- Role of Protein Phosphatase 1 and Inhibitor of Protein Phosphatase-1 in Nitric Oxide-Dependent Inhibition of the DNA Damage Response in Pancreatic β-Cells. [Journal Article]
- DDiabetes 2018 Feb 14
- Nitric oxide is produced at micromolar levels by pancreatic β-cells during exposure to proinflammatory cytokines. While classically viewed as damaging, nitric oxide also activates pathways that promo...
Nitric oxide is produced at micromolar levels by pancreatic β-cells during exposure to proinflammatory cytokines. While classically viewed as damaging, nitric oxide also activates pathways that promote β-cell survival. We have shown that nitric oxide, in a cell type selective manner, inhibits the DNA damage response (DDR) and, in doing so, protects β-cells from DNA damage-induced apoptosis. This study explores potential mechanisms by which nitric oxide inhibits DDR signaling. We show that inhibition of DDR signaling (measured by γH2AX formation and the phosphorylation of KAP1) is selective for nitric oxide, as other forms of reactive oxygen/nitrogen species do not impair DDR signaling. The kinetics and broad range of DDR substrates that are inhibited suggest that protein phosphatase activation may be one mechanism by which nitric oxide attenuates DDR signaling in β-cells. While protein phosphatase 1 (PP1) is a primary regulator of DDR signaling and an inhibitor of protein phosphatase-1 (IPP-1) is selectively expressed only in β-cells, disruption of either IPP-1 or PP1 does not modify the inhibitory actions of nitric oxide on DDR signaling in β-cells. These findings support a PP1-independent mechanism by which nitric oxide selectively impairs DDR signaling and protects β-cells from DNA damage-induced apoptosis.
- Metabolic Syndrome is Associated with Impaired Diastolic Function Independently of Mri-Derived Myocardial Extracellular Volume: the Mesa Study. [Journal Article]
- DDiabetes 2018 Feb 14
- The relationship of MetS (metabolic syndrome) and insulin resistance (one of its key pathophysiological mediators) with diastolic dysfunction and myocardial fibrosis is not well understood. This stud...
The relationship of MetS (metabolic syndrome) and insulin resistance (one of its key pathophysiological mediators) with diastolic dysfunction and myocardial fibrosis is not well understood. This study aimed to evaluate the association of MetS with diastolic function and myocardial extracellular matrix (ECM) using cardiac magnetic resonance imaging (CMR) in a large community-based population.This cross-sectional analysis included 1,582 participants from the Multi-Ethnic Study of Atherosclerosis with left ventricular ejection fraction ≥50% and no past history of cardiac events. Diastolic function was assessed using tagged-CMR parameters including end-diastolic strain rate (EDSR) and strain relaxation index (SRI). ECM was evaluated using extracellular volume (ECV) quantification.Participants' mean age was 67.4±8.6 years and 48.1% were males. MetS was present in 533 individuals (33.7%) and type 2 diabetes in 250 (15.8%). In the multivariable analyses, MetS (irrespective of the presence of type 2 diabetes) and higher insulin resistance were associated with impaired diastolic function (higher SRI and lower EDSR), independently of ECV.In conclusion, MetS, irrespective of the presence of type 2 diabetes, was independently associated with impaired diastole. These functional myocardial changes seem to result from intrinsic cardiomyocytes' alterations, irrespective of the myocardial interstitium (including fibrosis).
- Regulation of KATPChannel Trafficking in Pancreatic β Cells by Protein Histidine Phosphorylation. [Journal Article]
- DDiabetes 2018 Feb 12
- Protein histidine phosphatase 1 (PHPT-1) is an evolutionarily conserved 14 kDa protein that dephosphorylates phosphohistidine.PHPT-1-/- mice were generated to gain insight into the role of PHPT-1 and...
Protein histidine phosphatase 1 (PHPT-1) is an evolutionarily conserved 14 kDa protein that dephosphorylates phosphohistidine.PHPT-1-/- mice were generated to gain insight into the role of PHPT-1 and histidine phosphorylation/dephosphorylation in mammalian biology.PHPT-1 -/- mice exhibited neonatal hyperinsulinemic hypoglycemia due to impaired trafficking of KATPchannels to the plasma membrane in pancreatic β cells in response to low glucose and leptin and resembled patients with congenital hyperinsulinism (CHI). The defect in KATPchannel trafficking in PHPT-1-/-β cells was due to the failure of PHPT-1 to directly activate transient receptor potential channel 4 (TRPC4) resulting in decreased Ca2+influx and impaired downstream activation of AMPK. Thus, these studies demonstrate a critical role for PHPT-1 in normal pancreatic β cell function and raise the possibility that mutations in PHPT-1 and/or TRPC4 may account for yet to be defined cases of CHI.
- Perilipin 3 Deficiency Stimulates Thermogenic Beige Adipocytes Through PPARα Activation. [Journal Article]
- DDiabetes 2018 Feb 13
- Beige adipocytes can dissipate energy as heat. Elaborate communication between metabolism and gene expression is important in the regulation of beige adipocytes. While lipid droplet (LD)-binding prot...
Beige adipocytes can dissipate energy as heat. Elaborate communication between metabolism and gene expression is important in the regulation of beige adipocytes. While lipid droplet (LD)-binding proteins play important roles in adipose tissue biology, it remains unknown whether perilipin 3 (Plin3) is involved in the regulation of beige adipocyte formation and thermogenic activities. Here, we demonstrate thatPlin3ablation stimulates beige adipocytes and thermogenic gene expression in inguinal white adipose tissue (iWAT). Compared to wild-type mice,Plin3knockout mice were cold-tolerant and displayed enhanced basal and stimulated lipolysis in iWAT, inducing PPARα activation. In adipocytes,Plin3deficiency promoted PPARα target gene and UCP1 expression and multilocular LD formation upon cold stimulus. Moreover, FGF21 expression and secretion were upregulated, which was attributable to activated PPARα inPlin3-deficient adipocytes. These data suggest thatPlin3acts as an intrinsic protective factor preventing futile beige adipocyte formation by limiting lipid metabolism and thermogenic gene expression.
- Elevated Medium Chain-Acylcarnitines are Associated with Gestational Diabetes, and Early Progression to Type-2 Diabetes, and Induce Pancreatic β-Cell Dysfunction. [Journal Article]
- DDiabetes 2018 Feb 07
- Specific circulating metabolites have emerged as important risk factors for the development of diabetes. The acylcarnitines (acylCs) are a family of metabolites known to be elevated in type-2 diabete...
Specific circulating metabolites have emerged as important risk factors for the development of diabetes. The acylcarnitines (acylCs) are a family of metabolites known to be elevated in type-2 diabetes (T2D) and linked to peripheral insulin resistance. However, the impact of AcylCs on pancreatic β-cell function is not well understood. Here, we profiled circulating acylCs in two diabetes cohorts: 1) women with gestational diabetes (GDM) and 2) women with recent GDM who later developed impaired glucose tolerance (IGT), new-onset T2D or returned to normoglycemia within a two-year follow-up period. We observed a specific elevation in serum medium chain (M)-acylCs, particularly hexanoyl- and octanoylcarnitine among women with GDM and individuals with T2D without alteration in long (L)-acylCs. Mice treated with M-acylCs exhibited glucose intolerance, attributed to impaired insulin secretion. Murine and human islets exposed to elevated levels of M-acylCs developed defects in glucose-stimulated insulin secretion and this was directly linked to reduced mitochondrial respiratory capacity and subsequent ability to couple glucose metabolism to insulin secretion. In conclusion, our study reveals that an elevation in circulating M-acylCs is associated with GDM and early stages of T2D onset, and that this elevation directly impairs β-cell function.
- CDKN2A/B T2D GWAS Risk-SNPs Impact Locus Gene Expression and Proliferation in Human Islets. [Journal Article]
- DDiabetes 2018 Feb 06
- Genome-wide association studies link theCDKN2A/Blocus with T2D risk, but mechanisms increasing risk remain unknown. TheCDKN2A/Blocus encodes cell cycle inhibitorsp14,p15, andp16, MTAP,andANRIL, a lnc...
Genome-wide association studies link theCDKN2A/Blocus with T2D risk, but mechanisms increasing risk remain unknown. TheCDKN2A/Blocus encodes cell cycle inhibitorsp14,p15, andp16, MTAP,andANRIL, a lncRNA. The goal of this study was to determine whetherCDKN2A/BT2D risk-SNPs impact locus gene expression, insulin secretion, or beta cell proliferation, in human islets. Islets from non-diabetic donors (n=95) were tested for SNP genotype (rs10811661,rs2383208,rs564398,rs10757283), gene expression (p14,p15,p16,MTAP,ANRIL,PCNA,KI67,CCND2), insulin secretion (n=61) and beta cell proliferation (n=47). Intriguingly, locus genes were co-regulated in islets in two physically overlapping cassettes:p14-p16-ANRIL, which increased with age, andMTAP-p15, which did not. Risk-alleles atrs10811661andrs2383208were differentially associated with expression ofANRIL, but notp14,p15, p16orMTAP, in age-dependent fashion, such that younger homozygous-risk donors had higherANRILexpression, equivalent to older donor levels. We identified several risk-SNP haplotype combinations that may impact locus gene expression, suggesting possible mechanisms by which SNPs impact locus biology. Risk-allele carriers atANRILcoding SNPrs564398had reduced beta cell proliferation index. In conclusion,CDKN2A/Blocus SNPs may impact T2D risk by modulating islet gene expression and beta cell proliferation.
- Catestatin Inhibits Obesity-Induced Macrophage Infiltration and Inflammation in the Liver and Suppresses Hepatic Glucose Production Leading to Improved Insulin Sensitivity. [Journal Article]
- DDiabetes 2018 Feb 06
- The activation of Kupffer cells (KCs) and monocyte (Mc)-derived recruited macrophages (McMΦs) in the liver contributes to obesity-induced insulin resistance and type 2 diabetes. Diet-induced obese (D...
The activation of Kupffer cells (KCs) and monocyte (Mc)-derived recruited macrophages (McMΦs) in the liver contributes to obesity-induced insulin resistance and type 2 diabetes. Diet-induced obese (DIO) mice treated with Chromogranin A (CgA) peptide catestatin (CST) showed several positive results. These included decreased hepatic/plasma lipids and plasma insulin, diminished expression of gluconeogenic genes, attenuated expression of pro-inflammatory genes, increased expression of anti-inflammatory genes in McMΦs, and inhibition of the infiltration of McMΦs resulting in improvement of insulin sensitivity. Systemic CST knockout (CST-KO) mice on normal chow diet (NCD) ate more food, gained weight, and displayed elevated blood glucose and insulin levels. Supplementation of CST normalized glucose and insulin levels. To verify that the CST deficiency caused macrophages to be very pro-inflammatory in CST-KO-NCD mice and produced glucose intolerance, we tested the effects of FACS-sorted F4/80+Ly6C-cells (representing KCs) and F4/80-Ly6C+cells (representing McMΦs) on hepatic glucose production (HGP). Both basal and glucagon-induced HGP was markedly increased in hepatocytes co-cultured with KCs and McMΦs from NCD-fed CST-KO mice, and the effect was abrogated upon pre-treatment of CST-KO-MΦs with CST. Thus, we provide a novel mechanism of HGP suppression through CST-mediated inhibition of macrophage infiltration and function.
- PDGF-BB Carried by Endothelial Cell-derived Extracellular Vesicles Reduces Vascular Smooth Muscle Cell Apoptosis in Diabetes. [Journal Article]
- DDiabetes 2018 Jan 31
- Endothelial cell-derived extracellular vesicles (CD31EVs) are a new entity for therapeutic/prognostic purposes. The roles of CD31EVs as mediators of smooth muscle cell (VSMC) dysfunction in type 2 di...
Endothelial cell-derived extracellular vesicles (CD31EVs) are a new entity for therapeutic/prognostic purposes. The roles of CD31EVs as mediators of smooth muscle cell (VSMC) dysfunction in type 2 diabetes (T2D) is investigated herein.We demonstrated that, unlike non-diabetic, diabetic serum-derived-EVs (D-CD31EVs) boosted apoptosis resistance of VSMCs cultured in hyperglycaemic condition. Biochemical analysis revealed that this effect relies on changes in the balance between anti-apoptotic/pro-apoptotic signals: increase of bcl-2 and decrease of bak/bax. D-CD31EV cargo analysis demonstrated that D-CD31EVs are enriched in membrane-bound-platelet-derived-growth-factor-BB (mbPDGF-BB). Thus, we postulated that mbPDGF-BB transfer by D-CD31EVs could account for VSMC resistance to apoptosis. By depleting CD31EVs of PDGF-BB or blocking the PDGF-BB-receptorβ on VSMCs, we demonstrated that mbPDGF-BB contributes to D-CD31EV-mediated bak/bax and bcl-2 levels. Moreover, we found that bak expression is under the control of PDGF-BB-mediated miR-296-5p expression. In fact, while PDGF-BB-treatment recapitulated D-CD31EV-mediated anti-apoptotic program and VSMC resistance to apoptosis, PDGF-BB-depleted CD31EVs failed. D-CD31EVs also increased VSMC migration and recruitment to neovessels, by means of PDGF-BB. Finally, we found that VSMCs, from human atherosclerotic arteries of T2D individuals, express low bak/bax and high bcl-2 and miR-296-5p levels.This study identifies the mbPDGF-BB in D-CD31EVs as a relevant mediator of diabetes-associated VSMC resistance to apoptosis.
- Long Non-coding RNA LncSHGL Recruits hnRNPA1 to Suppress Hepatic Gluconeogenesis and Lipogenesis. [Journal Article]
- DDiabetes 2018 Jan 30
- Mammalian genomes encode a huge number of LncRNAs with unknown functions. This study determined the role and mechanism of a new LncRNA, LncRNA Suppressor of Hepatic Gluconeogenesis and Lipogenesis (L...
Mammalian genomes encode a huge number of LncRNAs with unknown functions. This study determined the role and mechanism of a new LncRNA, LncRNA Suppressor of Hepatic Gluconeogenesis and Lipogenesis (LncSHGL), in regulating hepatic glucose/lipid metabolism. In the livers of obese mice and NAFLD patient, the expression levels of mouse LncSHGL and its human homologous LncRNA B4GALT1-AS1 were reduced. Hepatic LncSHGL restoration improved hyperglycemia, insulin resistance and steatosis in obese diabetic mice, whereas hepatic LncSHGL inhibition promoted fasting hyperglycemia and lipid deposition in normal mice. LncSHGL overexpression increased Akt phosphorylation, and repressed gluconeogenic and lipogenic gene expression in obese mouse livers, whereas LncSHGL inhibition exerted the opposite effects in normal mouse livers. Mechanistically, LncSHGL recruited hnRNPA1 to enhance the translation efficiency of CALM mRNAs to increase CaM protein level without affecting their transcription, leading to the activation of PI3K/Akt pathway and repression of mTOR/SREBP-1C pathway independent of insulin and calcium in hepatocytes. Hepatic hnRNPA1 overexpression also activated CaM/Akt pathway and repressed mTOR/SREBP-1C pathway to ameliorate hyperglycemia and steatosis in obese mice. In conclusion, LncSHGL is a novel insulin-independent suppressor of hepatic gluconeogenesis and lipogenesis. Activating LncSHGL/hnRNPA1 axis represents a potential strategy for the treatment of type 2 diabetes and steatosis.
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- Perilipin 5 Deletion Unmasks an Endoplasmic Reticulum Stress - Fibroblast Growth Factor 21 Axis in Skeletal Muscle. [Journal Article]
- DDiabetes 2018 Jan 29
- Lipid droplets are critical for the regulation of lipid metabolism, and dysregulated lipid metabolism contributes to the pathogenesis of several diseases including type 2 diabetes. We generated mice ...
Lipid droplets are critical for the regulation of lipid metabolism, and dysregulated lipid metabolism contributes to the pathogenesis of several diseases including type 2 diabetes. We generated mice with muscle-specific deletion of the lipid droplet-associated protein, perilipin 5 (PLIN5,Plin5MKO ), and investigated PLIN5's role in regulating skeletal muscle lipid metabolism, intracellular signalling and whole-body metabolic homeostasis. High-fat feeding induced changes in muscle lipid metabolism ofPlin5 MKO mice, which included increased fatty acid oxidation and oxidative stress, but surprisingly, a reduction in inflammation and endoplasmic reticulum (ER) stress. These muscle-specific effects were accompanied by whole-body glucose intolerance, adipose tissue insulin resistance, and reduced circulating insulin and C-peptide levels inPlin5 MKO mice. This coincided with reduced secretion of fibroblast growth factor (FGF) 21 from skeletal muscle and liver, resulting in reduced circulating FGF21. Intriguingly, muscle-secreted factors fromPlin5 MKO , but not wild-type mice, reduced hepatocyte FGF21 secretion. Exogenous correction of FGF21 levels restored glycemic control and insulin secretion inPlin5 MKO mice. These results show that changes in lipid metabolism resulting from PLIN5 deletion reduce ER stress in muscle, decrease FGF21 production by muscle and liver, and impair glycemic control. Further, these studies highlight the importance for muscle-liver cross talk in metabolic regulation.