Emerging Targets in Type 2 Diabetes and Diabetic Complications

Abstract

Type 2 diabetes is a metabolic, chronic disorder characterized by insulin resistance and elevated blood glucose levels. Although a large drug portfolio exists to keep the blood glucose levels under control, these medications are not without side effects. More importantly, once diagnosed diabetes is rarely reversible. Dysfunctions in the kidney, retina, cardiovascular system, neurons, and liver represent the common complications of diabetes, which again lack effective therapies that can reverse organ injury. Overall, the molecular mechanisms of how type 2 diabetes develops and leads to irreparable organ damage remain elusive. This review particularly focuses on novel targets that may play role in pathogenesis of type 2 diabetes. Further research on these targets may eventually pave the way to novel therapies for the treatment-or even the prevention-of type 2 diabetes along with its complications.

Keywords: insulin resistance; metabolism; signaling pathways; type 2 diabetes, diabetic complications.

Figure 1

Canonical insulin signaling pathway. Binding of insulin to insulin receptor (IR) triggers phosphorylation of IRS, which in turn phosphorylates PI3K. Activated PI3K recruits PDK1 to the cell membrane. Akt is phosphorylated by PDK1 (on T308) and mTORC2 (on S473). Activated Akt targets a wide range of downstream targets including TSC2, GSK3β, and FoxO1 to regulate essential metabolic events. Insulin binding to its receptor also activates SHC adaptor proteins which target RAS and ERK to promote cell proliferation. Activated IR can also translocate to cell nucleus to induce the expression of genes that play role in lipid metabolism and protein synthesis. ECM, extracellular matrix.

Figure 2

Insulin resistance at IRS‐1/2. Insulin receptor substrate‐1/2 (IRS‐1/2) is a critical target that can be phosphorylated by various kinases to regulate its interaction with insulin receptor (IR). As Grb10, SOCS, or IQGAP1 proteins impair IR‐IRS1/2 interaction; JNK, IKKβ, S6K1, mTORC1, and PIM kinases phosphorylate IRS‐1/2 to promote its proteasomal degradation.

Figure 3

Selective insulin resistance. In healthy individuals, insulin promotes lipogenesis while suppressing hepatic gluconeogenesis to lower the blood glucose levels. In type 2 diabetes, distorted insulin action promotes lipogenesis yet fails to inhibit gluconeogenesis. This phenomenon is known as selective insulin resistance.

Figure 4

Glucagon signaling. Upon glucagon binding, GCGR activates adenylate cyclase that increases cAMP levels in the cytoplasm. cAMP activates PKA which phosphorylates CREB and leads to its translocation to nucleus. CREB forms a complex with CBP and CRTC2 to regulate gluconeogenic gene expression and fatty acid oxidation via targets such as PGC1α, FoxO1, hepatic HNF4α, FXR, and LXR. ECM: Extracellular matrix.

Figure 5

Role of β‐cells in type 2 Diabetes. Β‐cells, located in Langerhans islet of pancreas, maintain islet function by regulating insulin release upon glucose stimulation. Glucose stimulated insulin secretion (GSIS), β‐cell mass and function are also promoted by different transcription factors regulated via pancreatic macrophages and pericytes. Inceptor, insulin inhibitory receptor, promotes insulin receptor (IR) internalization via clathrin‐mediated endocytosis. Exhausted β‐cells in type 2 diabetes increase their number and size to secrete more insulin to blood stream. Challenged β cells can either dedifferentiate or undergo apoptosis. Dysfunctional β cells cause cytotoxic effects exacerbating type 2 diabetes symptoms.

Figure 6

Diabetic kidney disease. Hyperglycemia and insulin resistance increase angiotensin II expression which activates TGFβ1 via ROS and JAK/STAT signaling. Baricinitib, selective inhibitor of JAK1/2, can reduce albuminuria in type 2 diabetes patients. TGFβ1 can also be activated via AGEs, mechanical stretch and thrombospondin 1. Activated TGFβ1 stimulates a wide range of targets including Wnt/β‐catenin, Smad 2/3 complex, PKC, MAPK, and ILK to promote fibrogenesis in kidney.

Figure 7

Cardiovascular complications. Hyperglycemia and AGEs cause endothelial cell dysfunction by increasing VCAM‐1 expression on the cell membrane. Monocytes bind to VCAM‐1 and infiltrate to ECM where monocytes differentiate into foam cells. Hyperglycemia also promotes quiescent vascular smooth muscle cell (qVSMC) activation which also contributes foam cell differentiation. In endothelial cells, eNOS can be regulated by Akt and CaMKII induced‐Ca²⁺ levels via endothelin B receptor (ETB). Sarcolipin inhibits SERCA2a function which exacerbates Ca²⁺ dysregulation.

Figure 8

Diabetic retinopathy. Endothelial cells and pericytes are the two regulators of diabetic retinopathy. Hyperglycemia and oxidative stress cause pericyte detachment from the endothelial cells via Notch1/3, HIF1α, and VEGF‐1 signaling pathways. Anti‐VEGF‐1 therapies are used to inhibit detachment of pericytes. Glial cells express Sema4d during hypoxia and upon Sema4d binding to its receptor Plexin B1 in pericytes, mDia/Src pathway gets activated. Activated Src promotes VE‐cadherin internalization and loosens the tight junctions between endothelial cells. Ang1‐Tie2 binding also impairs Src function, while Ang2 inhibits Ang1‐Tie interaction. cPWWP2A circular RNA downregulates miR579, which in turn promotes Ang1 expression.

Figure 9

Diabetic neuropathy in axon terminals. Notch and TLR4 promotes the expression of TNFα which exacerbates hyperalgesia. Increased cAMP/PKA signaling leads to aberrant Na(v)1.8 channel and HCN2 channel function which also leads to hyperalgesia in diabetes. Hyperglycemia induced Methylglyoxal (MG) also modifies Na(v)1.8 and TRPA1 receptors and promotes hyperalgesia. CXCL12 and CXCR4 are novel targets that can initiate mechanical allodynia in diabetic neuropathy.