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)

The majority of the presentations a the conference were on three highly sought-after targets for type 2 diabetes mellitus, namely PTP1B, PPARs and DPP-IV, reflecting the current focus and trend in the industry. A couple of novel targets were discussed, including the potential of myostatin as a type 2 diabetes mellitus target and a novel GPCR target. While small molecules were dominant, several biological-based approaches were covered: antibody therapeutics and oligonucleotide-based approaches (ASO and siRNA). In searching for small-molecule leads, structure-based rational design and focused combination chemistry appear to produce better results than a random high-throughput approach over the entire chemical library. The biggest challenges for diabetes and obesity drugs remain similar to those mentioned in previous meetings: increasing specificity to reduce side effects and maintaining long-term effect while maintaining or increasing efficacy. Due to the tremendous interest of the pharmaceutical industry in metabolic disease drug development, our knowledge of food intake and metabolism regulation has increased exponentially. Overall, the prospect of better drugs for, and better control of, type 2 diabetes mellitus and obesity is promising.
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PMID:Metabolic Diseases Drug Discovery-Strategic Research Institute's Third International World Summit. Dipeptidyl peptidase-IV inhibitors 26-27 July 2004, San Diego, CA, USA. 1547 Jun

Oregano (Origanum vulgare) is a rich source of natural phenolic antioxidants and has potential to be a source of nutritional ingredients for functional foods. Herbs such as oregano have long been used in food preservation and in traditional medicine in the treatment of common ailments and have potential for positive modulation of oxidation-linked diseases such as diabetes. One of the potentially important components of anti-diabetic activity by oregano extract is mild amylase inhibition by phenolic antioxidants to help contribute towards management of hyperglycemia. Previously, we reported the ability of rosmarinic acid, one of the principal phenolic components of oregano, to inhibit porcine pancreatic amylase (PPA) activity. Here, we investigated the effect of 50% ethanol extracts of eleven phenolic antioxidant-rich oregano clonal lines on the activity of PPA in vitro. To this end, we analyzed extract total soluble phenolic content by the Folin-Ciocalteu reagent method, rosmarinic acid (RA), protochatechuic acid (PA), quercetin, and p-coumaric acid (pCA) contents by HPLC, antioxidant activity as 1,1-diphenyl-2-picryl-hydrazyl (DPPH) radical scavenging, and PPA-inhibitory activity by incubation of the enzyme with clonal oregano extracts and characterization of the activity of the phenolic-bound enzyme. Clonal oregano extracts inhibited the activity of PPA in vitro by 9-57%. Amylase inhibition by oregano extract was associated with extract total phenolic content and RA, quercetin, PA, and pCA content, as well as extract antioxidant activity and protein content. Our finding that clonal oregano extracts can inhibit PPA supports a potential new functionality for oregano as an anti-hyperglycemic agent. This provides an opportunity for a food-based strategy for modulation of starch breakdown to glucose, which could contribute to the management of hyperglycemia and diabetes complications in the long term.
Asia Pac J Clin Nutr 2004
PMID:Inhibitory effect of clonal oregano extracts against porcine pancreatic amylase in vitro. 1556 48

Chronic illness is one of the major causes of mortality and morbidity among the elderly. To determine the prevalence and factors associated with chronic illness among the elderly in a rural community setting. A cross sectional study design was used. Stratified proportionate cluster sampling method was used to select respondents in Mukim Sepang, Sepang, Selangor, Malaysia. Out of 263 elderly residents (6.2% of the total population), 223 agreed to participate in the study giving a response rate of 84.8%. The prevalence of chronic illness among the elderly in Mukim Sepang was 60.1%. Out of 223 respondents, 134 were diagnosed as having chronic illness such as hypertension, diabetes mellitus, ischaemic heart disease, bronchial asthma or gout. Chronic illness was found to be significantly associated with functional dependence among the elderly (chi2=6.863, df=1, p<0.05). The prevalence of chronic illness among the elderly in the rural community is very high. Problems facing this age-group should be addressed comprehensively in order to formulate appropriate programmes for the health care of the elderly.
Asia Pac J Public Health 2004
PMID:Factors associated with chronic illness among the elderly in a rural community in Malaysia. 1562 88

Glucagon-like peptide-1 (GLP-1) is an incretin hormone with antidiabetic action through its ability to stimulate insulin secretion, increase beta cell neogenesis, inhibit beta cell apoptosis, inhibit glucagon secretion, delay gastric emptying and induce satiety. It has therefore been explored as a novel treatment of type 2 diabetes. A problem is, however, that GLP-1 is rapidly inactivated by the dipeptidyl peptidase-4 (DPP-4) enzyme, which results in a short circulating half-life of the active form of GLP-1 (< 2 min). Two strategies have been employed to overcome this obstacle as a treatment of diabetes. One is to use GLP-1 receptor agonists that have a prolonged half-life due to reduced degradation by DPP-4. These GLP-1 mimetics include exenatide and liraglutide. Another strategy is to inhibit the enzyme DPP-4, which prolongs the half-life of endogenously released active GLP-1. Both these strategies have been successful in animal studies and in clinical studies of up to one year's treatment. This review will summarize the background and the current (mid 2004) clinical experience with these two strategies.
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PMID:GLP-1 receptor agonists and DPP-4 inhibitors in the treatment of type 2 diabetes. 1565 21

DPP8 is a prolyl dipeptidase homologous to DPP-IV, which is a drug target for Type II diabetes. The biological function of DPP8 is not known. To identify potent and selective chemical compounds against DPP8, we have synthesized a series of isoquinoline and isoindoline derivatives and have tested their inhibitory activity against DPP8, DPP-IV and DPP-II. Isoindoline derivatives were found to be more potent DPP8 inhibitors than isoquinoline derivatives. Isoindoline with a 1-(4,4'-difluor-benzhydryl)-piperazine group at the P2 site was observed to be a very potent DPP8 inhibitor, having an IC(50) value of 14nM with at least a 2500-fold selectivity over either DPP-IV or DPP-II. From SAR results, we speculate that the S1 site of DPP8 may be larger than that of DPP-IV, which would allow the accommodation of larger C-terminal residues, such as isoquinoline or isoindoline.
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PMID:Novel isoindoline compounds for potent and selective inhibition of prolyl dipeptidase DPP8. 1566 38

Previous studies have suggested the need to revise the World Health Organization (WHO) cut-off values for the various indices of obesity and fat distribution in Singapore. The purpose of this study was to delineate cut-off points of body mass index (BMI), waist-hip ratio (WHR), waist circumference (WC), and waist-stature ratio (WSR) as screening tools for cardiovascular risk factors in Singaporean women. Anthropometric indices were measured in a cross sectional survey of 566 subjects (60% Chinese individuals, 28% Malay individuals and 12% Indian individuals). Cardiovascular risk factors were determined by measuring blood pressure, serum lipids, and fasting blood glucose levels. Receiver Operating Characteristic (ROC) curves were constructed to determine cut-off points. Forward logistic regression and area under curves (AUC) were used to determine the best anthropometric index. For at least one cardiovascular risk factor (hypertension, dyslipidaemia and diabetes mellitus), the cut-off points for BMI, WHR, WC and WSR were around 23.6 kg/m(2), 0.80, 77.8 cm and 0.48 for Singaporean females. The AUC of WSR was the highest for all three risk factors in females (0.79 for hypertension, 0.70 for dyslipidaemia, 0.88 for diabetes mellitus). Regression analyses revealed that WSR was independently associated with all risk factors. For Singaporean female adults, the cut-off points were lower than the criteria suggested by the WHO, but were in agreement with those reported for Asians. BMI, WHR, WC and WSR may be used as screening tools for cardiovascular risk factors, of which WSR may be the best anthropometric index.
Asia Pac J Clin Nutr 2005
PMID:Anthropometric indices as screening tools for cardiovascular risk factors in Singaporean women. 1573 11

After many decades of relative therapeutic stagnation since the initial discovery of insulin, followed by some modifications on its structure and only having sulfonylureas and biguanides for many years, the last decade has seen a surge in new therapeutic options for the management of diabetes. The results of the United Kingdom Prospective Diabetes Study and Kumamoto study indicate the need for aggressive glycemic control and the slow inexorable clinical deterioration associated with type 2 diabetes overtime. The propensity for weight gain and hypoglycemia are the two major limitations that subcutaneous insulin and sulfonylureas have been particularly prone to. The newer antidiabetic medications and those on the horizon attempt to address these limitations. GLP-1 agonists and the DPP-IV inhibitors exploit the innate incretin system to improve glycemia while promoting satiety and weight management. Like GLP-1 related compounds, pramlintide offers the potential to address postprandial hyperglucagonemia associated with type 2 diabetes only limited by the multiple injections and gastrointestinal side effects. The glitazars offer the hope ofa new approach to diabetes care addressing not just glycemia, but dyslipidemia and other components of the metabolic syndrome, though the side effect profile remains a major unknown. The INGAP peptide represents the holy grail of diabetes care as it offers the potential of a new paradigm: that of islet regeneration and potential for a cure. But at this stage, with no human data available, it remains highly speculative. Beyond these and other novel agents being developed to meet the challenge of the worldwide epidemic of diabetes, the central place of insulin in diabetes care cannot be forgotten. In view of this the continued efforts of improvement in insulin delivery, kinetics and action have spurred such innovations as the various inhaled insulins and new insulin analogues. There is cause for guarded optimism and excitement about the years ahead. There is reason to expect that despite the growing burden of diabetes worldwide, we will be better equipped to manage it and its comorbidities and prevent its onset and possibly even cure it.
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PMID:Novel pharmacologic agents for type 2 diabetes. 1575 27

Glucagon-like peptide-1 (GLP-1) is synthesized from proglucagon in enteroendocrine cells and regulates glucose homeostasis via multiple complementary actions on appetite, gastrointestinal motility and islet hormone secretion. GLP-1 is secreted from the distal gut in response to food ingestion, and levels of circulating GLP-1 may be diminished in patients with type 2 diabetes mellitus. GLP-1 administration stimulates glucose-dependent insulin secretion, inhibits glucagon secretion, and lowers blood glucose in normal and diabetic rodents and in humans. GLP-1 exerts additional glucose-lowering actions in patients with diabetes mellitus already treated with metformin or sulfonylurea therapy. GLP-1 inhibits gastric emptying in healthy individuals and those with diabetes mellitus, and excess GLP-1 administration may cause nausea or vomiting in susceptible individuals. Chronic GLP-1 treatment of normal or diabetic rodents is associated with bodyweight loss and GLP-1 agonists transiently inhibit food intake and may prevent bodyweight gain in humans. The potential for GLP-1 therapy to prevent deterioration of beta-cell function is exemplified by studies demonstrating that GLP-1 analogs stimulate proliferation and neogenesis of beta-cells, leading to expansion of beta-cell mass in diabetic rodents. The rapid N-terminal inactivation of bioactive GLP-1 by dipeptidyl peptidase-IV (DPP-IV) limits the utility of the native peptide for the treatment of patients with diabetes mellitus, and has fostered the development of more potent and stable protease-resistant GLP-1 analogs which exhibit longer durations of action. The importance of DPP-IV for glucose control is illustrated by the phenotype of rodents with genetic inactivation of DPP-IV which exhibit reduced glycemic excursion and increased levels of circulating GLP-1 in vivo. Inhibitors of DPP-IV potentiate incretin action by preventing degradation of GLP-1 and glucose-dependent insulinotropic peptide, and lower blood glucose in normal rodents and in experimental models of diabetes mellitus. Hence, orally available DPP-IV inhibitors also represent a new class of therapeutic agents that enhance incretin action for the treatment of patients with type 2 diabetes mellitus.
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PMID:Harnessing the therapeutic potential of glucagon-like peptide-1: a critical review. 1576 27

Glucagon-like peptide-1-(7-36) (GLP-1) is a hormone derived from the proglucagon molecule, which is considered a highly desirable antidiabetic agent mainly due to its unique glucose-dependent stimulation of insulin secretion profiles. However, the development of a GLP-1-based pharmaceutical agent has a severe limitation due to its very short half-life in plasma, being primarily degraded by dipeptidyl peptidase IV (DPP-IV) enzyme. To overcome this limitation, in this article we propose a novel and potent DPP-IV-resistant form of a poly(ethylene glycol)-conjugated GLP-1 preparation and its pharmacokinetic evaluation in rats. Two series of mono-PEGylated GLP-1, (i) N-terminally modified PEG(2k)-N(ter)-GLP-1 and (ii) isomers of Lys(26), Lys(34) modified PEG(2k)-Lys-GLP-1, were prepared by using mPEG-aldehyde and mPEG-succinimidyl propionate, respectively. To determine the optimized condition for PEGylation, the reactions were monitored at different pH buffer and time intervals by RP-HPLC and MALDI-TOF-MS. The in vitro insulinotropic effect of PEG(2k)-Lys-GLP-1 showed comparable biological activity with native GLP-1 (P = 0.11) in stimulating insulin secretion in isolated rat pancreatic islet and was significantly more potent than the PEG(2k)-N(ter)-GLP-1 (P < 0.05) that showed a marked reduced potency. Furthermore, PEG(2k)-Lys-GLP-1 was clearly resistant to purified DPP-IV in buffer with 50-fold increased half-life compared to unmodified GLP-1. When PEG(2k)-Lys-GLP-1 was administered intravenously and subcutaneously into rats, PEGylation improved the half-life, which resulted in substantial improvement of the mean plasma residence time as a 16-fold increase for iv and a 3.2-fold increase for sc. These preliminary results suggest a site specifically mono-PEGylated GLP-1 greatly improved the pharmacological profiles; thus, we anticipated that it could serve as potential candidate as an antidiabetic agent for the treatment of non-insulin-dependent diabetes patients.
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PMID:Synthesis, characterization, and pharmacokinetic studies of PEGylated glucagon-like peptide-1. 1576 92

Inhibitors of the regulatory protease dipeptidyl peptidase-IV (DPP-IV) are currently under development in preclinical and clinical studies (several pharmaceutical companies, now in Phase III) as potential drugs for the treatment of type 2 diabetes. Their development is based on the observation that DPP-IV rapidly inactivates the incretin hormone glucagon-like peptide-1 (GLP-1), which is released postprandially from the gut and increases insulin secretion. DPP-IV inhibitors stabilise endogenous GLP-1 at physiological concentrations, and induce insulin secretion in a glucose-dependent manner; therefore, they do not demonstrate any hypoglycaemic effects. Furthermore, they are orally bioavailable. In addition to their ability to protect GLP-1 against degradation, DPP-IV inhibitors also stabilise other incretins, including gastric inhibitory peptide and pituitary adenylate cyclase-activating peptide. They also reduce the antagonistic and desensitising effects of the fragments formed by truncation of the incretins. In clinical studies, when used for the treatment of diabetes over a 1-year period, DPP-IV inhibitors show improved efficacy over time. This finding can be explained by a GLP-1-induced increase in the number of beta cells. Potential risks associated with DPP-IV inhibitors include the prolongation of the action of other peptide hormones, neuropeptides and chemokines cleaved by the protease, and their interaction with DPP-IV-related proteases. Based on their mode of action, DPP-IV inhibitors seem to be of particular value in early forms of type 2 diabetes, either alone or in combination with other types of oral agents.
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PMID:Dipeptidyl peptidase inhibitors as new drugs for the treatment of type 2 diabetes. 1577 Apr 66


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