin levels. In addition, near-normal glucose tolerance was found despite an insignificant insulin response. Since vanadium accumulates in several tissue sites (e.g. bone, kidney) when pharmacological doses are administered, it is possible that stored vanadium may be important in maintaining near-normal glucose tolerance at least in the short-term following withdrawal from treatment. Recently, following withdrawal of vanadyl treatment up to 30 weeks, diabetic animals which had remained normoglycemic and had normalized glucose tolerance showed improvements in plasma insulin levels both in the basal state and in response to oral glucose, as compared to those which had reverted to hyperglycemia. The observed significant improvements in insulin capacity over the long-term ( > 3 months) suggests that a restored and/or preserved insulin secretion may be essential for maintained reversal of the diabetic state over a prolonged period after treatment is withdrawn.

Animals↗
PubMedDate not supplied

Rosiglitazone versus bedtime insulin in the treatment of patients with conventional oral antidiabetic drug failure: a 1-year randomized clinical trial.

This study was conducted to evaluate the efficacy and tolerability of rosiglitazone in the treatment of patients with secondary oral antidiabetic drug (OAD) failure and to directly compare its use with bedtime insulin. A total of 112 Chinese patients with type 2 diabetes and conventional OAD failure were recruited. Patients were randomly assigned to treatment with rosiglitazone or bedtime isophane insulin; they continued to take their original oral antidiabetic drugs. Glycemic index, other clinical profiles, and tolerability were assessed during treatment and 1 y after add-on treatment was provided. Among the 112 patients, mean age (+/-SD) was 58.2+/-11.0 y (median, 58 y; range, 37 to 84 y). Both rosiglitazone (n=56) and insulin (n=56) significantly improved fasting glucose (2.4 and 3.7 mmol/L, respectively) and hemoglobin A1c concentrations (1.1% and 1.3%, respectively). Both therapies increased body mass index after 1 y of treatment (0.9 and 0.8 kg/m2, respectively). Only rosiglitazone increased high-density lipoprotein cholesterol concentrations (0.1 mmol/L). Four patients (7.1%) who were given rosiglitazone developed adverse effects (2, ankle edema, and 2, gastrointestinal disturbance). Six insulin-treated patients (10.7%) described adverse effects (5, early morning hypoglycemia, and 1, anxiety). Investigators concluded that in Chinese patients with type 2 diabetes and secondary conventional OAD failure, 1 y of treatment with rosiglitazone or bedtime insulin added to the regular regimen resulted in similar improvements in glycemic control. Rosiglitazone was also associated with improved high-density lipoprotein cholesterol levels. The addition of rosiglitazone may offer a safe and effective alternative to bedtime insulin treatment.

Adult↗
PubMed2004

Pleiotropic effects of thiazolidinediones: taking a look beyond antidiabetic activity.

Thiazolidinediones (TZD) [Troglitazone (TRO), Pioglitazone (PGZ), Rosiglitazone, (RGZ)] are a novel class of antidiabetic drugs for patients with Type-2 diabetes mellitus (T2DM) able to decrease blood glucose, working through a reduction of insulin resistance. The family of TZD exerts its effect specifically bound to peroxisome proliferator-activated receptor y (PPARy). This is a member of the nuclear hormone receptor superfamily of ligand-dependent transcription factors, together with PPARalpha and deltabeta. Although PPARgamma is essentially expressed in adipose tissue, it has also been found in endothelial cells, macrophages, vascular smooth muscle cells, glomerular mesangial cells, hepatic stellate cells and in several cancer cell lines. In these cells, the PPARgamma activation by TZD determines modulatory effects on growth factor release, production of cytokine, cell proliferation and migration, extracellular matrix remodeling and control on cell cycle progression and differentiation. In addition, TZD have been shown to have a potent antioxidant effect. This review, taking a quick look beyond the antidiabetic activity of PPARgamma, shows the dramatic ranging of medical implications that the use of TZD could have modulating the PPARgamma activity in several diseases with a strong social impact, such as insulin resistance syndrome, chronic inflammation, atherosclerosis and cancer.

Arteriosclerosis↗
PubMed2004

Oral antidiabetic therapy in patients with heart disease. A cardiologic standpoint.

Five types of oral antihyperglycemic drugs are currently approved for the treatment of diabetes: biguanides, sulfonylureas, meglitinides, glitazones, and alpha-glucosidase inhibitors. The cardiovascular effects of the most commonly used antidiabetic drugs in these groups are briefly reported, in an attempt to improve knowledge and awareness regarding their influences and potential risks when treating patients with coronary artery disease (CAD). Regarding biguanides, gastrointestinal disturbances such as diarrhea are frequent, and the intestinal absorption of group B vitamins and especially folate is impaired during chronic therapy. This deficiency may lead to increased plasma homocysteine levels which, in turn, accelerate the progression of vascular disease due to adverse effects on platelets, clotting factors, and endothelium. The existence of a graded association between homocysteine levels and overall mortality in patients with CAD is well established. In addition, metformin may lead to lethal lactic acidosis, especially in patients with clinical conditions that predispose to this complication, such as heart failure or recent myocardial infarction. Sulfonylureas avoid ischemic preconditioning. During myocardial ischemia, they may prevent the opening of the ATP-dependent potassium channels, impeding the necessary hyperpolarization that protects the cell by blocking calcium influx. Meglitinides may exert similar effects, due to their analogous mechanism of action. During treatment with glitazones, edema has been reported in 5% of patients, and these drugs are contraindicated in diabetics with NYHA class III or IV cardiac status. The long-term effects of alpha-glucosidase inhibitors on morbidity and mortality rates and on diabetic micro- and macrovascular complications are yet unknown. The combined sulfonylurea/metformin therapy reveals additive effects on mortality. It is concluded that(1) four of the five oral antidiabetic drug groups present proven or potential cardiac hazards;(2) these hazards are not mere "side effects", but are deeply rooted in the drugs' mechanism of action;(3) current data indicate that the combined glibenclamide/metformin therapy seems to present special risk and should be avoided in the long-term management of type 2 diabetics with proven CAD; and(4) customized antihyperglycemic pharmacological approaches should be investigated for optimal treatment of diabetic patients with heart disease.

Administration, Oral↗
PubMed2002

Improved stability, insulin-releasing activity and antidiabetic potential of two novel N-terminal analogues of gastric inhibitory polypeptide: N-acetyl-GIP and pGlu-GIP.

AIMS/HYPOTHESIS: This study examined the plasma stability, biological activity and antidiabetic potential of two novel N-terminally modified analogues of gastric inhibitory polypeptide (GIP). METHODS: Degradation studies were carried out on GIP, N-acetyl-GIP (Ac-GIP) and N-pyroglutamyl-GIP (pGlu-GIP) in vitro following incubation with either dipeptidylpeptidase IV or human plasma. Cyclic adenosine 3'5' monophosphate (cAMP) production was assessed in Chinese hamster lung fibroblast cells transfected with the human GIP receptor. Insulin-releasing ability was assessed in vitro in BRIN-BD11 cells and in obese diabetic ( ob/ ob) mice. RESULTS: GIP was rapidly degraded by dipeptidylpeptidase IV and plasma (t(1/2) 2.3 and 6.2 h, respectively) whereas Ac-GIP and pGlu-GIP remained intact even after 24 h. Both Ac-GIP and pGlu-GIP were extremely potent ( p<0.001) at stimulating cAMP production (EC(50) values 1.9 and 2.7 nmol/l, respectively), almost a tenfold increase compared to native GIP (18.2 nmol/l). Both Ac-GIP and pGlu-GIP (10(-13)-10(-8) mmol/l) were more potent at stimulating insulin release compared to the native GIP ( p<0.001), with 1.3-fold and 1.2-fold increases observed at 10(-8) mol/l, respectively. Administration of GIP analogues (25 nmol/kg body weight, i.p.) together with glucose (18 mmol/kg) in ( ob/ ob) mice lowered ( p<0.001) individual glucose values at 60 min together with the areas under the curve for glucose compared to native GIP. This antihyperglycaemic effect was coupled to a raised ( p<0.001) and more prolonged insulin response after administration of Ac-GIP and pGlu-GIP (AUC, 644+/-54 and 576+/-51 ng.ml(-1) x min, respectively) compared with native GIP (AUC, 257+/-29 ng.ml(-1) x min). CONCLUSION/INTERPRETATION: Ac-GIP and pGlu-GIP, show resistance to plasma dipeptidylpeptidase IV degradation, resulting in enhanced biological activity and improved antidiabetic potential in vivo, raising the possibility of their use in therapy of Type II (non-insulin-dependent) diabetes mellitus.

Acetylation↗
PubMed2005

Restoration of ultrastructural and biochemical changes in alloxan-induced diabetic rat sciatic nerve on treatment with Na3VO4 and Trigonella--a promising antidiabetic agent.

Vanadium has been reported to have broad pharmacological activity both in vitro and in vivo. Vanadium compound, sodium orthovanadate, Na3VO4, is well known for its hypoglycaemic effects. However, Na3VO4 exerts these effects at relatively high doses (0.6 mg/ml) and exhibit several toxic effects. In the present study lower doses of Na3VO4 (0.2 mg/ml) are combined with Trigonella foenum graecum seed powder (TSP), another hypoglycaemic agent, to reduce its toxicity without compromising its antidiabetic potential. The efficacy of the lower doses of Na3VO4 has been investigated in restoring the altered glucose metabolism and histological structure in the sciatic nerves in 21 and 60 days alloxan diabetic rats. A portion of the glucose was found to be channelled from the normal glycolytic route to polyol pathway, evident by the reduced hexokinase activity and increased polyol pathway enzymes aldose reductase and sorbitol dehydrogenase activity causing accumulation of sorbitol and fructose in diabetic conditions. Ultrastructural observation of the sciatic nerve showed extensive demylination and axonal loss after eight weeks of diabetes induction. Blood glucose levels increased in diabetic rats were normalized with the lower dose of vanadium and Trigonella treatment. The treatment of the diabetic rats with vanadium and Trigonella prevented the activation of the polyol pathway and sugar accumulations. The sciatic nerves were also protected against the structural abnormalities found in diabetes with Trigonella foenum graecum as well as Na3VO4. Results suggest that lower doses of Na3VO4 may be used in combination with TSP as an efficient antidiabetic agent to effectively control the long-term complications of diabetes in tissues like peripheral nerve.

Aldehyde Reductase↗
PubMed2005

Metabolic syndrome therapy: prevention of vascular injury by antidiabetic agents.

More than 65 million Americans are currently obese. Type 2 diabetes mellitus, frequently seen in obese subjects, affects 17 million adults in the United States, with a continuous and alarmingly increasing rate. To prevent development of diabetes in those who are at high risk, it is recommended to optimize meal planning and enhance physical activity to make sustained weight reduction possible. In addition to lifestyle changes, various oral antidiabetic agents are available, with diverse mechanisms of action. Some target defective insulin secretion (sulphonylureas, benzoic acid derivatives) or glucose absorption (glycosidase inhibitors), whereas others target insulin resistance (metformin, thiazolidinediones). Patients with metabolic syndrome and diabetes have an increased risk for cardiovascular disease linked to a higher prevalence of hypertension, dyslipidemia, microalbuminuria, and altered hemostasis--parameters that may be modified by antidiabetic agents. In this article, we review the oral agents used to treat type 2 diabetes and the metabolic syndrome, and their effects on vascular tissue.

Administration, Oral↗
PubMed1995

Effect of the new oral antidiabetic agent (-)-BM 13.0913.Na on insulin resistance in lean and obese Zucker rats.

The new antidiabetic agent (-)-BM 13.0913.Na (BM) was administered to 12-week-old lean and obese Zucker rats, an animal model of insulin resistance, at a daily dose of 50 mg/kg for 14 days. Hyperinsulinemic-euglycemic clamps were performed on treated and untreated lean and obese Zucker rats. Basal hepatic glucose production (HGP) rates were similar in lean and obese untreated animals. Insulin-induced suppression of HGP was significantly less effective in obese animals. In addition, these animals exhibited the characteristic impaired glucose utilization. In obese animals, drug treatment improved insulin suppression of HGP and total glucose utilization (GU) during clamp studies. Furthermore, drug treatment decreased insulin levels during clamp studies, suggesting an acceleration of insulin clearance. Drug treatment also decreased basal plasma insulin levels and serum and liver concentrations of cholesterol in both fasted lean and obese rats. Additionally, blood glucose, plasma nonesterified fatty acids (NEFA), and serum triglyceride levels were reduced in fasted obese rats, but only minor changes in liver triglycerides were observed in lean and obese rats. On the basis of these results, we suggest that BM is an effective antidiabetic agent that may reduce abnormalities of glucose and lipid metabolism.

Administration, Oral↗
PubMed1988

Secondary failure of oral antidiabetic and dietetic therapy in non-insulin-dependent diabetes mellitus. Remission through short sessions of continuous intravenous insulin infusion.

The infusion of periodic intravenous insulin for the equilibrium of the diabetic state is proposed for cases of non-insulin-dependent diabetes mellitus (NIDDM) that have become resistant to oral treatment. In order to re-establish the efficacy of oral antidiabetic treatment, 37 patients with NIDDM presenting secondary failure to diet and oral antidiabetic therapy were subjected to sessions of continuous intravenous insulin infusion, resulting in transitory normal blood sugars. With a diminution of symptoms, an increase in the efficacy of oral treatment was noted in 18 cases (48.6%), allowing the continuation of treatment without disturbance of the equilibrium over periods of 6 and 12 months. This improvement is not concurrent with the rise in glucagon-stimulated insulin secretion as evidenced by C-peptiduria and basal C-peptidemia. An improvement in insulin sensitivity (not investigated in this study) might explain this beneficial effect. Periodic intravenous infusions of insulin, based on the diabetic equilibrium, are proposed for the treatment of NIDDM patients that have become resistant to oral therapy.

Blood Glucose↗
PubMed1988

Facts about combination therapy in NIDDM: insulin + oral antidiabetic agents.

Recent recommendations in textbooks suggest the use of the combination of insulin treatment with oral antidiabetic agents in NIDDM, especially in secondary failures and insulin resistance with exogenous insulin. This new view in treatment policy is based on literature data in C-peptide positive IDDM patients. Better metabolic control with lower exogenous insulin dosages could also be obtained in NIDDM. If no medical contraindication for drug treatment exists (liver or renal insufficiency, drug interactions, etc.), a combination therapy trial can be considered as an intermediate step between oral antidiabetic agents alone and insulin as monotherapy. Long-term maintenance of endogenous secretion and limited peripheral hyperinsulinism can be considered as potential benefits of this combination therapy.

Blood Glucose↗
PubMed1996

Differential inhibitory effects of antidiabetic drugs on arterial smooth muscle cell proliferation.

We compared three drugs representing different classes of antidiabetic pharmacology (glyburide, a sulfonylurea; pioglitazone, a thiazolidinedione; and metformin, a biguanide) in terms of their direct effects on proliferation of cultured arterial smooth muscle cells (SMC). Rat aortic SMC were seeded at 4 x 10(4)/35 mm well. After 24 h, they were treated every 2 to 4 days for 2 weeks with 5% fetal bovine serum (FBS) in normal culture medium containing either drug vehicles or a low and a high but nontoxic level of glyburide (0.5 and 2.5 mumol/L), pioglitazone (1 and 5 mumol/L), and metformin (20 and 100 mumol/L). Vehicle-treated cells increased from 2 +/- 0 to 6 +/- 1 to 42 +/- 3 to 210 +/- 14 (cells per well x 10(4); 5 wells each) from day zero to 4 to 9 to 14. From day 9 to 14 these cell numbers were decreased an average of 20% by the 2.5 mumol/L glyburide (P < .05) and 43% by the 5 mumol/L pioglitazone (P < .05). The low levels of glyburide and pioglitazone and both the low and high levels of metformin failed to influence cell numbers. In a second experiment, even half the abovementioned high level of pioglitazone (2.5 mumol/L) still exerted a markedly greater antiproliferative effect on aortic SMC than a high level of 2.0 mumol/L glyburide (P < .05). In addition, neither drug's antiproliferative effect was influenced by a high level of insulin added to the medium (10 mU/mL). Similarly, a small but significant stimulatory effect of this high insulin on cell proliferation (P < .05) was not significantly affected by these two drugs (although pioglitazone tended to inhibit it). These results suggest that thiazolidinediones may be more useful antidiabetic agents than sulfonylureas and biguanides in inhibiting abnormal arterial SMC proliferation associated with atherosclerosis and postangioplastic restenosis which are common in diabetic patients.

Animals↗
PubMed2005

Synthesis of docosahexaenoic acid derivatives designed as novel PPARgamma agonists and antidiabetic agents.

To discover novel peroxisome proliferator-activated receptor gamma (PPARgamma) agonists that could be used as antidiabetic agents, we designed docosahexaenoic acid (DHA) derivatives (2 and 3), which have a hydrophilic substituent at the C4-position, based on the crystal structure of the ligand-binding pocket of PPARgamma. These compounds were synthesized via iodolactone as a key intermediate. We found that both DHA derivatives (2 and 3) showed PPARgamma transactivation higher than, or comparable to, that of pioglitazone, which is a TZD derivative used as an antidiabetic agent. DHA derivatives related to these potent compounds 2 and 3 were also synthesized to study structure-activity relationships. Furthermore, 4-OH DHA 2, which shows strong PPARgamma transcriptional activity, was separated as an optically pure form.

Animals↗
PubMed2005

Identification of putative metabolites of docosahexaenoic acid as potent PPARgamma agonists and antidiabetic agents.

We found that putative metabolites of docosahexaenoic acid (DHA) are strong PPARgamma activators and potential antidiabetic agents. We designed DHA derivatives based on the crystal structure of PPARgamma, synthesized them and evaluated their activities in vitro and in vivo. The efficacy of 5E-4-hydroxy-DHA 2a as a PPARgamma activator was about fourfold stronger than that of pioglitazone. Furthermore, the 4-keto derivative (10b) showed antidiabetic activity in animal models without producing undesirable effects such as obesity and hepatotoxicity.

Animals↗
PubMed2005

Antidiabetic and antihyperlipemic effects of Clemeo felina.

Petroleum ether and benzene extracts of Clemeo felina, given orally at doses of 300 mg kg(-1) day(-1) for 30 days, were found to be antidiabetic and antihyperlipemic on alloxan diabetic rats. Moreover, a significant decrease in the activities of serum enzymes like alkaline phosphatase, acid phosphatase and HMGCoA reductase activity in the liver was observed. However, treatment of rats with the extracts as well as standard antidiabetic drugs increased liver hexakinase activity and serum LDH activity.

Animals↗
PubMed2006

Antidiabetic activity of Caesalpinia bonducella seed extracts in rats.

The seed extracts of Caesalpinia bonducella were subjected to screening of antidiabetic activity in alloxan induced hyperglycemia. The oral administration of the extracts (300 mg/kg) produced significant antihyperglycemic action as well as it lowered the BUN levels significantly. In the same study the action of the extracts on diabetes induced hyperlipidemia was analyzed where the extracts significantly lowered the elevated cholesterol as well as LDL level. The antihyperglycemic action of the extracts may be due to the blocking of glucose absorption. The drug has the potential to act as antidiabetic as well as antihyperlipidemic.

Administration, Oral↗
PubMed2004

Antidiabetic and antihyperlipidaemic effect of alcoholic Syzigium cumini seeds in alloxan induced diabetic albino rats.

Syzigium cumini, commonly known as 'jamun', is widely used in different parts of India for the treatment of diabetes mellitus. The present study was designed to evaluate the antidiabetic and antihyperlipidaemic effect of an alcoholic extract of Syzigium cumini seeds (JSEt) in alloxan diabetic rats. Diabetes was induced by single intraperitoneal injection of alloxan (150 mg kg(-1) body weight). Oral administration of alcoholic JSEt to diabetic rats at a dose of 100 mg kg(-1) body weight resulted in a significant reduction in blood glucose and urine sugar and lipids in serum and tissues in alloxan diabetic rats. The extract also increases total haemoglobin. The extract brought back all the parameters to normal levels. The effect of alcoholic JSEt was similar to that of insulin. Thus, our investigation clearly shows that alcoholic JSEt has both antidiabetic and antihyperlipidaemic effects.

Alloxan↗
PubMed2004

Antidiabetic activity of aqueous leaf extract of Annona squamosa in streptozotocin-nicotinamide type 2 diabetic rats.

The claim by some tribal populations in parts of Northern India that the young leaves of the custard apple tree, Annona squamosa L. (Annonaceae) has antidiabetic properties was investigated. Diabetes mellitus was induced with streptozotocin-nicotinamide and graded doses of the aqueous leaf extracts were then administered in drinking water to normal and experimental diabetic rats for 12 days. Fasting plasma glucose levels, serum insulin levels, serum lipid profiles and changes in body weight were evaluated in normal rats while liver glycogen levels and pancreatic TBARS levels were evaluated additionally in diabetic rats. The diabetic groups treated with the aqueous leaf extract were compared with standard glibenclamide. The findings of the study support the antidiabetic claims of Annona squamosa.

Animals↗
PubMed2005

Antidiabetic effects of extracts from Psidium guajava.

During a screening of medicinal plants for inhibition of protein tyrosine phosphatase1B (PTP1B), an extract from Psidium guajava (Myrtaceae) leaves exhibited significant inhibitory effect on PTP1B. Thus, its antidiabetic effect on Lepr(db)/Lepr(db) mice was evaluated. Significant blood glucose lowering effects of the extract were observed after intraperitoneal injection of the extract at a dose of 10mg/kg in both 1- and 3-month-old Lepr(db)/Lepr(db) mice. In addition, histological analysis of the liver from the butanol-soluble fraction treated Lepr(db)/Lepr(db) mice revealed a significant decrease in the number of lipid droplets compared to the control mice. Taken together, it was suggested that the extract from Psidium guajava leaves possesses antidiabetic effect in type 2 diabetic mice model and these effect is, at least in part, mediated via the inhibition of PTP1B.

Age Factors↗