Are we teetering on the edge of a diabetes pandemic? Where diabetes was once a solo condition occupying a quiet role in healthcare it is now a loud and vicious beast that rages in three classifiable forms. Its most common form – type 2 diabetes – is becoming less preferential of age weight physical activity and diet calling researchers to seek other factors that may be responsible for the expansion of this condition. One factor of growing interest is the role of ceramides in the pathogenesis of diabetes. 

Classification

Ceramides are members of the sphingolipids and make their home within the lipid bilayer of the cell membrane. They are particularly well-sourced within the epidermis of the skin and are in fact the white fatty substance often found on the surface of the skin of newborn infants. Ceramides are responsible for the water repellent nature of skin. 

Function

In the skin ceramides create a protective barrier with a dual purpose. Pathogenic microorganisms are barred entry into the body and internal hydration is maintained by preventing excess water loss. More importantly in the pathogenesis of diabetes ceramides play an important role in cell signaling and act as the mediators between extracellular signals and intracellular metabolism. They are critical in driving apoptosis and cell senescence and they also regulate cell proliferation differentiation migration and adhesion.

Pathological Connections

Ceramides have been of particular interest in a multitude of health conditions due to their diverse yet critical roles in cell metabolism and function. They have been implicated in the pathogenesis of cancer neurodegenerative diseases infectious lung diseases and more. However of particular interest to our topic is their role in a threefold health calamity: obesity inflammation and diabetes. Obesity is a well-known risk factor for diabetes. Inflammation can be considered both a risk factor and a consequence of diabetes. As a common thread among all three attention is drawn to the ceramides. 

Obesity

When comparing subcutaneous adipose tissue between diabetics and non-diabetics with similar BMI indices significantly more sphingolipids (including ceramides) were found in diabetic adipose tissue. Further reducing the number of these sphingolipids altered the quantity of brown and beige adipocytes and increased mitochondrial activity insulin sensitivity and anti-inflammatory M2 macrophages within adipose tissue. These changes influence whole-body energy expenditure which could impact that pathology of diabetes. Other studies have supported the fact that increased quantities of ceramides coincide with obesity and efforts to reduce these ceramides improves insulin resistance type 2 diabetes and other obesity-associated conditions.

Insulin Resistance

One of the main mechanisms by which ceramides increase diabetic risks is through insulin resistance. Research is still not clear on the exact mechanisms by which ceramides alter insulin sensitivity; however it is evident that ceramides can negatively alter direct intermediates in the insulin signaling pathways including insulin receptor substrate Akt and Glut-4 to promote insulin resistance.

Beta Cell Apoptosis

Increased ceramides can also promote pancreatic beta cell apoptosis and explains its role in the pathogenesis of type 1 diabetes as well as more progressed forms of type 2 diabetes. Ceramides induce beta cell apoptosis through a variety of mechanisms. They initiate intrinsic mitochondrial apoptosis by increasing the permeability of the mitochondrial membranes and generating reactive oxygen species. Ceramides induce endoplasmic reticulum stress which triggers apoptosis. They also inhibit Akt a serine/threonine kinase which regulates cell survival. Finally ceramides inhibit insulin gene expression thus reducing insulin production. 

Ceramide Production

Perhaps one of the most obvious questions at this point would focus on how ceramide levels accumulate to promote this cascade of diabetic risk factors. Ceramides are generated internally through de novo synthesis hydrolysis of complex sphingolipids and recycling of sphingosine. Dysregulation of any of these pathways can promote ceramide accumulation. Exposure to cytokines such as TNF-alpha and various leukotrienes can increase endogenous ceramide production. Prolonged exposure to free fatty acids such as palmitate a precursor to ceramide is another means by which endogenous ceramide production increases. Lipid dysregulation therefore is one of the primary means of ceramide accumulation and is a well-known risk factor for diabetes. A genetic predisposition toward lipid dysregulation and subsequent ceramide production and accumulation could offer an explanation for type 2 diabetes among normal weight individuals. Exogenous sources of accumulation are also worth considering although the evidence for their impact is limited. Studies have shown that ethanol increases ceramide levels. Ceramides are also found in a variety of skin care products including prescription-based creams recommended for skin conditions. Finally exposure to chemotherapeutic agents ionizing radiation and other environmental toxins that may increase oxidative stress could contribute to ceramide accumulation.

As ceramides become a more useful target for determining an individual’s risk for developing diabetes we should begin to see the focus shift toward ways to reduce ceramide production. Although science has not provided any clear answers as of yet a reasonable place to begin is to reduce free radical generation and stabilize healthy lipid production. The new research on ceramides only confirms the fact that lifestyle intervention is a key component to pulling in the reigns on diabetes.