Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P01275 (glucagon)
 26,492 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Alpha-glucosidase enzyme is present ubiquitously throughout the lumen of the small intestine. It is responsible for the breakdown of complex into simple carbohydrates. alpha-Glucosidase inhibitors such as miglitol, are drugs that have greater affinity towards this enzyme in comparison to carbohydrates. Miglitol regulates the postprandial glucose levels directly by inhibiting the enzyme reversibly and also indirectly by including the secretion of glucagon like peptide-1 (GLP-1). The aims of this study were (i) to design a controlled release (CR) mucoadhesive (in the intestine) formulation of miglitol which would inhibit the alpha-glucosidase enzyme for a longer duration of time (in comparison to the non-controlled release (IR) formulation) thus reducing the dosing frequency, and also controlling the postprandial glucose levels more effectively over a longer period of time; (ii) to assess the effect of different formulation parameters on the release of miglitol in vitro from the CR pellets; (iii) to evaluate the mucoadhesion of pellets in the intestine ex vivo; (iv) to study the effect of formulation parameters on plasma GLP-1 levels; and (v) to find out the effect of formulations on postprandial glucose levels. The data obtained was analysed to find out whether there was a correlation between these different parameters. Four controlled release formulations (CR1, CR2, CR3 and CR4) of miglitol comprising of multilayered pellets were designed successfully. The CR4 formulation containing 30% of 20 cps of ethyl cellulose (the retarding layer of the formulation) displayed slowest release of miglitol in vitro in comparison to other formulations. We designed an ex vivo experimental setup for studying the mucoadhesion of the pellets in the lumen of the intestine. Results indicated that amongst all of the adherent pellets, 5% were found to be adhering in the duodenal region, 61% in the jejunum, 32% in the ileum and 2% in the colon. Two of the controlled release formulations CR1 and CR4 were evaluated in vivo in dogs. Both the formulations displayed significantly higher and more prolonged (greater AUC) levels of GLP-1 in comparison to either the placebo or the immediate release (IR) formulations. They even displayed a significantly better control of postprandial glucose in comparison to either placebo or IR formulations. However, a comparison between the two controlled release formulations (CR1 and CR4) revealed that the plasma GLP-1 (AUC by CR1=63.1+/-1.32 and CR4=66.2+/-0.82) and postprandial glucose values due to both the formulations were rather similar despite their differences in in vitro release as well as pharmacokinetic profiles (plasma miglitol AUC of CR1=16.17+/-4.11 and CR4=27.17+/-4.33).
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PMID:Design and evaluation of oral bioadhesive controlled release formulations of miglitol, intended for prolonged inhibition of intestinal alpha-glucosidases and enhancement of plasma glucagon like peptide-1 levels. 1956 73

Classical non-insulin antihyperglycemic drugs currently approved for the treatment of type 2 diabetes mellitus (T2DM) comprise five groups: biguanides, sulfonylureas, meglitinides, glitazones and alpha-glucosidase inhibitors. Novel compounds are represented by the incretin mimetic drugs like glucagon like peptide-1 (GLP-1), the dipeptidyl peptidase 4 (DPP-4) inhibitors, dual peroxisome proliferator-activated receptors (PPAR) agonists (glitazars) and amylin mimetic drugs. We review the cardiovascular effects of these drugs in an attempt to improve knowledge regarding their potential risks when treating T2DM in cardiac patients. Metformin may lead to lethal lactic acidosis, especially in patients with clinical conditions that predispose to this complication, such as recent myocardial infarction, heart or renal failure. Sulfonylureas exert their effect by closing the ATP-dependent potassium channels. This prevents the opening of these channels during myocardial ischemia, impeding the necessary hyperpolarization that protects the cell. The combined sulfonylurea/metformin therapy reveals additive effects on mortality in patients with coronary artery disease (CAD). Meglitinides effects are similar to those of sulfonylureas, due to their almost analogous mechanism of action. Glitazones lower leptin levels, leading to weight gain and are unsafe in NYHA class III or IV. The long-term effects of alpha-glucosidase inhibitors on morbidity and mortality rates is yet unknown. The incretin GLP-1 is associated with reductions in body weight and appears to present positive inotropic effects. DPP-4 inhibitors influences on the cardiovascular system seem to be neutral and patients do not gain weight. The future of glitazars is presently uncertain following concerns about their safety. The amylin mimetic drug paramlintide, while a satisfactory adjuvant medication in insulin-dependent diabetes, is unlikely to play a major role in the management of T2DM. Summarizing the present information it can be stated that 1. Four out the five classical oral antidiabetic drug groups present proven or potential cardiac hazards; 2. These hazards are not mere 'side effects', but biochemical phenomena which 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 T2DM with proven CAD; 4. Glitazones should be avoided in patients with overt heart failure; 5, The novel incretin mimetic drugs and DPP-4 inhibitors--while usually inadequate as monotherapy--appear to be satisfactory adjuvant drugs due to the lack of known undesirable cardiovascular effects; 6. Customized antihyperglycemic pharmacological approaches should be implemented for the achievement of optimal treatment of T2DM patients with heart disease. In this context, it should be carefully taken into consideration whether the leading clinical status is CAD or heart failure.
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PMID:A cardiologic approach to non-insulin antidiabetic pharmacotherapy in patients with heart disease. 1961 27

The increasing proportions of older persons accounting for global populations, and the implications for increasing rates of chronic diseases such as type 2 diabetes mellitus, continue to be a cause of concern for clinicians. Considering that older persons are a very heterogeneous group of individuals, the management of type 2 diabetes is particularly challenging. Once type 2 diabetes is diagnosed, the principles of its management are similar to those in younger patients, but with special considerations linked to the increased prevalence of comorbidities and relative inability to tolerate adverse effects of medication and hypoglycemia. In addition, there are clinical aspects complicating diabetes care in the elderly including cognitive disorders, physical disability and geriatric syndromes, such as frailty. Available anti-diabetic oral drugs include insulin secretagogues (meglitinides and sulfonylureas), biguanides (metformin) alpha-glucosidase inhibitors, thiazolidinediones (TZDs) and newly introduced glucagon-like peptide-1 (GLP-1) analogues and inhibitors of GLP-1 degrading enzyme dipeptidyl peptidase-4 (DPP-4). Unfortunately, as type 2 diabetes progresses in older persons, polypharmacy intensification is required to reach adequate metabolic control with the risk of adverse effects due to age-related changes in drug metabolism. The present review discusses the European Diabetes Working Party guidelines for type 2 diabetes in older persons with and without frailty and their importance on preventing or at least slowing down diverse aspects of disability.
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PMID:Diabetes care targets in older persons. 2011 30

Life expectancy has significantly increased over the past 30 years, with a greater prevalence of diverse disease states, especially type 2 diabetes mellitus. As older persons are a very heterogeneous group with an increased prevalence of comorbidities and a relative inability to tolerate the adverse effects of oral antidiabetic agents, the treatment of type 2 diabetes is particularly demanding. The principles of its management are similar to those in younger patients, but with special considerations linked to comorbidities and clinical status. The available oral antidiabetic drugs include insulin secretagogues (meglitinides and sulfonylureas), biguanides (metformin), alpha-glucosidase inhibitors, thiazolidinediones and newly introduced inhibitors of glucagon-like peptide 1 degrading enzyme dipeptidyl peptidase 4 (DPP-4). In addition, clinical aspects complicate diabetes care in the elderly, including cognitive disorders, physical disability and geriatric syndromes, such as frailty. The European Diabetes Working Party for Older Persons has increased glycaemic recommendations for target haemoglobin A(1c) from <7% to <or=8% in the presence of frailty. This working party updated their guidelines in 2008 and their aim is to ensure that older Europeans with type 2 diabetes have high-quality diabetes care throughout their lives. The working party has created guidelines for the use of many drugs, and we will discuss some of these guidelines on the use of oral antidiabetic agents and their importance in the presence of frailty. Furthermore, as type 2 diabetes progresses in older persons, polypharmacy intensification is usually required to reach adequate glycaemic control, with the risk of adverse effects. In particular, clinical evidence shows that the use of sulfonylureas is associated with a greater risk of hypoglycaemica, whereas metformin and alpha-glucosidase inhibitors are associated with an increased risk of adverse gastrointestinal effects. The adverse effects of the recently introduced DPP-4 inhibitors are nasopharyngitis and/or upper respiratory tract infections. The literature suggests that oral antidiabetic agents are suitable for older persons; however, underappreciated risk factors, such as cognitive decline in frail individuals, have an important impact on oral antidiabetic treatment options.
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PMID:Antidiabetic oral treatment in older people: does frailty matter? 2013 69

Glucagon-like peptide 1 (GLP-1) reportedly exerts a protective effect against cardiac ischemia. We hypothesized that the alpha-glucosidase inhibitor voglibose, an unabsorbable antidiabetic drug with cardioprotective effects, may act through stimulation of GLP-1 receptors. The results of the present study suggest oral administration of voglibose reduces myocardial infarct size and mitigates cardiac dysfunction in rabbits after 30 minutes of coronary occlusion and 48 hours of reperfusion. Voglibose increased basal and postprandial plasma GLP-1 levels and reduced postprandial plasma glucose levels. The infarct size-reducing effect of voglibose was abolished by treatment with exendin(9-39), wortmannin, Nomega-nitro-L-arginine methylester, or 5-hydroxydecanoate), which inhibit GLP-1 receptors, phosphoinositide 3-kinase, nitric oxide synthase, and K(ATP) channels, respectively. Western blot analysis showed that treatment with voglibose upregulated myocardial levels of phospho-Akt, phosphoendothelial nitric oxide synthase after myocardial infarction. The upregulation of phospho-Akt was inhibited by exendin(9-39) and wortmannin. These findings suggest that voglibose reduces myocardial infarct size through stimulation of GLP-1 receptors, activation of the phosphoinositide 3-kinase-Akt-endothelial nitric oxide synthase pathways, and the opening of mitochondrial K(ATP) channels. These findings may provide new insight into therapeutic strategies for the treatment of patients with coronary artery disease.
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PMID:Antidiabetic drug voglibose is protective against ischemia-reperfusion injury through glucagon-like peptide 1 receptors and the phosphoinositide 3-kinase-Akt-endothelial nitric oxide synthase pathway in rabbits. 2035 64

Insulin replacement therapy in type 1 diabetes mellitus (T1DM) is nonphysiologic. Hyperinsulinemia is generated in the periphery to achieve normal insulin concentrations in the liver. This mismatch results in increased hypoglycemia, increased food intake with weight gain, and insufficient regulation of postprandial glucose excursions. Islet amyloid polypeptide is a hormone synthesized in pancreatic beta cells and cosecreted with insulin. Circulating islet amyloid polypeptide binds to receptors located in the hindbrain and increases satiety, delays gastric emptying and suppresses glucagon secretion. Thus, islet amyloid polypeptide complements the effects of insulin. T1DM is a state of both islet amyloid polypeptide and insulin deficiency. Pramlintide, a synthetic analog of islet amyloid polypeptide, can replace this hormone in patients with T1DM. When administered as adjunctive therapy to such patients treated with insulin, pramlintide decreases food intake and causes weight loss. Pramlintide therapy is also associated with suppression of glucagon secretion and delayed gastric emptying, both of which decrease postprandial plasma glucose excursions. Pramlintide therapy improves glycemic control and lessens weight gain. Agents that decrease intestinal carbohydrate digestion (alpha-glucosidase inhibitors) or decrease insulin resistance (metformin) might be alternative adjunctive therapies in T1DM, though its benefits are marginally supported by clinical data.
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PMID:Adjunct therapy for type 1 diabetes mellitus. 2040 54

The increasing proportions of older persons accounting for global populations, and the implications for increasing rates of chronic diseases such as type 2 diabetes mellitus, continue to be a cause of concern for clinicians. Considering that older persons are a very heterogeneous group of individuals, the management of type 2 diabetes is particularly challenging. Once type 2 diabetes is diagnosed, the principles of it's management are similar to those in younger patients, but with special considerations linked to the increased prevalence ofcomorbidities and relative inability to tolerate adverse effects of medication and hypoglycemia. In addition, there are clinical aspects complicating diabetes care in the elderly including cognitive disorders, physical disability and geriatric syndromes, such as frailty. Available anti-diabetic oral drugs include insulin secretagogues (meglitinides and sulfonylureas), biguanides (metformin), alpha-glucosidase inhibitors, thiazolidinediones (TZDs) and newly introduced glucagon-like peptide-1 (GLP-1) analogues and inhibitors of GLP-1 degrading enzyme dipeptidyl peptidase-4 (DPP-4). Unfortunately, as type 2 diabetes progresses in older persons, polypharmacy intensification is required to reach adequate metabolic control with the risk of adverse effects due to age-related changes in drug metabolism. The present review discusses the European Diabetes Working Party guidelines for type 2 diabetes in older persons with and without frailty and their importance on preventing or at least slowing down diverse aspects of disability.
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PMID:Pathophysiology of diabetes in elderly people. 2051 91

alpha-glucosidase inhibitors (alphaGIs) increase active glucagon-like peptide-1 (GLP-1) and reduce the total glucosedependent insulinotropic polypeptide (GIP) levels, but their ability to prevent diabetes remains uncertain. Dipeptidyl peptidase-4 (DPP-4) inhibitors, such as sitagliptin, increase active GLP-1 and GIP levels and improve hyperglycemia in a glucose-dependent fashion. However, the effectiveness of their combination in subjects with normal glucose tolerance (NGT) or impaired glucose tolerance (IGT) is uncertain. The present study evaluated the effect of miglitol, sitagliptin, and their combination on glucose, insulin and incretin levels in non-diabetic men. Miglitol and sitagliptin were administered according to four different intake schedules (C: no drug, M: miglitol; S: sitagliptin, M+S: miglitol and sitagliptin). The plasma glucose levels were significantly lower for M, S and M+S than for the control. The areas under the curve (AUCs) of the plasma active GLP-1 level in the M, S, and M+S groups were significantly greater than that in the control group. The AUC of the plasma active GLP-1 level was significantly greater for M+S group than for the M and S groups. The AUC of the plasma total GIP level was significantly smaller for M+S group than for the control and M and S groups. The results of our study suggest that miglitol, sitagliptin, or their combination contributes to the prevention of type 2 diabetes.
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PMID:Effects of miglitol, sitagliptin or their combination on plasma glucose, insulin and incretin levels in non-diabetic men. 2051 6

In addition to the hypoglycemia and weight gain associated with many treatments for type 2 diabetes, alpha-glucosidase inhibitors, thiazolidinediones, metformin, sulfonylureas, and the glinides do not address all of the multiple defects existing in the pathophysiology of the disease. Cumulatively, these oral agents address the influx of glucose from the gastrointestinal tract, impaired insulin activity, and acute beta-cell dysfunction in type 2 diabetes; however, until recently, there were no means to deal with the inappropriate hyperglucagonemia or chronic beta-cell-decline characteristic of the disease. The recently introduced incretin-based therapies serve to address some of the challenges associated with traditionally available oral antidiabetic agents. In addition to improving beta-cell function, stimulating insulin secretion, and inhibiting glucagon secretion, these agents reduce appetite, thereby stabilizing weight and/or promoting weight loss in patients with type 2 diabetes. Of the incretin-based therapies, both the dipeptidyl peptidase-4 (DPP-4) inhibitors and the glucagon-like peptide-1 (GLP-1) receptor agonists stimulate insulin secretion and inhibit glucagon secretion. The subsequent review outlines evidence from selected clinical trials of the currently available GLP-1 receptor agonists, exenatide and liraglutide, and DPP-4 inhibitors, sitagliptin and saxagliptin. Earlier and more frequent use of these incretin-based therapies is recommended in the treatment of type 2 diabetes, based on their overall safety and ability to achieve the glycosylated hemoglobin level goal. As such, both the American Diabetes Association and the American Association of Clinical Endocrinologists/American College of Endocrinology (AACE/ACE) treatment algorithms recommend the use of incretin-based therapy in both treatment-naive and previously treated patients. The AACE/ACE guidelines clearly state that these agents should not be limited to third- or fourth-line therapy.
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PMID:Incretin-based therapies in the management of type 2 diabetes: rationale and reality in a managed care setting. 2080 67

Obesity is a well known risk factor for type 2 diabetes mellitus. Individuals with type 2 diabetes mellitus are at risk for weight gain as a result of multiple influences, including sedentary lifestyle, high-calorie diet, diabetes medications, sociocultural factors, chronic medical and psychiatric illnesses, and a dysregulated enteroendocrine axis. Because both diabetes mellitus and obesity predispose patients to abnormal cardiometabolic profiles and increased cardiovascular disease, management of diabetes mellitus should focus on weight management and optimizing cardiometabolic parameters, concomitant with glycemic control. Lifestyle modification incorporating healthy, calorie-appropriate diets and increased physical activity, in addition to metformin, are central components to diabetes management and weight management. These interventions have been shown to improve body weight, glycemic control, and overall cardiometabolic profile. The weight-neutral and weight-losing diabetes medications include metformin, alpha-glucosidase inhibitors, glucagon-like peptide-1 analogs, dipeptidyl peptidase-4 inhibitors, and amylin analogs. It is essential that providers understand the metabolic and weight effects of diabetes medications in order to develop strategies for managing diabetes mellitus while helping patients maintain or lose weight in order to improve their overall health outcomes.
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PMID:Weight management in type 2 diabetes mellitus. 2096 May 55


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