Gene Expression Analysis in T2DM and Its Associated Microvascular Diabetic Complications: Focus on Risk Factor and RAAS Pathway.

Prolonged hyperglycemic conditions in type 2 diabetes mellitus (T2DM) cause pathological and functional damage to many organs and tissues, including the kidneys, retina, skin, and neuronal tissues, resulting in the development of microvascular diabetic complications. The altered renin angiotensin aldosterone system (RAAS) pathway has been reported to play an important role in the development of insulin resistance in T2DM and associated complications. The current study was carried out to evaluate the association of risk factors and altered expression of RAAS genes in T2DM patients without complications and T2DM patients with complications (retinopathy, nephropathy, and neuropathy). Four hundred and twenty subjects including 140 healthy controls, 140 T2DM patients with diabetic complications, and 140 T2DM patients without diabetic complications were included in the study. Risk factors associated with the development of T2DM and diabetic complications were evaluated. Further, expression analysis of RAAS genes (AGT, ACE, ACE2, and AGT1R) was carried out using qRTPCR in healthy controls, T2DM patients with complications, and T2DM patients without complications. Various risk factors like urban background, higher BMI, alcoholism, smoking, and family history of diabetes among others were found to be associated with the development of T2DM as well as diabetic complications. The expression level of AGT, ACE, and AGT1R was found to be upregulated whereas ACE2 was found to be downregulated in T2DM patients with complications and T2DM patients without complications as compared to controls. Altered expression of the studied genes of RAAS pathway is associated with the development of microvascular diabetic complications.

miRNA signatures in diabetic retinopathy and nephropathy: delineating underlying mechanisms

A worldwide failure to achieve glycemic targets has led to complications associated with diabetes mellitus. In addition to genetic and other risk factors, epigenetic factors like DNA methylation, histone modifications, and non-coding RNAs play a significant part in the pathogenesis of complications. Among non-coding RNAs, miRNAs have been explored extensively since they control various biological processes. Their dysregulation has been implicated in various diseases including diabetic complications. Diabetic retinopathy and nephropathy are two common microvascular diabetic complications. Diabetic retinopathy affects the retina of the eye whereas nephropathy damages kidneys on account of prolonged hyperglycemia. This review aims to evaluate the role of miRNAs in diabetic retinopathy and diabetic nephropathy with an emphasis on the dysregulation of various pathways involved. In addition, the role of significant miRNAs as biomarkers for the diagnosis and prognosis of complications has also been discussed. Further, an update on the role of important miRNAs as potential therapeutic modalities has been given. (AU)

miRNA signatures in diabetic retinopathy and nephropathy: delineating underlying mechanisms.

A worldwide failure to achieve glycemic targets has led to complications associated with diabetes mellitus. In addition to genetic and other risk factors, epigenetic factors like DNA methylation, histone modifications, and non-coding RNAs play a significant part in the pathogenesis of complications. Among non-coding RNAs, miRNAs have been explored extensively since they control various biological processes. Their dysregulation has been implicated in various diseases including diabetic complications. Diabetic retinopathy and nephropathy are two common microvascular diabetic complications. Diabetic retinopathy affects the retina of the eye whereas nephropathy damages kidneys on account of prolonged hyperglycemia. This review aims to evaluate the role of miRNAs in diabetic retinopathy and diabetic nephropathy with an emphasis on the dysregulation of various pathways involved. In addition, the role of significant miRNAs as biomarkers for the diagnosis and prognosis of complications has also been discussed. Further, an update on the role of important miRNAs as potential therapeutic modalities has been given.

Role of miRNAs in diabetic neuropathy: mechanisms and possible interventions.

Accelerating cases of diabetes worldwide have given rise to higher incidences of diabetic complications. MiRNAs, a much-explored class of non-coding RNAs, play a significant role in the pathogenesis of diabetes mellitus by affecting insulin release, ß-cell proliferation, and dysfunction. Besides, disrupted miRNAs contribute to various complications, diabetic retinopathy, nephropathy, and neuropathy as well as severe conditions like diabetic foot. MiRNAs regulate various processes involved in diabetic complications like angiogenesis, vascularization, inflammations, and various signaling pathways like PI3K, MAPK, SMAD, and NF-KB signaling pathways. Diabetic neuropathy is the most common diabetic complication, characterized mainly by pain and numbness, especially in the legs and feet. MiRNAs implicated in diabetic neuropathy include mir-9, mir-106a, mir-146a, mir-182, miR-23a and b, miR-34a, and miR-503. The diabetic foot is the most common diabetic neuropathy, often leading to amputations. Mir-203, miR-23c, miR-145, miR-29b and c, miR-126, miR-23a and b, miR-503, and miR-34a are associated with diabetic foot. This review has been compiled to summarize miRNA involved in initiation, progression, and miRNAs affecting various signaling pathways involved in diabetic neuropathy including the diabetic foot. Besides, potential applications of miRNAs as biomarkers and therapeutic targets in this microvascular complication will also be discussed.

Role of miRNAs in the pathogenesis of T2DM, insulin secretion, insulin resistance, and ß cell dysfunction: the story so far.

Diabetes, the most common endocrine disorder, also known as a silent killer disease, is characterized by uncontrolled hyperglycemia. According to the International Diabetes Federation, there were 451 million people with diabetes mellitus worldwide in 2017. It is a multifactorial syndrome caused by genetic as well as environmental factors. Noncoding RNAs, especially the miRNAs, play a significant role in the development as well as the progression of the disease. This is on account of insulin resistance or defects in ß cell function. Various miRNAs including miR-7, miR-9, miR-16, miR-27, miR-24, miR-29, miR-124a, miR-135, miR-130a, miR-144, miR-181a, and miR-375 and many more have been associated with insulin resistance and other pathogenic conditions leading to the development of the disease. These miRNAs play significant roles in various pathways underlying insulin resistance such as PI3K, AKT/GSK, and mTOR. The main target genes of these miRNAs are FOXO1, FOXA2, STAT3, and PTEN. The miRNAs carry out important functions in insulin target tissues like the adipose tissue, liver, and muscle. MiRNAs miR-9, miR-375, and miR-124a, are also associated with the secretion of insulin from pancreatic cells. There is an interplay between the miRNAs and pancreatic cell growth, especially the miRNAs affecting development and proliferation of these cells. Most of the miRNAs target more than one gene which not only justifies their use as biomarkers but also their therapeutic potential. The current review has been compiled with an aim to discuss the role of various miRNAs involved in various pathogenic mechanisms including insulin resistance, insulin secretion, and the ß cell dysfunction.