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Glucose Homeostasis and Cardiovascular Alterations in Diabetes

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Diabetes mellitus is an increasingly prevalent disease associated with a high morbidity and mortality burden. Many of the adverse outcomes secondary to diabetes occur as a result of the impaired glucose homeostasis and pathophysiological alterations to the cardiovascular system. The purpose of this overview is to broadly discuss many of the changes that occur in the context of diabetes that affect cardiovascular function. Following a brief introduction to the classification and etiologies of the various forms of diabetes, the mechanisms of impaired glucose homeostasis will be covered. Vascular endothelial dysfunction, which has been posited to play a major role in the development of target organ pathology, will be addressed, followed by a discussion of the effects of diabetes on the renal, cardiovascular, and pulmonary systems. © 2015 American Physiological Society. Compr Physiol 5:1815‐1839, 2015.

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Figure 1. Figure 1. Physiological alterations that occur in diabetes that contribute to hyperglycemia and hyperlipidemia. UCP‐2, uncoupling protein‐2; GLP‐1, glucagon‐like peptide‐1; ROS, reactive oxygen species.
Figure 2. Figure 2. Endocrine, neural, and inflammatory pathways contributing to stress hyperglycemia (stress diabetes) following major physical stress. SNA, sympathetic nerve activity; CRH, corticotropin‐releasing hormone; ACTH, adrenocorticotropic hormone.
Figure 3. Figure 3. Factors that contribute to the development of endothelial dysfunction in diabetes. eNOS, endothelial nitric oxide synthase; NO, nitric oxide; ROS, reactive oxygen species; AGEs, advanced glycation end‐products; ALEs, advanced lipoxidation end‐products; ER stress, endoplasmic reticulum stress.
Figure 4. Figure 4. Mechanisms by which diabetes and hyperglycemia contribute to an upregulation in superoxide production. UCP, uncoupling protein; BH4, tetrahydrobiopterin; eNOS, endothelial nitric oxide synthase; NOX, NADPH oxidase; O2, superoxide; ΔΨ, electron gradient. The dashed line indicates an inhibitory effect.
Figure 5. Figure 5. Schematic depicting mitochondrial production of reactive oxygen species. SOD, superoxide dismutase; O2, superoxide; H2O2, hydrogen peroxide; NO, nitric oxide; ONOO, peroxynitrite; H+, hydrogen ion; ADP, adenosine diphosphate; ATP, adenosine triphosphate; UCP, uncoupling protein; ΔΨ, electron gradient; I‐V, electron transport complexes I‐V. The dashed line indicates an inhibitory effect.
Figure 6. Figure 6. Mechanisms by which diabetes and chronic hyperglycemia lead to impaired kidney function and the development of diabetic kidney disease. GFR, glomerular filtration rate; TGF, tubuloglomerular feedback.
Figure 7. Figure 7. Schematic showing how diabetes and associated pathophysiological changes contribute to cardiovascular dysfunction and disease. ROS, reactive oxygen species; NO, nitric oxide; AGEs, advanced glycation end‐products; ALEs, advanced lipoxidation end‐products; VO2, oxygen consumption; ATP, adenosine triphosphate. The + symbol indicates a potentiating effect.
Figure 8. Figure 8. Overall schematic depicting how acute and chronic hyperglycemia contribute to end‐organ disease and mortality. ROS, reactive oxygen species. The + symbol indicates a potentiating effect.

Figure 1. Physiological alterations that occur in diabetes that contribute to hyperglycemia and hyperlipidemia. UCP‐2, uncoupling protein‐2; GLP‐1, glucagon‐like peptide‐1; ROS, reactive oxygen species.

Figure 2. Endocrine, neural, and inflammatory pathways contributing to stress hyperglycemia (stress diabetes) following major physical stress. SNA, sympathetic nerve activity; CRH, corticotropin‐releasing hormone; ACTH, adrenocorticotropic hormone.

Figure 3. Factors that contribute to the development of endothelial dysfunction in diabetes. eNOS, endothelial nitric oxide synthase; NO, nitric oxide; ROS, reactive oxygen species; AGEs, advanced glycation end‐products; ALEs, advanced lipoxidation end‐products; ER stress, endoplasmic reticulum stress.

Figure 4. Mechanisms by which diabetes and hyperglycemia contribute to an upregulation in superoxide production. UCP, uncoupling protein; BH4, tetrahydrobiopterin; eNOS, endothelial nitric oxide synthase; NOX, NADPH oxidase; O2, superoxide; ΔΨ, electron gradient. The dashed line indicates an inhibitory effect.

Figure 5. Schematic depicting mitochondrial production of reactive oxygen species. SOD, superoxide dismutase; O2, superoxide; H2O2, hydrogen peroxide; NO, nitric oxide; ONOO, peroxynitrite; H+, hydrogen ion; ADP, adenosine diphosphate; ATP, adenosine triphosphate; UCP, uncoupling protein; ΔΨ, electron gradient; I‐V, electron transport complexes I‐V. The dashed line indicates an inhibitory effect.

Figure 6. Mechanisms by which diabetes and chronic hyperglycemia lead to impaired kidney function and the development of diabetic kidney disease. GFR, glomerular filtration rate; TGF, tubuloglomerular feedback.

Figure 7. Schematic showing how diabetes and associated pathophysiological changes contribute to cardiovascular dysfunction and disease. ROS, reactive oxygen species; NO, nitric oxide; AGEs, advanced glycation end‐products; ALEs, advanced lipoxidation end‐products; VO2, oxygen consumption; ATP, adenosine triphosphate. The + symbol indicates a potentiating effect.

Figure 8. Overall schematic depicting how acute and chronic hyperglycemia contribute to end‐organ disease and mortality. ROS, reactive oxygen species. The + symbol indicates a potentiating effect.
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Lusha Xiang, Peter N. Mittwede, John S. Clemmer. Glucose Homeostasis and Cardiovascular Alterations in Diabetes. Compr Physiol 2015, 5: 1815-1839. doi: 10.1002/cphy.c150001