Insulin Resistance and Type 2 Diabetes

Taylor, Roy

doi:10.2337/db12-0073

Cited by 297 publications

(209 citation statements)

References 22 publications

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“…Based on recently accumulated evidence [163,164] , it was concluded that glucose-responsive β cells normally regulate juxtaposed α cells and that without intraislet insulin, unregulated α cells hypersecrete glucagon, which directly causes the symptoms of diabetes. Although patients with type 1 diabetes have an absolute deficiency of insulin, the pathogenesis of type 2 diabetes mellitus is associated with relative insulin deficiency and insulin resistance [165][166][167] . Therefore, in addition to insulin, a number of different classes of medication to treat patients with diabetes have been developed.…”

Section: New Strategies To Improve Glycemic Control In Diabetesmentioning

confidence: 99%

Diabetes-related alterations in the enteric nervous system and its microenvironment

Bagyánszki

Bódi²

2012

WJD

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Gastric intestinal symptoms common among diabetic patients are often caused by intestinal motility abnormalities related to enteric neuropathy. It has recently been demonstrated that the nitrergic subpopulation of myenteric neurons are especially susceptible to the development of diabetic neuropathy. Additionally, different susceptibility of nitrergic neurons located in different intestinal segments to diabetic damage and their different levels of responsiveness to insulin treatment have been revealed. These findings indicate the importance of the neuronal microenvironment in the pathogenesis of diabetic nitrergic neuropathy. The main focus of this review therefore was to summarize recent advances related to the diabetes-related selective nitrergic neuropathy and associated motility disturbances. Special attention was given to the findings on capillary endothelium and enteric glial cells. Growing evidence indicates that capillary endothelium adjacent to the myenteric ganglia and enteric glial cells surrounding them are determinative in establishing the ganglionic microenvironment. Additionally, recent advances in the development of new strategies to improve glycemic control in type 1 and type 2 diabetes mellitus are also considered in this review. Finally, looking to the future, the recent and promising results of metagenomics for the characterization of the gut microbiome in health and disease such as diabetes are highlighted.

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Section: New Strategies To Improve Glycemic Control In Diabetesmentioning

confidence: 99%

Diabetes-related alterations in the enteric nervous system and its microenvironment

Bagyánszki

Bódi²

2012

WJD

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“…In an AD study, an unrestricted high-fat diet increased GSK3 activity in mouse brains (56). GSK3-phosphorylated IRS1 causes IRS1 to be degraded (47), leading to less IRS1 and thus insulin resistance (41), which develops into T2D (57). Our data show the dual effects on IRS1 degradation, namely, high GSK3 activity and dissociation of PLIN2/IRS1 by long-term OA treat-ment.…”

Section: Discussionmentioning

confidence: 62%

Natural Functions of PLIN2 Mediating Wnt/LiCl Signaling and Glycogen Synthase Kinase 3 (GSK3)/GSK3 Substrate-Related Effects Are Modulated by Lipid

Liu

Song

et al. 2016

Molecular and Cellular Biology

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Belonging to the PLIN family, PLIN2 associates with lipid storage droplets (LSDs), but other functions of PLIN2 remain unclear. Here, we suggest that PLIN2 mediates Wnt signaling because PLIN2 small interfering RNA (siRNA) suppresses activation of Wnt/coreceptor pathways. The mediation in the Wnt/Frizzled pathway seems to occur from Dishevelleds to axin/glycogen synthase kinase 3(GSK3)/␤-catenin complexes (AG␤C) as Wnt decreases Dishevelled/PLIN2 but increases AG␤C/PLIN2 associations. Augmenting cellular LSDs that affect PLIN2 associations with these proteins, oleic acid (OA) treatment inhibits Wnt-increased AG␤C/PLIN2 associations and ␤-catenin T-cell factor signaling (␤-CTS). Revealing that PLIN2 is a GSK3-associated protein, the study explored PLIN2-mediated effects on GSK3/GSK3 substrates. PLIN2 siRNA reduces inhibitory GSK3 levels and lithium chloride (LiCl)-upregulated ␤-catenin or CCAAT/enhancer binding protein ␣ (c/EBP␣) expression. OA treatment decreases LiCl-increased c/EBP␣ via PLIN2-c/EBP␣ dissociation. In addition to PLIN2 overexpression increasing ␤-CTS, PLIN2 depletion or overexpression drops or adds expression of GSK3 substrates, such as ␤-catenin, c/EBP␣,c-Myc, cyclin D1, and insulin receptor substrate 1, and cell growth/survival. PLIN2 N or C terminus overexpression that is associated with higher levels of the substrates suggests that those substrates bind to specific regions of PLIN2. Mimicking the possible high lipid concentrations in cells in the human body under conditions of hyperlipidemia/obesity, OA-treated cells gain or reduce GSK3 substrate expression in parallel with a decrease (a Wnt-like effect) or increase in GSK3 activity, likely regulated by GSK3/PLIN2/GSK3 substrate associations. The PLIN family members are expressed in many species, including mammals, Drosophila, and Dictyostelium (1-6), where they associate with intracellular neutral lipid storage droplets (LSDs) and control cellular lipolytic activity (1-6). Strong sequence identity is found in PLIN proteins at their amino termini, whereas similarity in most of their other sequences is lower (1-6). In the PLIN family, PLIN2 (ADRP) and PLIN3 (TIP47) are ubiquitously distributed in cells of mammals and are the most closely related (1-6). The functions of the PLIN proteins other than the regulation of lipolysis are undefined (1-6).Wnt signaling that activates ␤-catenin/TCF signaling (␤-CTS) is crucial to many metazoan developmental processes (7-10). Without Wnt, adenomatous polyposis coli (APC) and axins scaffold with glycogen synthase kinase 3␤ (GSK3␤) and ␤-catenin, causing ␤-catenin phosphorylation and degradation, but Wnt ligands bind to coreceptors of Frizzled (Fz) and low-density lipoprotein (LDL) receptor-related proteins 5/6 (LRP5/6), which mediates the destabilization of the protein interactions within the axin/GSK3␤/␤-catenin complexes (AG␤C). Being no longer accessible to phosphorylation by GSK3␤, ␤-catenin is accumulated and is able to interact with lymphoid enhancer factor/T-cell factor (LEF/TCF) to promote expressi...

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“…First, although T2DM patients have different physiologic status from healthy subjects with respect to insulin sensitivity and glucagon regulation, our study was conducted in healthy subjects to minimize con founding factors. [16,17] However, we assumed that the effect of PMAT genetic polymorphism on the pharmacokinetics of metformin varies minimally between subject groups if the transporter is not affected by the disease state. This may not be true in some cases since our study had used two different doses Effect of PMAT genetic variants on metformin pharmacokinetics doses of metformin; the pharmacokinetic saturation of metformin could have been affected by different genotypes that administered different metformin doses.…”

Section: Discussionmentioning

confidence: 99%

Effect of plasma membrane monoamine transporter genetic variants on pharmacokinetics of metformin in humans

Moon

Lee

et al. 2018

Transl Clin Pharmacol

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Metformin, an oral hypoglycemic agent belonging to biguanide class, is widely used to treat type 2 diabetes mellitus, and several drug transporters such as organic cation transporters (OCTs), multidrug and toxin extrusion transporter (MATE), and plasma membrane monoamine transporter (PMAT) are thought to affect its disposition. We evaluated the role of PMAT genetic variations on the pharmacokinetic characteristics of metformin in a Korean population. In this retrospective study, 91 healthy subjects from four different metformin pharmacokinetic studies were analyzed; in each study, the subjects were administered two oral doses of metformin at intervals of 12 hours and dose-normalized pharmacokinetic parameters were compared between the subjects' genotypes. Subjects who had more than one allele of c.883-144A>G single nucleotide polymorphism (SNP) in PMAT gene (rs3889348) showed increased renal clearance of metformin compared to wild-type subjects (814.79 ± 391.73 vs. 619.90 ± 195.43 mL/min, p=0.003), whereas no differences in metformin exposure were observed between the PMAT variant subjects and wild-type subjects. Similarly, subjects with variant rs316019 SNP in OCT2 showed decreased renal clearance of metformin compared to wild-type subjects (586.01 ± 160.54 vs. 699.13 ± 291.40 mL/min, p=0.048). Other SNPs in PMAT and MATE1/2-K genes did not significantly affect metformin pharmacokinetics. In conclusion, the genetic variation of c.883-144A>G SNP in PMAT significantly affects the renal clearance of metformin in healthy Korean male subjects.

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Insulin Resistance and Type 2 Diabetes

Cited by 297 publications

References 22 publications

Diabetes-related alterations in the enteric nervous system and its microenvironment

Diabetes-related alterations in the enteric nervous system and its microenvironment

Natural Functions of PLIN2 Mediating Wnt/LiCl Signaling and Glycogen Synthase Kinase 3 (GSK3)/GSK3 Substrate-Related Effects Are Modulated by Lipid

Effect of plasma membrane monoamine transporter genetic variants on pharmacokinetics of metformin in humans

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