Association between Diabetes and Keratoconus: A Retrospective Analysis

Whelchel, Amy; McKay, Tina B.; Priyadarsini, Shrestha; Rowsey, Tyler; Karamichos, Dimitrios

doi:10.1038/s41598-019-50095-2

Cited by 15 publications

(10 citation statements)

References 41 publications

(75 reference statements)

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“…One method is to supplement culture media with ascorbic acid (vitamin C), which normally promotes collagen secretion and deposition without promoting myofibroblast differentiation [ 5 , 16 , 33 , 34 , 47 , 81 , 82 ]. This hCF stroma-like 3D model and their self-assembled matrix, which mimics the corneal stroma during development [ 33 , 47 , 83 ], but also useful in investigating other pathologies affecting the corneal stroma, such as keratoconus [ 84 , 85 , 86 ], wound healing [ 33 , 87 ], and diabetes [ 88 , 89 , 90 ]. Collectively, these studies highlight that by increasing ECM dimensionality around hCFs, which can significantly influence cell proliferation and survival, mechano-responses, and their differentiation capacity [ 33 , 47 , 83 ].…”

Section: Discussionmentioning

confidence: 99%

FAK Inhibition Attenuates Corneal Fibroblast Differentiation In Vitro

et al. 2021

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Corneal fibrosis (or scarring) occurs in response to ocular trauma or infection, and by reducing corneal transparency, it can lead to visual impairment and blindness. Studies highlight important roles for transforming growth factor (TGF)-β1 and -β3 as modulators in corneal wound healing and fibrosis, leading to increased extracellular matrix (ECM) components and expression of α-smooth muscle actin (αSMA), a myofibroblast marker. In this study, human corneal fibroblasts (hCF) were cultured as a monolayer culture (2D) or on poly-transwell membranes to generate corneal stromal constructs (3D) that were treated with TGF-β1, TGF-β3, or TGF-β1 + FAK inhibitor (FAKi). Results show that hCF 3D constructs treated with TGF-β1 or TGF-β3 impart distinct effects on genes involved in wound healing and fibrosis—ITGAV, ITGB1, SRC and ACTA2. Notably, in the 3D construct model, TGF-β1 enhanced αSMA and focal adhesion kinase (FAK) protein expression, whereas TGF-β3 did not. In addition, in both the hCF 2D cell and 3D construct models, we found that TGF-β1 + FAKi attenuated TGF-β1-mediated myofibroblast differentiation, as shown by abrogated αSMA expression. This study concludes that FAK signaling is important for the onset of TGF-β1-mediated myofibroblast differentiation, and FAK inhibition may provide a novel beneficial therapeutic avenue to reduce corneal scarring.

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Section: Discussionmentioning

confidence: 99%

FAK Inhibition Attenuates Corneal Fibroblast Differentiation In Vitro

et al. 2021

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“…The corneal stroma is also known to be affected, in diabetic keratopathy, although studies are lacking [ 46 , 47 ]. The process of stromal wound healing involves wound contracture, bringing the margins of open wounds together [ 48 ].…”

Section: Discussionmentioning

confidence: 99%

Cellular Contractility Profiles of Human Diabetic Corneal Stromal Cells

Lam

Nicholas

Choi

et al. 2021

Analytical Cellular Pathology

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Diabetic keratopathy is a corneal complication of diabetes mellitus (DM). Patients with diabetic keratopathy are prone to developing corneal haze, scarring, recurrent erosions, and significant wound healing defects/delays. The purpose of this study was to determine the contractility profiles in the diabetic human corneal stromal cells and characterize their molecular signatures. Primary human corneal fibroblasts from healthy, Type 1 DM (T1DM), and Type 2 DM (T2DM) donors were cultured using an established 3D collagen gel model. We tracked, measured, and quantified the contractile footprint over 9 days and quantified the modulation of specific corneal/diabetes markers in the conditional media and cell lysates using western blot analysis. Human corneal fibroblasts (HCFs) exhibited delayed and decreased contractility compared to that from T1DMs and T2DMs. Compared to HCFs, T2DMs demonstrated an initial downregulation of collagen I (day 3), followed by a significant upregulation by day 9. Collagen V was significantly upregulated in both T1DMs and T2DMs based on basal secretion, when compared to HCFs. Cell lysates were upregulated in the myofibroblast-associated marker, α-smooth muscle actin, in T2DMs on day 9, corresponding to the significant increase in contractility rate observed at the same time point. Furthermore, our data demonstrated a significant upregulation in IGF-1 expression in T2DMs, when compared to HCFs and T1DMs, at day 9. T1DMs demonstrated significant downregulation of IGF-1 expression, when compared to HCFs. Overall, both T1DMs and T2DMs exhibited increased contractility associated with fibrotic phenotypes. These findings, and future studies, may contribute to better understanding of the pathobiology of diabetic keratopathy and ultimately the development of new therapeutic approaches.

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“…Glycolysis and gluconeogenesis are two metabolic pathways involved in glucose catabolism and anabolism, respectively, which play a key role in cell survival [117,118]. Studies performed on in vitro models of KC demonstrated that glucose metabolism is upregulated [119][120][121]. In particular, anaerobic glycolysis appears to be the most affected, since concentrations of lactate are higher than pyruvate [102].…”

Section: Glycolysis and Gluconeogenesismentioning

confidence: 99%

“…Findings on glucose metabolism alterations led to the investigation of a possible role of diabetes mellitus (DM) in KC pathogenesis. However, results obtained from different studies were controversial, and clinical data suggest that DM is a protective rather than a risk factor for KC onset and progression [121,124].…”

Section: Glycolysis and Gluconeogenesismentioning

confidence: 99%

Nutritional and Metabolic Imbalance in Keratoconus

et al. 2022

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Keratoconus (KC) is a progressive corneal degeneration characterized by structural changes consisting of progressive thinning and steepening of the cornea. These alterations result in biomechanical weakening and, clinically, in vision loss. While the etiology of KC has been the object of study for over a century, no single agent has been found. Recent reviews suggest that KC is a multifactorial disease that is associated with a wide variety of genetic and environmental factors. While KC is typically considered a disease of the cornea, associations with systemic conditions have been well described over the years. In particular, nutritional and metabolic imbalance, such as the redox status, hormones, metabolites, and micronutrients (vitamins and metal ions), can deeply influence KC initiation and progression. In this paper, we comprehensively review the different nutritional (vitamins and minerals) and metabolic (hormones and metabolites) factors that are altered in KC, discussing their possible implication in the pathophysiology of the disease.

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Association between Diabetes and Keratoconus: A Retrospective Analysis

Cited by 15 publications

References 41 publications

FAK Inhibition Attenuates Corneal Fibroblast Differentiation In Vitro

FAK Inhibition Attenuates Corneal Fibroblast Differentiation In Vitro

Cellular Contractility Profiles of Human Diabetic Corneal Stromal Cells

Nutritional and Metabolic Imbalance in Keratoconus

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