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Type 2 diabetes mellitus (T2DM) has become a major contributor to long-term renal impairment. Pancreatic β-cells produce the hormone insulin, which significant impacts on carbohydrate, fat and protein metabolism and mineral homeostasis. As a result, abnormalities in insulin signalling have a vast impact throughout the body.[1] Impaired responsiveness to the actions of insulin on target organs, such as the liver, adipose tissue and skeletal muscles, is known as insulin resistance (IR).[2,3] Consequently, insulin production and secretion are increased by β-cells, leading to hyperinsulinaemia, to make up for the target organs’ diminished physiologic response to insulin.[4] In all nations, there are more individuals with T2DM are experiencing end-stage kidney disease and demanding renal replacement treatment, making this an issue of international public heath concern.[5] The usual target tissues for insulin activity are the liver, white adipose tissue and skeletal muscle. Most body parts and cellular components are impacted by insulin, including the kidney and the vascular endothelium.[6] There are multiple mechanisms connecting renal dysfunction to insulin sensitivity and hyperinsulinaemia. Diabetic nephropathy (DN) and diabetic glomerulosclerosis are the intricate combinations of diseases woven together by a complex web of oxidative stress, metabolic toxicities and vascular dysfunction.[7] About 35% of individuals with type 1 diabetes mellitus (T1DM) and 15%–20% of individuals with T2DM experience DN.[8,9]
INSULIN SIGNALLING
When blood glucose levels are raised, pancreatic cells produce and release the peptide hormone insulin, which regulates important energy processes like protein, lipid and glucose metabolism.[10] Insulin acts biologically through various cell surface receptors with intrinsic tyrosine kinase activity. Insulin receptor substrates (IRSs) such as IRS-1 to IRS-4 family members and signalling molecules such as Shc are phosphorylated when the insulin receptor (IR) is activated. The phosphatidyl-inositol 3 kinases (PI3K)/Akt signalling pathway and the mitogen-activated protein kinase (MAPK) paths are the two focal signalling paths that are activated in reply to insulin. Most of the insulin’s metabolic effects are facilitated by the PI3K/Akt pathway. In addition to this, the MAPK path regulates gene exhibition and cell proliferation. The activated IR phosphorylates the IRS proteins on several tyrosine residues, which activates PI3K. Several Src homology 2 domain-containing molecules, including PI3K, bind with IRS proteins after Tyr phosphorylation. The p110 subunit’s enzymatic activity is enhanced because of the interaction between the IRS proteins and PI3K through the enzyme’s p85 regulatory subunit. Numerous insulin-persuaded metabolic effects rely on PI3K, including acceleration of glucose transport, protein synthesis and glycogen formation, primarily through the stimulation of Akt [Figure 1].[11]
Figure 1: Insulin signaling pathway. This figure has been developed by utilizing the Premium version of BioRender (
https://biorender. com/) with License No.: KB24VB3Q91. Image Credit: Susmita Sinha. IRS: Insulin receptor substrate, PI3K: Phosphoinositide 3 kinase, PDK1: Phosphoinositide-dependent kinase-1, AKT: Protein kinase B, GSK3: Glycogen synthase kinase 3, GS: Glycogen synthase, ERK: Extracellular signal-regulated kinase, MAPK: Mitogen-activated protein kinase, Grb2: Growth factor receptor-bound protein 2, SHC: Signaling molecule, GLUT4: Glucose transporter type 4.
INSULIN AND ITS ACTION IN KIDNEY
Insulin’s typical target cells, such as adipocytes, hepatocytes and muscles, while exposed to high glucose concentrations, resulting in a variety of cellular abnormalities.[12] Furthermore, the focused tissue of insulin is most of the bodily organs and cellular constituents, together with the kidneys and vasculature, which might be affected by insulin through changing podocyte activity, microcirculation and tubular functioning. Typical consequences such as vision loss, renal failure and neuropathy might also occur.[13] In end-stage renal disease (ESRD) patients, IR frequently coexists with protein energy depletion and malnutrition. Renal failure may result from abnormal insulin activity and impact nutrition, metabolism and circulation.[14]
RENAL BLOOD FLOW
Like the typical insulin target tissue, the renal vasculature is anticipated to exhibit diminished nitric oxide (NO) signalling in the insulin-resistant condition.[15] Insulin-resistant Zucker rats’ renal arteries did not enlarge in response to insulin and acetylcholine, indicative of an endothelium malfunction.[16] Decreased insulin-stimulated NO generation would be attributed to higher renovascular impedance, which would lower glomerular filtration rate (GFR). The primary processes causing glomerular hyperfiltration are assumed to be decreased tubuloglomerular feedback and dilatation of afferent arterioles due to increased reabsorption of salt together with glucose.[17]
RENAL CELL PROLIFERATION
Insulin excites insulin-like growth factor 1 (IGF-1) receptor activity while increasing IGF-1 synthesis to encourage vascular growth. IGF-1 was reported to promote the viability of mesangial cells by inhibiting their programmed cell death in a dose-dependent fashion.[18,19]
GLOMERULAR ENDOTHELIUM
Insulin can affect almost all kidney cell varieties along with podocytes, mesangial cells and tubular epithelium. Glomerular endothelium expresses the insulin receptor and is responsive to insulin binding by increasing NO production. Insulin can easily pass through the glomerular endothelial fenestration, traverse the basal layer, pass through the Bowmann’s space, then tubules. Consequently, the transportation of insulin to subendothelium is not restricted by insulin-mediated endothelial NO signalling.[20] Renal mesangial cells and podocytes are easily affected by the changes in the plasma concentrations of insulin.
MESANGIAL CELLS
It has been demonstrated that enhanced insulin-induced MAPK signalling activates huge conductance Ca2+ activated K+ channels, causing mesangial cells to relax and possibly proliferate more. Mesangial cell insulin signalling dysfunction may contribute to decreased GFR.[21]
PODOCYTE
The filtration membrane of the kidney contains a special type of differentiated epithelial cell called a podocyte. By intricately controlling the actin cytoskeleton in their foot processes, podocytes aid in the prevention of proteinuria. Podocytes are insulin-responsive in recent investigations. This finding suggests that comprehending DN and the relationship between albuminuria and states of insulin resistance may depend critically on podocyte insulin sensitivity.[22,23]
Oversensitivity of podocytes
Podocytes, the glomerular basement membrane and endothelium from the specific glomerular filtration barrier, which restricts protein passage from the blood into the ultimate filtrate [Figure 2].[24] Podocytes are the most sensitive component of the glomerular filtration system because they cannot proliferate. In addition to circulatory factors such as mechanical strain brought on by differences in exchange vessel pressure, elevated glucose concentrations, excessive free fatty acid concentrations, reactive oxygen species (ROS), angiotensin II and transforming growth factor β can all harm podocytes.[25]
Figure 2: Schematic arrangement of glomerular filtration barrier. This figure has been developed by utilizing the Premium version of BioRender (
https://biorender.com/) with License No.: MR24VAYGQJ. Image Credit: Susmita Sinha.
Energy source for podocytes
Podocytes use glucose as their main energy source and obtain it through anaerobic glycolysis. Facilitated diffusion transports almost 80% of the glucose that enters podocytes; the remaining 20% is co-transported sodium-dependently.[26] Podocytes contain several transport proteins, such as GLUT 4 and 8, for the diffusion of glucose within the cell. Besides, GLUT-1 transports glucose into cells under normal circumstances, whereas GLUT-4 transports glucose when insulin is present. GLUT-4 is also primarily restricted to the intracellular vesicular chamber; however, insulin incentive consequences in GLUT-4 shift to the cellular membrane. Long-term exposure of podocytes to higher glucose concentrations decreased the expression of GLUT-1 and GLUT-4.[3]
RENIN ANGIOTENSIN SYSTEM
Studies have indicated that insulin is required for mesangial cell contraction brought on by angiotensin-II, establishing a connection between insulin and angiotensin-II-mediated renal damage.[27]
DIABETIC NEPHROPATHY
DN is the frequent cause of ESRD and another major microvascular consequence of diabetes mellitus, characterised by albuminuria, hypertension, decreasing GFR and an enhanced cardiovascular disease risk.[28] The stimulation of the inborn immune system and inflammatory responses are now being linked to a multitude of studies that recommend they have an involvement in the progression of DN. Almost all multicellular species have an innate immune system that responds to pathogens or tissue damage by identifying danger or pathogen-associated molecular patterns using pattern recognition receptors that are genetically programmed. Two main categories of pattern recognition receptors are Toll-like receptors (TLRs) and Nod-like receptors (NLRs).[29] Inhibition of IR and amelioration of renal impairment were achieved in the kidneys of T2DM rats by a specific hormone that many cells release to regulate circulation named prostaglandin-E1 (PGE1). They also showed that fibroblast growth factor-21, a substance produced as a result of the reduction in apoptosis, restored PGE1 and persuaded IR.[30] Multiple pathological processes in DN may be the primary hindrances to insulin’s activation and their conversion path in glomerular epithelial cells. Previous studies discovered a significant connection between DN and mechanical destruction and dysfunction of glomerular podocytes. Changes in endothelin-1 generation and activity were linked to significant renal vascular constriction that decreased mesangial cell compression and growth, renal plasma flow and GFR and increased withholding of water and sodium. Endothelin-1 might function in developing DN in individuals with T2DM, microalbuminuria and hypertension, according to evidence suggesting elevated endothelin-1 concentrations in these individuals.[31] Those with Stage III–IV chronic kidney disease (CKD) and individuals with early DN were observed to have higher degrees of production of ROS.[32] Another component related to insulin resistance that may contribute to kidney damage is plasminogen activator inhibitor type 1 (PAI-1). The basic biological function of this substance, which is generated mainly by the liver and endothelium, is to suppress the activity of the tissue plasminogen activator that causes the transformation. In addition, it was discovered that diabetic individuals and aggressive nephropathy had greater plasma concentrations of PAI-1.[33,34]
MEASUREMENT OF INSULIN SENSITIVITY
The hyperinsulinemic-euglycemic clamp provides a detailed assessment concerning the entire body’s responsiveness to insulin, predominantly voluntary striated muscles, making it the best method for IR assessment. Labeling glucose can provide information on how effectively small insulin dose inhibits the synthesis of endogenous glucose. This method allows for a precise, direct estimation of IR, besides distinguishing between peripheral and hepatic IR.[35] The rate of change in plasma glucose concentrations is correlated with the current insulin concentrations in an algorithm used to construct the insulin sensitivity index. Subsequently, long-term renal disorder limits insulin assimilation and fasting insulin level mostly indicates liver anomalies, assessments of IR based on fasting insulin concentrations in CKD patients could be less appropriate.[36]
The progress of cardiovascular and possibly renal impairment commences much before the initiation of T2DM. Hence, it is better to concentrate on those variables that are found initially involved in ‘diabetic’ renal injury and to recognise preventive measures for their acts. DN is still a significant community well-being concern, and additional investigation is required to clearly understand all the possible processes that link insulin resistance and hyperinsulinemia to renal dysfunction and build a strong case for a particular treatment strategy.
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The author reviewed and approved the final version and has agreed to be accountable for all aspects of the work, including any accuracy or integrity issues.
Disclosure
The author declares that they do not have any financial involvement or affiliations with any organization, association or entity directly or indirectly with the subject matter or materials presented in this article. This includes honoraria, expert testimony, employment, ownership of stocks or options, patents or grants received or pending or royalties.
Data availability
Information is taken from freely available sources for this review paper.
Authorship contribution
All authors contributed significantly to the work, whether it be in the conception, design, utilization, collection, analysis, and interpretation of data, or in all of these areas. They also participated in the article’s drafting, revision, or critical review, gave their final approval for the version that would be published, decided on the journal to which the article would be submitted, and made the responsible decision to be held accountable for all aspects of the work.
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