Reference
Galicia-Garcia, U., Benito-Vicente, A., Jebari, S., Larrea-Sebal, A., Siddiqi, H., Uribe, K. B., Ostolaza, H., & Martín, C. (2020). Pathophysiology of Type 2 Diabetes Mellitus. International Journal of Molecular Sciences, 21(17), Article 17. https://doi.org/10.3390/ijms21176275
Info
FirstAuthor:: Galicia-Garcia, Unai
Author:: Benito-Vicente, Asier
Author:: Jebari, Shifa
Author:: Larrea-Sebal, Asier
Author:: Siddiqi, Haziq
Author:: Uribe, Kepa B.
Author:: Ostolaza, Helena
Author:: Martín, César
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Title:: Pathophysiology of Type 2 Diabetes Mellitus
Year:: 2020
Citekey:: Galicia-GarciaEtAl_2020_PathophysiologyType2
itemType:: journalArticle
Journal:: International Journal of Molecular Sciences
Volume:: 21
Issue:: 17
Pages:: 6275
DOI:: 10.3390/ijms21176275
Link
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.
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Skeletal Muscle Skeletal muscle IR is considered to be the most important extra-pancreatic factor in the development of T2DM [157]. Under physiological conditions, insulin stimulates muscle glycogen synthesis by enhancing glucose uptake from plasma.
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Mutations that reduce the expression of insulin receptor or GLUT4, as well as any defect in either upstream or downstream signaling pathway would reduce glucose intake into the muscle resulting in a hyperglycaemic state [153,160].
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Obesity, which is associated with chronic inflammation, contributes to IR and T2DM. Increasing evidence suggests that as a consequence of obesity, increased immune cell infiltration and secretion of proinflammatory molecules in intermyocellular and perimuscular adipose tissue leads to skeletal muscle inflammation