Pathophysiology of Type 2 Diabetes Mellitus

Unai Galicia-Garcia, Asier Benito-Vicente, Shifa Jebari, Asier Larrea-Sebal, Haziq Siddiqi, Kepa B Uribe, Helena Ostolaza, César Martín, Unai Galicia-Garcia, Asier Benito-Vicente, Shifa Jebari, Asier Larrea-Sebal, Haziq Siddiqi, Kepa B Uribe, Helena Ostolaza, César Martín

Abstract

Type 2 Diabetes Mellitus (T2DM), one of the most common metabolic disorders, is caused by a combination of two primary factors: defective insulin secretion by pancreatic β-cells and the inability of insulin-sensitive tissues to respond appropriately to insulin. Because insulin release and activity are essential processes for glucose homeostasis, the molecular mechanisms involved in the synthesis and release of insulin, as well as in its detection are tightly regulated. Defects in any of the mechanisms involved in these processes can lead to a metabolic imbalance responsible for the development of the disease. This review analyzes the key aspects of T2DM, as well as the molecular mechanisms and pathways implicated in insulin metabolism leading to T2DM and insulin resistance. For that purpose, we summarize the data gathered up until now, focusing especially on insulin synthesis, insulin release, insulin sensing and on the downstream effects on individual insulin-sensitive organs. The review also covers the pathological conditions perpetuating T2DM such as nutritional factors, physical activity, gut dysbiosis and metabolic memory. Additionally, because T2DM is associated with accelerated atherosclerosis development, we review here some of the molecular mechanisms that link T2DM and insulin resistance (IR) as well as cardiovascular risk as one of the most important complications in T2DM.

Keywords: adipocyte; cardiovascular disease; insulin resistance; liver; muscle; pathophysiology; type 2 diabetes mellitus; β-cell.

Conflict of interest statement

The authors declare no conflict of interest.

Figures

Figure 1
Figure 1
Signaling pathways involved in insulin secretion in β-cells in physiological conditions (A) and mechanisms leading to dysfunction (B). (A) Insulin release is primarily triggered by a response to high glucose concentrations and glucose in mainly internalized mainly through GLUT2 transporter. Glucose catabolism increases ATP/ADP ratio, ATP-dependant potassium channels are closed leading to membrane depolarization and opening of the voltage dependant Ca2+ channels. The latter enables Ca2+ influx triggering insulin exocytosis. Additional Ca2+ channels as P2X, P2Y, SERCA and RYR contribute to Ca2+ mobilization and insulin secretion. (B) hyperglycemia and hyperlipidemia promote oxidative stress leading to ROS generation that inhibits Ca2+ mobilization and activates proapoptotic signals. Additionally, an excess of FFAs and hyperglycemia lead to the activation of the apoptotic unfolded protein response (UPR) pathways and generation of ER stress. Sustained high glucose levels increase proinsulin and IAAP biosynthesis, which generate ROS. GLUT2: glucose transporter 2, P2X: purinergic receptor X; P2Y: purinergic receptor Y; IP2: inositol 1,3-bisphosphate; IP3: inositol 1,4,5-trisphosphate; RYR: ryanodine receptor channel; SERCA: sarco-endoplasmic reticulum Ca2+-ATPase; FFA: free fatty acid, ROS: reactive oxygen species; UPR: unfolded protein response.
Figure 2
Figure 2
Type 2 Diabetes Mellitus (T2DM) risk factors and the pathological changes leading to the perpetuation of insulin dysfunction. Complex combinations of genetic, metabolic and environmental factors that interact with one another constitute both non-modifiable (ethnicity and family history/genetic predisposition) and modifiable risk factors (obesity, low physical activity and an unhealthy diet). These states affect cell function resulting in a complex network of pathological changes that influence mutually and lead to the perpetuation of insulin dysfunction. ROS: reactive oxygen species; ER: endoplasmic reticulum; AGEs: advanced glycation end products; PKC: protein kinase C; LPS: lipopolysaccharide; miRNA: microRNA.
Figure 3
Figure 3
Mitochondrial dysfunction and contribution to T2DM development. Oxidative stress, defective mitochondrial biogenesis and impaired mitophagy promote mitochondrial dysfunction. Generation of ROS links mitochondrial dysfunction and IR. As a consequence of nutrient overload, electron supply to the mitochondrial ETC increases and the electron excess is transferred to oxygen generating O2− and H2O2. ROS oxidize proteins, damage DNA and membrane lipids. Mitofusin-2 and PGC 1α are downregulated leading to reduced mitochondrial biogenesis. Cellular stress and ROS production contribute to higher mitochondrial fission and impaired mitophagy. PCG 1α: Peroxisome proliferator-activated receptor-gamma coactivator-1.
Figure 4
Figure 4
Insulin stimulation effects on healthy and hypertrophic adipose tissue. In healthy adipose tissue insulin stimulates glucose uptake and TG synthesis, induces FFA uptake and diminishes macrophage-mediated inflammation. Hypertrophic adipose tissue leads to diminished glucose uptake, TG synthesis and enhances FFA release, hypoxia and macrophage-mediated inflammation. FFA: free fatty acid.
Figure 5
Figure 5
Signaling pathways involved in insulin signaling in hepatocytes. Binding of insulin to INSR induces IRSs recruitment and phosphorylation. Phosphorylated IRSs activate PI3K, generating PIP3 which activates PDK resulting in AKT phosphorylation. AKT is fully activated by further mTORC2 phosphorylation and participates in several downstream pathways that regulate multiple metabolic processes including glycogen synthesis, gluconeogenesis, glycolysis and lipid synthesis. INSR: insulin receptor; PIP2: inositol 1,3-bisphosphate; PIP3: inositol 1,4,5-trisphosphate; IRS1: insulin receptor substrate 1; PI3K: phosphoinositide 3 kinase; mTORC2: mammalian target of rapamycin complex 2; PDK1: Phosphoinositide-dependent kinase-1; AKT: protein kinase B; AS160: Akt substrate of 160 kDa; GLUT4: glucose transporter 4; GSk3β: Glycogen Synthase Kinase 3 Beta; GS: Glycogen synthase; FOXO1: Forkhead box protein O1; G6pc:Glucose 6 phosphate; Pck1: Phosphoenolpyruvate Carboxykinase 1.
Figure 6
Figure 6
Factors implicated in cardiovascular risk outcomes from T2DM and the interactions between them. T2DM derived hyperglycemia, hyperinsulinemia and IR causes endothelial dysfunction, diabetic dyslipidemia and inflammation leading to CVD. The flowchart illustrates the multiple interactions among the implicated factors.
Figure 7
Figure 7
Diabetic dyslipidemia: mechanisms leading to T2DM dyslipidemia and lipoprotein clearance in physiological an IR conditions. (A) IR leads to an impaired adipose tissue fat storage, resulting in constitutive FFA release from the intracellular TG stores of adipocytes. The released FFAs are taken up by hepatocytes, where they can be directed to the mitochondria and undergo β-oxidation; be re-assimilated into TG to assemble new VLDL particles; shifted to gluconeogenesis resulting in a worsening of hyperglycemia; or stored as TG leading to hepatic steatosis. (B) Under physiological conditions, VLDL particles incorporate apo-CII and apoE from HDL allowing VLDL to be progressively lipolyzed leading to the generation of smaller VLDL particles (upper panel). T2DM and IR impair metabolism and clearance of chylomicrons and VLDLs. Activation of CETP promotes an exchange of TG out of RLPs and incorporates CE from HDL and LDL particles leading to reduced levels of circulating HDL-C and an increase in the more atherogenic sdLDL particles (lower panel). TG: triglyceride; FFA: free fatty acid, LPL: lipoprotein Lipase; CR: chylomicron remnants; HL: hepatic lipase; CETP: Cholesteryl Ester Transfer Protein; ApoE: apolopoprotein E; ApoC-II: apolipoprotein CII; apoC-III: apolipoprotein CIII; VLDL: very low-density lipoprotein; sdLDL: small dense lipoprotein.

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Source: PubMed

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