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)

It has been known for at least one century that agents secreted from the intestine during meal absorption regulates glucose assimilation. Extensive research during the past three decades has identified two gut hormones, glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic peptide (GIP, also known as gastric inhibitory polypeptide) that are important in postprandial glucose metabolism. Both peptides are incretins; they are secreted during carbohydrate absorption and increase insulin secretion. Since they are potent insulin secretagogues, GIP and GLP-1 have received considerable attention as potential diabetes therapeutics. However, only GLP-1 exerts insulinotropic properties when administered to patients with Type 2 diabetes. Both GLP-1 and GIP are rapidly inactivated in the circulation by the enzyme dipeptidyl peptidase IV (DPP-IV). The application of GLP-1 into clinical practice has been delayed due to the need to develop compounds that overcome this rapid inactivation. Two approaches have been taken to utilise the insulinotropic and glucose-lowering actions of GLP-1 as an antidiabetic agent: the development of DPP-IV-resistant analogues and the inhibition of DPP-IV. This review focuses on the physiology of GLP-1 and GIP and the advances that have been made thus far in developing treatments based on these physiological incretins for Type 2 diabetes.
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PMID:Gut peptides in the treatment of diabetes mellitus. 1501 38

DPP8 is a new member of the prolyl dipeptidases, many of which have important biological functions in vivo. DPP8 catalyzes the cleavage at the carboxyl side of the proline residue at the penultimate position. To study its structure and biochemical properties, we have overexpressed the human DPP8 protein in baculovirus infected Sf9 cells. The protein is soluble and can be purified to homogeneity. Using the chromogenic H-Gly-Pro-pNA as the substrate, a kinetic study shows that purified DPP8 is active and has a similar kcat value as that of DPP-IV, a prolyl dipeptidase that is a drug target for type II diabetes. The kinetic constants of DPP8 are also determined for other chromogenic substrates, and the results indicate that DPP8 has substrate preference at both the P1 and P2 sites. The expression system provides means of better understanding the structure, catalytic mechanism, and biological function of DPP8 protein.
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PMID:Purification and characterization of human prolyl dipeptidase DPP8 in Sf9 insect cells. 1503 77

Many epidemiological studies have provided support for the hypothesis that type II diabetes can increase the risk of colorectal cancer, but time trends, geographical distributions and host factors for the two diseases remain largely to be clarified. To address these issues, we investigated the epidemic pattern of colon cancer and type II diabetes among Japanese in Japan (J-Japanese), with consideration of the westernization of dietary habits. Over the last three decades, the increase in crude mortality rates of colon cancer from the Vital Statistics has closely paralleled the increment in prevalence rates (PRs) from hospital based surveys of diabetes. Age-standardized incidence rates (ASIRs) for colon cancer among Japanese in the United States (US-Japanese) were higher than those among J-Japanese and almost the same as those among US-Whites, while PRs for type II diabetes among US-Japanese were the highest in the three populations. Correlation analysis showed that PRs for type II diabetes had a positive association with ASIRs for colon cancer among the combination of Japanese and US-Japanese (r=0.79, p<0.01). Since 1950, intake of milk, meat, eggs and fat/oil has increased, while that of rice and potatoes has gradually decreased. Our findings indicate that the increment of ASIRs for colon cancer among J-Japanese might be closely associated with the increment of PRs for type II diabetes, reflecting the westernization of food intake.
Asian Pac J Cancer Prev
PMID:Association between type II diabetes and colon cancer among Japanese with reference to changes in food intake. 1507 1

Glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide 1 (GLP-1) are gut-derived incretins that potentiate glucose clearance following nutrient ingestion. Elimination of incretin receptor action in GIPR(-/-) or GLP-1R(-/-) mice produces only modest impairment in glucose homeostasis, perhaps due to compensatory upregulation of the remaining incretin. We have now studied glucose homeostasis in double incretin receptor knockout (DIRKO) mice. DIRKO mice exhibit normal body weight and fail to exhibit an improved glycemic response after exogenous administration of GIP or the GLP-1R agonist exendin-4. Plasma glucagon and the hypoglycemic response to exogenous insulin were normal in DIRKO mice. Glycemic excursion was abnormally increased and levels of glucose-stimulated insulin secretion were decreased following oral but not intraperitoneal glucose challenge in DIRKO compared with GIPR(-/-) or GLP-1R(-/-) mice. Similarly, glucose-stimulated insulin secretion and the response to forskolin were well preserved in perifused DIRKO islets. Although the dipeptidyl peptidase-IV (DPP-IV) inhibitors valine pyrrolidide (Val-Pyr) and SYR106124 lowered glucose and increased plasma insulin in wild-type and single incretin receptor knockout mice, the glucose-lowering actions of DPP-IV inhibitors were eliminated in DIRKO mice. These findings demonstrate that glucose-stimulated insulin secretion is maintained despite complete absence of both incretin receptors, and they delineate a critical role for incretin receptors as essential downstream targets for the acute glucoregulatory actions of DPP-IV inhibitors.
Diabetes 2004 May
PMID:Double incretin receptor knockout (DIRKO) mice reveal an essential role for the enteroinsular axis in transducing the glucoregulatory actions of DPP-IV inhibitors. 1511 3

The stimulation of insulin vs. inhibition of glucagon secretion in relation to the antidiabetic action of glucagon-like peptide-1 (GLP-1) is not established. Here, the influence of a 4-wk increase in circulating GLP-1 by inhibition of dipeptidyl peptidase-4 (DPP-4) on 24-h glucose and insulin and glucagon responses to breakfast was studied in subjects with dietary controlled diabetes [age: 65 +/- 8 yr (SD), body mass index: 27.3 +/- 3.3 kg/m(2), fasting plasma glucose: 9.0 +/- 1.3 mmol/liter]. Compared with placebo (n = 19), a specific DPP-4 inhibitor [(1-[[(3-hydroxy-1-adamantyl) amino] acetyl]-2-cyano-(S)-pyrrolidine) (LAF237); 100 mg daily, n = 18] reduced fasting glucose by 0.70 mmol/liter (P = 0.037), 4-h prandial glucose excursion by 1.45 mmol/liter (P < 0.001), and mean 24-h glucose by 0.93 mmol/liter (P < 0.001). Baseline and postprandial active GLP-1 were increased by LAF237. The glucagon response to breakfast was reduced by LAF237 (glucagon levels at 60 min were 88 +/- 8 pg/ml before treatment vs. 77 +/- 5 pg/ml after; P = 0.001). In contrast, the overall insulin levels were not altered. The 4-wk reduction in glucagon correlated with the reduction in 2-h glucose (r = 0.61; P = 0.008). No such association was observed for insulin. Thus, improved metabolic control by DPP-4 inhibition in type 2 diabetes is seen in association with reduced glucagon levels and, despite the lower glycemia, unaltered insulin levels.
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PMID:Inhibition of dipeptidyl peptidase-4 reduces glycemia, sustains insulin levels, and reduces glucagon levels in type 2 diabetes. 1512 24

Glucagon-like peptide-1 (GLP-1) is a peptide hormone from the gut that stimulates insulin secretion and protects beta-cells, inhibits glucagon secretion and gastric emptying, and reduces appetite and food intake. In agreement with these actions, it has been shown to be highly effective in the treatment of Type 2 diabetes, causing marked improvements in glycaemic profile, insulin sensitivity and beta-cell performance, as well as weight reduction. The hormone is metabolised rapidly by the enzyme dipeptidyl peptidase IV (DPP-IV) and, therefore, cannot be easily used clinically. Instead, resistant analogues of the hormone (or agonists of the GLP-1 receptor) are in development, along with DPP-IV inhibitors, which have been demonstrated to protect the endogenous hormone and enhance its activity. Agonists include both albumin-bound analogues of GLP-1 and exendin-4, a lizard peptide. Clinical studies with exendin have been carried out for > 6 months and have indicated efficacy in patients inadequately treated with oral antidiabetic agents. Orally active DPP-IV inhibitors, suitable for once-daily administration, have demonstrated similar efficacy. Diabetes therapy, based on GLP-1 receptor activation, therefore, appears very promising.
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PMID:Treatment of type 2 diabetes mellitus with agonists of the GLP-1 receptor or DPP-IV inhibitors. 1515 41

Regional diets and associated cuisines and their contribution to overall regional nutrition are increasingly being scrutinized by scientists for their relationships to human health. The Hangzhou region in China has lower mortality rates associated with cardiovascular disease, lower incidences of diabetes mellitus and better blood pressure in the local population and the links between these lower rates of disease and the traditional regional cuisine are a source of interest. Zhejiang is located on the East Coast of China. The Northern part is well known for the extensive network of channels that produce a vast array of aquatic foods. The South West region and its extensive foothills are known for the production of rare and expensive venison and many types of fungi. The region is also known for the production of over ten different types of edible bamboos. The cuisine also involves many different types of green vegetables that accompany every meal. The best way to describe Hangzhou cuisine is the wide use of southern ingredients cooked in the typical northern manner. This combination leads to a unique taste combining the dainty and the smooth, the crisp and the tender, the simple and the elegant, the small and the exquisite. Overall the cuisine is known for it's low saturated fat and high PUFA, particularly long-chain omega-3 PUFA and fibre. There is extensive use of plant based foods high in complex phytochemicals and trace elements. This combination leads to a balanced nutrition that contributes to the community health in Hangzhou.
Asia Pac J Clin Nutr 2004
PMID:Cuisine: Hangzhou foods and their role in community health and nutrition. 1522 80

In Zhejiang province economic development and changes in nutrition appear to have increased both life expectancy and nutrition-related chronic disease morbidity. Life expectancy is longer in urban populations than in rural and in both urban and rural females. From 1997 to 2002 urban females had an average life expectancy of 81.4 years. In 2002 the estimated incidence of ischaemic heart disease was higher in rural males and females whereas diabetes mellitus was higher in urban males and females. From 1990 to 2002 lung cancer had large increases in all groups, cancers of the oesophagus and stomach increased in rural males and females, and cancer of the large intestine increased 40 per cent in urban males. In 2002 deaths from cerebrovascular disease were much higher in rural males and females. Apart from differences in lifestyle factors between urban and rural, access to medical resources may also be relevant to the differences within the province in chronic disease rates and in life expectancy.
Asia Pac J Clin Nutr 2004
PMID:Nutrition-related disease and death in Zhejiang Province? 1522 83

Glucagon-like peptide (GLP)-1 is an incretin hormone with potent glucose-dependent insulinotropic and glucagonostatic actions, trophic effects on the pancreatic beta-cells, and inhibitory effects on gastrointestinal secretion and motility, which combine to lower plasma glucose and reduce glycemic excursions. Furthermore, via its ability to enhance satiety, GLP-1 reduces food intake, thereby limiting weight gain, and may even cause weight loss. Taken together, these actions give GLP-1 a unique profile, considered highly desirable for an antidiabetic agent, particularly since the glucose dependency of its antihyperglycemic effects should minimize any risk of severe hypoglycemia. However, its pharmacokinetic/pharmacodynamic profile is such that native GLP-1 is not therapeutically useful. Thus, while GLP-1 is most effective when administered continuously, single subcutaneous injections have short-lasting effects. GLP-1 is highly susceptible to enzymatic degradation in vivo, and cleavage by dipeptidyl peptidase IV (DPP-IV) is probably the most relevant, since this occurs rapidly and generates a noninsulinotropic metabolite. Strategies for harnessing GLP-1's therapeutic potential, based on an understanding of factors influencing its metabolic stability and pharmacokinetic/pharmacodynamic profile, have therefore been the focus of intense research in both academia and the pharmaceutical industry. Such strategies include DPP-IV-resistant GLP-1 analogs and selective enzyme inhibitors to prevent in vivo degradation of the peptide.
Diabetes 2004 Sep
PMID:Therapeutic strategies based on glucagon-like peptide 1. 1533 25

DPP-IV is a prolyl dipeptidase, cleaving the peptide bond after the penultimate proline residue. It is an important drug target for the treatment of type II diabetes. DPP-IV is active as a dimer, and monomeric DPP-IV has been speculated to be inactive. In this study, we have identified the C-terminal loop of DPP-IV, highly conserved among prolyl dipeptidases, as essential for dimer formation and optimal catalysis. The conserved residue His750 on the loop contributes significantly for dimer stability. We have determined the quaternary structures of the wild type, H750A, and H750E mutant enzymes by several independent methods including chemical cross-linking, gel electrophoresis, size exclusion chromatography, and analytical ultracentrifugation. Wild-type DPP-IV exists as dimers both in the intact cell and in vitro after purification from human semen or insect cells. The H750A mutation results in a mixture of DPP-IV dimer and monomer. H750A dimer has the same kinetic constants as those of the wild type, whereas the H750A monomer has a 60-fold decrease in kcat. Replacement of His750 with a negatively charged Glu (H750E) results in nearly exclusive monomers with a 300-fold decrease in catalytic activity. Interestingly, there is no dynamic equilibrium between the dimer and the monomer for all forms of DPP-IVs studied here. This is the first study of the function of the C-terminal loop as well as monomeric mutant DPP-IVs with respect to their enzymatic activities. The study has important implications for the discovery of drugs targeted to the dimer interface.
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PMID:One site mutation disrupts dimer formation in human DPP-IV proteins. 1544 55


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