Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0011860 (type 2 diabetes)
 57,723 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Efforts to further elucidate structure-activity relationships (SAR) within our previously disclosed series of beta-quaternary amino acid linked l-cis-4,5-methanoprolinenitrile dipeptidyl peptidase IV (DPP-IV) inhibitors led to the investigation of vinyl substitution at the beta-position of alpha-cycloalkyl-substituted glycines. Despite poor systemic exposure, vinyl-substituted compounds showed extended duration of action in acute rat ex vivo plasma DPP-IV inhibition models. Oxygenated putative metabolites were prepared and were shown to exhibit the potency and extended duration of action of their precursors in efficacy models measuring glucose clearance in Zucker(fa/fa) rats. Extension of this approach to adamantylglycine-derived inhibitors led to the discovery of highly potent inhibitors, including hydroxyadamantyl compound BMS-477118 (saxagliptin), a highly efficacious, stable, and long-acting DPP-IV inhibitor, which is currently undergoing clinical trials for treatment of type 2 diabetes.
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PMID:Discovery and preclinical profile of Saxagliptin (BMS-477118): a highly potent, long-acting, orally active dipeptidyl peptidase IV inhibitor for the treatment of type 2 diabetes. 1603 81

Glucagon-like peptide-1 (GLP-1) is an important insulinotropic hormone with potential in the treatment of type 2 diabetes. However, the short biological half-life of the peptide after cleavage by dipeptidylpeptidase IV (DPP IV) is a major limitation. Inhibition of DPP IV activity and the development of resistant GLP-1 analogues is the subject of ongoing research. In this study, we determined cell growth, insulin content, insulin accumulation and insulin secretory function of a insulin-secreting cell line cultured for 3 days with either GLP-1, GLP-1 plus the DPP IV inhibitor diprotin A (DPA) or stable N-acetyl-GLP-1. Native GLP-1 was rapidly degraded by DPP IV during culture with accumulation of the inactive metabolite GLP-1(9-36)amide. Inclusion of DPA or use of the DPP IV-resistant analogue, N-acetyl-GLP-1, improved cellular function compared to exposure to GLP-1 alone. Most notably, basal and accumulated insulin secretion was enhanced, and glucose responsiveness was improved. However, prolonged GLP-1 treatment resulted in GLP-1 receptor desensitization regardless of DPP IV status. The results indicate that prevention of DPP IV action is necessary for beneficial effects of GLP-1 on pancreatic beta cells and that prolonged exposure to GLP-1(9-36)amide may be detrimental to insulin secretory function. These observations also support the ongoing development of DPP-IV-resistant forms of GLP-1, such as N-acetyl-GLP-1.
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PMID:Function of a long-term, GLP-1-treated, insulin-secreting cell line is improved by preventing DPP IV-mediated degradation of GLP-1. 1605 Sep 49

Dipeptidyl peptidase-IV (DPP-IV) is involved in the inactivation of glucagon-like peptide-1 (GLP-1), a potent insulinotropic peptide. Thus, DPP-IV inhibition can be an effective approach to treat type 2 diabetes mellitus by potentiating insulin secretion. This study describes the biological effects of a new DPP-IV inhibitor, KR-62436 (6-{2-[2-(5-cyano-4,5-dihydropyrazol-1-yl)-2-oxoethylamino]ethylamino}nicotinonitrile) in vitro and in vivo. KR-62436 inhibited rat plasma DPP-IV, porcine kidney DPP-IV as well as human DPP-IV (Caco-2) with IC50 values of 0.78, 0.49, 0.14 microM, respectively. In addition, the compound (10 microM) almost completely inhibited DPP-IV-mediated degradation of GLP-1 in vitro. KR-62436 inhibited the enzyme in a competitive manner, and exhibited selectivity against several proteases including proline-specific proteases. In vivo efficacy of the compound was examined by using normal C57BL/6J mice and ob/ob mice, a type 2 diabetes animal model. Administration of KR-62436 to C57BL/6J mice either orally or subcutaneously resulted in the suppression of plasma DPP-IV activity, increase in intact GLP-1 and insulin levels in plasma. Furthermore, the plasma glucose concentrations during oral glucose tolerance test (OGTT) were reduced upon oral administration of KR-62436. This study demonstrates that KR-62436 could be a good lead compound for further development as a new anti-diabetic agent.
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PMID:KR-62436, 6-{2-[2-(5-cyano-4,5-dihydropyrazol-1-yl)-2-oxoethylamino]ethylamino}nicotinonitrile, is a novel dipeptidyl peptidase-IV (DPP-IV) inhibitor with anti-hyperglycemic activity. 1610 24

Incretin hormones are defined as intestinal hormones released in response to nutrient ingestion, which potentiate the glucose-induced insulin response. In humans, the incretin effect is mainly caused by two peptide hormones, glucose-dependent insulin releasing polypeptide GIP, and glucagon-like peptide-1 GLP-1. GIP is secreted by K cells from the upper small intestine while GLP-1 is mainly produced in the enteroendocrine L cells located in the distal intestine. Their effect is mediated through their binding with specific receptors, though part of their biological action may also involve neural modulation. GIP and GLP-1 are both rapidly degraded into inactive metabolites by the enzyme dipeptidyl-peptidase-IV (DPP-IV). In addition to its effects on insulin secretion, GLP-1 exerts other significant actions, including stimulation of insulin biosynthesis, inhibition of glucagon secretion, inhibition of gastric emptying and acid secretion, reduction of food intake, and trophic effects on the pancreas. As the insulinotropic action of GLP-1 is preserved in type 2 diabetic patients, this peptide was a candidate as a therapeutic agent for this disease. A number of pharmacological strategies have been developed to provide continuous delivery of GLP-1 and to prevent degradation of GLP-1, including continuous administration of GLP-1, DPP-IV inhibitors and DPP-IV resistant GLP-1 analogues. Recent results of the most clinically advanced incretin mimetics confirmed their efficacy to improve glycemic control in type 2 diabetic patients. Further results are expected to confirm the efficacy/safety profile of these compounds, and to find their place in the therapeutic strategy of type 2 diabetes.
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PMID:Biological actions of the incretins GIP and GLP-1 and therapeutic perspectives in patients with type 2 diabetes. 1614 14

Prevalence of type 2 diabetes has increased dramatically in the last decades. Current medicines are not yet capable to efficiently prevent or reverse progression of the disease and its associated comorbidities. As a consequence, there is a great need for novel antidiabetic drugs. Treatments of type 2 diabetes that are based on enhanced and sustained action of insulinotropic incretin hormones such as GLP-1 have received much attention in the past years. Treatment strategies include administration of: 1) GLP-1 analogues that are resistant to degradation by the serine protease DPP-IV, and 2) small molecule DPP-IV inhibitors that are able to provide sustained action of endogenous GLP-1, again by preventing its degradation. This review summarizes recent research results for the second approach. It briefly touches upon the advantages that treatment of type 2 diabetes with DPP-IV inhibitors may offer over current medications. In the main section, several important structural classes of DPP-IV inhibitors are described and compared based on literature data. Specific attention is given to the analysis of several X-ray structures of enzyme-inhibitor co-crystals. Finally, as clinical data are steadily emerging for some of the most advanced development candidates, the last section of this review is providing a brief overview of some efficacy data from recent clinical studies with DPP-IV inhibitors.
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PMID:Inhibitors of dipeptidyl peptidase IV--recent advances and structural views. 1637 46

The incretin hormones are intestinal polypeptides that enhance postprandial insulin secretion. Gastric inhibitory polypeptide (GIP) was initially thought to regulate gastric acid secretion, whereas glucagon-like peptide-1 (GLP-1) was discovered as a result of a systematic search for intestinal insulinotropic products of proglucagon gene expression. The incretin effect is markedly impaired or absent in patients with type 2 diabetes because of decreased secretion of GLP-1 and a loss of the insulinotropic effects of GIP. Metabolic control can be restored or greatly improved by administration of exogenous GLP-1, but this peptide is almost immediately degraded by dipeptidyl peptidase IV (DPP-IV), and therefore has little clinical value. DPP-IV-resistant analogues (incretin mimetics) have been identified or developed, and inhibitors of DPP-IV have also proved effective in protecting endogenous GLP-1 (and GIP) from degradation. Both principles have been tested in clinical studies. The incretin mimetics, administered by sc injection, have demonstrated lasting improvement in HbA(1)c in patients insufficiently treated with conventional oral therapy, and their use has been associated with steady weight loss for up to 2 years. The DPP-IV inhibitors, given once or twice daily by mouth, also appear to provide lasting improvement in HbA(1)c, but are weight-neutral. The first incretin mimetic has reached the market in the US, and applications for approval of the first inhibitors are expected to be filed early in 2006.
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PMID:Glucagon-like peptide-1: from extract to agent. The Claude Bernard Lecture, 2005. 1641 46

The metabolic syndrome, a cluster of metabolic abnormalities linked to insulin resistance, has attracted much interest as a risk factor for cardiovascular disease and type 2 diabetes. Hyperinsulinemia is also a postulated biological risk factor for colorectal carcinogenesis. We therefore here examined the relation between the metabolic syndrome and colorectal adenoma development. The study subjects were 756 cases of colorectal adenoma and 1751 controls with no polyps who underwent total colonoscopy during the period January 1995 to March 2002 at two Self Defense Forces (SDF) hospitals in Japan. The metabolic syndrome was defined with reference to abdominal obesity in combination with any two of the following conditions: elevated triglycerides (150 mg/dL); lowered HDL cholesterol (<40 mg/dL); elevated blood pressure (systolic blood pressure 130 mmHg and/or diastolic blood pressure 85 mmHg); and raised fasting glucose (110 mg/dL). Abdominal obesity was defined as a waist circumference of 85 cm or more(Japanese criterion) or 90 cm (Asian criterion). Statistical adjustment was made for age, hospital, and rank in the SDF. The metabolic syndrome was found to be associated with a moderately increased risk of colorectal adenomas whether either of the Japanese and Asian criteria was used; adjusted odds ratios with the Japanese and Asian criteria were 1.38 (95% confidence interval [CI] 1.13-1.69) and 1.48 (95% CI 1.13-1.93), respectively. Increased risk was more evident for proximal than distal colon or rectal adenomas, and was almost exclusively observed for large lesions (5 mm in diameter). Thus the metabolic syndrome appears to be an important entity with regard to the prevention of colorectal cancer, as well as cardiovascular disease and type 2 diabetes.
Asian Pac J Cancer Prev
PMID:The metabolic syndrome is associated with increased risk of colorectal adenoma development: the Self-Defense Forces health study. 1643 97

Obesity is a worldwide problem which impacts the risk and prognosis of some of the more common forms of cancer, including breast cancer in post-menopausal women. As the basis for understanding the potential mechanisms of obesity and cancer relationship has advanced, a number of new hypotheses have emerged. The adipocytokines are a complex group of biologically active polypeptides. Leptin is a growth hormone, secreted by adipose tissue, whose levels are normally elevated in obese individuals and may have a promoting effect on carcinogenesis and metastasis of breast cancer, possibly in an autocrine manner. Leptin interferes with the insulin signaling pathway and in type 2 diabetes plasma leptin levels are found to be correlated with the degree of insulin resistance, a relationship independent of body mass. This relationship might provide a mechanistic explanation for promotion potential.
Asian Pac J Cancer Prev
PMID:Obesity, breast cancer and the role of adipocytokines. 1643 10

Type 2 diabetes mellitus is a major and growing health problem throughout the world. Current treatment approaches include diet, exercise, and a variety of pharmacological agents including insulin, biguanides, sulfonylureas and thiazolidinediones. New therapies are still needed to control metabolic abnormalities, and also to preserve beta-cell mass and to prevent loss of beta-cell function. Glucagon-like peptide 1 (GLP-1) is a drug candidate which potentially fulfils these conditions. GLP-1 is an incretin hormone secreted by intestinal L-cells in response to meal ingestion is a novel pharmacological target with multiple antihyperglycemic actions. GLP-1 glucoregulatory actions include glucose-dependent enhancement of insulin secretion, inhibition of glucagon secretion, slowing of gastric emptying and reduction of food intake. GLP-1 is rapidly inactivated by amino peptidase, dipeptidyl peptidase IV (DPP-IV) and the utility of DPP-IV inhibitors are also under investigation. There is a recent upsurge in the development of GLP-1 mimetics and DPP-IV inhibitors as potential therapy for type 2 diabetes. However, both the strategies are having their own advantages and limitations. The present review summarizes the concepts of GLP-1 based therapy for type 2 diabetes and the current preclinical and clinical development in GLP-1 mimetics and DPP-IV inhibitors. Further, the potential advantages and the limitations of both the strategies are discussed.
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PMID:GLP-1 based therapy for type 2 diabetes. 1648 79

This study determined the influence of light curing protocols and matrix type on the margin quality and marginal seal of Class II resin-based composite restorations. In extracted human molars, box-shaped MOD cavities with 1 mm wide interproximal bevels were prepared with cervical margins located at least 1 mm coronal to the cemento-enamel junction. The prepared teeth were mounted in a jig featuring artificial training teeth that served as adjacent teeth. A contoured sectional metal matrix band was placed in one interproximal area, and a section of a contoured transparent matrix band was placed in the opposite interproximal area. Both were kept in position using wooden wedges. After etching (35% H3PO4 gel) and the application of a three-step etch & rinse dentin adhesive (Optibond FL, Kerr), a thin layer of flowable resin-based composite (Revolution, Kerr) was applied to the interproximal margins. The cavities were restored by placing one horizontal and two oblique increments of a fine hybrid resin-based composite (Herculite XRV, Kerr). The curing protocols included one standard halogen protocol (Elipar Trilight, 3M ESPE, 40 seconds @ 800 mW/cm2), 3 halogen soft-start protocols (Step: Elipar HiLight, 3M ESPE; 10 seconds @ 150 mW/cm2, 30 seconds @ 850 mW/cm2; Ramp: Elipar TriLight, 3M ESPE, 5 seconds @ 100 mW/cm2, exponential increase for 10 seconds, 25 seconds @ 800 mW/cm2; Pulse delay: VIP Light, BISCO, cervical increment: 10 seconds @ 500 mW/cm2, occlusal increments: 3 seconds @ 200 mW/cm2, final irradiation after a 5 minute interval: 30 seconds @ mW/cm2) and 2 plasma arc high intensity protocols (PAC: Lightning Cure, ADT, 10 seconds @ 1400 mW/cm2; APO: Apollo 95E, DMDS, 2 x 3 seconds @ 1570 mW/cm2). The restored teeth were stored in 0.9% saline at 37 degrees C for 4 weeks and submitted to thermal cycling [TC] with 2500 cycles between 5 degrees C and 55 degrees C after 2 weeks. The margin quality before and after TC was analyzed in SEM using the replica technique, and the marginal seal was determined using the dye penetration test (50% AgNO3, 2 hours) at the end of the study. The matrix type did not significantly influence the quality and seal of the respective margins. For the complete restoration margin, one of the high intensity protocols (APO) produced a higher percentage of "continuous margin" compared to pulse delay irradiation after TC and lower percentages of "marginal opening" compared to halogen standard irradiation before and after TC. Halogen step irradiation produced a superior marginal seal compared to pulse delay curing at the occlusal margins; equivalent results were observed for all curing modes at the cervical margins. Neither a general advantage of soft-start irradiation nor a general disadvantage of high intensity curing was confirmed.
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PMID:Influence of curing methods and matrix type on the marginal seal of class II resin-based composite restorations in vitro. 1653


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