The Role of Biofactors in Diabetic Microvascular Complications

Abstract

Microvascular complications are responsible for a major proportion of the burden associated with diabetes contributing to substantial morbidity, mortality, and healthcare burden in people with diabetes. Retinopathy, nephropathy, and neuropathy constitute the leading causes of blindness, end-stage renal disease, and lower-extremity amputations, respectively. Since the efficacy of causal therapies of diabetic microvascular complications is limited, especially in type 2 diabetes, there is an unmet need for adjunct treatments which should be effective despite ongoing hyperglycemia. Experimental studies have indicated that diabetic microvascular complications can be prevented or ameliorated by various biofactors in animal models by interfering with the pathophysiology of the underlying condition. Some of the findings related to biofactors, like α-lipoic acid and benfotiamine, could be translated into the clinical arena and confirmed in clinical trials, especially in those focusing on diabetic polyneuropathy. Given the micronutrient nature of these compounds, their safety profile is excellent. Thus, they have the potential to favorably modify the natural history of the underlying complication, but long-term clinical trials are required to confirm this notion. Ultimately, biofactors should expand our therapeutic armamentarium against these common, debilitating, and even life-threatening sequelae of diabetes.

Keywords: Biofactors; cardiovascular autonomic neuropathy; diabetic microvascular complications; diabetic nephropathy; diabetic retinopathy; diabetic sensorimotor polyneuropathy.

Fig. (1)

Cellular pathways implicated in the pathogenesis of diabetic neuropathy and mechanisms of action of specific biofactors (highlighted in green) that are linked to the various maladaptive processes with STOP signs indicating experimentally verified blocking of the corresponding pathways. Adapted from [8]. Abbreviations: AGEs, Advanced Glycation End products; AMPK, 5' Adenosine Monophosphate-activated Protein Kinase; AR, Aldose Reductase; ATP, Adenosine Triphosphate; BiP, Binding immunoglobulin Protein; CHOP, CCAAT/enhancer-binding Protein Homologous Protein; COX2, Cyclooxygenase 2; CR, Cytokine Receptor; ER, Endoplasmic Reticulum; FFAs, Free Fatty Acids; G6P, Glucose-6-Phosphate; GAPDH, Glyceraldehyde 3-Phosphate Dehydrogenase; GLUT, Glucose Transporter; IKK, IκB Kinase; IR, Insulin Receptor; JNK, c-Jun N-terminal Kinase; NAD⁺, oxidized Nicotinamide adenine Dinucleotide; NF-κB, Nuclear Factor kappa-light-chain-enhancer of activated B cells; PKC, Protein Kinase C; PPP, Pentose Phosphate Pathway; PARP1, Poly (ADP-ribose) Polymerase 1; RAGE, Receptor of AGEs; SNPs, Single-Nucleotide Polymorphisms; UPR, Unfolded Protein Response (A higher resolution / colour version of this figure is available in the electronic copy of the article).

Fig. (2)

Pathogenesis of diabetic retinopathy and mechanisms of action of various biofactors. Abbreviations: AGEs, Advanced Glycation End products; ALA, α-Lipoic Acid; Ang-2, Angiopoietin 2; DAG, Diacylglycerol; EC, Endothelial Cells; PKC, Protein Kinase C; ROS, Reactive Oxygen Species; VEGF, Vascular Endothelial Growth Factor (A higher resolution / colour version of this figure is available in the electronic copy of the article).

Fig. (3)

Pathogenesis of diabetic nephropathy and mechanisms of action of various biofactors. Adapted from [232]. Abbreviations: ACR, Albumin-to-Creatinine Ratio; AGE, Advanced Glycation end products; ALA, α-Lipoic Acid; Ang-2, Angiopoietin 2; CRP, C-Reactive Protein; DAG, Diacylglycerol; GFR, Glomerular Filtration Rate; IGF-1, Insulin-like Growth Factor 1; IL-6, Interleukin-6; JAK-STAT, Janus kinase/signal transducer and activator of transcription; NF-κB, Nuclear Factor kappa-light-chain-enhancer of activated B cells; NO, Nitric Oxide; PAI-1, Plasminogen activator inhibitor-1; PDGF, Platelet-Derived Growth Factor; PG, Plasma Glucose; PKC, Protein Kinase C; PPP, Pentose Phosphate Pathway; RAAS, Renin-Angiotensin-Aldosterone System; ROS, Reactive Oxygen Species; SGLT₂, Sodium dependent glucose co-transporter 2; TGF-α, Transforming Growth factor-alpha; TGF-β, Transforming Growth Factor-beta; TNF-α, Tumor Necrosis Factor-alpha; VEGF, Vascular Endothelial Growth Factor; VEGF-A, Vascular endothelial Growth factor-A (A higher resolution / colour version of this figure is available in the electronic copy of the article).