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 124,988 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Type 2 diabetes mellitus is a metabolic disease leading to microvascular and macrovascular complications including coronary artery disease and stroke. Management of diabetes has been challenging, particularly in the presence of the enormous prevalence of obesity. In recent years, various inhibitors of the enzyme dipeptidyl peptidase (DPP)-4 have been developed to treat diabetes. The enzyme DPP-4 cleaves incretins, which, among other functions, stimulate insulin and suppresses glucagon. Inhibition of this enzyme results in an increase in the half-life and the sustained physiologic action of incretins, leading to an improvement in hyperglycemia. One such agent, namely sitagliptin (MK-04,310), has been introduced into the United States market, and another agent, vildagliptin (LAF237), is being used in Europe and elsewhere. This article is intended to evaluate the effectiveness of DPP-4 inhibitors as a therapeutic modality for managing type 2 diabetes. The authors conducted a literature search of various databases to identify the clinical trials involving the DPP inhibitors and concluded that the DPP-4 inhibitors, for example, sitagliptin and vildagliptin, are efficacious for managing diabetes as monotherapy or combination therapy.
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PMID:Dipeptidyl peptidase-4 as a new target of action for type 2 diabetes mellitus: a systematic review. 1892 37

Data from the Centers for Disease Control and Prevention indicate that the prevalence of diabetes is increasing steadily and is coupled with a rise in obesity. Studies such as the Nurses' Health Study show that even slight glucose abnormalities, namely insulin resistance, increase the risk of myocardial infarctions, strokes, other cardiovascular disease, and mortality. Insulin resistance was found to accelerate atherosclerosis, inflammation, the onset of diabetes, cardiovascular disease, obesity, hypertension, chronic kidney disease, and dyslipidemia. Adiponectin was found to have potent antiinflammatory and antiatherosclerotic effects. Similarly, studies indicate that peroxisome proliferators-activated receptor agonists have the potential to treat obesity, diabetes, and atherosclerosis. From a preventive standpoint, it was shown that intensive glucose control reduces long-term cardiovascular risk. This intensive control approach included the use of thiazolidinediones (TZDs; troglitazone, pioglitazone, and rosiglitazone), which were demonstrated to have vascular and nonglycemic effects beyond glucose-lowering. A drawback of using TZDs is peripheral fluid retention. The DREAM study showed that participants with impaired fasting glucose or impaired glucose tolerance who are free from cardiovascular disease benefited significantly from taking 8 mg rosiglitazone per day. The ADOPT study provided evidence that rosiglitazone is more efficient at controlling glycemic loss and maintaining low glycosylated hemoglobin levels than metformin and glyburide. Data from the CHICAGO study indicate that the progression of carotid artery intima-media thickness, a marker of atherosclerosis and a surrogate end point for cardiovascular disease, was slowed more with pioglitazone than glimepiride in a racially diverse population of men and women with diabetes mellitus type 2. Overall, investigators have shifted from a focus on hyperglycemia to a multifactorial approach to risk management in diabetes. This multifactorial approach includes intensive glycemic control, lifestyle intervention, and intensive management of comorbid (dyslipidemia, hypertension, early renal disease) conditions. The implementation of a regular, rigorous exercise and diet program greatly decreased insulin resistance and allowed far more patients to reach their glycosylated hemoglobin goals. Studies with atrovastatin show significant improvement in cardiovascular risk factors in patients with diabetes and hypertension. Short-term studies provide support for the administration of a combination of TZD + sulfonylureas in patients with diabetes mellitus type 2. Likewise, studies have shown that a combination of TZDs + metformin reduced the risk of myocardial infarction. Finally, dipeptidyl peptidase-IV inhibitors and glycolipoprotein-1 analogs show potential for helping prevent the deterioration of glucose metabolism in early diabetes mellitus type 2.
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PMID:Cardiovascular manifestations of insulin resistance. 1911 74

Incretin-based therapies address the progressive nature of type 2 diabetes mellitus, not only by addressing glucose control but also with weight-neutral (i.e., dipeptidyl peptidase-4 inhibitors sitagliptin and vildagliptin) and weight-reducing effects (i.e., glucagonlike peptide-1 [GLP-1] receptor agonists exenatide and liraglutide). Preclinical data suggest that incretin-based therapies may also preserve beta-cell function, holding promise of a truly disease-modifying therapy. This article examines clinical trial data and accepted algorithms with a view toward elucidating the application of these agents in routine clinical practice. We propose a systematic approach to treatment, addressing (1) patient selection, (2) optimal treatment combinations, and (3) timing and guidance for both initiation and intensification of therapy. The GLP-1 receptor agonists, for example, could be particularly beneficial in patients whose weight significantly increases cardiovascular risk. Early use of these agents may be effective in preventing diabetes in those at risk, or in halting or retarding disease progression in patients with frank diabetes. Additional clinical investigation will be required to test such hypotheses. Given the ever-increasing incidence of diabetes worldwide, the link between obesity and the development of type 2 diabetes, and the need for more effective, weight-focused, convenient and sustainable treatments, the data from such studies will be invaluable to further clarify the role of the incretins in the management of patients with type 2 diabetes.
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PMID:Clinical application of incretin-based therapy: therapeutic potential, patient selection and clinical use. 1946 27

Incretin-based therapies address the progressive nature of type 2 diabetes mellitus, not only by addressing glucose control but also with weight-neutral (i.e., dipeptidyl peptidase-4 inhibitors sitagliptin and vildagliptin) and weight-reducing effects (i.e., glucagonlike peptide-1 [GLP-1] receptor agonists exenatide and liraglutide). Preclinical data suggest that incretin-based therapies may also preserve beta-cell function, holding promise of a truly disease-modifying therapy. This article examines clinical trial data and accepted algorithms with a view toward elucidating the application of these agents in routine clinical practice. We propose a systematic approach to treatment, addressing (1) patient selection, (2) optimal treatment combinations, and (3) timing and guidance for both initiation and intensification of therapy. The GLP-1 receptor agonists, for example, could be particularly beneficial in patients whose weight significantly increases cardiovascular risk. Early use of these agents may be effective in preventing diabetes in those at risk, or in halting or retarding disease progression in patients with frank diabetes. Additional clinical investigation will be required to test such hypotheses. Given the ever-increasing incidence of diabetes worldwide, the link between obesity and the development of type 2 diabetes, and the need for more effective, weight-focused, convenient and sustainable treatments, the data from such studies will be invaluable to further clarify the role of the incretins in the management of patients with type 2 diabetes.
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PMID:Clinical application of incretin-based therapy: therapeutic potential, patient selection and clinical use. 1958 Sep 52

The prevalence of type 2 diabetes mellitus, which is directly associated with overweight/obesity and increased cardiovascular disease risk, is projected to continue to increase during the next few decades. Traditionally, treatment has focused primarily on glycemic control, but accumulating evidence suggests that the clinical management of patients with type 2 diabetes requires a more comprehensive approach to minimize associated morbidity and mortality. Because the majority (80%-90%) of patients with type 2 diabetes are overweight or obese, effective glucose control and weight loss are the cornerstones of initial management. Both effective glucose control and therapy to reduce cardiovascular risk factors, including overweight/obesity, are needed to prevent the complications of type 2 diabetes. Most conventional antidiabetes agents, including sulfonylureas, thiazolidinediones, and insulin, improve glycemic control but are associated with weight gain or, as with metformin, are weight-neutral or weight-sparing. The incretin-based therapies, such as the glucagon-like peptide-1 (GLP-1) receptor agonists and the dipeptidyl peptidase-4 inhibitors, have been shown to be safe and effective in lowering glucose while eliciting favorable effects on weight (ie, weight-reducing and weight-neutral, respectively). The effects of these agents on other parameters of cardiovascular risk are also being studied. Advances in GLP-1 receptor agonist therapy include development of agents with longer durations of activity allowing for more convenient dosing of therapies for patients with type 2 diabetes, which should lead to better patient compliance, adherence, and overall clinical outcomes.
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PMID:Beyond glycemic control: treating the entire type 2 diabetes disorder. 1982 Feb 76

Patients with type 2 diabetes, approximately 85% of whom are overweight or obese, often have an increased incidence of cardiovascular disease (CVD) risk factors such as hypertension and dyslipidemia. Both type 2 diabetes and obesity are independent risk factors for CVD. Unfortunately, many therapies aimed at maintaining and improving glucose control are associated with weight gain. Among the older antidiabetes agents, most, including the insulin secretagogues and sensitizers, can lead to weight gain, except for metformin, which is weight-neutral. Among the newer agents, the dipeptidyl peptidase-4 inhibitors generally are weight-neutral in addition to lowering glucose, while the glucagon-like peptide-1 receptor agonists lead to weight reduction. Patients with type 2 diabetes are at an increased risk for both diabetes- and CV-related outcomes, and weight reduction is an important component of diabetes management. Weight gain in patients with type 2 diabetes can contribute to patient frustration and may negatively impact their compliance to therapeutic regimens. The selection of antidiabetes agents that not only improve glucose control but reduce or have a neutral effect on weight with beneficial effects on lipids are ideal options for managing patients with type 2 diabetes.
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PMID:The impact of weight gain on motivation, compliance, and metabolic control in patients with type 2 diabetes mellitus. 1982 Feb 78

Type 2 diabetes mellitus (T2DM) is intrinsically connected to overweight and obesity. It is a complex metabolic disorder that predisposes patients to, and is associated with, cardiovascular disease. In addition to the triumvirate of core defects associated with T2DM (involvement of the pancreatic beta cell, the muscle, and the liver), other mechanisms including hyperglucagonemia, accelerated gastric emptying, and incretin deficiency/resistance are also involved. This has led to the development of incretinbased therapies, such as glucagon-like peptide-1 (GLP-1) receptor agonists and dipeptidyl peptidase-4 (DPP-4) inhibitors. These newer therapies have beneficial effects on glycosylated hemoglobin A1c (HbA1c) levels, weight, and pancreatic beta-cell function.
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PMID:Advances in therapy for type 2 diabetes: GLP-1 receptor agonists and DPP-4 inhibitors. 1995 1

Despite advances in diagnosis and treatment, type 2 diabetes mellitus (T2DM), overweight/obesity, cardiovascular disease, and their sequelae are major public health burdens worldwide. The understanding of the pathophysiology of T2DM has traditionally emphasized decreased insulin secretion and increased insulin resistance, but evolving concepts now include the role of incretin hormones in disease progression. A comprehensive approach to managing patients with T2DM requires targeting both the fundamental defects of the disease and its comorbidities, including the sequelae of nonoptimal control of blood glucose, blood pressure, body weight, and lipids. Newer antidiabetes agents, such as the glucagon-like peptide-1 (GLP-1) receptor agonists and the dipeptidyl peptidase-4 (DPP-4) inhibitors, address fundamental defects related to glycemic control in T2DM and may have potential effects on other markers of cardiovascular risk. A redefinition of treatment success may be warranted as more data become available.
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PMID:Redefining treatment success in type 2 diabetes mellitus: Comprehensive targeting of core defects. 1995 2

GLP-1 (9-36)amide is the cleavage product of GLP-1(7-36) amide, formed by the action of diaminopeptidyl peptidase-4 (Dpp4), and is the major circulating form in plasma. Whereas GLP-1(7-36)amide stimulates glucose-dependent insulin secretion, GLP-1(9-36)amide has only weak partial insulinotropic agonist activities on the GLP-1 receptor, but suppresses hepatic glucose production, exerts antioxidant cardioprotective actions and reduces oxidative stress in vasculature tissues. These insulin-like activities suggest a role for GLP-1 (9-36)amide in the modulation of mitochondrial functions by mechanisms independent of the GLP-1 receptor. In this paper, we discuss the current literature suggesting that GLP-1(9-36)amide is an active peptide with important insulin-like actions. These findings have implications in nutrient assimilation, energy homeostasis, obesity, and the use of Dpp4 inhibitors for the treatment of diabetes.
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PMID:Insulin-like actions of glucagon-like peptide-1: a dual receptor hypothesis. 2001 25

Cathepsin S is a lysosomal cysteine peptidase of the papain superfamily which is implicated in physiological and pathological states. The enzyme is highly expressed in antigen presenting cells and is thought to play an important role in the processing of the major histocompatibility complex (MHC) class II-associated invariant chain. In pathological processes, cathepsin S is associated with Alzheimer's disease, atherosclerosis and obesity and can be regarded as a potential target in related disorders. However, due to the broad substrate specificities of the lysosomal cathepsins, the specific detection of cathepsin S is difficult when other cathepsins are present. In an attempt to distinguish cathepsin S from other cathepsins we synthesized and tested fluorescence resonance energy transfer (FRET) peptides derived from two of its putative natural substrates, namely insulin beta-chain and class II-associated invariant chain (CLIP). The influence of ionic strength on the catalytic activity and the enzyme stability in neutral pH was also analyzed. Using data gathered from our study we developed a selective substrate for cathepsin S and establish the assay conditions to differentiate the enzyme from cathepsins L, B, V and K. The peptide Abz-LEQ-EDDnp (Abz=ortho-aminobenzoic acid; EDDnp=N-[2,4-dinitrophenyl]ethylenediamine]) in 50mM sodium phosphate buffer, pH 7.4, containing 1M NaCl was hydrolyzed by cathepsin S with k(cat)/K(m) value of 3585mM(-1)s(-1), and was resistant to hydrolysis by cathepsins L, V, K and B. Thus, we developed a sensitive and selective cathepsins S substrate that permits continuous measurement of the enzymatic activity even in crude tissue extracts.
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PMID:Improvement of cathepsin S detection using a designed FRET peptide based on putative natural substrates. 2004 15


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