Abstract
A fundamental role of pancreatic β-cells to maintain proper blood glucose level is controlled by the Ras superfamily of small GTPases that undergo post-translational modifications, including prenylation. This covalent attachment with either a farnesyl or a geranylgeranyl group controls their localization, activity, and protein–protein interactions. Small GTPases are critical in maintaining glucose homeostasis acting in the pancreas and metabolically active tissues such as skeletal muscles, liver, or adipocytes. Hyperglycemia-induced upregulation of small GTPases suggests that inhibition of these pathways deserves to be considered as a potential therapeutic approach in treating T2D. This Perspective presents how inhibition of various points in the mevalonate pathway might affect protein prenylation and functioning of diabetes-affected tissues and contribute to chronic inflammation involved in diabetes mellitus (T2D) development. We also demonstrate the currently available molecular tools to decipher the mechanisms linking the mevalonate pathway’s enzymes and GTPases with diabetes.
Highlights
The incidence of diabetes has increased tremendously over the last 50 years, affecting approximately 463 million adults
By 2045, there will be 700 million patients with diabetes.[1]. This epidemic is predominantly caused by a rise in the prevalence of type 2 diabetes (T2D), a complex disorder that is characterized by pancreatic β-cell failure with up to 50% cell loss at diagnosis coupled with impaired insulin sensitivity of target tissues, termed insulin resistance (IR)
Ras GTPases Epac[2], a cAMP binding protein, regulates insulin exocytosis modulates the dynamics of the actin cytoskeleton tethers secretory granules through its regulated association with the exocyst (Sec6) complex RalA binds α2δ-1 on insulin granules to tether granules to plasma membrane Ca2+channels
Summary
The incidence of diabetes has increased tremendously over the last 50 years, affecting approximately 463 million adults. Expanded adipose tissue supports local and systemic inflammation by enhancing pro-inflammatory mediators secretion, including cytokines, chemokines, and adipokines Both increased systemic fat and inflammation contribute to the development of IR in the liver and skeletal muscles. The exposure to BPs (alendronate, risedronate) was associated with reduced T2D incidence.[12] the administration of BPs was shown to positively affect diabetes-related indices, insulin, fasting plasma glucose (FPG), and hemoglobin A1c (HbA1c).[13] On the other hand, overexpression of muscle,[14] adipose,[15] and liver[16] GGPPS may contribute to insulin resistance pathogenesis. We discuss the mechanisms of small GTPase prenylation and how inhibition of various points in the mevalonate pathway might affect protein prenylation and functioning of pancreas and liver, skeletal muscle, kidneys, adipose tissue, and contribute to chronic inflammation involved in T2D development
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