Deletion of GPR21 improves glucose homeostasis and inhibits the CCL2-CCR2 axis by divergent mechanisms

IntroductionA potential role for the orphan G protein-coupled receptor, GPR21, in linking immune cell infiltration into tissues and obesity-induced insulin resistance has been proposed, although limited studies in mice are complicated by non-selective deletion of Gpr21.Research design and methodsWe hypothesized that a Gpr21-selective knockout mouse model, coupled with type 2 diabetes patient samples, would clarify these issues and enable clear assessment of GPR21 as a potential therapeutic target.ResultsHigh-fat feeding studies in Gpr21−/− mice revealed improved glucose tolerance and modest changes in inflammatory gene expression. Gpr21−/− monocytes and intraperitoneal macrophages had selectively impaired chemotactic responses to monocyte chemoattractant protein (MCP)-1, despite unaltered expression of Ccr2. Further genotypic analysis revealed that chemotactic impairment was due to dysregulated monocyte polarization. Patient samples revealed elevated GPR21 expression in peripheral blood mononuclear cells in type 2 diabetes, which was correlated with both %HbA1c and fasting plasma glucose levels.ConclusionsCollectively, human and mouse data suggest that GPR21 influences both glucose homeostasis and MCP-1/CCL2-CCR2-driven monocyte migration. However, a Gpr21−/− bone marrow transplantation and high-fat feeding study in mice revealed no effect on glucose homeostasis, suggesting that there is no (or limited) overlap in the mechanism involved for monocyte-driven inflammation and glucose homeostasis.

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The effect of a short-term low-carbohydrate, high-fat diet with or without postmeal walks on glycemic control and inflammation in type 2 diabetes: a randomized trial

AJP Regulatory Integrative and Comparative Physiology ◽

10.1152/ajpregu.00240.2018 ◽

2018 ◽

Vol 315 (6) ◽

pp. R1210-R1219 ◽

Cited By ~ 8

Author(s):

Étienne Myette-Côté ◽

Cody Durrer ◽

Helena Neudorf ◽

Tyler D. Bammert ◽

José Diego Botezelli ◽

...

Keyword(s):

Type 2 Diabetes ◽

Glycemic Control ◽

Cell Activation ◽

Mononuclear Cells ◽

Immune Cell ◽

High Fat ◽

Peripheral Blood Mononuclear ◽

Time Interaction ◽

Low Carbohydrate

Lowering carbohydrate consumption effectively lowers glucose, but impacts on inflammation are unclear. The objectives of this study were to: 1) determine whether reducing hyperglycemia by following a low-carbohydrate, high-fat (LC) diet could lower markers of innate immune cell activation in type 2 diabetes (T2D) and 2) examine if the combination of an LC diet with strategically timed postmeal walking was superior to an LC diet alone. Participants with T2D ( n = 11) completed a randomized crossover study involving three 4-day diet interventions: 1) low-fat low-glycemic index (GL), 2) and 3) LC with 15-min postmeal walks (LC+Ex). Four-day mean glucose was significantly lower in the LC+Ex group as compared with LC (−5%, P < 0.05), whereas both LC+Ex (−16%, P < 0.001) and LC (−12%, P < 0.001) conditions were lower than GL. A significant main effect of time was observed for peripheral blood mononuclear cells phosphorylated c-Jun N-terminal kinase ( P < 0.001), with decreases in all three conditions (GL: −32%, LC: −45%, and LC+Ex: −44%). A significant condition by time interaction was observed for monocyte microparticles ( P = 0.040) with a significant decrease in GL (−76%, P = 0.035) and a tendency for a reduction in LC (−70%, P = 0.064), whereas there was no significant change in LC+Ex (0.5%, P = 0.990). Both LC (−27%, P = 0.001) and LC+Ex (−35%, P = 0.005) also led to significant reductions in circulating proinsulin. An LC diet improved 4-day glycemic control and fasting proinsulin levels when compared with GL, with added glucose-lowering benefits when LC was combined with postmeal walking.

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New Insights on the PBMCs Phospholipidome in Obesity Demonstrate Modulations Associated with Insulin Resistance and Glycemic Status

Nutrients ◽

10.3390/nu13103461 ◽

2021 ◽

Vol 13 (10) ◽

pp. 3461

Author(s):

Chloé Wilkin ◽

Megan Colonval ◽

Jonas Dehairs ◽

Nathalie Esser ◽

Margaud Iovino ◽

...

Keyword(s):

Insulin Resistance ◽

Type 2 Diabetes ◽

Mononuclear Cells ◽

Immune Cell ◽

Negative Relationship ◽

Peripheral Blood Mononuclear ◽

Cell Dysfunction ◽

Lipid Species ◽

And Function

(1) Background: Obesity and type 2 diabetes have been suspected to impact both intrinsic metabolism and function of circulating immune cells. (2) Methods: To further investigate this immunometabolic modulation, we profiled the phospholipidome of the peripheral blood mononuclear cells (PBMCs) in lean, normoglycemic obese (OBNG) and obese with dysglycemia (OBDysG) individuals. (3) Results: The global PBMCs phospholipidome is significantly downmodulated in OBDysG unlike OBNG patients when compared to lean ones. Multiple linear regression analyses show a strong negative relationship between the global PBMCs phospholipidome and parameters assessing insulin resistance. Even though all classes of phospholipid are affected, the relative abundance of each class is maintained with the exception of Lyso-PC/PC and Lyso-PE/PE ratios that are downmodulated in PBMCs of OBDysG compared to OBNG individuals. Interestingly, the percentage of saturated PC is positively associated with glycated hemoglobin (HbA1c). Moreover, a few lipid species are significantly downmodulated in PBMCs of OBDysG compared to OBNG individuals, making possible to distinguish the two phenotypes. (4) Conclusions: This lipidomic study highlights for the first-time modulations of the PBMCs phospholipidome in obese patients with prediabetes and type 2 diabetes. Such phospholipidome remodeling could disrupt the cell membranes and the lipid mediator’s levels, driving an immune cell dysfunction.

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Changes in Glycemia by Leptin Administration or High- Fat Feeding in Rodent Models of Obesity/Type 2 Diabetes Suggest a Link between Resistin Expression and Control of Glucose Homeostasis

Endocrinology ◽

10.1210/en.2003-1679 ◽

2004 ◽

Vol 145 (5) ◽

pp. 2206-2213 ◽

Cited By ~ 40

Author(s):

Cédric Asensio ◽

Philippe Cettour-Rose ◽

Claudia Theander-Carrillo ◽

Françoise Rohner-Jeanrenaud ◽

Patrick Muzzin

Keyword(s):

Type 2 Diabetes ◽

Glucose Homeostasis ◽

Rodent Models ◽

High Fat ◽

And Control ◽

Fat Feeding

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Increased Expression of Tissue Factor and Receptor for Advanced Glycation End Products in Peripheral Blood Mononuclear Cells of Patients With Type 2 Diabetes Mellitus with Vascular Complications

Experimental Diabesity Research ◽

10.1080/15438600490424325 ◽

2004 ◽

Vol 5 (2) ◽

pp. 163-169 ◽

Cited By ~ 8

Author(s):

A. E. Buchs ◽

A. Kornberg ◽

M. Zahavi ◽

D. Aharoni ◽

C. Zarfati ◽

...

Keyword(s):

Type 2 Diabetes ◽

Advanced Glycation End Products ◽

Mononuclear Cells ◽

Vascular Complications ◽

Advanced Glycation ◽

Peripheral Blood Mononuclear ◽

Glycation End Products ◽

End Products ◽

Blood Mononuclear Cells

The aim of the study was to determine the correlation between the expression of tissue factor (TF) and the receptor for advanced glycation end products (RAGEs) and vascular complications in patients with longstanding uncontrolled type 2 diabetes (T2D). TF and RAGE mRNAs as well as TF antigen and activity were investigated in 21 T2D patients with and without vascular complications. mRNA expression was assessed by reverse transcriptase–polymerase chain reaction (RT-PCR) in nonstimulated and advanced glycation end product (AGE) albumin–stimulated peripheral blood mononuclear cells (PBMCs). TF antigen expression was determined by enzyme-linked immunosorbent assay (ELISA) and TF activity by a modified prothrombin time assay. Basal RAGE mRNA expression was 0.2 ± 0.06 in patients with complications and 0.05 ± 0.06 patients without complications (P= .004). Stimulation did not cause any further increase in either group. TF mRNA was 0.58 ± 0.29 in patients with complications and 0.21 ± 0.18 in patients without complications (P= .003). Stimulation resulted in a nonsignificant increase in both groups. Basal TF activity (U/106PBMCs) was 18.4 ± 13.2 in patients with complications and 6.96 ± 5.2 in patients without complications (P= .003). It increased 3-fold in both groups after stimulation (P= .001). TF antigen (pg/106PBMCs) was 33.7 ± 28.6 in patients with complications, 10.4 ± 7.8 in patients without complications (P= .02). Stimulation tripled TF antigen in both groups of patients (P= .001). The RAGE/TF axis is up-regulated inT2Dpatients with vascular complications as compared to patients without complications. This suggests a role for this axis in the pathogenesis of vascular complications in T2D.

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Clinical significance of insulin peptide-specific interferon-γ-related immune responses in ketosis-prone type 2 diabetes

The Journal of Clinical Endocrinology & Metabolism ◽

10.1210/clinem/dgab912 ◽

2021 ◽

Author(s):

Atsushi Satomura ◽

Yoichi Oikawa ◽

Akifumi Haisa ◽

Seiya Suzuki ◽

Shunpei Nakanishi ◽

...

Keyword(s):

Type 2 Diabetes ◽

Immune Responses ◽

Elispot Assay ◽

Mononuclear Cells ◽

Cell Function ◽

Β Cell ◽

Peripheral Blood Mononuclear ◽

Β Cell Function ◽

Ifn Γ

Abstract Context Unprovoked A−β+ ketosis-prone type 2 diabetes (KPD) is characterized by the sudden onset of diabetic ketosis/ketoacidosis (DK/DKA) without precipitating factors, negative anti-islet autoantibodies (“A−”), and preservation of β-cell function (“β+”) after recovery from DKA. Although this phenotype often appears with acute hyperglycemia and DK/DKA just like acute-onset type 1 diabetes (AT1D), the involvement of anti-islet immune responses remains unknown. Objective We sought to clarify the immunological role of insulin-associated molecules in unprovoked A−β+ KPD. Methods In this cross-sectional study, blood samples from 75 participants (42 with AT1D and 33 with KPD) were evaluated for interferon (IFN)-γ-secreting peripheral blood mononuclear cells (PBMCs) reactive to four insulin B-chain amino acid 9–23-related peptides (B:9–23rPep) using an enzyme-linked immunospot (ELISpot) assay. Results Overall, 36.4% (12/33) of KPD participants showed positive IFN-γ ELISpot assay results; the positivity rate in KPD was similar to that in AT1D (38.1%; 16/42) and significantly higher than the previously reported rate in type 2 diabetes (8%; 2/25; P < 0.0167). Moreover, B:9–23rPep-specific IFN-γ-producing PBMC frequency was negatively correlated with age and ad lib serum C-peptide levels in all KPD participants and positively correlated with HbA1c level in KPD participants with positive IFN-γ ELISpot results. Conclusions These findings suggest the involvement of B:9–23rPep-specific IFN-γ-related immunoreactivity in the pathophysiology of some unprovoked A−β+ KPD. Moreover, increased immunoreactivity may reflect transiently decreased β-cell function and increased disease activity at the onset of DK/DKA, thereby playing a key role in DK/DKA development in this KPD phenotype.

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miR-145 improves metabolic inflammatory disease through multiple pathways

Journal of Molecular Cell Biology ◽

10.1093/jmcb/mjz015 ◽

2019 ◽

Vol 12 (2) ◽

pp. 152-162 ◽

Cited By ~ 7

Author(s):

Min He ◽

Nan Wu ◽

Man Cheong Leong ◽

Weiwei Zhang ◽

Zi Ye ◽

...

Keyword(s):

Type 2 Diabetes ◽

Therapeutic Strategy ◽

Mononuclear Cells ◽

Metabolic Diseases ◽

Diabetic Patients ◽

Peripheral Blood Mononuclear ◽

Reduced Body ◽

Type 2 Diabetics ◽

Induced Apoptosis

Abstract Chronic inflammation plays a pivotal role in insulin resistance and type 2 diabetes, yet the mechanisms are not completely understood. Here, we demonstrated that serum LPS levels were significantly higher in newly diagnosed diabetic patients than in normal control. miR-145 level in peripheral blood mononuclear cells decreased in type 2 diabetics. LPS repressed the transcription of miR-143/145 cluster and decreased miR-145 levels. Attenuation of miR-145 activity by anti-miR-145 triggered liver inflammation and increased serum chemokines in C57BL/6 J mice. Conversely, lentivirus-mediated miR-145 overexpression inhibited macrophage infiltration, reduced body weight, and improved glucose metabolism in db/db mice. And miR-145 overexpression markedly reduced plaque size in the aorta in ApoE−/− mice. Both OPG and KLF5 were targets of miR-145. miR-145 repressed cell proliferation and induced apoptosis partially by targeting OPG and KLF5. miR-145 also suppressed NF-κB activation by targeting OPG and KLF5. Our findings provide an association of the environment with the progress of metabolic disorders. Increasing miR-145 may be a new potential therapeutic strategy in preventing and treating metabolic diseases such as type 2 diabetes and atherosclerosis.

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DBC1, p300, HDAC3, and Siah1 coordinately regulate ELL stability and function for expression of its target genes

Proceedings of the National Academy of Sciences ◽

10.1073/pnas.1912375117 ◽

2020 ◽

Vol 117 (12) ◽

pp. 6509-6520 ◽

Cited By ~ 1

Author(s):

Subham Basu ◽

Mahesh Barad ◽

Dipika Yadav ◽

Arijit Nandy ◽

Bidisha Mukherjee ◽

...

Keyword(s):

Type 2 Diabetes ◽

Rna Polymerase Ii ◽

Target Genes ◽

Mononuclear Cells ◽

Elongation Factor ◽

Diabetes Patient ◽

Elongation Complex ◽

Peripheral Blood Mononuclear ◽

And Function

Among all of the Super Elongation Complex (SEC) components, ELL1 (also known as ELL) is the only bona fide elongation factor that directly stimulates transcription elongation by RNA polymerase II. However, the mechanism(s) of functional regulation of ELL1 (referred to as ELL hereafter), through its stabilization, is completely unknown. Here, we report a function of human DBC1 in regulating ELL stability involving HDAC3, p300, and Siah1. Mechanistically, we show that p300-mediated site-specific acetylation increases, whereas HDAC3-mediated deacetylation decreases, ELL stability through polyubiquitylation by the E3 ubiquitin ligase Siah1. DBC1 competes with HDAC3 for the same binding sites on ELL and thus increases its acetylation and stability. Knockdown of DBC1 reduces ELL levels and expression of a significant number of genes, including those involved in glucose metabolism. Consistently, Type 2 diabetes patient-derived peripheral blood mononuclear cells show reduced expression of DBC1 and ELL and associated key target genes required for glucose homeostasis. Thus, we describe a pathway of regulating stability and functions of key elongation factor ELL for expression of diverse sets of genes, including ones that are linked to Type 2 diabetes pathogenesis.

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