Sweet Killing in Obesity and Diabetes: The Metabolic Role of the BH3-only Protein BIM

Miani, Michela; Elvira, Bernat; Gurzov, Esteban Nicolas

doi:10.1016/j.jmb.2018.07.022

Cited by 10 publications

(7 citation statements)

References 96 publications

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“…The inhibitory effects of miR-222-3p on Bim were evidenced by the increase in the expression of Bim after inhibition of miR-222-3p in macrophages. Bim has been found to act as a key mediator of both pancreatic β-cell death and hepatic insulin resistance and is thus a potential therapeutic target for diabetes [47]. We found in our study that as e cient protectors against β-cell death and insulin resistance, Exos Lean induced miR-222-3p activation, thus leading to Bim inhibition.…”

Section: Discussionsupporting

confidence: 52%

Lean Adipose Tissue Macrophage Derived Exosome Confers Immunoregulation to Improve Wound Healing in Diabetes

Xia

Liu

Jiang

et al. 2022

Preprint

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Chronic non-healing wounds, an important complication of diabetes, are associated with increased mortality in patients afflicted with this disease. Excessive accumulation of M1 macrophages in diabetic wounds promotes inflammation and results in dysregulated tissue repair. Adipose tissue macrophages (ATMs) derived from healthy lean donors have the abilities to improve glucose tolerance and insulin sensitivity, and modulate inflammation. MiRNAs (miRs), which can be packaged into exosomes (Exos) and secreted from cells, serve as essential regulators of macrophage polarization. Here, we reveal that adipose tissue macrophages (ATMs) isolated from lean mice secrete miR-containing Exos, which modulate macrophage polarization and promote rapid diabetic wound healing when administered to diabetes-prone db/db mice. MiRs sequence of tissue samples from wounds treated with Exos secreted by lean ATMs (ATM-Exos) revealed that miR-222-3p was upregulated. Further analyses showed that inhibition of miR-222-3p using miR inhibitor impaired the macrophage-reprogramming effect of lean ATM-Exos. In the excisional skin wound mouse model, locally inhibiting miR-222-3p disrupted healing dynamics and failed to modulate macrophage polarization. Mechanistic studies revealed a link between miR-222-3p; Bcl2l11/Bim, an inflammatory response effector; macrophage polarization; and diabetic wound healing. In summary, lean ATM-Exos act as positive regulators of macrophage polarization by regulating miR levels in wounds and accelerating wound healing and thus have important implications for wound management in diabetes.

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Section: Discussionsupporting

confidence: 52%

Lean Adipose Tissue Macrophage Derived Exosome Confers Immunoregulation to Improve Wound Healing in Diabetes

Xia

Liu

Jiang

et al. 2022

Preprint

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“…6a). Culture of MIN6 cells and primary mouse islets with palmitate resulted in an increase in the levels of proapoptotic proteins BIM and PUMA, which are members of BH3 family of proteins that regulate cellular apoptosis 37,38 (Fig. 6b, c).…”

Section: Smad3 and Foxo1 Interaction During β-Cell Apoptosismentioning

confidence: 99%

Protection from β-cell apoptosis by inhibition of TGF-β/Smad3 signaling

et al. 2020

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Prevailing insulin resistance and the resultant hyperglycemia elicits a compensatory response from pancreatic islet beta cells (β-cells) that involves increases in β-cell function and β-cell mass. However, the sustained metabolic stress eventually leads to β-cell failure characterized by severe β-cell dysfunction and progressive loss of β-cell mass. Whereas, β-cell dysfunction is relatively well understood at the mechanistic level, the avenues leading to loss of β-cell mass are less clear with reduced proliferation, dedifferentiation, and apoptosis all potential mechanisms. Butler and colleagues documented increased β-cell apoptosis in pancreas from lean and obese human Type 2 diabetes (T2D) subjects, with no changes in rates of β-cell replication or neogenesis, strongly suggesting a role for apoptosis in β-cell failure. Here, we describe a permissive role for TGF-β/Smad3 in β-cell apoptosis. Human islets undergoing β-cell apoptosis release increased levels of TGF-β1 ligand and phosphorylation levels of TGF-β's chief transcription factor, Smad3, are increased in human T2D islets suggestive of an autocrine role for TGF-β/Smad3 signaling in β-cell apoptosis. Smad3 phosphorylation is similarly increased in diabetic mouse islets undergoing β-cell apoptosis. In mice, β-cell-specific activation of Smad3 promotes apoptosis and loss of β-cell mass in association with β-cell dysfunction, glucose intolerance, and diabetes. In contrast, inactive Smad3 protects from apoptosis and preserves β-cell mass while improving β-cell function and glucose tolerance. At the molecular level, Smad3 associates with Foxo1 to propagate TGF-β-dependent β-cell apoptosis. Indeed, genetic or pharmacologic inhibition of TGF-β/Smad3 signals or knocking down Foxo1 protects from β-cell apoptosis. These findings reveal the importance of TGF-β/Smad3 in promoting β-cell apoptosis and demonstrate the therapeutic potential of TGF-β/Smad3 antagonism to restore β-cell mass lost in diabetes.

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“…The release of cytochrome c by mitochondria into the cytoplasm is an important step of mitochondrial apoptosis. The following activation phase of initiator caspase-9 is important, causing cleavage of executive caspases-3/7 36,39 . Proteins in the Bcl-2 family are involved in mitochondrial integrity 36,40,41 .…”

Section: Discussionmentioning

confidence: 99%

Investigation of the relationship between NFKB1 polymorphisms and telomere length and apoptosis in patients with type-2 diabetes

Dirican

Kaya

2023

Cukurova Medical Journal

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Purpose: Type 2 diabetes mellitus (T2DM) is a heterogeneous, chronic, and metabolic disease that affects a significant proportion of the global population. This study aimed to evaluate the effect of NFKB1 -94 ATTG ins/del polymorphisms on the expression of apoptosis genes and telomere length (TL) in patients with T2DM compared with healthy individuals. Materials and Methods: Sixty-nine T2DM patients and sixty healthy people were enrolled in the study. DNA and RNA were isolated from the blood samples. NFKB1 genotypes were identified by Sanger sequencing. For TL analyses and to investigate the expression of the caspase-3, caspase-9, bax, and bcl2 genes, RT-PCR was utilized. Results: There was a significant difference between the NFKB1 -94 ins/del genotype patients and the control group (OR:0.4792 (0.2345-1.011)). However, the distribution of other genotype/alleles (ins/ins and del/del) showed no difference between T2DM and control groups. The allelic frequency of NFKB1 -94 ins/del was 0.455/0.235 for the T2DM group and 0.435/0.165 for the control group. An increase in the mRNA expression of caspase-3, caspase-9 and Bax genes was observed in the T2DM group compared with the healthy group, while a decrease in the Bcl2 gene was found in the T2DM group. TL in T2DM patients was shorter than in healthy individuals. Conclusion: NFKB1 -94 ins/del polymorphisms show significant differences in T2DM patients. We observed that apoptosis was activated and TL was shortened in patients with T2DM. However, no relationship between NFKB1 polymorphisms and apoptosis and TL could not be determined.

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Sweet Killing in Obesity and Diabetes: The Metabolic Role of the BH3-only Protein BIM

Cited by 10 publications

References 96 publications

Lean Adipose Tissue Macrophage Derived Exosome Confers Immunoregulation to Improve Wound Healing in Diabetes

Lean Adipose Tissue Macrophage Derived Exosome Confers Immunoregulation to Improve Wound Healing in Diabetes

Protection from β-cell apoptosis by inhibition of TGF-β/Smad3 signaling

Investigation of the relationship between NFKB1 polymorphisms and telomere length and apoptosis in patients with type-2 diabetes

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