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

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.
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PMID:Chronic inhibition of circulating dipeptidyl peptidase IV by FE 999011 delays the occurrence of diabetes in male zucker diabetic fatty rats. 1197 43

Dipeptidyl peptidase IV (DPP-IV) inhibition has the potential to become a valuable therapy for type 2 diabetes. We report the first use of solid-phase synthesis in the discovery of a new DPP-IV inhibitor class and a solution-phase synthesis that is practical up to the multikilogram scale. One compound, NVP-DPP728 (2), is profiled as a potent, selective, and short-acting DPP-IV inhibitor that has excellent oral bioavailability and potent antihyperglycemic activity.
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PMID:1-[2-[(5-Cyanopyridin-2-yl)amino]ethylamino]acetyl-2-(S)-pyrrolidinecarbonitrile: a potent, selective, and orally bioavailable dipeptidyl peptidase IV inhibitor with antihyperglycemic properties. 1203 46

Evolutionary pressures have probably amplified the mechanisms for minimizing the impact of environmental factors through compensatory maternal mechanisms. Nevertheless, experimentally there are clear long-term programming effects of manipulations to the maternal diet on the likelihood of neural-tube defects associated with folate deficiency The fat/lean ratios of the newborn, and subsequent development, seem to be linked to amino acid or folate supply. An altered balance in the hypothalamic-pituitary-adrenal axis, which experimentally has profound effects on brain development, is induced by low-protein maternal diets. Such diets are linked to a reduced pancreatic capacity for insulin production and to an altered hepatic architecture, with a change in the control of glucose metabolism. Human studies suggest that what happens in pregnancy is modified by the child's diet in the first months of life. Low birthweight is linked to early stunting, and predisposes to abdominal obesity and metabolic syndrome in later life. Metabolic syndrome amplifies the risks of diabetes, hypertension, coronary heart disease and probably some cancers. Mothers with gestational diabetes are themselves prone to early type 2 diabetes and produce heavier babies prone to childhood obesity and adolescent type 2 diabetes. There is increasing evidence of an intergenerational effect, with big babies being prone to excess weight gain, which then, in girls, predisposes them to diabetes in pregnancy, which, in turn, promotes an accelerating cycle of early diabetes in subsequent generations. Essential fatty acids and fat soluble vitamins are important, but we need early interventions and monitoring systems to justify coherent policies.
Asia Pac J Clin Nutr 2002
PMID:Will feeding mothers prevent the Asian metabolic syndrome epidemic? 1249 42

A degree of success has been achieved in controlling several epidemics of infectious and non-infectious causes of death in countries, such as, Australia and New Zealand. Using the epidemiological triad (host, vector, environment) as a model, the key components of the control of these epidemics have been identified and compared to the current status of interventions to prevent obesity and its main disease consequence, type 2 diabetes. Reductions in mortality from tobacco, cardiovascular diseases, road crashes, cervical cancer and sudden infant death syndrome have been achieved by addressing all corners of the triad. Similarly, prevention programs have minimized the mortality from HIV AIDS and melanoma mortality rates are no longer rising. The main lessons learned from these prevention programs that could be applied to the obesity/diabetes epidemic are: taking a more comprehensive approach by increasing the environmental (mainly policy-based) initiatives; increasing the 'dose' of interventions through greater investment in programs; exploring opportunities to further influence the energy density of manufactured foods (one of the main vectors for increased energy intake); developing and communicating specific, action messages; and developing a stronger advocacy voice so that there is greater professional, public and political support for action. Successes in the other epidemics have been achieved in the face of substantial barriers within individuals, society, the private sector and government. The barriers for preventing obesity/diabetes are no less formidable, but the strategies for surmounting them have been well tested in other epidemics.
Asia Pac J Clin Nutr 2002
PMID:Sustaining dietary changes for preventing obesity and diabetes: lessons learned from the successes of other epidemic control programs. 1249 53

Incretins are peptide hormones, exemplified by glucose-dependent insulinotropic peptide and glucagon-like peptide 1 that are released from the gut in response to nutrient ingestion and enhance glucose-stimulated insulin secretion. Incretin action is terminated due to N-terminal cleavage of the peptides by the aminopeptidase dipeptidyl peptidase IV (DPP-IV). Hence, inhibition of glucose-dependent insulinotropic peptide and glucagon-like peptide 1 degradation via reduction of DPP-IV activity represents an innovative strategy for enhancing incretin action in vivo. This review summarises the biology of incretin action, the structure, expression and pleiotropic biological activities of DPP-IV and provides an overview of the rationale, potential merits and theoretical pitfalls in the development of DPP-IV inhibitors for the treatment of type 2 diabetes.
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PMID:Therapeutic potential of dipeptidyl peptidase IV inhibitors for the treatment of type 2 diabetes. 1251 56

The aim of this study was to investigate the presence of mutations in the islet amyloid polypeptide (IAPP) gene in a Spanish population with type 2 diabetes and gestational diabetes mellitus (GDM). Using polymerase chain reaction single-stranded conformation polymorphism, we examined the coding region and the 5'-untranslated region (UTR) of the IAPP gene in 177 unrelated type 2 diabetic patients, 110 healthy control subjects, 38 women with GDM, and 38 gestational control subjects. Mutations were confirmed by DNA sequencing. A heterozygous C-to-A nucleotide substitution at +79 bp in intron 2 of the IAPP gene was detected. The frequencies of the +79-bp polymorphism (A allele) were 6.8% in type 2 diabetic patients, 7.7% in nondiabetic control subjects, 11.8% in women with GDM, and 9.2% in gestational control subjects. No AA genotypes were detected. Nondiabetic subjects and patients with type 2 diabetes bearing the CA genotype had lower low-density lipoprotein (LDL) cholesterol levels than subjects bearing wild genotype. Multivariate logistic regression analysis showed an independent association (p < 0.001; odds ratio: 0.33; 95% confidence interval: 0.17-0.63). We did not detect any sequence variant within exons 1 or 2. One diabetic patient was heterozygous for a silent mutation at codon 31 of exon 3 (Asn31 AAC --> AAT). Our findings indicate that the presence of the +79-bp polymorphism of the IAPP gene in nondiabetic subjects and in patients with type 2 diabetes is associated with lower levels of LDL cholesterol. Furthermore, abnormalities of the coding regions or the 5'-UTR of the IAPP gene are not associated with type 2 diabetes or GDM in the Spanish population.
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PMID:Polymorphism in intron 2 of islet amyloid polypeptide gene is associated with lower low-density lipoprotein cholesterol in nondiabetic subjects and in type 2 diabetic patients. 1258 49

GLP-1 is a peptide hormone from the intestinal mucosa. It is secreted in response to meal ingestion and normally functions in the so-called ileal brake i. e. inhibition of upper gastrointestinal motility and secretion when nutrients are present in the distal small intestine. It also induces satiety and promotes tissue deposition of ingested glucose by stimulating insulin secretion. Thus, it is an essential incretin hormone. In addition, the hormone has been demonstrated to promote insulin biosynthesis and insulin gene expression and to have trophic effects on the beta cells. The trophic effects include proliferation of existing beta cells, maturation of new cells from duct progenitor cells and inhibition of apoptosis. Furthermore glucagon secretion is inhibited. Because of these effects, the hormone effectively improves metabolism in patients with type 2 diabetes mellitus. However, continuous administration of the peptide is necessary because of an exceptionally rapid rate of degradation catalyzed the enzyme dipeptidyl peptidase IV. With inhibitors of this enzyme, it is possible to protect the endogenous hormone and thereby elevate both fasting and postprandial levels of the active hormone. This leads to enhanced insulin secretion and glucose turnover. But will DPP-IV inhibition enhance all effects of the endogenous peptide? The mode of action of GLP-1 is complex involving also interactions with sensory neurons and the central nervous system, where a DPP-IV mediated degradation does not seem to occur. Therefore, it is as yet uncertain wether DDP-IV inhibitors will affect gastrointestinal motility, appetite and food intake. Even the effects of GLP-1 effects on the pancreatic islets may be partly neurally mediated and therefore uninfluenced by DPP-IV inhibition.
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PMID:Implementation of GLP-1 based therapy of type 2 diabetes mellitus using DPP-IV inhibitors. 1267 49

Dipeptidyl peptidase IV (DPP-IV) inhibition has the potential to become a valuable therapy for type 2 diabetes. The synthesis and structure-activity relationship of a new DPP-IV inhibitor class, N-substituted-glycyl-2-cyanopyrrolidines, are described as well as the path that led from clinical development compound 1-[2-[5-cyanopyridin-2-yl)amino]ethylamino]acetyl-2-cyano-(S)-pyrrolidine (NVP-DPP728, 8c) to its follow-up, 1-[[(3-hydroxy-1-adamantyl) amino]acetyl]-2-cyano-(S)-pyrrolidine (NVP-LAF237, 12j). The pharmacological profile of 12j in obese Zucker fa/fa rats along with pharmacokinetic profile comparison of 8c and 12j in normal cynomolgus monkeys is discussed. The results suggest that 12j is a potent, stable, selective DPP-IV inhibitor possessing excellent oral bioavailability and potent antihyperglycemic activity with potential for once-a-day administration.
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PMID:1-[[(3-hydroxy-1-adamantyl)amino]acetyl]-2-cyano-(S)-pyrrolidine: a potent, selective, and orally bioavailable dipeptidyl peptidase IV inhibitor with antihyperglycemic properties. 1280 Dec 40

Lifestyle programmes provide the greatest opportunity to stem the developing epidemic of type 2 diabetes. This is especially relevant to indigenous people worldwide, and to Maori in New Zealand. The shift from traditional diets and activities to a westernised energy dense diet and a sedentary lifestyle has precipitated the rapid increase in Maori developing type 2 diabetes in New Zealand. Attendance of Maori to mainstream health clinics or programmes has been poor, and a unique approach developed specifically for Maori is required if Maori are going to attend and benefit from lifestyle programmes. We describe the process involved in developing a successful community programme for Maori and outline the novel aspects of the programme which contribute to its acceptability and success in the local community.
Asia Pac J Clin Nutr 2003
PMID:A new approach to design and implement a lifestyle intervention programme to prevent type 2 diabetes in New Zealand Maori. 1467 65

Lifestyle programmes have been shown to reduce the risk of type 2 diabetes in European populations. The participation of Maori in many mainstream health programmes is poor. This study evaluates a lifestyle intervention programme which is acceptable to Maori and which has objective outcome measures to determine the effectiveness of the programme. Thirty six Maori men and women were recruited for a 4 month programme involving modification of diet and exercise. Insulin sensitivity was measured using a euglycaemic insulin clamp, body composition using dual-energy-absorptiometry and fitness using a submaximal exercise test. Secondary outcome measures included anthropometry, blood pressure, fasting glucose and insulin levels, and lipid profiles. There was a 24% improvement in insulin sensitivity (from 5.1 to 6.3 G/mIU/L, P=0.03, N=29). This was associated with a reduction of 3.1 kg in weight (95%CI -4 to -2) and a reduction of 7 mmHg in systolic blood pressure (95%CI -13, -1). This approach successfully reduced risk for type 2 diabetes and cardiovascular disease in New Zealand Maori in the short term.
Asia Pac J Clin Nutr 2003
PMID:Implementation of a successful lifestyle intervention programme for New Zealand Maori to reduce the risk of type 2 diabetes and cardiovascular disease. 1467 66


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