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)

Recent studies have identified a common proline-to-alanine substitution (Pro12Ala) in the peroxisome proliferator-activated receptor-gamma2 (PPAR-gamma2), a nuclear receptor that regulates adipocyte differentiation and possibly insulin sensitivity. The Pro12Ala variant has been associated in some studies with diabetes-related traits and/or protection against type 2 diabetes. We examined this variant in 935 Finnish subjects, including 522 subjects with type 2 diabetes, 193 nondiabetic spouses, and 220 elderly nondiabetic control subjects. The frequency of the Pro12Ala variant was significantly lower in diabetic subjects than in nondiabetic subjects (0.15 vs. 0.21; P = 0.001). We also compared diabetes-related traits between subjects with and without the Pro12Ala variant within subgroups. Among diabetic subjects, the variant was associated with greater weight gain after age 20 years (P = 0.023) and lower triglyceride levels (P = 0.033). Diastolic blood pressure was higher in grossly obese (BMI >40 kg/m2) diabetic subjects with the variant. In nondiabetic spouses, the variant was associated with higher fasting insulin (P = 0.033), systolic blood pressure (P = 0.021), and diastolic blood pressure (P = 0.045). These findings support a role for the PPAR-gamma2 Pro12Ala variant in the etiology of type 2 diabetes and the insulin resistance syndrome.
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PMID:The peroxisome proliferator-activated receptor-gamma2 Pro12A1a variant: association with type 2 diabetes and trait differences. 1128 57

Human islet amyloid polypeptide (hIAPP) accumulates as pancreatic amyloid in type 2 diabetes and readily forms fibrils in vitro. Investigations into the mechanism of hIAPP fibril formation have focused largely on residues 20 to 29, which are considered to comprise a primary amyloidogenic domain. In rodents, proline substitutions within this region and the subsequent beta-sheet disruption, prevents fibril formation. An additional amyloidogenic fragment within the C-terminal sequence, residues 30 to 37, has been identified recently. We have extended these observations by examining a series of overlapping peptide fragments from the human and rodent sequences. Using protein spectroscopy (CD/FTIR), electron microscopy and X-ray diffraction, a previously unrecognised amyloidogenic domain was localised within residues 8 to 20. Synthetic peptides corresponding to this region exhibited a transition from random coil to beta-sheet conformation and assembled into fibrils having a typical amyloid-like morphology. The comparable rat 8-20 sequence, which contains a single His18Arg substitution, was also capable of assembling into amyloid-like fibrils. Examination of peptide fragments corresponding to residues 1 to 13 revealed that the immediate N-terminal region is likely to have only a modulating influence on fibril formation or conformational conversion. The contributions of charged residues as they relate to the amyloid-forming 8-20 sequence were also investigated using IAPP fragments and by assessing the effects of pH and counterions. The identification of these principal amyloidogenic sequences and the effects of associated factors provide details on the IAPP aggregation pathway and structure of the peptide in its fibrillar state.
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PMID:Identification of a novel human islet amyloid polypeptide beta-sheet domain and factors influencing fibrillogenesis. 1132 84

The antidiabetic biguanide metformin has been shown to increase faecal excretion of bile salts in type 2 diabetes. Cultured human intestinal Caco-2 cell monolayers provide a model of human enterocytes. These monolayers are used here to determine the effect of metformin on the secondary-active, sodium-linked transfer of 14C-glycocholate from the apical (brush border) to the basolateral (serosal) surface. During 24-h incubations, 10-2 mol/l metformin significantly reduced 14C-glycocholate transfer. This could not be attributed to alterations of monolayer integrity or Na+-K+ ATPase pump activity. For example, the secondary-active transport of glucose and proline was not interrupted, and the inhibitory effect of metformin on bile salt transport was additive to the inhibitory effect of ouabain. The results suggest that metformin can act directly on intestinal enterocytes to reduce the active transfer of bile salts by a mechanism that is independent of Na+-K+ ATPase activity.
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PMID:Effects of metformin on bile salt transport by monolayers of human intestinal Caco-2 cells. 1240 42

Adis CommentsPramlintide [AC 0137, AC 137, tripro-amylin, Symlin] is a synthetic human amylin analogue with proline substitutions at positions 25, 28 and 29, which limits the self-aggregation seen with native amylin. Pramlintide improves glycaemic control, and appears to reduce postprandial blood glucose peaks and flatten the glucose peaks and troughs observed in diabetic patients. The reduction of hypoglycaemia would be an immediate advantage, and the reduction of hyperglycaemia could potentially prevent diabetic complications. Development - US: Amylin has submitted an NDA in the US for pramlintide acetate (Symlin trade mark ) as an adjunctive therapy for the treatment of type 1 and type 2 diabetes mellitus. However, the FDA's Endocrinologic and Metabolic Drugs Advisory Committee at their meeting on 26 July 2001, voted not to recommend approval of pramlintide for type 1 and type 2 diabetes. Although eight out of nine Committee members were convinced of the potential of pramlintide therapy, the Committee expressed concerns regarding safety issues and requested additional data addressing these concerns. Finally, on 12 October 2001, Amylin received an 'approvable letter' for Symlin- for the treatment of diabetes. In April 2002, Amylin commenced a trial in 250 patients with type 1 diabetes to evaluate the safety issues regarding cases of severe hypoglycaemia with pramlintide in combination with insulin reported in this group of patients. The trial will investigate dose titration in the initial first month of the treatment period combined with insulin adjustment for the optimisation of glucose control. Patients are then treated for 6 months at a steady-state dose of pramlintide or placebo, accompanied by the additional insulin adjustments. Amylin has completed patient enrolment in September 2002. Final approval is subject to satisfactory results from this safety and dose titration study and the four small pharmacology studies already completed or underway. Amylin plans to file an amendment to the pramlintide's NDA in the Q1 of 2003. Development - non-USA: A wholly owned subsidiary of Amylin Pharmaceuticals, Amylin Europe, filed a regulatory submission with the European Agency for Evaluation of Medicinal Products (EMEA) and Switzerland for pramlintide for the treatment of both type 1 and type 2 diabetes under the centralised procedure. Amylin completed pivotal phase III clinical trials with pramlintide acetate (Symlin trade mark ) for the treatment of type 1 and type 2 diabetes mellitus in North America and Europe. However, in October 2002, Amylin announced that following consultation with the Committee for Proprietary Medicinal Products (CPMP) of the EMEA, it has found that additional information is necessary to proceed with review of the MAA for pramlintide for diabetes. Since, the centralised procedure does not allow the adding of new information to the application that is already under review, Amylin has decided to withdraw the MAA for pramlintide. The company will continue discussions with the EMEA to clarify the information required for a resubmission of the application. The submission for pramlintide in Switzerland is currently under review. In a separate phase II programme, Amylin is investigating the use of pramlintide in type 2 diabetes mellitus patients who are not achieving satisfactory results with oral hypoglycaemic agents but who have not progressed to using insulin. Collaborations: Pramlintide was under joint development with Amylin Pharmaceuticals and Johnson and Johnson, as an injectable partner hormone for insulin for the treatment of both type 1 and type 2 diabetes mellitus. The terms of the agreement between Amylin and Johnson and Johnson were that Amylin had primary responsibility for development and regulatory submissions, while Johnson and Johnson had primary responsibility for marketing; development costs and eventual profits were to be shared equally. Later, Johnson and Johnson decided to terminate the collaboration to commercialise pramlintide. An earlier development collaboration betweion between Amylin and Glaxo Wellcome was also discontinued. However, Amylin is in new ongoing discussions with collaborative partners for pramlintide in Europe and Japan. Amylin has signed an agreement with CP Pharmaceuticals in the UK to manufacture pramlintide.
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PMID:Pramlintide: (AC 137, AC 0137, Symlin, Tripro-Amylin). 1253 23

Pancreatic amyloid deposits, composed of the 37 amino acid residue peptide amylin, represent an integral part of type 2 diabetes mellitus pathology. Human amylin (hA) forms fibrils in vitro and is toxic to cultured pancreatic islet beta-cells. In contrast, rat amylin (rA) which differs from hA by only six amino acid residues in the central region of the peptide, residues 18-29, does not form fibrils and is not cytotoxic. To elucidate the role of individual residues in fibril formation, we have generated a series of full-length rA variants and examined their ability to form fibrils in vitro. Single-residue substitutions with amino acids from corresponding positions of the hA sequence, i.e. R18H, L23F, or V26I, were sufficient to render rA competent for fibril formation albeit at a small yield. Combining two or three of these substitutions generally increased the ability to produce fibrils. Variant rA fibril morphologies were examined by negative stain electron microscopy and found to be similar to those generated by hA itself. Bulk assays, i.e. involving thioflavin-T fluorescence and sedimentation, showed that the amount of fibril formation was relatively small for these rA variants when compared to hA under the same conditions. Fibril growth was demonstrated by time-lapse atomic force microscopy, and MALDI-TOF mass spectrometry was used to verify that fibrils consisted of full-length peptide. Our observations confirm previous reports that the three proline residues play a dominant negative role in fibril formation. However, their presence is not sufficient to completely abolish the ability of rA to form fibrils, as each of the other three implicated residues (i.e. R18, L23 and V26) also has a dominant modulating effect.
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PMID:Full-length rat amylin forms fibrils following substitution of single residues from human amylin. 1258 59

Peroxisome proliferator-activated receptor gamma (PPARgamma)-2 is a member of the nuclear hormone receptor superfamily that is expressed predominantly in adipocytes and is thought to have a role in energy homeostasis, adipogenesis, and insulin sensitivity. A functional single nucleotide polymorphism (SNP) that predicts a proline to alanine substitution (Pro12Ala) within the coding region of this gene has previously been associated with obesity and type 2 diabetes in several populations. In this study, we identified several novel SNPs in the promoter region of PPARgamma2 and genotyped them, along with the previously identified Pro12Ala SNP. In 241 nondiabetic Pima subjects, the Pro12Ala was associated with whole-body insulin action (P = 0.05), hepatic insulin action (P = 0.03), and fasting plasma insulin concentrations (P = 0.01). One of the promoter SNPs positioned within a putative E2 box was in high linkage disequilibrium (/D'/ = 0.98) with the Pro12Ala. This promoter SNP was similarly associated with whole-body insulin action (P = 0.04) and hepatic insulin action (P = 0.05), but not fasting plasma insulin concentrations. Functional studies in transfected 3T3-L1 cells demonstrated that this single base substitution in the putative E2 box significantly altered transcriptional activity from a luciferase reporter construct. These data indicate that this promoter SNP, via its effect on PPARgamma2 expression, may also have functional consequences on PPARgamma2-activated pathways, and perhaps both the promoter SNP and the Pro12Ala contribute to PPARgamma2-related phenotypes.
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PMID:A functional variant in the peroxisome proliferator-activated receptor gamma2 promoter is associated with predictors of obesity and type 2 diabetes in Pima Indians. 1282 58

Dipeptidyl-peptidase IV/CD26 (DPP IV) is a cell-surface protease belonging to the prolyloligopeptidase family. It selectively removes the N-terminal dipeptide from peptides with proline or alanine in the second position. Apart from its catalytic activity, it interacts with several proteins, for instance, adenosine deaminase, the HIV gp120 protein, fibronectin, collagen, the chemokine receptor CXCR4, and the tyrosine phosphatase CD45. DPP IV is expressed on a specific set of T lymphocytes, where it is up-regulated after activation. It is also expressed in a variety of tissues, primarily on endothelial and epithelial cells. A soluble form is present in plasma and other body fluids. DPP IV has been proposed as a diagnostic or prognostic marker for various tumors, hematological malignancies, immunological, inflammatory, psychoneuroendocrine disorders, and viral infections. DPP IV truncates many bioactive peptides of medical importance. It plays a role in glucose homeostasis through proteolytic inactivation of the incretins. DPP IV inhibitors improve glucose tolerance and pancreatic islet cell function in animal models of type 2 diabetes and in diabetic patients. The role of DPP IV/ CD26 within the immune system is a combination of its exopeptidase activity and its interactions with different molecules. This enables DPP IV/CD26 to serve as a co-stimulatory molecule to influence T cell activity and to modulate chemotaxis. DPP IV is also implicated in HIV-1 entry, malignant transformation, and tumor invasion.
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PMID:Dipeptidyl-peptidase IV from bench to bedside: an update on structural properties, functions, and clinical aspects of the enzyme DPP IV. 1289 17

Glucagon-like peptide-1(7-36)amide (GLP-1) is an incretin hormone with therapeutic potential for type 2 diabetes. Rapid removal of the N-terminal dipeptide, His7-Ala8, by the ubiquitous enzyme dipeptidyl peptidase IV (DPP IV) curtails the biological activity of GLP-1. Chemical modifications or substitutions of GLP-1 at His7 or Ala8 improve resistance to DPP-IV action, but this often reduces potency. Little attention has focused on the metabolic stability and functional activity of GLP-1 analogues with amino acid substitution at Glu9, adjacent to the DPP IV cleavage site. We generated three novel Glu9-substituted GLP-1 analogues, (Pro9)GLP-1, (Phe9)GLP-1 and (Tyr9)GLP-1 and show for the first time that Glu9 of GLP-1 is important in DPP IV degradation, since replacing this amino acid, particularly with proline, substantially reduced susceptibility to degradation. All three novel GLP-1 analogues showed similar or slightly enhanced insulinotropic activity compared with native GLP-1 despite a moderate 4-10-fold reduction in receptor binding and cAMP generation. In addition, (Pro9)GLP-1 showed significant ability to moderate the plasma glucose excursion and increase circulating insulin concentrations in severely insulin resistant obese diabetic (ob/ob) mice. These observations indicate the importance of Glu9 for the biological activity of GLP-1 and susceptibility to DPP IV-mediated degradation.
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PMID:Metabolic stability, receptor binding, cAMP generation, insulin secretion and antihyperglycaemic activity of novel N-terminal Glu9-substituted analogues of glucagon-like peptide-1. 1471 96

Ingested protein results in an increase in circulating insulin and glucagon concentrations and no change, or a slight decrease, in circulating glucose. In subjects with type 2 diabetes, when protein is ingested with glucose, insulin is further increased and the glucose rise is less than when glucose is ingested alone. Presumably these effects are due to the amino acids present in the proteins. The effects of individual amino acids, ingested in physiologic amounts, with or without glucose, have not been determined. Therefore, we have begun a systematic study of the response to ingested amino acids. Eight young, non-obese, subjects (4 men, 4 women) ingested 1 mmol proline/kg lean body mass, 25 g glucose, 25 g glucose + 1 mmol proline/kg lean body mass or water only on 4 separate occasions at 8 am. Blood was obtained before and after ingestion of the test meal over the following 150 minutes. Proline ingestion resulted in a 13-fold increase in the plasma proline concentration. This was decreased by 50% when glucose was ingested with proline. Proline alone had little effect on glucose, insulin, or glucagon concentrations. However, ingestion of proline with glucose resulted in a 23% attenuation of the glucose area response and no change in insulin response compared with the response to that of glucose alone. A glucose-stimulated decrease in glucagon was further facilitated by proline. Ingested proline is readily absorbed. It reduces the glucose-induced increase in glucose concentration in the presence of an unchanged insulin and a decreased glucagon response.
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PMID:The metabolic response to ingestion of proline with and without glucose. 1476 78

A series of methanoprolinenitrile-containing dipeptide mimetics were synthesized and assayed as inhibitors of the N-terminal sequence-specific serine protease dipeptidyl peptidase IV (DPP-IV). The catalytic action of DPP-IV is the principle means of degradation of glucagon-like peptide-1, a key mediator of glucose-stimulated insulin secretion, and DPP-IV inhibition shows clinical benefit as a novel mechanism for treatment of type 2 diabetes. However, many of the reversible inhibitors to date suffer from chemical instability stemming from an amine to nitrile intramolecular cyclization. Installation of a cyclopropyl moiety at either the 3,4- or 4,5-position of traditional 2-cyanopyrrolidide proline mimetics led to compounds with potent inhibitory activity against the enzyme. Additionally, cis-4,5-methanoprolinenitriles with beta-branching in the N-terminal amino acid provided enhanced chemical stability and high inhibitory potency. This class of inhibitors also exhibited the ability to suppress prandial glucose elevations after an oral glucose challenge in male Zucker rats.
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PMID:Synthesis of novel potent dipeptidyl peptidase IV inhibitors with enhanced chemical stability: interplay between the N-terminal amino acid alkyl side chain and the cyclopropyl group of alpha-aminoacyl-l-cis-4,5-methanoprolinenitrile-based inhibitors. 1511


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