Protective Factors and the Pathogenesis of Complications in Diabetes

Abstract

Chronic complications of diabetes are due to myriad disorders of numerous metabolic pathways that are responsible for most of the morbidity and mortality associated with the disease. Traditionally, diabetes complications are divided into those of microvascular and macrovascular origin. We suggest revising this antiquated classification into diabetes complications of vascular, parenchymal, and hybrid (both vascular and parenchymal) tissue origin, since the profile of diabetes complications ranges from those involving only vascular tissues to those involving mostly parenchymal organs. A major paradigm shift has occurred in recent years regarding the pathogenesis of diabetes complications, in which the focus has shifted from studies on risks to those on the interplay between risk and protective factors. While risk factors are clearly important for the development of chronic complications in diabetes, recent studies have established that protective factors are equally significant in modulating the development and severity of diabetes complications. These protective responses may help explain the differential severity of complications, and even the lack of pathologies, in some tissues. Nevertheless, despite the growing number of studies on this field, comprehensive reviews on protective factors and their mechanisms of action are not available. This review thus focused on the clinical, biochemical, and molecular mechanisms that support the idea of endogenous protective factors, and their roles in the initiation and progression of chronic complications in diabetes. In addition, this review also aimed to identify the main needs of this field for future studies.

Keywords: complications-macrovascular; complications-microvascular; diabetes mellitus; type 1 diabetes; type 2 diabetes.

Graphical Abstract

Figure 1.

Vascular and tissue pathologies of complications in diabetes. ECM, extracellular matrix; Smooth M. Cell, smooth muscle cell; CNS, central nervous system.

Figure 2.

Interactions of systemic and tissue-specific risk and protective factors in diabetes complications. AGEs, advanced glycation end products; APC, activated protein C.

Figure 3.

Disruption of cellular signaling by risk factors. GLUT, glucose transporter; FFA, free fatty acids; FABP, fatty acid binding protein; B-oxidation, beta-oxidation; DAG, diacylglycerol; MGO, methylglyoxal; PKC, protein kinase C; SHC-1, Src homology 2 domain-containing protein tyrosine phosphatase 1; PI3K/Akt, phosphoinositide-3 kinase/Akt pathway; NF-KB, nuclear factor kappa B; NOX, NADPH phosphate oxidase; AGE, advanced glycation end-products; TLR, toll-like receptor; RAGE, receptor for advanced glycation end-products; ECM, extracellular matrix; TGF-β, transforming growth factor-beta; ET-1, endothelin-1.

Figure 4.

Contribution of risk factors and protective mechanisms to the development of diabetes complications. RBP3, retinol-binding protein 3; PP Shunt, pentose phosphate shunt; GSH, glutathione; O⁻, oxidant; PKM2, pyruvate kinase M2; FFA, free fatty acid; B-oxidation, beta-oxidation; AGE, advanced glycation end-products; NF-KB, nuclear factor kappa B; PI3K/Akt, phosphoinositide-3 kinase/Akt pathway; KEAP/NRF2, Kelch-like-ECH-associated protein/nuclear factor erythroid 2-related factor; IGF, insulin-like growth factor; VEGF, vascular endothelial growth factor; MAPK, mitogen-activated protein kinase; ECM, extracellular matrix.