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)

Non-insulin-dependent diabetes mellitus (NIDDM), or type II diabetes is rapidly becoming one of the most common chronic disease in the United States and worldwide, with more than 7% of the adult population affected. NIDDM is even more common in the elderly and in minority population including Hispanic Americans, African Americans, Asian and Pacific Island Americans, and Native Americans. In these populations, NIDDM may be present in 10% to as much as 50% of the adult population. However diagnosed NIDDM is only the tip of the iceberg of an epidemic of glucose intolerance. Impaired glucose intolerance (IGT) is even more prevalent that NIDDM; and in addition to be a major risk factor for the development of NIDDM, IGT is associated with an increased risk of macrovascular disease. Recent advances in research into the etiology and natural history of diabetes have increased the knowledge to such an extent that primary prevention of NIDDM is becoming a reality. This primary prevention can be implemented a) through a population strategy, i.e. changing the lifestyle and environmental determinants that are known to be risk factors for diabetes, and b) through high-risk strategy, i.e. targeting preventive measures only at those specific individuals or groups that are at high risk for the future development of NIDDM. The latter is the strategy of the Diabetes Prevention Program (DDP), a clinical study sponsored by the National Institute of Diabetes and Digestive and Kidney Disease in USA. Twenty five centers were selected to participate in this program. The purpose of DPP is prevent or delay the development of NIDDM in those persons who are at high risk because they have IGT. DPP will also evaluate if the interventions selected to prevent the development of NIDDM can decrease the frequency of cardiovascular events and the occurrence and magnitude of the cardiovascular risk factors that accompany NIDDM and IGT. Four thousand volunteers will be recruited from populations known to be at particular high risk fo IGT and NIDDM including the following: elderly, overweight individuals, persons with family history of NIDDM, women with history of gestational diabetes, and minority populations. In order to be eligible, persons who are older than 25 years will have to demonstrate IGT with plasma glucose levels 100-139 mg/dl fasting and 140-199 mg/dL two hours after a 75 g OGTT. Three study intervention were selected based on their potential efficacy in ameliorating abnormal glucose metabolism in IGT and on their safety and tolerable profile of side-effects. The interventions include: intensive lifestyle intervention which focuses on a healthy diet to achieve and maintain at least a 7% loss of body weight and an increase in caloric expenditure of at least 700 kcal per week. The drug therapy interventions include the biguanide metformin and the thiazolidinedione troglizatone. Standard life-style recommendations, which include conventional instructions regarding diet and exercise, will be provided to all participants, including a placebo treated group which will serve as the control group for the study. After randomization, participants will have quarterly evaluations and have, in addition, a fasting plasma glucose at semi-annual visits and a 75 g OGTT at annual visits. All participants will be followed for three years after the study-wide closing date for recruitment, resulting in 3 to 6 years of participant follow-up. The primary outcome is the development of NIDDM according to WHO criteria (fasting plasma glucose level 140 mg/dL or 2-hour plasma glucose 200 mg/dL after a 75 g OGTT). Secondary outcome will focus en cardiovascular disease and its risk factors and change of glycemia, insulin secretion and sensitivity, obesity, physical activity and nutrient intake, quality of life, and the occurrence of adverse events.
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PMID:[Steps toward the primary prevention of type II diabetes mellitus. Various epidemiological considerations]. 923 72

Proglucagon contains the sequence of two glucagon-like peptides, GLP-1 and GLP-2, secreted from enteroendocrine cells of the small and large intestine. GLP-1 lowers blood glucose in both NIDDM and IDDM patients and may be therapeutically useful for treatment of patients with diabetes. GLP-1 regulates blood glucose via stimulation of glucose-dependent insulin secretion, inhibition of gastric emptying, and inhibition of glucagon secretion. GLP-1 may also regulate glycogen synthesis in adipose tissue and muscle; however, the mechanism for these peripheral effects remains unclear. GLP-1 is produced in the brain, and intracerebroventricular GLP-1 in rodents is a potent inhibitor of food and water intake. The short duration of action of GLP-1 may be accounted for in part by the enzyme dipeptidyl peptidase 4 (DPP-IV), which cleaves GLP-1 at the NH2-terminus; hence GLP-1 analogs or the lizard peptide exendin-4 that are resistant to DPP-IV cleavage may be more potent GLP-1 molecules in vivo. GLP-2 has recently been shown to display intestinal growth factor activity in rodents, raising the possibility that GLP-2 may be therapeutically useful for enhancement of mucosal regeneration in patients with intestinal disease. This review discusses recent advances in our understanding of the biological activity of the glucagon-like peptides.
Diabetes 1998 Feb
PMID:Glucagon-like peptides. 951 8

The insulinotropic hormone, glucagon-like peptide 1 (GLP-1), which has been proposed as a new treatment for type 2 diabetes, is metabolized extremely rapidly by the ubiquitous enzyme, dipeptidyl peptidase IV (DPP-IV), resulting in the formation of a metabolite, which may act as an antagonist at the GLP-1 receptor. Because of this, the effects of single injections of GLP-1 are short-lasting, and for full demonstration of its antidiabetogenic effects, continuous intravenous infusion is required. To exploit the therapeutic potential of GLP-1 clinically, we here propose the use of specific inhibitors of DPP-IV. We have demonstrated that the administration of such inhibitors may completely protect exogenous GLP-1 from DPP-IV-mediated degradation, thereby greatly enhancing its insulinotropic effect, and provided evidence that endogenous GLP-1 may be equally protected. Preliminary studies by others in glucose-intolerant experimental animals have shown that DPP-IV inhibition greatly ameliorates the condition. GLP-1 has multifaceted actions, which include stimulation of insulin gene expression, trophic effects on the beta-cells, inhibition of glucagon secretion, promotion of satiety, inhibition of food intake, and slowing of gastric emptying, all of which contribute to normalizing elevated glucose levels. Because of this, we predict that inhibition of DPP-IV, which will elevate the levels of active GLP-1 and reduce the levels of the antagonistic metabolite, may be useful to treat impaired glucose tolerance and perhaps prevent transition to type 2 diabetes. The actions of DPP-IV, other than degradation of GLP-1, particularly in the immune system are discussed, but it is concluded that side effects of inhibition therapy are likely to be mild. Thus, DPP-IV inhibition may be an effective supplement to diet and exercise treatment in attempts to prevent the deterioration of glucose metabolism associated with the Western lifestyle.
Diabetes 1998 Nov
PMID:Inhibition of the activity of dipeptidyl-peptidase IV as a treatment for type 2 diabetes. 979 33

As a therapeutic principle, the insulinotropic peptide, GLP-1, of the secretin-glucagon family of peptides, has turned out to possess some remarkably attractive properties, including the capability of normalizing blood glucose concentrations in patients with non-insulin-dependent diabetes mellitus and promoting satiety and reducing food intake in healthy volunteers. Because of rapid and extensive metabolization, the peptide is not immediately clinically applicable and, as a therapeutic principle, GLP-1 is still in its infancy. Some possible avenues for circumventing these difficulties are the development of DPP-IV-resistant analogs, the inhibition of DPP-IV, enhancement of GLP-1 secretion, GLP delivery systems using continuous subcutaneous infusion or buccal tablets, GLP-1 absorption, and orally active, stable analogs. It seems likely that one or more of these approaches could result in a clinically useful development program.
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PMID:On the treatment of diabetes mellitus with glucagon-like peptide-1. 992 27

The search for intestinal factors regulating the endocrine secretion of the pancreas started soon after the discovery of secretin, i.e. nearly 100 years ago. Insulinotropic factors of the gut released by nutrients and stimulating insulin secretion in physiological concentrations in the presence of elevated blood glucose levels have been named incretins. Of the known gut hormones only gastric inhibitory polypeptide (GIP) and glucagon-like polypeptide-1 (GLP-1 [7-36] amide) fulfill this definition.--The incretin effect (i.e. the ratio between the integrated insulin response to an oral glucose load and an isoglycaemic intravenous glucose infusion) is markedly diminished in patients with type 2 diabetes mellitus, while the plasma levels of GIP and GLP-1 and their responses to nutrients are in the normal range. Therefore, a reduced responsiveness of the islet B-cells to incretins has been postulated. This insensitivity of the diabetic B-cells towards incretins can be overcome by supraphysiological (pharmacological) concentrations of GLP-1 [7-36], however not of GIP. Accordingly, fasting and postprandial glucose levels can be normalized in patients with type 2 diabetes by infusions of GLP-1 [7-36]. Further studies revealed that this is partially due to the fact that GLP-1 [7-36]--in addition to its insulinotropic effect--also inhibits glucagon secretion and delays gastric emptying. These three antidiabetic effects qualify GLP-1 [7-36] as an interesting therapeutic tool, mainly for type 2 diabetes. However, because of its short plasma half life time natural GLP-1 [7-36] is not suitable for subcutaneous application. At present methods are being developed to improve the pharmacokinetics of GLP-1 by inhibition of the cleaving enzyme dipeptidyl peptidase IV (DPP-IV) or by synthesis of DPP-IV resistant GLP-1 analogues. Also naturally occurring GLP-1 analogues (for instance exendin-4) with a much longer half life time than GLP-1 [7-36] are being tested.--Thus, after 100 years of speculations and experimentations, incretins and their analogues are emerging as new antidiabetic drugs.
Exp Clin Endocrinol Diabetes 2001
PMID:The entero-insular axis in type 2 diabetes--incretins as therapeutic agents. 1146 May 78

Acute suppression of dipeptidyl peptidase IV (DPP-IV) activity improves glucose tolerance in the Zucker fatty rat, a rodent model of impaired glucose tolerance, through stabilization of glucagon-like peptide (GLP)-1. This study describes the effects of a new and potent DPP-IV inhibitor, FE 999011, which is able to suppress plasma DPP-IV activity for 12 h after a single oral administration. In the Zucker fatty rat, FE 999011 dose-dependently attenuated glucose excursion during an oral glucose tolerance test and increased GLP-1 (7-36) release in response to intraduodenal glucose. Chronic treatment with FE 999011 (10 mg/kg, twice a day for 7 days) improved glucose tolerance, as suggested by a decrease in the insulin-to-glucose ratio. In the Zucker diabetic fatty (ZDF) rat, a rodent model of type 2 diabetes, chronic treatment with FE 999011 (10 mg/kg per os, once or twice a day) postponed the development of diabetes, with the twice-a-day treatment delaying the onset of hyperglycemia by 21 days. In addition, treatment with FE 999011 stabilized food and water intake to prediabetic levels and reduced hypertriglyceridemia while preventing the rise in circulating free fatty acids. At the end of treatment, basal plasma GLP-1 levels were increased, and pancreatic gene expression for GLP-1 receptor was significantly upregulated. This study demonstrates that DPP-IV inhibitors such as FE 999011 could be of clinical value to delay the progression from impaired glucose tolerance to type 2 diabetes.
Diabetes 2002 May
PMID:Chronic inhibition of circulating dipeptidyl peptidase IV by FE 999011 delays the occurrence of diabetes in male zucker diabetic fatty rats. 1197 43

The rapid degradation of native glucagon-like peptide 1 (GLP-1) by dipeptidyl peptidase-IV (DPP-IV) has fostered new approaches for generation of degradation-resistant GLP-1 analogues. We examined the biological activity of CJC-1131, a DPP-IV-resistant drug affinity complex (DAC) GLP-1 compound that conjugates to albumin in vivo. The CJC-1131 albumin conjugate bound to the GLP-1 receptor (GLP-1R) and activated cAMP formation in heterologous fibroblasts expressing a GLP-1R. CJC-1131 lowered glucose in wild-type mice, but not in GLP-1R-/- mice. Basal glucose and glycemic excursion following glucose challenge remained significantly reduced 10-12 h following a single injection of CJC-1131. Twice daily administration of CJC-1131 to db/db mice significantly reduced glycemic excursion following oral and IP glucose challenge (P < 0.01 to 0.05) but did not significantly lower body weight during the 4-week study period. Levels of random fed glucose were significantly lower in CJC-1131-treated +/+ and db/db mice and remained significantly lower even 1 week following discontinuation of CJC-1131 administration. CJC-1131 increased levels of pancreatic proinsulin mRNA transcripts, percent islet area, and the number of bromodeoxyuridine-positive islet cells. These findings demonstrate that an albumin-conjugated DAC:GLP-1 mimics the action of native GLP-1 and represents a new approach for prolonged activation of GLP-1R signaling.
Diabetes 2003 Mar
PMID:Development and characterization of a glucagon-like peptide 1-albumin conjugate: the ability to activate the glucagon-like peptide 1 receptor in vivo. 1260 17

The patent literature for dipeptidyl peptidase IV (DPP-IV) inhibitors for the period of January 2001 to May 2002 is reviewed. There has been increased interest in DPP-IV inhibitors since their potential for the treatment of diabetes was identified. This review will focus on reversible inhibitors of the enzyme, for which the primary interest has been for use in the treatment of Type II diabetes. The majority of the new chemical entities reported are dipeptide-like inhibitors that mimic the preferred substrates and the best of these display nanomolar activity. There have been fewer reports of non-peptide inhibitors suggesting that it is much more difficult to identify new classes of inhibitors. In addition to new chemical entities this review will cover new indications for DPP-IV inhibitors that have been identified using previously reported inhibitors as research tools.
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PMID:Dipeptidyl peptidase IV inhibitors. 1280 6

Inhibition of dipeptidyl peptidase IV (DPP-IV), the main glucagon-like peptide 1 (GLP1)-degrading enzyme, has been proposed for the treatment of type II diabetes. We expressed and purified the ectodomain of human DPP-IV in Pichia pastoris and determined the X-ray structure at 2.1 A resolution. The enzyme consists of two domains, the catalytic domain, with an alpha/beta hydrolase fold, and a beta propeller domain with an 8-fold repeat of a four-strand beta sheet motif. The beta propeller domain contributes two important functions to the molecule that have not been reported for such structures, an extra beta sheet motif that forms part of the dimerization interface and an additional short helix with a double Glu sequence motif. The Glu motif provides recognition and a binding site for the N terminus of the substrates, as revealed by the complex structure with diprotin A, a substrate with low turnover that is trapped in the tetrahedral intermediate of the reaction in the crystal.
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PMID:Structural basis of proline-specific exopeptidase activity as observed in human dipeptidyl peptidase-IV. 1290 26

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


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