Caloric restriction recovers impaired β-cell-β-cell gap junction coupling, calcium oscillation coordination, and insulin secretion in prediabetic mice

Amaral, Maria Esméria Corezola do; Kravets, Vira; Dwulet, JaeAnn M.; Farnsworth, Nikki L.; Piscopio, Robert A.; Schleicher, Wolfgang E.; Miranda, Jose G.; Benninger, Richard K.P.

doi:10.1152/ajpendo.00132.2020

Cited by 38 publications

(40 citation statements)

References 81 publications

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“…Targeting Cx36 is also strongly supported by its role in the pathogenesis in T2D. Several studies, including results presented here, demonstrate its disruption under diabetogenic conditions [37–39,51,60]. We further demonstrate its disruption in human donors with T2D compared to age matched healthy donors.…”

Section: Discussionsupporting

confidence: 75%

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Restoring Connexin-36 Function in Diabetogenic Environments Precludes Mouse and Human Islet Dysfunction

Clair

Westacott

Farnsworth

et al. 2020

Preprint

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Type2 diabetes results from failure of the β-cell to compensate for insulin resistance, such as in obesity. Insulin secretion is governed by a series of metabolic and electrical events which can fail during the progression of diabetes. β-cells are electrically coupled via Cx36 gap junction channels, thereby coordinating the pulsatile dynamics of electrical activity, Ca2+ and insulin release across the islet, enhancing insulin action. Pulsatile insulin release is disrupted in human type2 diabetes, although whether this disruption results from diminished gap junction coupling is unclear. Factors such as pro-inflammatory cytokines and free fatty acids disrupt gap junction coupling under invitro conditions. Here we test whether gap junction coupling and coordinated Ca2+ dynamics are disrupted in type2 diabetes, and whether recovery of gap junction coupling can recover islet function. We examine islets from healthy donors and those with type2 diabetes, as well as islets from db/db mice and islets treated with a cocktail of proinflammatory cytokines (TNF-α, IL-1β, IFN-ɣ) or free fatty acids (palmitate). We modulate gap junction coupling using Cx36 over-expression or pharmacological activation via modafinil. We also develop a peptide mimetic (S293) of the c-terminal regulatory tail of Cx36 designed to compete against its phosphorylation and downregulation. Cx36 gap junction permeability and coordinated Ca2+ dynamics were disrupted in islets from human donors with type2 diabetes, as well as in islets from db/db mice or treated with proinflammatory cytokines or palmitate. Cx36 over-expression, modafinil treatment and S293 peptide all enhanced Cx36 gap junction coupling and protected against declines in coordinated Ca2+ dynamics. Cx36 over-expression and S293 peptide also reduced apoptosis induced by proinflammatory cytokines. Critically S293 peptide rescued gap junction coupling and Ca2+ dynamics in islets from both db/db mice and a sub-set of T2D donors. Thus, recovering or enhancing Cx36 gap junction coupling can improve islet function in diabetes.

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Section: Discussionsupporting

confidence: 75%

“…Chronic FFA exposure can also induce GJ uncoupling within mouse and human islets [38]. In animal models of obesity, dysregulated [Ca 2+ ] dynamics have also been observed [39,40]. Taken together, this suggests a role for GJ uncoupling in the development of islet dysfunction in T2D.…”

Section: Introductionmentioning

confidence: 99%

Restoring Connexin-36 Function in Diabetogenic Environments Precludes Mouse and Human Islet Dysfunction

Clair

Westacott

Farnsworth

et al. 2020

Preprint

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“…CX36 gap junctions enable Ca 2+ oscillations to be coordinated across the islets. Its deletion significantly affects the synchro-nization of calcium oscillations, and CX36-deficient mice show disrupted first-phase and pulsatile second phase of insulin release [234,235]. CX36-dependent signaling may be thus disrupted under prediabetic conditions.…”

Section: β-Cell Communication In Islets Under Redox Regulationmentioning

confidence: 99%

Redox Homeostasis in Pancreatic β-Cells: From Development to Failure

2021

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Redox status is a key determinant in the fate of β-cell. These cells are not primarily detoxifying and thus do not possess extensive antioxidant defense machinery. However, they show a wide range of redox regulating proteins, such as peroxiredoxins, thioredoxins or thioredoxin reductases, etc., being functionally compartmentalized within the cells. They keep fragile redox homeostasis and serve as messengers and amplifiers of redox signaling. β-cells require proper redox signaling already in cell ontogenesis during the development of mature β-cells from their progenitors. We bring details about redox-regulated signaling pathways and transcription factors being essential for proper differentiation and maturation of functional β-cells and their proliferation and insulin expression/maturation. We briefly highlight the targets of redox signaling in the insulin secretory pathway and focus more on possible targets of extracellular redox signaling through secreted thioredoxin1 and thioredoxin reductase1. Tuned redox homeostasis can switch upon chronic pathological insults towards the dysfunction of β-cells and to glucose intolerance. These are characteristics of type 2 diabetes, which is often linked to chronic nutritional overload being nowadays a pandemic feature of lifestyle. Overcharged β-cell metabolism causes pressure on proteostasis in the endoplasmic reticulum, mainly due to increased demand on insulin synthesis, which establishes unfolded protein response and insulin misfolding along with excessive hydrogen peroxide production. This together with redox dysbalance in cytoplasm and mitochondria due to enhanced nutritional pressure impact β-cell redox homeostasis and establish prooxidative metabolism. This can further affect β-cell communication in pancreatic islets through gap junctions. In parallel, peripheral tissues losing insulin sensitivity and overall impairment of glucose tolerance and gut microbiota establish local proinflammatory signaling and later systemic metainflammation, i.e., low chronic inflammation prooxidative properties, which target β-cells leading to their dedifferentiation, dysfunction and eventually cell death.

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“…An impairment or loss of pulsatility is an early marker of β-cell stress and overload [ 4 , 81 ] and in the future could be used as an early marker of β-cell failure. At least in the early stages, these defects seem to be reversible [ 60 , 91 , 92 ]. Targeting insulin pulsatility may have therapeutic benefit in prediabetic subjects.…”

Section: Summary and Future Directionsmentioning

confidence: 99%

Measurement of Pulsatile Insulin Secretion: Rationale and Methodology

2021

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Pancreatic β-cells are responsible for the synthesis and exocytosis of insulin in response to an increase in circulating glucose. Insulin secretion occurs in a pulsatile manner, with oscillatory pulses superimposed on a basal secretion rate. Insulin pulses are a marker of β-cell health, and secretory parameters, such as pulse amplitude, time interval and frequency distribution, are impaired in obesity, aging and type 2 diabetes. In this review, we detail the mechanisms of insulin production and β-cell synchronization that regulate pulsatile insulin secretion, and we discuss the challenges to consider when measuring fast oscillatory secretion in vivo. These include the anatomical difficulties of measuring portal vein insulin noninvasively in humans before the hormone is extracted by the liver and quickly removed from the circulation. Peripheral concentrations of insulin or C-peptide, a peptide cosecreted with insulin, can be used to estimate their secretion profile, but mathematical deconvolution is required. Parametric and nonparametric approaches to the deconvolution problem are evaluated, alongside the assumptions and trade-offs required for their application in the quantification of unknown insulin secretory rates from known peripheral concentrations. Finally, we discuss the therapeutical implication of targeting impaired pulsatile secretion and its diagnostic value as an early indicator of β-cell stress.

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Caloric restriction recovers impaired β-cell-β-cell gap junction coupling, calcium oscillation coordination, and insulin secretion in prediabetic mice

Cited by 38 publications

References 81 publications

Restoring Connexin-36 Function in Diabetogenic Environments Precludes Mouse and Human Islet Dysfunction

Restoring Connexin-36 Function in Diabetogenic Environments Precludes Mouse and Human Islet Dysfunction

Redox Homeostasis in Pancreatic β-Cells: From Development to Failure

Measurement of Pulsatile Insulin Secretion: Rationale and Methodology

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