Effects of Insulin and High Glucose on Human Meibomian Gland Epithelial Cells.

Meibomian glands play an extremely important role in the health and well-being of the ocular surface. The acinar epithelial cells of these glands secrete a proteinaceous lipid mixture (i.e., meibum) that promotes the stability and prevents the evaporation of the tear film.1 Conversely, meibomian gland dysfunction (MGD), and the resulting meibum insufficiency, destabilizes the tear film, increases its evaporation and osmolarity, and is the most common cause of dry eye disease (DED). Dry eye disease afflicts tens of millions of people in the United States alone and is one of the most frequent causes of patient visits to eye care practitioners.2 Recently, investigators have discovered that diabetes is a significant risk factor for the development of MGD.1,3 Such an association might have been predicted, given that the meibomian gland is a large sebaceous gland,4 and that sebaceous gland structure and function are compromised in diabetic patients.5–7 However, the molecular mechanisms that underlie the impact of diabetes on the human meibomian gland are unknown. We hypothesize that insulin resistance/deficiency and hyperglycemia, which are pathognomonic features of diabetes, are critical factors in the pathogenesis of MGD in diabetic patients. Our rationale is 2-fold. First, insulin is essential for optimal sebaceous gland activity, and is known to induce glandular cell proliferation and lipid accumulation.8 Lack of insulin, in turn, would promote dysfunction. Second, hyperglycemia contributes to lipolysis in adipocytes,9,10 and this response, if occurring in the meibomian gland, could dramatically reduce the quality of meibum. The purpose of this study was to begin to test our hypotheses by examining the influence of insulin and high glucose on immortalized human meibomian gland epithelial cells (IHMGECs).11 We evaluated whether insulin, as it does in other cells,12 promotes activation of the AKT pathway by binding to the insulin receptor (IR) or insulin-like growth factor–1 (IGF-1) receptor (IGF-1R). We also determined whether insulin stimulates cell proliferation and lipid accumulation in, and whether high glucose is toxic to, IHMGECs. For the toxicity studies, we focused on high glucose's impact on the levels of IR, IGF-1R, AKT, FOXO1, as well as the lipogenesis regulator SREBP-1.