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)

Treatment with statins reduces coronary risk In all people but do not remove the risk associated with a low HDL-C or with other features of the metabolic syndrome such as an elevated level of plasma triglyceride or with a high BMI. Treatment with a fibrate such as gemfibrozil (a PPAR alpha agonist) has been shown to be especially effective in people with low HDL-C and other features of the metabolic syndrome. Potential beneficial effects of the combination of a statin and an agent with PPAR alpha activity in patients with type 2 diabetes is currently being addressed in the ongoing Action to Control Cardiovascular Risk in Diabetes (ACCORD) study.
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PMID:Managing diabetic dyslipidaemia--beyond LDL-C:HDL-C and triglycerides. 1682 46

More than 70% of patients with Type 2 diabetes mellitus (T2DM) die because of cardiovascular diseases. Current therapeutic strategies are based on separate treatment of insulin resistance and dyslipidaemia. Development of drugs with multimodal activities should improve management of the global cardiovascular risk of T2DM patients and result in better patient compliance. New therapeutic strategies are aimed at targeting the entire spectrum of dysfunctioning organs, cells and regulatory pathways implicated in the pathogenesis of T2DM, dyslipidaemia and atherosclerosis. PPAR family members play major roles in the regulation of lipid metabolism, glucose homeostasis and inflammatory processes, making these transcription factors ideal targets for therapeutic strategies against these diseases. This review discusses why PPARs and development of novel selective PPAR modulators, dual and pan PPAR agonists constitute promising approaches for the treatment of diabetes, dyslipidaemia and atherosclerosis.
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PMID:Selective PPAR modulators, dual and pan PPAR agonists: multimodal drugs for the treatment of type 2 diabetes and atherosclerosis. 1693 80

The design and synthesis of the dual peroxisome proliferator-activated receptor (PPAR) gamma/delta agonist (R)-3-{4-[3-(4-chloro-2-phenoxy-phenoxy)-butoxy]-2-ethyl-phenyl}-propionic acid (20) for the treatment of type 2 diabetes and associated dyslipidemia is described. The compound possesses a potent dual hPPAR gamma/delta agonist profile (IC(50) = 19 nM/4 nM; EC(50) = 102 nM/6 nM for hPPARgamma and hPPARdelta, respectively). In preclinical models, the compound improves insulin sensitivity and reverses diabetic hyperglycemia with less weight gain at a given level of glucose control relative to rosiglitazone.
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PMID:Design and synthesis of dual peroxisome proliferator-activated receptors gamma and delta agonists as novel euglycemic agents with a reduced weight gain profile. 1697 Mar 91

Novel tetrahydroisoquinolines have been developed as potent PPAR ligands. Evaluation of these compounds in PPARgamma responsive models of type 2 diabetes is described.
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PMID:Tetrahydroisoquinoline PPARgamma agonists: design of novel, highly selective non-TZD antihyperglycemic agents. 1700 93

PPAR ligands with varied subtype selectivity have been synthesized using an achiral aminomethyl dihydrocinnamate template. Several compounds in this series have demonstrated potent plasma glucose and triglyceride lowering capability in rodent models of type 2 diabetes.
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PMID:Synthesis and evaluation of aminomethyl dihydrocinnamates as a new class of PPAR ligands. 1700 94

Lipid droplet proteins of the PAT (perilipin, adipophilin, and TIP47) family regulate cellular neutral lipid stores. We have studied a new member of this family, PAT-1, and found that it is expressed in highly oxidative tissues. We refer to this protein as "OXPAT." Physiologic lipid loading of mouse liver by fasting enriches OXPAT in the lipid droplet tissue fraction. OXPAT resides on lipid droplets with the PAT protein adipophilin in primary cardiomyocytes. Ectopic expression of OXPAT promotes fatty acid-induced triacylglycerol accumulation, long-chain fatty acid oxidation, and mRNAs associated with oxidative metabolism. Consistent with these observations, OXPAT is induced in mouse adipose tissue, striated muscle, and liver by physiological (fasting), pathophysiological (insulin deficiency), pharmacological (peroxisome proliferator-activated receptor [PPAR] agonists), and genetic (muscle-specific PPARalpha overexpression) perturbations that increase fatty acid utilization. In humans with impaired glucose tolerance, PPARgamma agonist treatment induces adipose OXPAT mRNA. Further, adipose OXPAT mRNA negatively correlates with BMI in nondiabetic humans. Our collective data in cells, mice, and humans suggest that OXPAT is a marker for PPAR activation and fatty acid oxidation. OXPAT likely contributes to adaptive responses to the fatty acid burden that accompanies fasting, insulin deficiency, and overnutrition, responses that are defective in obesity and type 2 diabetes.
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PMID:OXPAT/PAT-1 is a PPAR-induced lipid droplet protein that promotes fatty acid utilization. 1713 Apr 88

The development of type 2 diabetes in obese individuals is linked to lipid accumulation in non-adipose tissues. A series of N-acetyl-L-tyrosine derivatives were synthesized and evaluated for PPAR transactivation. Compounds 4d and 4f were found to show better PPARalpha transactivation as compared to PPARgamma. Molecular docking analysis was carried out to study their important interactions with the active site of PPARalpha.
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PMID:Synthesis and evaluation of N-acetyl-L-tyrosine based compounds as PPARalpha selective activators. 1718 4

Evidence from rodent and in vitro models suggests that activation of PPAR-gamma by thiazolidinediones (TZDs) causes increased bone marrow adiposity and decreased osteoblastogenesis, resulting in bone loss. TZDs are prescribed for the treatment of diabetes, providing an opportunity to determine whether PPAR-gamma activation also impacts bone in humans. In addition, since type 2 diabetes is associated with higher fracture risk, an understanding of the clinical impact of TZDs on bone is needed to guide fracture prevention efforts in this population. This review summarizes current findings regarding type 2 diabetes and increased fracture risk and then considers the available evidence regarding TZD use and bone metabolism in humans.
PPAR Res 2006
PMID:Diabetes, TZDs, and Bone: A Review of the Clinical Evidence. 1725 63

At a time when the twin epidemics of obesity and type 2 diabetes threaten to engulf even the most well-resourced Western healthcare systems, the nuclear receptor peroxisome proliferator-activated receptor gamma (PPARgamma) has emerged as a bona fide therapeutic target for treating human metabolic disease. The novel insulin-sensitizing antidiabetic thiazolidinediones (TZDs, e.g., rosiglitazone, pioglitazone), which are licensed for use in the treatment of type 2 diabetes, are high-affinity PPARgamma ligands, whose beneficial effects extend beyond improvement in glycaemic control to include amelioration of dyslipidaemia, lowering of blood pressure, and favourable modulation of macrophage lipid handling and inflammatory responses. However, a major drawback to the clinical use of exisiting TZDs is weight gain, reflecting both enhanced adipogenesis and fluid retention, neither of which is desirable in a population that is already overweight and prone to cardiovascular disease. Accordingly, the "search is on" to identify the next generation of PPARgamma modulators that will promote maximal clinical benefit by targeting specific facets of the metabolic syndrome (glucose intolerance/diabetes, dyslipidaemia, and hypertension), while simultaneously avoiding undesirable side effects of PPARgamma activation (e.g., weight gain). This paper outlines the important clinical and laboratory observations made in human subjects harboring genetic variations in PPARgamma that support such a therapeutic strategy.
PPAR Res 2007
PMID:'Striking the Right Balance' in Targeting PPARgamma in the Metabolic Syndrome: Novel Insights from Human Genetic Studies. 1738 71

The increasing prevalence of obesity is a fundamental contributor to the growing prevalence of the metabolic syndrome. Rexinoids, a class of compounds that selectively bind and activate RXR, are being studied as a potential option for the treatment of metabolic syndrome. These compounds have glucose-lowering, insulin-sensitizing, and antiobesity effects in animal models of insulin resistance and type 2 diabetes. However, undesirable side effects such as hypertriglyceridemia and suppression of the thyroid hormone axis also occur. This review examines and compares the effects of four RXR-selective ligands: LGD1069, LG100268, AGN194204, and LG101506, a selective RXR modulator. Similar to selective modulators of other nuclear receptors such as the estrogen receptor (SERMs), LG101506 binding to RXR selectively maintains the desirable characteristic effects of rexinoids while minimizing the undesirable effects. These recent findings suggest that, with continued research efforts, RXR-specific ligands with improved pharmacological profiles may eventually be available as additional treatment options for the current epidemic of obesity, insulin resistance, type 2 diabetes, and all of the associated metabolic sequelae.
PPAR Res 2007
PMID:Therapeutic potential of retinoid x receptor modulators for the treatment of the metabolic syndrome. 1749 22


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