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At least 883 records · Page 49Linked to original sources
PubMed2003

Do peroxisome proliferation receptor-gamma antagonists have clinical potential as combined antiobesity and antidiabetic drugs?

There is genetic evidence that reducing the activity of peroxisome proliferation receptor-gamma (PPAR-gamma) may increase insulin sensitivity. SR-202 is a selective antagonist at PPAR-gamma, which inhibits the adipocyte differentiation normally seen with the PPAR-gamma agonist rosiglitazone. SR-202 also reduces the ability of young mice to put on weight and accumulate fat. The levels of circulating TNF-alpha correlates with body fat stores and/or hyperinsulinaemia. SR-202- treated wild-type mice have reduced TNF-alpha levels. When wild-type mice are fed a high-fat diet, the plasma levels of TNF-alpha are raised, and SR-202 treatment protects against this rise. Feeding mice with a high-fat diet induced insulin resistance measured as increased plasma levels of glucose, insulin and free fatty acids, and SR-202 protected against these changes. The ob/ob mouse is diabetic at 8 weeks and plasma glucose and insulin levels continue to rise over the next 3 weeks, and treatment with SR-202 prevents these increases. The development of PPAR-gamma antagonists should continue as the results to date suggest that they have clinical potential for the treatment of diabetes Type 2 and obesity.

Animals↗
PubMed2005

Therapeutic assessment of glucagon-like peptide-1 agonists compared with dipeptidyl peptidase IV inhibitors as potential antidiabetic drugs.

The most prevalent form of diabetes is non-insulin-dependent or Type 2 diabetes. Innovative strategies to enhance insulin secretion and thereby improve glucose tolerance in patients with this type of diabetes are currently under preclinical and clinical investigation. These therapies include the applications of incretin hormones; gut hormones released postprandially that stimulate insulin secretion in pancreatic beta-cells. Because incretin actions are rapidly terminated by N-terminal cleavage of these peptide hormones by the amino-peptidase dipeptidyl peptidase IV (DPP IV, CD26), the utility of DPP IV inhibitors for the treatment of Type 2 diabetes is also under investigation. This review compares the therapeutic potential and possible side effects of metabolically stable analogues/peptide agonists of the incretin glucagon-like peptide-1 (GLP-1) with the application of DPP IV inhibitors that reduce the rate of endogenous degradation of GLP-1 and other incretins. GLP-1 analogues have been shown to be highly efficacious in the treatment of Type 2 diabetes, with minimal side effects. Of particular importance is the fact that they do not induce hypoglycaemia. However, they are currently available only in an injectable form. In contrast, DPP IV inhibitors have the clear advantage of oral application resulting in better patient compliance. Furthermore, they also potentiate the actions of other incretins normally degraded by the action of DPP IV. However, they possess more potential side effects. Taken together, both approaches offer promising new drugs for the treatment of Type 2 diabetes.

Animals↗
PubMed2005

The oral antidiabetic pioglitazone protects from neurodegeneration and amyotrophic lateral sclerosis-like symptoms in superoxide dismutase-G93A transgenic mice.

Amyotrophic lateral sclerosis (ALS) represents a fatal neurodegenerative disorder characterized by progressive death of the upper and lower motor neurons. Because accompanying inflammation may interact with and promote neurodegeneration, anti-inflammatory treatment strategies are being evaluated. Because peroxisome proliferator-activated receptor gamma (PPARgamma) agonists act as potent anti-inflammatory drugs, we tested whether superoxide dismutase (SOD1)-G93A transgenic mice, a mouse model of ALS, benefit from oral treatment with the PPARgamma agonist pioglitazone (Pio). Pio-treated transgenic mice revealed improved muscle strength and body weight, exhibited a delayed disease onset, and survived significantly longer than nontreated SOD1-G93A mice. Quantification of motor neurons of the spinal cord at day 90 revealed complete neuroprotection by Pio, whereas nontreated SOD1-G93A mice had lost 30% of motor neurons. This was paralleled by preservation of the median fiber diameter of the quadriceps muscle, indicating not only morphological but also functional protection of motor neurons by Pio. Activated microglia were significantly reduced at sites of neurodegeneration in Pio-treated SOD1-G93A mice, as were the protein levels of cyclooxygenase 2 and inducible nitric oxide synthase. Interestingly, mRNA levels of the suppressor of cytokine signaling 1 and 3 genes were increased by Pio, whereas both the mRNA and protein levels of endogenous mouse SOD1 and of transgenic human SOD1 remained unaffected.

Administration, Oral↗
PubMed1998

Mechanisms of the antidiabetic action of subcutaneous glucagon-like peptide-1(7-36)amide in non-insulin dependent diabetes mellitus.

Twelve patients with non-insulin dependent diabetes mellitus (NIDDM) under secondary failure to sulfonylureas were studied to evaluate the effects of subcutaneous glucagon-like peptide-1(7-36)amide (GLP-1) on (a) the gastric emptying pattern of a solid meal (250 kcal) and (b) the glycemic and endocrine responses to this solid meal and an oral glucose tolerance test (OGTT, 300 kcal). 0.5 nmol/kg of GLP-1 or placebo were subcutaneously injected 20 min after meal ingestion. GLP-1 modified the pattern of gastric emptying by prolonging the time to reach maximal emptying velocity (lag period) which was followed by an acceleration in the post-lag period. The maximal emptying velocity and the emptying half-time remained unaltered. With both meals, GLP-1 diminished the postprandial glucose peak, and reduced the glycemic response during the first two postprandial hours by 54.5% (solid meal) and 32.7% (OGTT) (P < 0.05). GLP-1 markedly stimulated insulin secretion with an effect lasting for 105 min (solid meal) or 150 min (OGTT). The postprandial increase of plasma glucagon was abolished by GLP-1. GLP-1 diminished the postprandial release of pancreatic polypeptide. The initial and transient delay of gastric emptying, the enhancement of postprandial insulin release, and the inhibition of postprandial glucagon release were independent determinants (P < 0.002) of the postprandial glucose response after subcutaneous GLP-1. An inhibition of efferent vagal activity may contribute to the inhibitory effect of GLP-1 on gastric emptying.

Aged↗
PubMed2006

Inhibition of diabetic nephropathy in rats by an oral antidiabetic material extracted from yeast.

Diabetic nephropathy is one of the major complications of diabetes. The glucose tolerance factor (GTF) is a dietary agent extracted from several natural sources; the richest among them is brewer's yeast. Extraction and purification of an active and stable GTF preparation from brewer's yeast previously was successful, and a remarkable decrease in plasma glucose and lipids from administration of GTF to animals with type 1 diabetes was demonstrated. The purpose of the present study was to examine whether GTF affects nephropathy in diabetic rats. The average urinary volume and protein excretion throughout the collection period in diabetic rats was 56.95 +/- 2.2 ml/d and 5.42 +/- 0.95 mg/d, respectively. These values were significantly (P < 0.001 versus baseline values) higher compared with healthy controls (average urine volume 15.12 +/- 0.5 ml/d; average protein excretion 0.15 +/- 0.08 mg/d). Treatment with GTF reduced average urine volume and protein excretion to 29.1 +/- 1.94 ml/d (P < 0.01) and 1.55 +/- 1.17 mg/d (P < 0.05), respectively. Kidney weight, which was elevated in diabetic rats, slightly decreased in diabetic animals that were treated with GTF, in association with reduction of lipid peroxidation levels in the renal cortex and the heart. Endothelial nitric oxide immunoreactivity in the renal cortex of both healthy and diabetic rats that were treated with GTF was remarkably lower than that found in renal cortex of untreated diabetic animals. This study demonstrates that yeast-derived material, GTF, can inhibit the development of nephropathy that is induced by diabetes.

Administration, Oral↗
PubMed1993

Features, prevention and management of acute overdose due to antidiabetic drugs.

Hypoglycaemic medication forms a disparate group of therapeutic compounds including insulin, the sulphonylureas and biguanides. They are all designed to prevent hyperglycaemia and in general are well tolerated. Careful prescribing practice and patient education by the physician can do much to reduce the risk of adverse effects from diabetic therapy. However, the presentation of adverse effects, together with accidental and non-accidental overdose, is a frequent clinical problem. Furthermore, the possible impairment of hypoglycaemic awareness in patients prescribed human insulin has added complexity to diabetic management. The cardinal features of insulin overdose are hypoglycaemia and hypokalaemia. The sulphonylureas predominantly cause hypoglycaemia, while the biguanides may precipitate lactataemia and acidosis. Recognition of hypoglycaemia is therefore crucial in avoidance of toxicity. Intravenous dextrose is the mainstay of therapy following gut decontamination (for the oral agents). The efficacy of glucagon is dependent on hepatic glycogen stores and should therefore be used with caution. Diazoxide is not recommended. More recently, octreotide has been shown to be effective in sulphonylurea overdose. Patients should be admitted and monitored with serial blood sugar measurements for a minimum of 1 to 2 days as clinically warranted.

Acute Disease↗
PubMed1994

Comparative tolerability profiles of oral antidiabetic agents.

The sulphonylureas and the biguanides are widely used as adjuncts to dietary measures in the treatment of non-insulin-dependent (type 2) diabetes mellitus (NIDDM). Adverse effect profiles differ markedly between the sulphonylureas and biguanides, reflecting differences in chemical structure and mode of action. Sulphonylureas are generally well tolerated, although pharmacokinetic differences between these agents have important clinical implications. The main adverse effect associated with sulphonylureas is hypoglycaemia. This effect is a predictable consequence of the principal pharmacological effect of these drugs, i.e. sensitisation of the islet beta-cell to glucose, resulting in enhanced endogenous insulin secretion. Sulphonylurea-induced suppression of hepatic glucose production may cause profound and protracted hypoglycaemia, especially in elderly patients, in individuals with intercurrent illnesses and reduced caloric intake, or when taken in combination with other compounds with hypoglycaemic potential, e.g. alcohol (ethanol). Sulphonylureas with a longer duration of action, notably chlorpropamide and glibenclamide (glyburide), are more liable to induce serious hypoglycaemia, particularly when drug elimination is reduced by renal impairment. Other drugs such as salicylates may potentiate the actions of sulphonylureas, thereby increasing the risk of hypoglycaemia. Biguanide therapy is associated with alterations in lactate homeostasis which under certain clinical circumstances may result in fatal lactic acidosis. Phenformin is associated with a markedly greater risk of lactic acidosis than metformin. Phenformin has been withdrawn in many countries for this reason. All biguanides must be avoided in patients with renal impairment, hepatic dysfunction and cardiac failure--conditions where drug accumulation or disordered lactate metabolism may predispose to lactic acidosis. Phenformin should not be given to individuals who exhibit a severe, genetically conferred hepatic defect of hydroxylation which impedes metabolism of this drug. Less seriously, the biguanides are associated with a relatively high incidence of gastrointestinal adverse effects which limit compliance. Acarbose, a competitive inhibitor of intestinal alpha-glucosidases, has recently been introduced. In contrast to the sulphonylureas and biguanides, acarbose has not been associated with life-threatening adverse effects. This reflects the low systemic absorption of the drug and, predictably, its principal unwanted effects are gastrointestinal disturbances resulting from iatrogenic carbohydrate malabsorption.

Acarbose↗
PubMed1996

Oral antidiabetic drug use in the elderly.

Non-insulin-dependent diabetes mellitus (NIDDM) is a metabolic disease that is common in the elderly, and is characterised by insulin insufficiency and resistance. Measures such as bodyweight reduction and exercise improve the metabolic defects, but pharmacological therapy is the most frequently used and successful therapy. The sulphonylureas stimulate insulin secretion. Metformin and troglitazone increase glucose disposal and decrease hepatic glucose output without causing hypoglycaemia. Acarbose is a dietary aid that spreads the dietary carbohydrate challenge to endogenous insulin over time. These pharmacological agents, either alone or in combination, should improve blood glucose regulation in patients with NIDDM.

Administration, Oral↗
PubMed1989

Sulphonylurea antidiabetic drugs. An update of their clinical pharmacology and rational therapeutic use.

Apart from the amelioration of symptoms, a major aim of the treatment of non-insulin-dependent diabetes mellitus (NIDDM, type 2 diabetes) should be the prevention of cardiovascular complications. These are associated with the chronic hyperglycaemia that is characteristic of NIDDM, and the risk of complications is already increased in subjects with impaired glucose tolerance (IGT). For these reasons, and because hyperglycaemia appears to be a self-perpetuating condition, treatment should be introduced as early as possible and should be aimed at normalisation of blood glucose. To enable early detection and intervention, screening is necessary. As diet regulation alone rarely suffices to normalise blood glucose, addition of sulphonylurea drugs is indicated in many cases. If introduced in the IGT phase, sulphonylureas drugs combined with diet regulation may postpone the development of IGT to manifest NIDDM, and may reduce the increased risk of cardiovascular morbidity and mortality. Sulphonylureas stimulate insulin release, possibly via interaction with receptors in the pancreatic B cells. In addition, such treatment enhances the reduced insulin action. This might be a primary effect but is also a consequence of the increased access to insulin and the subsequent reduction of hyperglycaemia. Sulphonylureas may enhance insulin availability by reducing insulin clearance. Effects on blood lipids are probably secondary phenomena. Fast and short acting sulphonylureas may improve the impaired meal-induced acute insulin release. If combined with weight-reducing diet regulation and introduced early, such treatment can maintain (near) normal blood glucose levels and an improved insulin action for several years without increasing basal insulin secretion, without chronic hyperinsulinaemia, and without weight increase. If not combined with diet regulation, sulphonylurea therapy is likely to fail. If introduced when NIDDM is advanced, the efficacy of these drugs is limited, with secondary failures developing at a rate of 5 to 10% per year. Continuous (24-hour-a-day) exposure to drug treatment could possibly desensitise the B cell to sulphonylurea stimulation. 'Second-generation' sulphonylurea drugs have a higher potency than 'first-generation' drugs, but this need not signify a greater clinical efficacy. The effect of several of these drugs may be increased if they are ingested half an hour before meal(s). Short acting sulphonylureas may be safer than long acting ones, which seem more likely to cause long lasting and fatal hypoglycaemia, at least in elderly patients.(ABSTRACT TRUNCATED AT 400 WORDS)

Diabetes Mellitus, Type 2↗
PubMed1992

Oral antidiabetic agents. The emergence of alpha-glucosidase inhibitors.

Hyperglycaemia in patients with non-insulin-dependent diabetes mellitus (NIDDM) results from impaired insulin action and/or deficient insulin secretion. These abnormalities lead to increased hepatic glucose production, the primary cause of fasting hyperglycaemia, and decreased peripheral glucose uptake, the major mechanism responsible for postprandial hyperglycaemia. Hyperglycaemia in patients with NIDDM can be decreased by several different mechanisms: (1) a decrease in nutrient ingestion; (2) an increase in insulin secretion; (3) a decrease in hepatic glucose production; (4) an increase in peripheral glucose uptake. Oral agents used to treat NIDDM operate through 1 or more of the above mechanisms. alpha-Glucosidase inhibitors, a new class of drugs that delay carbohydrate digestion and absorption, reduce postprandial glycaemic rises by about 3 mmol/L. Metformin decreases fasting and postprandial hyperglycaemia through increasing glucose uptake and perhaps decreasing appetite. Sulphonylureas lower hyperglycaemia by increasing insulin secretion and to a lesser degree potentiating insulin action on the liver and peripheral tissues. alpha-Glucosidase inhibitors are particularly useful as primary therapy for patients with mild to moderate hyperglycaemia and in those patients who may be at risk for hypoglycaemia or lactic acidosis. Sulphonylureas are indicated for the more severely hyperglycaemic NIDDM patients who are not yet candidates for insulin therapy. Metformin is useful in obese moderately hyperglycaemic NIDDM patients. These oral agents can be used in combination to give better glycaemic control than is possible with each alone.

Administration, Oral↗
PubMed1998

Oral antidiabetic agents. A guide to selection.

Type 2 diabetes mellitus (formerly named non-insulin-dependent diabetes mellitus or NIDDM) is a heterogeneous disease resulting from a dynamic interaction between defects in insulin secretion and insulin action. Various pharmacological approaches can be used to improve glucose homeostasis via different modes of action: sulphonylureas essentially stimulate insulin secretion, biguanides (metformin) act by promoting glucose utilisation and reducing hepatic-glucose production, alpha-glucosidase inhibitors (acarbose) slow down carbohydrate absorption from the gut and thiazolidinediones (troglitazone) enhance cellular insulin action on glucose and lipid metabolism. These pharmacological treatments may be used individually for certain types of patients, or may be combined in a stepwise fashion to provide more ideal glycaemic control for most patients. Selection of oral antihyperglycaemic agents as first-line drug or combined therapy should be based on both the pharmacological properties of the compounds (efficacy and safety, profile) and the clinical characteristics of the patient (stage of disease, bodyweight, etc.). Mildly hyperglycaemic patients should preferably be treated with metformin, acarbose or thiazolidinediones (which are not associated with any hypoglycaemic risk), while more severely hyperglycaemic individuals should receive a sulphonylurea. In moderately hyperglycaemic patients, sulphonylureas should be preferred in nonobese patients while metformin, and probably also thiazolidinediones, should have priority in obese insulin-resistant type 2 diabetic patients. Acarbose is mainly indicated to reduce post-prandial glucose fluctuations and improve glycaemic stability. Each antihyperglycaemic agent may also be combined with insulin therapy to improve glycaemic control and/or reduce the insulin requirement of diabetic patients after secondary failure to oral treatment. Finally, safety should be taken into account in elderly patients and/or those with renal impairment, especially as far as the use of sulphonylureas (higher risk of hypoglycaemia) and metformin (higher risk of lactic acidosis) is concerned.

Administration, Oral↗
PubMed2000

Antidiabetic drugs present and future: will improving insulin resistance benefit cardiovascular risk in type 2 diabetes mellitus?

Results from the United Kingdom Prospective Diabetes Study showed that intensive treatment of type 2 (non-insulin-dependent) diabetes mellitus, with sulphonylureas or insulin, significantly reduced microvascular complications but did not have a significant effect on macrovascular complications after 10 years. Insulin resistance plays a key role in type 2 diabetes mellitus and is linked to a cluster of cardiovascular risk factors. Optimal treatment for type 2 diabetes mellitus should aim to improve insulin resistance and the associated cardiovascular risk factors in addition to achieving glycaemic control. Treatment with sulphonylureas or exogenous insulin improves glycaemic control by increasing insulin supplies rather than reducing insulin resistance. Metformin and the recently introduced thiazolidinediones have beneficial effects on reducing insulin resistance as well as providing glycaemic control. There is evidence that, like metformin, thiazolidinediones also improve cardiovascular risk factors such as dyslipidaemia and fibrinolysis. Whether these differences will translate into clinical benefit remains to be seen. The thiazolidinediones rosiglitazone and pioglitazone have been available in the US since 1999 (with pioglitazone also being available in Japan). Both products are now available to physicians in Europe.

Biguanides↗
PubMed2005

Cardiovascular risk factors associated with insulin resistance: effects of oral antidiabetic agents.

Patients with type 2 diabetes mellitus have a greater risk of cardiovascular disease than nondiabetic individuals. These patients are often insulin resistant and have an associated clustering of risk factors that contribute to cardiovascular disease. The risk factors include dyslipidemia, hypertension, altered hemostasis, and chronic inflammation. A primary objective in the management of type 2 diabetes mellitus is normalization of blood glucose levels; however, some of the oral drugs used to control blood glucose levels have significant effects on these risk factors. In this article, we review the current data involving the modification of these cardiovascular risk factors by the biguanide (metformin), the thiazolidinediones (troglitazone, rosiglitazone, and pioglitazone), the alpha-glucosidase inhibitors (miglitol, acarbose), and the insulin secretagogs (glyburide [glibenclamide], glipizide, chlorpropamide, tolbutamide, tolazamide, glimepiride, repaglinide, and nateglinide). Generally, the thiazolidinediones improve hemostasis and endothelial function and reduce blood pressure, while having variable effects on dyslipidemia. Metformin improves dyslipidemia and altered hemostasis and decreases plasma C-reactive protein levels with little or no effect on blood pressure. Data on the effects of the alpha-glucosidase inhibitors and insulin secretagogs are sparse; however, these drugs appear to have little or no effect on cardiovascular risk factors.

Administration, Oral↗