Time for a paradigm shift in treating type 1 diabetes mellitus: coupling inflammation to islet regeneration

Cobo-Vuilleumier, Nadia; Gauthier, Benoit R.

doi:10.1016/j.metabol.2020.154137

Cited by 24 publications

(33 citation statements)

References 147 publications

(181 reference statements)

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“…This growth factor along with a subset of genes implicated in cytoskeletonintegrin connection previously shown to be involved in wound healing were down regulated in siHMG20A treated astrocytes. Taken together these molecular data further support our model that HMG20A likely potentiates the degree of astrogliosis promoting an anti-inflammatory and pro-regenerative phenotype, analogous to our recent studies establishing the role of the orphan nuclear receptor LRH-1/NR5A2 in immunomodulation and trans-regeneration of islet beta cells [39,67,68].…”

Section: Discussionsupporting

confidence: 89%

The Metabesity Factor HMG20A Potentiates Astrocyte Survival and Reactivity Preserving Neuronal Integrity

Lorenzo

Fuente-Martín

Mellado-Gil

et al. 2021

Preprint

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Rationale: We recently demonstrated that the Metabesity factor HMG20A regulates islet beta-cell functional maturity and adaptation to physiological stress such as pregnancy and pre-diabetes. HMG20A also dictates central nervous system (CNS) development via inhibition of the LSD1/CoREST complex but its expression pattern and function in the adult brain remains unknown. Herein we sought to determine whether HMG20A is expressed in the adult CNS, specifically in hypothalamic astrocytes that are key in glucose homeostasis and whether similar to islets, HMG20A potentiates astrocyte function in response to environmental cues. Methods: HMG20A expression profile was assessed by quantitative PCR (RT-PCR) and/or immunofluorescence in 1) the hypothalamus of mice exposed or not to a high-fat diet, 2) human blood leukocytes and adipose tissue obtained from healthy or diabetic individuals 3) primary mouse hypothalamic astrocytes exposed to either high glucose or palmitate. To investigate the function and regulatory mechanism of HMG20A, RNA-seq and cell metabolic parameters were performed on astrocytes treated or not with a siHMG20A. The regulatory function of HMG20A on astrogliosis was also assessed pharmacologically using ORY1001. Astrocyte-mediated neuronal survival was evaluated using conditioned media from siHMG20A-treated astrocytes. Results: We show that Hmg20a is predominantly expressed in hypothalamic astrocytes, the main nutrient-sensing cell type of the brain. Hmg20A expression was upregulated in diet-induced obesity and glucose-intolerant mice, correlating with increased transcript levels of Gfap and Il1b indicative of inflammation and astrogliosis. Expression levels were also increased in adipose tissue of obese non-diabetic individuals as compared to obese diabetic patients. HMG20A silencing in astrocytes resulted in repression of inflammatory, cholesterol biogenesis and epithelial-to-mesenchymal transition pathways with a concomitant increase in apoptosis and reduced mitochondrial bioenergetics. Motoneuron viability was also hindered in HMG20A-depleted astrocyte-derived conditioned media. Astrogliosis was induced using ORY1001, a pharmacological inhibitor of the LSD1/CoREST complex, mimicking the effect of HMG20A. Conclusion: HMG20A coordinates the astrocyte polarization state. Under physiological pressure such as obesity and insulin resistance that induces low-grade inflammation, HMG20A expression is increased to induce astrogliosis in an attempt to preserve the neuronal network and glucose homeostasis. Nonetheless, a chronic metabesity state or functional mutations will result in lower levels of HMG20A, failure to promote astrogliosis and increase the susceptibility of neurons to stress-mediated apoptosis. Such effects could be therapeutically reversed by ORY1001-induced astrogliosis.

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Section: Discussionsupporting

confidence: 89%

The Metabesity Factor HMG20A Potentiates Astrocyte Survival and Reactivity Preserving Neuronal Integrity

Lorenzo

Fuente-Martín

Mellado-Gil

et al. 2021

Preprint

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“…Remarkably, in a mouse model of experimental autoimmune diabetes, BL001-mediated β-cell regeneration occurred concomitantly with the expansion of the anti-inflammatory Tregs and T helper 2, and primed macrophages towards the immunosuppressive and tissue remodeling M2 phenotype [82]. Interestingly, the abundance of the bihormonal INS+/GCG+ cells after BL001 treatment in this mouse model was markedly higher than in the STZ model, indicating the important contribution of Tregs and M2 macrophages in αto β-cell transdifferentiation [82,84]. Supporting this immunecoupled β-cell regeneration, the combined therapy of induction of MHC-mismatched mixed chimerism to attenuate the immune response together with gastrin and EGF administration resulted in β-cell regeneration and glucose homeostasis recovery in firmly established diabetic NOD mice [85].…”

Section: Can Gaba Stimulate αTo β-Cell Transdifferentiation?mentioning

confidence: 78%

“…Lineage-tracing studies revealed that αto β-cell transdifferentiation is the major source of β-cells, which only reaches these levels of activation after attenuation of the immune response [85]. This integrated non-mutually exclusive and mandatory islet-immune dialogue may provide some clues on failures of clinical trials targeting solely the immune system, which will likely compromise β-cell replenishment [84,86].…”

Section: Can Gaba Stimulate αTo β-Cell Transdifferentiation?mentioning

confidence: 99%

Harnessing the Endogenous Plasticity of Pancreatic Islets: A Feasible Regenerative Medicine Therapy for Diabetes?

Lorenzo

Cobo-Vuilleumier

Martín-Vázquez

et al. 2021

IJMS

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Diabetes is a chronic metabolic disease caused by an absolute or relative deficiency in functional pancreatic β-cells that leads to defective control of blood glucose. Current treatments for diabetes, despite their great beneficial effects on clinical symptoms, are not curative treatments, leading to a chronic dependence on insulin throughout life that does not prevent the secondary complications associated with diabetes. The overwhelming increase in DM incidence has led to a search for novel antidiabetic therapies aiming at the regeneration of the lost functional β-cells to allow the re-establishment of the endogenous glucose homeostasis. Here we review several aspects that must be considered for the development of novel and successful regenerative therapies for diabetes: first, the need to maintain the heterogeneity of islet β-cells with several subpopulations of β-cells characterized by different transcriptomic profiles correlating with differences in functionality and in resistance/behavior under stress conditions; second, the existence of an intrinsic islet plasticity that allows stimulus-mediated transcriptome alterations that trigger the transdifferentiation of islet non-β-cells into β-cells; and finally, the possibility of using agents that promote a fully functional/mature β-cell phenotype to reduce and reverse the process of dedifferentiation of β-cells during diabetes.

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“…Singh et al [27] explained serological, biochemical, and genetic aspects related to gene HLA-DQB1 and its association with the T1DM. Nadia et al [28] explained the paradigm shift in treating T1DM by coupling inflammation to islet regeneration. Buzzetti et al [29] comprehensively explained the role of obesity in the increasing incidence of T1DM around the globe.…”

Section: Current Treatment Modalities Available For Diabetes In Medicinementioning

confidence: 99%

Artificial Pancreas Control Strategies Used for Type 1 Diabetes Control and Treatment: A Comprehensive Analysis

Mehmood

Ahmad

Arif

et al. 2020

ASI

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This paper presents a comprehensive survey about the fundamental components of the artificial pancreas (AP) system including insulin administration and delivery, glucose measurement (GM), and control strategies/algorithms used for type 1 diabetes mellitus (T1DM) treatment and control. Our main focus is on the T1DM that emerges due to pancreas’s failure to produce sufficient insulin due to the loss of beta cells (β-cells). We discuss various insulin administration and delivery methods including physiological methods, open-loop, and closed-loop schemes. Furthermore, we report several factors such as hyperglycemia, hypoglycemia, and many other physical factors that need to be considered while infusing insulin in human body via AP systems. We discuss three prominent control algorithms including proportional-integral- derivative (PID), fuzzy logic, and model predictive, which have been clinically evaluated and have all shown promising results. In addition, linear and non-linear insulin infusion control schemes have been formally discussed. To the best of our knowledge, this is the first work which systematically covers recent developments in the AP components with a solid foundation for future studies in the T1DM field.

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Time for a paradigm shift in treating type 1 diabetes mellitus: coupling inflammation to islet regeneration

Cited by 24 publications

References 147 publications

The Metabesity Factor HMG20A Potentiates Astrocyte Survival and Reactivity Preserving Neuronal Integrity

The Metabesity Factor HMG20A Potentiates Astrocyte Survival and Reactivity Preserving Neuronal Integrity

Harnessing the Endogenous Plasticity of Pancreatic Islets: A Feasible Regenerative Medicine Therapy for Diabetes?

Artificial Pancreas Control Strategies Used for Type 1 Diabetes Control and Treatment: A Comprehensive Analysis

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