Peripheral immune circadian variation, synchronisation and possible dysrhythmia in established type 1 diabetes

Beam, Craig A.; Beli, Eleni; Wasserfall, Clive; Woerner, Stéphanie; Legge, Megan T; Evans‐Molina, Carmella; McGrail, Kieran; Silk, Ryan; Grant, Maria B.; Atkinson, Mark A.; DiMeglio, Linda A.

doi:10.1007/s00125-021-05468-6

Cited by 8 publications

(4 citation statements)

References 41 publications

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“…Study subjects underwent clinical characterization (Tables S1 and S2) with their peripheral blood obtained during a morning blood draw to reduce circadian-related variation. 29 Peripheral blood immunophenotyping demonstrated the presence of granulocytosis (Figure 1A) with an increase in IL-1β + myeloid cells (CD15 + ; Figure 1B) in T1D subjects compared with controls. Increased circulating B-cells (CD19 + ; Figure 1C) and regulatory T cells (CD4 + CD25 + FoxP3 + ; Figure 1D), with a reduction in Th17 cells (CD4 + RORγt + ; Figure 1E) and an increase in gut-derived ILC1s (CD127 + CD161 + CD117 − CD294 − ) were also observed (Figure 1F) in T1D subjects compared with controls.…”

Section: Retinopathy Severity Correlates With Serum Markers Of Intest...mentioning

confidence: 97%

Maintenance of Enteral ACE2 Prevents Diabetic Retinopathy in Type 1 Diabetes

Prasad

Floyd

Dupont

et al. 2023

Circulation Research

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BACKGROUND: We examined components of systemic and intestinal renin-angiotensin system on gut barrier permeability, glucose homeostasis, systemic inflammation, and progression of diabetic retinopathy (DR) in human subjects and mice with type 1 diabetes. METHODS: Type 1 diabetes individual with (n=18) and without (n=20) DR and controls (n=34) were examined for changes in gut-regulated components of the immune system, gut leakage markers (FABP2 [fatty acid binding protein 2] and PGN [peptidoglycan]), and Ang II (angiotensin II); Akita mice were orally administered a Lactobacillus paracasei (LP) probiotic expressing humanized ACE2 (angiotensin-converting enzyme 2) protein (LP-ACE2) as either a prevention or an intervention. Akita mice with genetic overexpression of humanAce2 by small intestine epithelial cells ( Vil-Cre.hAce2KI-Akita ) were similarly examined. After 9 months of type 1 diabetes, circulatory, enteral, and ocular end points were assessed. RESULTS: Type 1 diabetes subjects exhibit elevations in gut-derived circulating immune cells (Th17 and ILC1 cells) and higher gut leakage markers, which were positively correlated with plasma Ang II and DR severity. The LP-ACE2 prevention cohort and genetic overexpression of intestinal ACE2 preserved barrier integrity, reduced inflammatory response, improved hyperglycemia, and delayed development of DR. Improvements in glucose homeostasis were due to intestinal MasR activation, resulting in a GSK-3β/c-Myc-mediated decrease in intestinal glucose transporter expression. In the LP-ACE2 intervention cohort, gut barrier integrity was improved and DR reversed, but no improvement in hyperglycemia was observed. These data support that the beneficial effects of LP-ACE2 on DR are due to the action of ACE2, not improved glucose homeostasis. CONCLUSIONS: Dysregulated systemic and intestinal renin-angiotensin system was associated with worsening gut barrier permeability, gut-derived immune cell activation, systemic inflammation, and progression of DR in human subjects. In Akita mice, maintaining intestinal ACE2 expression prevented and reversed DR, emphasizing the multifaceted role of the intestinal renin-angiotensin system in diabetes and DR.

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Section: Retinopathy Severity Correlates With Serum Markers Of Intest...mentioning

confidence: 97%

Maintenance of Enteral ACE2 Prevents Diabetic Retinopathy in Type 1 Diabetes

Prasad

Floyd

Dupont

et al. 2023

Circulation Research

Self Cite

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“…These changes can be reversed by melatonin [ 57 , 58 ], highlighting the importance of pineal melatonin in the circadian optimization of pancreatic β-cell function. Circadian dysregulation is also intimately linked to a diverse array of T1DM symptomatology [ 59 ], including nocturnal non-dipping blood pressure increasing kidney disease [ 60 ], cardiac autonomic neuropathy [ 61 ], platelet morphology [ 62 ], microvascular complications [ 63 ], and patterned immune activity [ 64 ], whilst circadian variation in basal insulin requirement can be an early marker of autoimmune polyendocrine syndromes in T1DM [ 65 ]. Such data highlight the role of alterations in the circadian rhythm in T1DM pathophysiology.…”

Section: Wider T1dm Pathophysiologymentioning

confidence: 99%

Type I Diabetes Pathoetiology and Pathophysiology: Roles of the Gut Microbiome, Pancreatic Cellular Interactions, and the ‘Bystander’ Activation of Memory CD8+ T Cells

Anderson¹

2023

IJMS

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Type 1 diabetes mellitus (T1DM) arises from the failure of pancreatic β-cells to produce adequate insulin, usually as a consequence of extensive pancreatic β-cell destruction. T1DM is classed as an immune-mediated condition. However, the processes that drive pancreatic β-cell apoptosis remain to be determined, resulting in a failure to prevent ongoing cellular destruction. Alteration in mitochondrial function is clearly the major pathophysiological process underpinning pancreatic β-cell loss in T1DM. As with many medical conditions, there is a growing interest in T1DM as to the role of the gut microbiome, including the interactions of gut bacteria with Candida albicans fungal infection. Gut dysbiosis and gut permeability are intimately associated with raised levels of circulating lipopolysaccharide and suppressed butyrate levels, which can act to dysregulate immune responses and systemic mitochondrial function. This manuscript reviews broad bodies of data on T1DM pathophysiology, highlighting the importance of alterations in the mitochondrial melatonergic pathway of pancreatic β-cells in driving mitochondrial dysfunction. The suppression of mitochondrial melatonin makes pancreatic β-cells susceptible to oxidative stress and dysfunctional mitophagy, partly mediated by the loss of melatonin’s induction of PTEN-induced kinase 1 (PINK1), thereby suppressing mitophagy and increasing autoimmune associated major histocompatibility complex (MHC)-1. The immediate precursor to melatonin, N-acetylserotonin (NAS), is a brain-derived neurotrophic factor (BDNF) mimic, via the activation of the BDNF receptor, TrkB. As both the full-length and truncated TrkB play powerful roles in pancreatic β-cell function and survival, NAS is another important aspect of the melatonergic pathway relevant to pancreatic β-cell destruction in T1DM. The incorporation of the mitochondrial melatonergic pathway in T1DM pathophysiology integrates wide bodies of previously disparate data on pancreatic intercellular processes. The suppression of Akkermansia muciniphila, Lactobacillus johnsonii, butyrate, and the shikimate pathway—including by bacteriophages—contributes to not only pancreatic β-cell apoptosis, but also to the bystander activation of CD8+ T cells, which increases their effector function and prevents their deselection in the thymus. The gut microbiome is therefore a significant determinant of the mitochondrial dysfunction driving pancreatic β-cell loss as well as ‘autoimmune’ effects derived from cytotoxic CD8+ T cells. This has significant future research and treatment implications.

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“…Indeed, an animal study showed that TH17 cell differentiation follows the circadian clock 76 . Nevertheless, data on circadian rhythms of immune cells in MS are still very limited, in contrast to other autoimmune diseases such as type 1 diabetes, where phase shifts of 3–5 h in the circadian peak of blood levels have been demonstrated for B and T cells and their naive and effector memory subsets 77 . Circadian disruption might thus contribute to metabolic and immune cell dysregulation and malfunction in MS (Figure 2).…”

Section: Circadian Disturbances In Msmentioning

confidence: 99%

Multiple sclerosis and circadian rhythms: Can diet act as a treatment?

2023

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Multiple sclerosis (MS) is an autoimmune inflammatory and neurodegenerative disease of the central nervous system (CNS) with increasing incidence and prevalence. MS is associated with inflammatory and metabolic disturbances that, as preliminary human and animal data suggest, might be mediated by disruption of circadian rhythmicity. Nutrition habits can influence the risk for MS, and dietary interventions may be effective in modulating MS disease course.Chronotherapeutic approaches such as time-restricted eating (TRE) may benefit people with MS by stabilizing the circadian clock and restoring immunological and metabolic rhythms, thus potentially counteracting disease progression. This review provides a summary of selected studies on dietary intervention in MS, circadian rhythms, and their disruption in MS, including clock gene variations, circadian hormones, and retino-hypothalamic tract changes. Furthermore, we present studies that reported diurnal variations in MS, which might result from circadian disruption. And lastly, we suggest how chrononutritive approaches like TRE might counteract MS disease activity.

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Peripheral immune circadian variation, synchronisation and possible dysrhythmia in established type 1 diabetes

Cited by 8 publications

References 41 publications

Maintenance of Enteral ACE2 Prevents Diabetic Retinopathy in Type 1 Diabetes

Maintenance of Enteral ACE2 Prevents Diabetic Retinopathy in Type 1 Diabetes

Type I Diabetes Pathoetiology and Pathophysiology: Roles of the Gut Microbiome, Pancreatic Cellular Interactions, and the ‘Bystander’ Activation of Memory CD8+ T Cells

Multiple sclerosis and circadian rhythms: Can diet act as a treatment?

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