Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0011849 (diabetes)
 277,896 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Inhibitors of the protease dipeptidyl peptidase IV (DPP-IV) are promising new drugs for the treatment of type 2 diabetes. They are thought to act by inhibiting the breakdown of glucagon-like peptide-1 and, thereby, selectively enhancing insulin release under conditions when it is physiologically required. These drugs are selective for DPP-IV, but the enzyme itself has a broad range of substrates other than glucagon-like peptide-1. Other high affinity substrates of DPP-IV including peptide YY may also play a role in the regulation of energy homeostasis. Moreover, DPP-IV is also known as CD26 and considered to be a moonlighting protein because it has a wide range of other functions unrelated to energy homeostasis, e.g. in immunity. The potential role of DPP-IV inhibition on substrates other than glucagon-like peptide-1 in diabetes patients remains to be elucidated.
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PMID:Dipeptidyl peptidase IV inhibitors in diabetes: more than inhibition of glucagon-like peptide-1 metabolism? 1839 99

Sitagliptin (brand name Januvia) the first of a new class of oral agents, the DPP4 inhibitors, which lower blood glucose in type 2 diabetes has recently been launched in UK. Another DPP4 inhibitor vildagliptin is due to be launched soon, and there are several others in the pipeline. This article gives an overview of this new class of medications.
Prim Care Diabetes 2007 Dec
PMID:New treatments for type 2 diabetes--the DPP4 inhibitors. 1863 49

This review tries to delineate how to insert the GLP-1 based agents, DPP4-inhibitors (sitagliptin and vildagliptin) and GLP-1 analogues (exenatide and liraglutide), in the guidelines and the daily practice for the management of type 2 diabetes (T2DM). Orally administered DPP-4 inhibitors reduce HbA(1c) by 0.5-1.1%, without hypoglycaemic events and no weight gain. The subcutaneous injected GLP-1 analogues show larger reductions in HbA(1c) by 0.8-1.7% and a weight loss (1.75-3.8 kg) with most gastrointestinal common adverse events contributing to a significant treatment interruption. Regarding the efficacy, the cost and the safety of these drugs they will no challenge the use of metformin as the initial therapy of T2DM. In patients'not tolerating metformin or in older patients, DPP-4 inhibitors seem to be an excellent alternative monotherapy. Several studies argue in favour of the use of DPP-4 inhibitors in combination with metformin as a promising second line treatment. This combination offers advantages when compared to others currently used, particularly if one considers the more stringent guidelines with a higher risk of hypoglycaemic events in patient receiving sulfonylureas and mild hyperglycaemia or weight gain with thiazolidinedione (TZD). Oral triple therapy, metformin + TZD + incretin-based drug, has several theoretical advantages but is not supported by any published trial. Finally, obtaining the acceptance of injections once to twice daily vs. oral administration of OADs will probably remain difficult during the first years of treatment in many patients. Nevertheless a long-acting release exenatide formulation (i.e. once weekly), for subcutaneous injection in patients with type 2 diabetes under development shows promising preliminary results. If confirmed, the use of this new class of drugs should be largely developed from monotherapy to combinations (bitherapy or tritherapy), and even instead of insulin or in association with insulin. The long-term effect of GLP-1 based agents on glycaemic control has not yet been established, and their potential impact on beta-cell function in humans remains an area of active investigation. So, further studies are required and will allow progressively determining the use of incretin-based agents in T2DM treatment strategy. Their efficacy, safety and their cost vs. older strategies, will be really evaluated by physicians in the real daily practice and by large and long term systematic surveys, as recently shown in other therapeutic fields.
Diabetes Metab 2008 Feb
PMID:DPP-4 inhibitors and GLP-1 analogues: for whom? Which place for incretins in the management of type 2 diabetic patients? 1864 May 91

With vildagliptin and sitagliptin on the market for the treatment of type 2 diabetes, dipeptidyl peptidase 4 (DPP4, EC 3.4.14.5) research has entered a new era. Scientists aim to uncover the broader pharmacological profile of DPP4 inhibitors and search for therapeutic opportunities outside diabetes. During the pre-clinical and clinical evaluation of vildagliptin and sitagliptin, there has been a growing awareness of the presence of other DPP4-like peptidases in various cells and tissues. This fuelled the development of more inhibitors with defined selectivity for DPP2, 8 and 9 that were used to investigate the expression, distribution and regulation of these peptidases. In turn, these studies increased the insights in the role of DPP4 in the body's response to various insults.
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PMID:DPP4 inhibitors for diabetes--what next? 1875 55

We examined the role of dipeptidyl peptidase IV (DPP4) in the development of diabetes, dyslipidaemia and renal dysfunction induced by streptozotocin (STZ). F344/DuCrlCrlj rats, which lack DPP4 activity, and wild-type rats were treated with STZ. Plasma DPP4 activity and biochemical parameters were measured until 42 days after STZ treatment. At the end of the experiment, renal function and DPP4 expressions of the kidney, liver, pancreas and adipose tissues were determined. Increases in blood glucose, cholesterol and triglycerides were evoked by STZ in both rat strains; however, the onset of hyperglycaemia was delayed in DPP4-deficient rats as compared with wild-type rats. By contrast, more severe dyslipidaemia was observed in DPP4-deficient rats than in wild-type rats after STZ treatment. Plasma DPP4 activity increased progressively with time after STZ treatment in wild-type rats. The kidney of wild-type rats showed decreased DPP4 activity with increased Dpp4 mRNA after STZ treatment. In addition, kidney weight, serum creatinine and excreted amounts of urinary protein, glucose and DPP4 enzyme were enhanced by STZ. DPP4-deficient rats showed increased serum creatinine in accordance with decreased creatinine clearance as compared with wild-type rats after STZ treatment. In conclusion, plasma DPP4 activity increased after STZ treatment, positively correlating to blood glucose. DPP4-deficient rats were resistant to developing diabetes, while susceptible to dyslipidaemia and reduction of glomerular filtration rate by STZ. DPP4 activation may be responsible for hyperglycaemia, lipid metabolism and preservation of renal function.
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PMID:Interrelationship of dipeptidyl peptidase IV (DPP4) with the development of diabetes, dyslipidaemia and nephropathy: a streptozotocin-induced model using wild-type and DPP4-deficient rats. 1893 Oct 22

As CD26 (dipeptidyl peptidase 4/DPP4) rapidly truncates incretins N-terminally, including glucagon-like peptide-1, DPP4-inhibitors have been developed for treatment of diabetes type 2. To some extent this is surprising, as CD26/DPP4 is also deeply involved in immune regulation. Long-term pharmacological studies are hampered by off-target inhibition of DPP4-homologues. Therefore, we studied the effects of genetic CD26/DPP4-deficiency by investigating blood, spleen and thymus leucocyte subpopulations of wild-type and CD26-deficient F344-rats at different ages. In young animals at 1 and 3 months of age, there were no differences in leucocyte subsets, while in older animals the T cell composition was changed significantly. From the age of 6 months onwards, reduced numbers of recent thymic emigrants and memory T cells, and consequently an increased amount of naive T cells were observed in CD26-deficient rats. In addition, the architecture of the thymus was altered, as observed by a reduced density of lymphocytes in the medulla. Furthermore, the number of proliferating cells in the thymus was decreased in CD26-deficient rats at a higher age. Moreover, CD26-deficiency resulted in markedly reduced numbers of B cells in later life. Additionally, an age- but not CD26-dependent increase of regulatory T cells and a decrease of natural killer cell numbers were detected in the blood and spleen. Our findings indicate an important role of CD26 in maintaining lymphocyte composition, memory T cell generation and thymic emigration patterns during immunosenescence, with possible implications for using DPP4-inhibitors.
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PMID:CD26/dipeptidyl peptidase 4-deficiency alters thymic emigration patterns and leukcocyte subsets in F344-rats age-dependently. 1905 85

Type 1 diabetes was induced in Wistar rats by injection of streptozotocin (STZ). Changes in the myocardial capillary network were examined using the double-staining enzymatic method for alkaline phosphatase (AP) and dipeptidylpeptidase IV (DPPIV) This method allows the identification of the arteriolar (AP-containing) and the venular (DPPIV-containing) portions of the capillary network. In addition, blood plasma was analysed. The AP- and AP/DPPIV-containing capillary portions increased significantly, accompanied by a decrease in the DPPIV-containing portions in 60 days. A significant increase in AP was observed in the plasma. The capillary domain areas of each capillary portion were larger in the STZ-injected group than in the controls. It appears that oxygen transport to the subendocardial myocardial tissues may be decreased in the STZ group. In rats fed with Saji-supplemented chow there was a decrease in plasma AP, with increases in hemoglobin, hematocrit and vitamin C, suggesting a partial improvement of metabolic function and oxygen supply in these diabetic Wistar rats.
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PMID:Myocardial capillary net and blood constituents in streptozotocin (STZ)-induced diabetic rats. 1922 70

Curcumin, the bioactive component of curry spice turmeric, and its related structures possess potent anti-oxidant and anti-inflammatory properties. Several lines of evidence suggest that curcumin may play a beneficial role in animal models of diabetes, both by lowering blood glucose levels and by ameliorating the long-term complications of diabetes. However, current understanding of the mechanism of curcumin action is rudimentary and is limited to its anti-oxidant and anti-inflammatory effects. In this study we examine potential anti-diabetic mechanisms of curcumin, curcumin C3 complex), and tetrahydrocurcuminoids (THC). Curcuminoids did not exert a direct effect on receptor tyrosine kinase activity, 2-deoxy glucose uptake in L6-GLUT4myc cells, or intestinal glucose metabolism measured by DPP4/alpha-glucosidase inhibitory activity. We demonstrate that curcuminoids effectively suppressed dexamethasone-induced phosphoenol pyruvate carboxy kinase (PEPCK) and glucose6-phosphatase (G6Pase) in H4IIE rat hepatoma and Hep3B human hepatoma cells. Furthermore, curcuminoids increased the phosphorylation of AMP-activated protein kinase (AMPK) and its downstream target acetyl-CoA carboxylase (ACC) in H4IIE and Hep3B cells with 400 times (curcumin) to 100,000 times (THC) the potency of metformin. These results suggest that AMPK mediated suppression of hepatic gluconeogenesis may be a potential mechanism mediating glucose-lowering effects of curcuminoids.
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PMID:Curcumin activates AMPK and suppresses gluconeogenic gene expression in hepatoma cells. 1966 95

Syzigium cumini (L.) Skeels from the Myrtaceae family is among the most common medicinal plants used to treat diabetes in Brazil. Leaves, fruits, and barks of S. cumini have been used for their hypoglycemic activity. Adenosine deaminase (ADA) is an important enzyme that plays a relevant role in purine and DNA metabolism, immune responses, and peptidase activity. ADA is suggested to be an important enzyme for modulating the bioactivity of insulin, but its clinical significance in diabetes mellitus (DM) has not yet been proven. In this study, we examined the effect of aqueous leaf extracts of S. cumini (L.) (ASC) on ADA activity of hyperglycemic subjects and the activity of total ADA, and its isoenzymes in serum and erythrocytes. The present study indicates that: (i) the ADA activity in hyperglycemic serum was higher than normoglycemic serum and ADA activity was higher when the blood glucose level was more elevated; (ii) ASC (60-1000 microg/mL) in vitro caused a concentration-dependent inhibition of total ADA activity and a decrease in the blood glucose level in serum; (iii) ADA1 and 2 were reduced both in erythrocytes and in hyperglycemic serum. These results suggest that the decrease of ADA activity provoked by ASC may contribute to control adenosine levels and the antioxidant defense system of red cells and could be related to the complex ADA/DPP-IV-CD26 and the properties of dipeptidyl peptidase IV (DPP-IV) inhibitors which serve as important regulators of blood glucose.
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PMID:Syzygium cumini inhibits adenosine deaminase activity and reduces glucose levels in hyperglycemic patients. 1970 27

Dipeptidyl peptidase IV (DPP4) inhibitors have recently become widely used for treating type 2 diabetes, but in meta-analyses are associated with a mildly increased risk of all-cause infections. CD26 is a cell-surface form of DPP4 which can costimulate T-cell proliferation, raising the possibility that DPP4 inhibitors might adversely affect immune function. To address this issue in an observational study, two groups of 20 subjects each were recruited from a private endocrinology practice; one group consisted of type 2 diabetes patients treated for at least 6 months with the DPP4 inhibitor, sitagliptin, whereas patients in the other group had never been treated with this agent. The groups were similar with regard to sex and racial composition, body mass index, hemoglobin A(1c), and use of other medications for diabetes, but the sitagliptin group was slightly older. A blood sample from each patient was analyzed for CD4+ T-cell activation in response to phytohemagglutinin using adenosine triphosphate (ATP)-stimulated bioluminescence. There was not a significant difference in T-cell activation between the treatment groups (median, 419 and 481 ng/ml ATP in the groups that were and were not treated with sitagliptin, respectively). Thus the observed increased rate of infection in diabetic patients treated with sitagliptin cannot be explained by a major effect on T-cell activation. Randomized studies, preferably using several assays of immune function, should be performed to confirm and extend these findings.
J Diabetes Complications
PMID:Sitagliptin treatment of patients with type 2 diabetes does not affect CD4+ T-cell activation. 1985 74


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