Materiały źródłowe

• #1 Figure 1. [Pathogenesis of hyperglycemia. Hyperglycemia results…]. – Endotext – NCBI Bookshelf

  https://www.ncbi.nlm.nih.gov/books/NBK279093/figure/mgmt-diab-hosp-patnt.F1/

  Pathogenesis of hyperglycemia. Hyperglycemia results from increased hepatic glucose production and impaired glucose utilization in peripheral tissues. Reduced insulin and excess counter-regulatory hormones (glucagon, cortisol, catecholamines, and growth hormone) increase lipolysis and protein breakdown (proteolysis) and impair glucose uptake by peripheral tissues. Hyperglycemia causes osmotic diuresis, leading to volume depletion, decreasing glomerular filtration rate, and worsening hyperglycemia. At the cellular level, increased blood glucose concentrations result in mitochondrial injury by generating reactive oxygen species and endothelial dysfunction by inhibiting nitric oxide production. Hyperglycemia increases levels of pro-inflammatory cytokines such as tumor necrosis factor- (TNF-) and interleukin [IL]-6, leading to immune system dysfunction. These changes can eventually lead to an increased risk of infection, impaired wound healing, multiple organ failure, prolonged hospital stay, and death. […] Figure 1. [Pathogenesis of hyperglycemia. Hyperglycemia results…].

• #2 Figure 1. [Pathogenesis of hyperglycemia. Hyperglycemia results…]. – Endotext – NCBI Bookshelf

  https://www.ncbi.nlm.nih.gov/sites/books/NBK279093/figure/mgmt-diab-hosp-patnt.F1/?report=objectonly

  Hyperglycemia results from increased hepatic glucose production and impaired glucose utilization in peripheral tissues. […] Reduced insulin and excess counter-regulatory hormones (glucagon, cortisol, catecholamines, and growth hormone) increase lipolysis and protein breakdown (proteolysis) and impair glucose uptake by peripheral tissues. […] At the cellular level, increased blood glucose concentrations result in mitochondrial injury by generating reactive oxygen species and endothelial dysfunction by inhibiting nitric oxide production. […] Hyperglycemia increases levels of pro-inflammatory cytokines such as tumor necrosis factor- (TNF-) and interleukin [IL]-6, leading to immune system dysfunction. […] These changes can eventually lead to an increased risk of infection, impaired wound healing, multiple organ failure, prolonged hospital stay, and death.

• #3 Hyperglycemia (High Blood Sugar): Symptoms & Treatment

  https://my.clevelandclinic.org/health/diseases/9815-hyperglycemia-high-blood-sugar

  Hyperglycemia (high blood sugar) is common in people who have diabetes. If its left untreated, chronic hyperglycemia can lead to diabetes complications, such as nerve damage, eye disease and kidney damage. […] Hyperglycemia usually means you have diabetes, and people with diabetes can experience hyperglycemia episodes frequently. […] If you have hyperglycemia thats untreated for long periods of time, it can damage your nerves, blood vessels, tissues and organs. […] Severe hyperglycemia can also lead to an acute (sudden and severe) life-threatening complication called diabetes-related ketoacidosis (DKA), especially in people with diabetes who take insulin or people with undiagnosed Type 1 diabetes. This requires immediate medical treatment. […] Hyperglycemia most often results from a lack of insulin. This can happen due to insulin resistance and/or issues with your pancreas the organ that makes insulin.

• #4 Hyperglycemia in diabetes – Symptoms & causes – Mayo Clinic

  https://www.mayoclinic.org/diseases-conditions/hyperglycemia/symptoms-causes/syc-20373631

  High blood sugar, also called hyperglycemia, affects people who have diabetes. Several factors can play a role in hyperglycemia in people with diabetes. They include food and physical activity, illness, and medications not related to diabetes. Skipping doses or not taking enough insulin or other medication to lower blood sugar also can lead to hyperglycemia. […] Diabetes drastically reduces insulin’s effects on the body. This may be because your pancreas is unable to produce insulin, as in type 1 diabetes. Or it may be because your body is resistant to the effects of insulin, or it doesn’t make enough insulin to keep a normal glucose level, as in type 2 diabetes. […] In people who have diabetes, glucose tends to build up in the bloodstream. This condition is called hyperglycemia. It may reach dangerously high levels if it is not treated properly. Insulin and other drugs are used to lower blood sugar levels.

• #5 Diabetes Mellitus (DM) – Endocrine and Metabolic Disorders – Merck Manual Professional Edition

  https://www.merckmanuals.com/professional/endocrine-and-metabolic-disorders/diabetes-mellitus-and-disorders-of-carbohydrate-metabolism/diabetes-mellitus-dm

  Diabetes mellitus is impaired insulin secretion and variable degrees of peripheral insulin resistance leading to hyperglycemia. […] Years of poorly controlled hyperglycemia lead to multiple, primarily vascular complications that affect small vessels (microvascular), large vessels (macrovascular), or both. […] In type 2 diabetes mellitus (previously called adult-onset or noninsulin-dependent), insulin secretion is inadequate because patients have developed resistance to insulin. Hepatic insulin resistance leads to an inability to suppress hepatic glucose production, and peripheral insulin resistance impairs peripheral glucose uptake. This combination gives rise to fasting and postprandial hyperglycemia. […] Pathogenesis is complex and incompletely understood. Hyperglycemia develops when insulin secretion can no longer compensate for insulin resistance.

• #6 Hyperglycemia in diabetes – Symptoms & causes – Mayo Clinic

  https://www.mayoclinic.org/diseases-conditions/hyperglycemia/symptoms-causes/syc-20373631

  High blood sugar, also called hyperglycemia, affects people who have diabetes. Several factors can play a role in hyperglycemia in people with diabetes. They include food and physical activity, illness, and medications not related to diabetes. Skipping doses or not taking enough insulin or other medication to lower blood sugar also can lead to hyperglycemia. […] Diabetes drastically reduces insulin’s effects on the body. This may be because your pancreas is unable to produce insulin, as in type 1 diabetes. Or it may be because your body is resistant to the effects of insulin, or it doesn’t make enough insulin to keep a normal glucose level, as in type 2 diabetes. […] In people who have diabetes, glucose tends to build up in the bloodstream. This condition is called hyperglycemia. It may reach dangerously high levels if it is not treated properly. Insulin and other drugs are used to lower blood sugar levels.

• #7 Hyperglycemia (High Blood Sugar): Symptoms & Treatment

  https://my.clevelandclinic.org/health/diseases/9815-hyperglycemia-high-blood-sugar

  A common cause of hyperglycemia is insulin resistance. Insulin resistance, also known as impaired insulin sensitivity, happens when cells in your muscles, fat and liver dont respond as they should to insulin. […] When your cells dont properly respond to insulin, your body requires more and more insulin to regulate your blood sugar. If your body is unable to produce enough insulin (or you dont inject enough insulin), it results in hyperglycemia. […] Insulin resistance is the main cause of Type 2 diabetes, but anyone can experience it, including people without diabetes and people with other types of diabetes. It can be temporary or chronic. […] Damage to your pancreas can lead to a lack of insulin production and hyperglycemia. […] In Type 1 diabetes, your immune system attacks the insulin-producing cells in your pancreas for unknown reasons. This means your pancreas can no longer make insulin, resulting in hyperglycemia.

• #8 Insulin Resistance: From Mechanisms to Therapeutic Strategies

  https://www.e-dmj.org/journal/view.php?number=2614

  Insulin resistance is the pivotal pathogenic component of many metabolic diseases, including type 2 diabetes mellitus, and is defined as a state of reduced responsiveness of insulin-targeting tissues to physiological levels of insulin. […] Insulin resistance precedes non-physiologic elevated plasma glucose levels, which is the primary clinical symptom of T2DM. […] Although the mechanism of insulin resistance has not been fully established, several theories are generally considered reasonable. […] This review summarizes the function of insulin in glucose metabolism in metabolic tissues, such as liver, skeletal muscle, and adipose tissue, and describes several putative mechanisms of insulin resistance, including the ectopic accumulation of lipids in liver and skeletal muscle. […] The liver critically controls postprandial carbohydrate levels by suppressing HGP and stimulating the deposition of glucose as glycogen and is the primary source of glucose production during fasting.

• #9 Insulin Resistance: From Mechanisms to Therapeutic Strategies

  https://www.e-dmj.org/journal/view.php?number=2614

  In T2DM patients, insulin cannot regulate hepatic glycogen synthesis or glucose production, and increased hepatic gluconeogenesis is the primary cause of fasting hyperglycemia in T2DM. […] Defective suppression of hepatic gluconeogenesis in insulin resistance is largely associated with lipolysis defects in adipose tissue and the de-suppression of FOXO1 transcription factor in liver. […] The most plausible hypothesis of the mechanism whereby ectopic lipid accumulation induces insulin resistance is that several lipid metabolites, including diacylglycerol (DAG), lysophosphatidic acid (LPA), ceramides, and acylcarnitines, are involved in the pathogenesis of insulin resistance in liver and skeletal muscle. […] High-fat-induced and genetically obese rodents exhibited hepatic insulin resistance and elevated hepatic DAG contents.

• #10 Insulin Resistance: From Mechanisms to Therapeutic Strategies

  https://www.e-dmj.org/journal/view.php?number=2614

  In T2DM patients, insulin cannot regulate hepatic glycogen synthesis or glucose production, and increased hepatic gluconeogenesis is the primary cause of fasting hyperglycemia in T2DM. […] Defective suppression of hepatic gluconeogenesis in insulin resistance is largely associated with lipolysis defects in adipose tissue and the de-suppression of FOXO1 transcription factor in liver. […] The most plausible hypothesis of the mechanism whereby ectopic lipid accumulation induces insulin resistance is that several lipid metabolites, including diacylglycerol (DAG), lysophosphatidic acid (LPA), ceramides, and acylcarnitines, are involved in the pathogenesis of insulin resistance in liver and skeletal muscle. […] High-fat-induced and genetically obese rodents exhibited hepatic insulin resistance and elevated hepatic DAG contents.

• #11 Hyperglycemia – Wikipedia

  https://en.wikipedia.org/wiki/Hyperglycemia

  For diabetics, glucose levels that are considered to be too hyperglycemic can vary from person to person, mainly due to the person’s renal threshold of glucose and overall glucose tolerance. […] On average, however, chronic levels above 10-12 mmol/L (180-216 mg/dL) can produce noticeable organ damage over time. […] Chronic, persistent hyperglycaemia is most often a result of diabetes. […] In diabetes mellitus, hyperglycemia is usually caused by low insulin levels (diabetes mellitus type 1) and/or by resistance to insulin at the cellular level (diabetes mellitus type 2), depending on the type and state of the disease. […] The leading cause of hyperglycemia in type 2 diabetes is the failure of insulin to suppress glucose production by glycolysis and gluconeogenesis due to insulin resistance.

• #12 Figure 1. [Pathogenesis of hyperglycemia. Hyperglycemia results…]. – Endotext – NCBI Bookshelf

  https://www.ncbi.nlm.nih.gov/books/NBK279093/figure/mgmt-diab-hosp-patnt.F1/

  Pathogenesis of hyperglycemia. Hyperglycemia results from increased hepatic glucose production and impaired glucose utilization in peripheral tissues. Reduced insulin and excess counter-regulatory hormones (glucagon, cortisol, catecholamines, and growth hormone) increase lipolysis and protein breakdown (proteolysis) and impair glucose uptake by peripheral tissues. Hyperglycemia causes osmotic diuresis, leading to volume depletion, decreasing glomerular filtration rate, and worsening hyperglycemia. At the cellular level, increased blood glucose concentrations result in mitochondrial injury by generating reactive oxygen species and endothelial dysfunction by inhibiting nitric oxide production. Hyperglycemia increases levels of pro-inflammatory cytokines such as tumor necrosis factor- (TNF-) and interleukin [IL]-6, leading to immune system dysfunction. These changes can eventually lead to an increased risk of infection, impaired wound healing, multiple organ failure, prolonged hospital stay, and death. […] Figure 1. [Pathogenesis of hyperglycemia. Hyperglycemia results…].

• #13 Figure 1. [Pathogenesis of hyperglycemia. Hyperglycemia results…]. – Endotext – NCBI Bookshelf

  https://www.ncbi.nlm.nih.gov/sites/books/NBK279093/figure/mgmt-diab-hosp-patnt.F1/?report=objectonly

  Hyperglycemia results from increased hepatic glucose production and impaired glucose utilization in peripheral tissues. […] Reduced insulin and excess counter-regulatory hormones (glucagon, cortisol, catecholamines, and growth hormone) increase lipolysis and protein breakdown (proteolysis) and impair glucose uptake by peripheral tissues. […] At the cellular level, increased blood glucose concentrations result in mitochondrial injury by generating reactive oxygen species and endothelial dysfunction by inhibiting nitric oxide production. […] Hyperglycemia increases levels of pro-inflammatory cytokines such as tumor necrosis factor- (TNF-) and interleukin [IL]-6, leading to immune system dysfunction. […] These changes can eventually lead to an increased risk of infection, impaired wound healing, multiple organ failure, prolonged hospital stay, and death.

• #14 Type 2 Diabetes Mellitus: Background, Pathophysiology, Etiology

  https://emedicine.medscape.com/article/117853-overview

  Type 2 diabetes mellitus consists of an array of dysfunctions characterized by hyperglycemia and resulting from the combination of resistance to insulin action, inadequate insulin secretion, and excessive or inappropriate glucagon secretion. […] A role for excess glucagon cannot be underestimated; indeed, type 2 diabetes is an islet paracrinopathy in which the reciprocal relationship between the glucagon-secreting alpha cell and the insulin-secreting beta cell is lost, leading to hyperglucagonemia and hence the consequent hyperglycemia. […] For type 2 diabetes mellitus to occur, both insulin resistance and inadequate insulin secretion must exist. […] Hyperglycemia appears to be the determinant of microvascular and metabolic complications.

• #15 Diabetic Ketoacidosis (DKA): Practice Essentials, Background, Pathophysiology

  https://emedicine.medscape.com/article/118361-overview

  The absence of insulin, the primary anabolic hormone, means that tissues such as muscle, fat, and liver do not uptake glucose. Counterregulatory hormones, such as glucagon, growth hormone, and catecholamines, enhance triglyceride breakdown into free fatty acids and gluconeogenesis, which is the main cause for the elevation in serum glucose level in DKA. […] Hyperglycemia usually exceeds the renal threshold of glucose absorption and results in significant glucosuria. […] The hyperglycemia-induced osmotic diuresis depletes sodium, potassium, phosphates, and water.

• #16 How hyperglycemia promotes atherosclerosis: molecular mechanisms | Cardiovascular Diabetology | Full Text

  https://cardiab.biomedcentral.com/articles/10.1186/1475-2840-1-1

  Prolonged exposure to hyperglycemia is now recognized a major factor in the pathogenesis of atherosclerosis in diabetes. […] Hyperglycemia induces a large number of alterations at the cellular level of vascular tissue that potentially accelerate the atherosclerotic process. […] Currently, three major mechanisms have emerged that encompass most of the pathological alterations observed in the vasculature of diabetic animals and humans: 1) Nonenzymatic glycosylation of proteins and lipids 2) oxidative stress 3) protein kinase C (PKC) activation. […] Importantly, these mechanisms are not independent. For example, hyperglycemia-induced oxidative stress promotes the formation of advanced glycosylation end products and PKC activation. […] One of the important mechanisms responsible for the accelerated atherosclerosis in diabetes is the nonenzymatic reaction between glucose and proteins or lipoproteins in arterial walls, collectively known as Maillard, or browning reaction.

• #17 Figure 1. [Pathogenesis of hyperglycemia. Hyperglycemia results…]. – Endotext – NCBI Bookshelf

  https://www.ncbi.nlm.nih.gov/books/NBK279093/figure/mgmt-diab-hosp-patnt.F1/

  Pathogenesis of hyperglycemia. Hyperglycemia results from increased hepatic glucose production and impaired glucose utilization in peripheral tissues. Reduced insulin and excess counter-regulatory hormones (glucagon, cortisol, catecholamines, and growth hormone) increase lipolysis and protein breakdown (proteolysis) and impair glucose uptake by peripheral tissues. Hyperglycemia causes osmotic diuresis, leading to volume depletion, decreasing glomerular filtration rate, and worsening hyperglycemia. At the cellular level, increased blood glucose concentrations result in mitochondrial injury by generating reactive oxygen species and endothelial dysfunction by inhibiting nitric oxide production. Hyperglycemia increases levels of pro-inflammatory cytokines such as tumor necrosis factor- (TNF-) and interleukin [IL]-6, leading to immune system dysfunction. These changes can eventually lead to an increased risk of infection, impaired wound healing, multiple organ failure, prolonged hospital stay, and death. […] Figure 1. [Pathogenesis of hyperglycemia. Hyperglycemia results…].

• #18 Figure 1. [Pathogenesis of hyperglycemia. Hyperglycemia results…]. – Endotext – NCBI Bookshelf

  https://www.ncbi.nlm.nih.gov/books/NBK279093/figure/mgmt-diab-hosp-patnt.F1/

  Pathogenesis of hyperglycemia. Hyperglycemia results from increased hepatic glucose production and impaired glucose utilization in peripheral tissues. Reduced insulin and excess counter-regulatory hormones (glucagon, cortisol, catecholamines, and growth hormone) increase lipolysis and protein breakdown (proteolysis) and impair glucose uptake by peripheral tissues. Hyperglycemia causes osmotic diuresis, leading to volume depletion, decreasing glomerular filtration rate, and worsening hyperglycemia. At the cellular level, increased blood glucose concentrations result in mitochondrial injury by generating reactive oxygen species and endothelial dysfunction by inhibiting nitric oxide production. Hyperglycemia increases levels of pro-inflammatory cytokines such as tumor necrosis factor- (TNF-) and interleukin [IL]-6, leading to immune system dysfunction. These changes can eventually lead to an increased risk of infection, impaired wound healing, multiple organ failure, prolonged hospital stay, and death. […] Figure 1. [Pathogenesis of hyperglycemia. Hyperglycemia results…].

• #19 Figure 1. [Pathogenesis of hyperglycemia. Hyperglycemia results…]. – Endotext – NCBI Bookshelf

  https://www.ncbi.nlm.nih.gov/sites/books/NBK279093/figure/mgmt-diab-hosp-patnt.F1/?report=objectonly

  Hyperglycemia results from increased hepatic glucose production and impaired glucose utilization in peripheral tissues. […] Reduced insulin and excess counter-regulatory hormones (glucagon, cortisol, catecholamines, and growth hormone) increase lipolysis and protein breakdown (proteolysis) and impair glucose uptake by peripheral tissues. […] At the cellular level, increased blood glucose concentrations result in mitochondrial injury by generating reactive oxygen species and endothelial dysfunction by inhibiting nitric oxide production. […] Hyperglycemia increases levels of pro-inflammatory cytokines such as tumor necrosis factor- (TNF-) and interleukin [IL]-6, leading to immune system dysfunction. […] These changes can eventually lead to an increased risk of infection, impaired wound healing, multiple organ failure, prolonged hospital stay, and death.

• #20 Hyperglycemia – Wikipedia

  https://en.wikipedia.org/wiki/Hyperglycemia

  Hyperglycemia may be caused by: diabetes, various (non-diabetic) endocrine disorders (insulin resistance and thyroid, adrenal, pancreatic, and pituitary disorders), sepsis and certain infections, intracranial diseases (e.g. encephalitis, brain tumors (especially if near the pituitary gland), brain haemorrhages, and meningitis) (frequently overlooked), convulsions, end-stage terminal disease, prolonged/major surgeries, stress, and excessive eating of carbohydrates. […] Hyperglycemia causes a decrease in cognitive performance, specifically in processing speed, executive function, and performance. […] The chronic inflammatory state induced by high glucose levels can also lead to dysfunction in various parts of the immune system. […] Hyperglycemia has been linked to increased susceptibility to a range of infectious diseases.

• #21 How hyperglycemia promotes atherosclerosis: molecular mechanisms | Cardiovascular Diabetology | Full Text

  https://cardiab.biomedcentral.com/articles/10.1186/1475-2840-1-1

  Prolonged exposure to hyperglycemia is now recognized a major factor in the pathogenesis of atherosclerosis in diabetes. […] Hyperglycemia induces a large number of alterations at the cellular level of vascular tissue that potentially accelerate the atherosclerotic process. […] Currently, three major mechanisms have emerged that encompass most of the pathological alterations observed in the vasculature of diabetic animals and humans: 1) Nonenzymatic glycosylation of proteins and lipids 2) oxidative stress 3) protein kinase C (PKC) activation. […] Importantly, these mechanisms are not independent. For example, hyperglycemia-induced oxidative stress promotes the formation of advanced glycosylation end products and PKC activation. […] One of the important mechanisms responsible for the accelerated atherosclerosis in diabetes is the nonenzymatic reaction between glucose and proteins or lipoproteins in arterial walls, collectively known as Maillard, or browning reaction.

• #22 How hyperglycemia promotes atherosclerosis: molecular mechanisms | Cardiovascular Diabetology | Full Text

  https://cardiab.biomedcentral.com/articles/10.1186/1475-2840-1-1

  Prolonged exposure to hyperglycemia is now recognized a major factor in the pathogenesis of atherosclerosis in diabetes. […] Hyperglycemia induces a large number of alterations at the cellular level of vascular tissue that potentially accelerate the atherosclerotic process. […] Currently, three major mechanisms have emerged that encompass most of the pathological alterations observed in the vasculature of diabetic animals and humans: 1) Nonenzymatic glycosylation of proteins and lipids 2) oxidative stress 3) protein kinase C (PKC) activation. […] Importantly, these mechanisms are not independent. For example, hyperglycemia-induced oxidative stress promotes the formation of advanced glycosylation end products and PKC activation. […] One of the important mechanisms responsible for the accelerated atherosclerosis in diabetes is the nonenzymatic reaction between glucose and proteins or lipoproteins in arterial walls, collectively known as Maillard, or browning reaction.

• #23 How hyperglycemia promotes atherosclerosis: molecular mechanisms | Cardiovascular Diabetology | Full Text

  https://cardiab.biomedcentral.com/articles/10.1186/1475-2840-1-1

  Prolonged exposure to hyperglycemia is now recognized a major factor in the pathogenesis of atherosclerosis in diabetes. […] Hyperglycemia induces a large number of alterations at the cellular level of vascular tissue that potentially accelerate the atherosclerotic process. […] Currently, three major mechanisms have emerged that encompass most of the pathological alterations observed in the vasculature of diabetic animals and humans: 1) Nonenzymatic glycosylation of proteins and lipids 2) oxidative stress 3) protein kinase C (PKC) activation. […] Importantly, these mechanisms are not independent. For example, hyperglycemia-induced oxidative stress promotes the formation of advanced glycosylation end products and PKC activation. […] One of the important mechanisms responsible for the accelerated atherosclerosis in diabetes is the nonenzymatic reaction between glucose and proteins or lipoproteins in arterial walls, collectively known as Maillard, or browning reaction.

• #24 How hyperglycemia promotes atherosclerosis: molecular mechanisms | Cardiovascular Diabetology | Full Text

  https://cardiab.biomedcentral.com/articles/10.1186/1475-2840-1-1

  Prolonged exposure to hyperglycemia is now recognized a major factor in the pathogenesis of atherosclerosis in diabetes. […] Hyperglycemia induces a large number of alterations at the cellular level of vascular tissue that potentially accelerate the atherosclerotic process. […] Currently, three major mechanisms have emerged that encompass most of the pathological alterations observed in the vasculature of diabetic animals and humans: 1) Nonenzymatic glycosylation of proteins and lipids 2) oxidative stress 3) protein kinase C (PKC) activation. […] Importantly, these mechanisms are not independent. For example, hyperglycemia-induced oxidative stress promotes the formation of advanced glycosylation end products and PKC activation. […] One of the important mechanisms responsible for the accelerated atherosclerosis in diabetes is the nonenzymatic reaction between glucose and proteins or lipoproteins in arterial walls, collectively known as Maillard, or browning reaction.

• #25 SciELO Brazil – Kidney Disease in Diabetes Mellitus: Cross-Linking between Hyperglycemia, Redox Imbalance and Inflammation Kidney Disease in Diabetes Mellitus: Cross-Linking between Hyperglycemia, Redox Imbalance and Inflammation

  https://www.scielo.br/j/abc/a/8DSdzvT5sd4tbTFM6N6PZCD/?lang=en

  AGEs are formed through non-enzymatic amino-carbonyl reactions, or Maillard reaction between the carbonyl group of glucose, fructose, galactose and ribose, or intermediates of glucose metabolism, with an amine group and other molecules, to form a reversible Schiff base, and subsequently, Amadori products, which are initial products of the Maillard reaction. […] The generation of RONs occurs in many types of cells in the kidneys and infiltrating cells, such as immune cells, neutrophils and macrophages. […] The overproduction of RON induced by hyperglycemia reduces the expression of antioxidant enzymes, including the superoxide dismutase (SOD) […] In diabetic kidney, RONs decreases the expression of sirtuins (SIRT), enzymes responsible or modulating the regeneration of antioxidants via acetylation of the ETC, essential for the stimulation of mitochondrial SOD and induction of transcription factors, attenuating mitochondrial stress and NRF2 activation. […] Recently, there has been increasing evidence that redox imbalance and inflammation in response to intermittent or chronic exposure to hyperglycemia play an important role in initiation and perpetuation of DM complications, including DKD.

• #26 How hyperglycemia promotes atherosclerosis: molecular mechanisms | Cardiovascular Diabetology | Full Text

  https://cardiab.biomedcentral.com/articles/10.1186/1475-2840-1-1

  AGEs can accelerate the atherosclerotic process by diverse mechanism, which can be classified as non-receptor dependent and receptor-mediated. […] The cellular interactions of AGEs are mediated through a specific receptor for AGE determinants on cell surfaces. […] AGE interaction with RAGE on endothelial cells results in the induction of oxidative stress and consequently of the transcription factor NF-B and VCAM-1. […] The metabolic consequences of hyperglycemia can be expressed in cells in which glucose transport is largely independent of insulin. […] High ambient glucose concentrations activate PKC by increasing the formation of diacylglycerol (DAG), the major endogenous cellular co-factor for PKC activation, from glycolytic intermediates such as dihydroxy-acetone phosphate and glyceraldehyde-3-phosphate.

• #27 How hyperglycemia promotes atherosclerosis: molecular mechanisms | Cardiovascular Diabetology | Full Text

  https://cardiab.biomedcentral.com/articles/10.1186/1475-2840-1-1

  AGEs can accelerate the atherosclerotic process by diverse mechanism, which can be classified as non-receptor dependent and receptor-mediated. […] The cellular interactions of AGEs are mediated through a specific receptor for AGE determinants on cell surfaces. […] AGE interaction with RAGE on endothelial cells results in the induction of oxidative stress and consequently of the transcription factor NF-B and VCAM-1. […] The metabolic consequences of hyperglycemia can be expressed in cells in which glucose transport is largely independent of insulin. […] High ambient glucose concentrations activate PKC by increasing the formation of diacylglycerol (DAG), the major endogenous cellular co-factor for PKC activation, from glycolytic intermediates such as dihydroxy-acetone phosphate and glyceraldehyde-3-phosphate.

• #28 How hyperglycemia promotes atherosclerosis: molecular mechanisms | Cardiovascular Diabetology | Full Text

  https://cardiab.biomedcentral.com/articles/10.1186/1475-2840-1-1

  AGEs can accelerate the atherosclerotic process by diverse mechanism, which can be classified as non-receptor dependent and receptor-mediated. […] The cellular interactions of AGEs are mediated through a specific receptor for AGE determinants on cell surfaces. […] AGE interaction with RAGE on endothelial cells results in the induction of oxidative stress and consequently of the transcription factor NF-B and VCAM-1. […] The metabolic consequences of hyperglycemia can be expressed in cells in which glucose transport is largely independent of insulin. […] High ambient glucose concentrations activate PKC by increasing the formation of diacylglycerol (DAG), the major endogenous cellular co-factor for PKC activation, from glycolytic intermediates such as dihydroxy-acetone phosphate and glyceraldehyde-3-phosphate.

• #29 SciELO Brazil – Kidney Disease in Diabetes Mellitus: Cross-Linking between Hyperglycemia, Redox Imbalance and Inflammation Kidney Disease in Diabetes Mellitus: Cross-Linking between Hyperglycemia, Redox Imbalance and Inflammation

  https://www.scielo.br/j/abc/a/8DSdzvT5sd4tbTFM6N6PZCD/?lang=en

  Both hyperglycemia and increased stimulation of glycolysis by-products increase the synthesis of glyceraldehyde-3-phosphate and its conversion into dihydroxyacetone, and thereby promote the synthesis of DAG, a PKC-activating factor. […] Increased expression of PKC leads to activation of the transforming growth factor-beta (TGF-) and the plasminogen activator inhibitor-1 (PAI-1), resulting in increased deposition of fibronectin, collagen types I and IV and extracellular matrix deposition, and consequently, renal hypertrophy, glomerulosclerosis and renal fibrosis. […] The hyperfunction of this pathway, stimulated by hyperglycemia, promotes the conversion of fructose 6-phosphate, and the synthesis of uridine diphosphate N-acetylglucosamine (UDP-GlcNAc) as end product, which is O-glycosylated into N-acetylglucosamine (O-GlcNAc) by the O-GlcNAc transferase.

• #30 Complications of Acute and Chronic Hyperglycemia – touchENDOCRINOLOGY

  https://touchendocrinology.com/diabetes/journal-articles/complications-of-acute-and-chronic-hyperglycemia/

  Hyperglycemia contributes to the development of vascular complications through several mechanisms: activation of the polyol and hexosamine pathways, diacylglycerol-protein kinase C (DAG-PKC), increased production of advanced glycation end products (AGE), increased synthesis of growth factors, cytokines, and oxidative stress. […] Growing evidence suggests that increased oxidative stress, induced by the above hyperglycemia-activated pathways, is a key factor in the pathogenesis of endothelial dysfunction and vascular disease. […] In contrast, the role of glucose variability in the development of vascular complications is not yet clear.

• #31 SciELO Brazil – Kidney Disease in Diabetes Mellitus: Cross-Linking between Hyperglycemia, Redox Imbalance and Inflammation Kidney Disease in Diabetes Mellitus: Cross-Linking between Hyperglycemia, Redox Imbalance and Inflammation

  https://www.scielo.br/j/abc/a/8DSdzvT5sd4tbTFM6N6PZCD/?lang=en

  Both hyperglycemia and increased stimulation of glycolysis by-products increase the synthesis of glyceraldehyde-3-phosphate and its conversion into dihydroxyacetone, and thereby promote the synthesis of DAG, a PKC-activating factor. […] Increased expression of PKC leads to activation of the transforming growth factor-beta (TGF-) and the plasminogen activator inhibitor-1 (PAI-1), resulting in increased deposition of fibronectin, collagen types I and IV and extracellular matrix deposition, and consequently, renal hypertrophy, glomerulosclerosis and renal fibrosis. […] The hyperfunction of this pathway, stimulated by hyperglycemia, promotes the conversion of fructose 6-phosphate, and the synthesis of uridine diphosphate N-acetylglucosamine (UDP-GlcNAc) as end product, which is O-glycosylated into N-acetylglucosamine (O-GlcNAc) by the O-GlcNAc transferase.

• #32 SciELO Brazil – Kidney Disease in Diabetes Mellitus: Cross-Linking between Hyperglycemia, Redox Imbalance and Inflammation Kidney Disease in Diabetes Mellitus: Cross-Linking between Hyperglycemia, Redox Imbalance and Inflammation

  https://www.scielo.br/j/abc/a/8DSdzvT5sd4tbTFM6N6PZCD/?lang=en

  In this review we discuss current knowledge of metabolic pathways involving redox imbalance and inflammation induced by chronic exposure to hyperglycemia in the pathogenesis of DKD, aiming to propose new paradigms. […] The pathophysiology of DKD and the consequent end-stage renal disease requiring dialysis is caused by a chronic hyperglycemic state that leads to activation and changes of metabolic pathways and hemodynamic dysfunction. […] Glucotoxicity is caused by an inability of the cells to compensate for the increased glucose uptake in case of IR/hyperglycemia, as in DM. Increased stimulation of glucose oxidation pathways in non-insulin-dependent cells leads to the activation of alternative pathways, increased production of RONS and oxidative stress (OS) in hyperglycemic state. […] The increase in O2- inhibits the activity of glyceraldehyde 3-phosphate dehydrogenase (GAPDH), which, in turn, inhibits glycolysis and activates alternative pathways.

• #33 SciELO Brazil – Kidney Disease in Diabetes Mellitus: Cross-Linking between Hyperglycemia, Redox Imbalance and Inflammation Kidney Disease in Diabetes Mellitus: Cross-Linking between Hyperglycemia, Redox Imbalance and Inflammation

  https://www.scielo.br/j/abc/a/8DSdzvT5sd4tbTFM6N6PZCD/

  Although diabetic hyperglycemia is an important but not crucial factor for the development of glomerular lesions in DKD, we will describe metabolic changes induced by intermittent and chronic exposure to hyperglycemia. […] Glucotoxicity is caused by an inability of the cells to compensate for the increased glucose uptake in case of IR/hyperglycemia, as in DM. Increased stimulation of glucose oxidation pathways in non-insulin-dependent cells leads to the activation of alternative pathways, increased production of RONS and oxidative stress (OS) in hyperglycemic state. […] The increased stimulation of glycolysis and Krebs cycle result in elevated production of reduced flavin adenine dinucleotide (FADH2) and reduced nicotinamide adenine dinucleotide (NADH), fed into the ETC. […] In diabetic kidney cells, highly stimulated, hyperpolarized mitochondria with high redox potential, produce increased levels of adenosine triphosphate (ATP) and superoxide anion (O2-) through the complexes I and II.

• #34 Diabetes Mellitus (DM) – Endocrine and Metabolic Disorders – Merck Manual Professional Edition

  https://www.merckmanuals.com/professional/endocrine-and-metabolic-disorders/diabetes-mellitus-and-disorders-of-carbohydrate-metabolism/diabetes-mellitus-dm

  Hyperglycemia itself may impair insulin secretion, because high glucose levels desensitize beta cells, cause beta-cell dysfunction (glucose toxicity), or both. […] Obesity and weight gain are important determinants of insulin resistance in type 2 diabetes. […] The pathogenesis of the autoimmune beta-cell destruction involves incompletely understood interactions between susceptibility genes, autoantigens, and environmental factors. […] The disease generally develops in adults and becomes more common with increasing age; up to one third of adults age 65 years have impaired glucose tolerance. […] The most common symptoms of diabetes mellitus are those of hyperglycemia. […] More significant hyperglycemia causes glycosuria and thus an osmotic diuresis, leading to urinary frequency, polyuria, and polydipsia that may progress to orthostatic hypotension and dehydration. […] Hyperglycemia can also cause weight loss, nausea and vomiting, and blurred vision, and it may predispose to bacterial or fungal infections. […] Hyperglycemia responds to non-insulin antihyperglycemic medications.

• #35 Type 2 diabetes mellitus in adults: pathogenesis, prevention and therapy | Signal Transduction and Targeted Therapy

  https://www.nature.com/articles/s41392-024-01951-9

  The metabolites of chronic overnutrition, such as high glucose and non-esterified fatty acids (NEFAs), interfere with the activation of insulin receptor and its subsequent IRS-1/PI3K/Akt2 pathways, leading to the development of chronic inflammation in adipose tissue and ectopic lipid deposition in the liver and muscles, along with ERS and oxidative stress, etc. These alterations in target organs interact with each other to aggravate metabolic disorders, ultimately leading to IR. […] Continuous insulin production and secretion in cells under chronic hyperglycemia and IR result in the overload of protein folding machinery and the accumulation of excessive misfolded or unfolded proteins in the ER, therefore triggering UPR and the ERS. […] Hyperglycemia can induce target organ damage (TOD) by increasing the risk of panvascular disease, including microvascular disease (such as diabetic retinopathy, nephropathy and neuropathy), and atherosclerotic macrovascular disease (cardiovascular, cerebrovascular, and other peripheral vascular diseases). […] The used term chronic diabetic complications is misleading for both doctors and patients, leading to the blood glucose-focused management, while ignoring the development of TOD related to other metabolic disorders in the MDS.

• #36 A short note on pathogenesis of chronic hyperglycemia

  https://www.africanjournalofdiabetesmedicine.com/articles/a-short-note-on-pathogenesis-of-chronic-hyperglycemia-95666.html

  A short note on pathogenesis of chronic hyperglycemia […] Type 2 diabetes is commonly bulimia. It is caused by insulin resistance and impaired insulin secretion. These are mainly induced gradually by hyperglycemia combined with other factors such as obesity, aging, genetic predisposition and lack of exercise. Sustained binge eating leads to consistently high blood sugar levels that are toxic to the macrovasculature and microvasculature, an effect known as glycotoxicity. […] Oxidative stress is thought to contribute to the pathogenesis of glucose toxicity during the onset of diabetes and diabetic complications, but reductive stress due to excess NADH produced by hyperglycemia has received less attention. […] Persistent hyperglycemia is highly toxic. It not only induces insulin resistance, but also impairs insulin secretion by pancreatic -cells. Over time, hyperglycemia adversely affects the macrovasculature and microvasculature. Hyperglycemia causes overproduction of acetyl-CoA, which feeds into the Krebs cycle and generates excess NADH, thus subjecting the mitochondrial electron transport chain to strong electron pressure. Thus, oxidation of overproduced NADH by mitochondria would inevitably lead to the production of more superoxide and thus more ROS, which could attack and inactivate GAPDH. This causes the accumulation of glycolytic metabolites upstream of glyceraldehyde-3-phosphate, activating alternative glucose disposal pathways, all associated with ROS production, and increasing levels of oxidative stress.

• #37 A short note on pathogenesis of chronic hyperglycemia

  https://www.africanjournalofdiabetesmedicine.com/articles/a-short-note-on-pathogenesis-of-chronic-hyperglycemia-95666.html

  A short note on pathogenesis of chronic hyperglycemia […] Type 2 diabetes is commonly bulimia. It is caused by insulin resistance and impaired insulin secretion. These are mainly induced gradually by hyperglycemia combined with other factors such as obesity, aging, genetic predisposition and lack of exercise. Sustained binge eating leads to consistently high blood sugar levels that are toxic to the macrovasculature and microvasculature, an effect known as glycotoxicity. […] Oxidative stress is thought to contribute to the pathogenesis of glucose toxicity during the onset of diabetes and diabetic complications, but reductive stress due to excess NADH produced by hyperglycemia has received less attention. […] Persistent hyperglycemia is highly toxic. It not only induces insulin resistance, but also impairs insulin secretion by pancreatic -cells. Over time, hyperglycemia adversely affects the macrovasculature and microvasculature. Hyperglycemia causes overproduction of acetyl-CoA, which feeds into the Krebs cycle and generates excess NADH, thus subjecting the mitochondrial electron transport chain to strong electron pressure. Thus, oxidation of overproduced NADH by mitochondria would inevitably lead to the production of more superoxide and thus more ROS, which could attack and inactivate GAPDH. This causes the accumulation of glycolytic metabolites upstream of glyceraldehyde-3-phosphate, activating alternative glucose disposal pathways, all associated with ROS production, and increasing levels of oxidative stress.

• #38 Complications of Acute and Chronic Hyperglycemia – touchENDOCRINOLOGY

  https://touchendocrinology.com/diabetes/journal-articles/complications-of-acute-and-chronic-hyperglycemia/

  Hyperglycemia is due to a dysregulation in the complex mechanisms implicated in glucose homeostasis. Chronic hyperglycemia, as measured by hemoglobin A1c (HbA1c), is a key risk factor for the development of microvascular and macrovascular complications, which in turn negatively influence the prognosis of patients with diabetes. […] Several studies have shown that acute hyperglycemia can add to the effect of chronic hyperglycemia in inducing tissue damage. Acute hyperglycemia can manifest as high fasting plasma glucose (FPG) or high postprandial plasma glucose (PPG) and can activate the same metabolic and hemodynamic pathways as chronic hyperglycemia. […] Hyperglycemia is a key determinant of vascular complications of diabetes, also known as chronic diabetes complications. There is extensive evidence indicating that both acute and chronic hyperglycemia play a key role in the pathogenesis of these complications.

• #39 SciELO Brazil – Kidney Disease in Diabetes Mellitus: Cross-Linking between Hyperglycemia, Redox Imbalance and Inflammation Kidney Disease in Diabetes Mellitus: Cross-Linking between Hyperglycemia, Redox Imbalance and Inflammation

  https://www.scielo.br/j/abc/a/8DSdzvT5sd4tbTFM6N6PZCD/?lang=en

  Chronic hyperglycemia is the key point of macro- and microvascular complications associated with diabetes mellitus. […] The pathogenesis of the disease is complex, multifactorial and not fully elucidated; many factors and mechanisms are involved in the development, progression and clinical outcomes of the disease. […] The is clear evidence that a chronic hyperglycemic state triggers oxidative stress and inflammation mediated by altered metabolic pathways in a self-perpetuating cycle, promoting progression of cell injury and of end-stage renal disease. […] DKD is a progressive and irreversible condition, whose pathogenesis has been associated with functional and structural changes of renal cells in response to metabolic stress induced by excessive glucose inflow, by means of activation of specific metabolic pathways linked to redox imbalance and inflammation.

• #40 SciELO Brazil – Kidney Disease in Diabetes Mellitus: Cross-Linking between Hyperglycemia, Redox Imbalance and Inflammation Kidney Disease in Diabetes Mellitus: Cross-Linking between Hyperglycemia, Redox Imbalance and Inflammation

  https://www.scielo.br/j/abc/a/8DSdzvT5sd4tbTFM6N6PZCD/?lang=en

  Chronic hyperglycemia is the key point of macro- and microvascular complications associated with diabetes mellitus. […] The pathogenesis of the disease is complex, multifactorial and not fully elucidated; many factors and mechanisms are involved in the development, progression and clinical outcomes of the disease. […] The is clear evidence that a chronic hyperglycemic state triggers oxidative stress and inflammation mediated by altered metabolic pathways in a self-perpetuating cycle, promoting progression of cell injury and of end-stage renal disease. […] DKD is a progressive and irreversible condition, whose pathogenesis has been associated with functional and structural changes of renal cells in response to metabolic stress induced by excessive glucose inflow, by means of activation of specific metabolic pathways linked to redox imbalance and inflammation.

• #41 How hyperglycemia promotes atherosclerosis: molecular mechanisms | Cardiovascular Diabetology | Full Text

  https://cardiab.biomedcentral.com/articles/10.1186/1475-2840-1-1

  Prolonged exposure to hyperglycemia is now recognized a major factor in the pathogenesis of atherosclerosis in diabetes. […] Hyperglycemia induces a large number of alterations at the cellular level of vascular tissue that potentially accelerate the atherosclerotic process. […] Currently, three major mechanisms have emerged that encompass most of the pathological alterations observed in the vasculature of diabetic animals and humans: 1) Nonenzymatic glycosylation of proteins and lipids 2) oxidative stress 3) protein kinase C (PKC) activation. […] Importantly, these mechanisms are not independent. For example, hyperglycemia-induced oxidative stress promotes the formation of advanced glycosylation end products and PKC activation. […] One of the important mechanisms responsible for the accelerated atherosclerosis in diabetes is the nonenzymatic reaction between glucose and proteins or lipoproteins in arterial walls, collectively known as Maillard, or browning reaction.

• #42 Type 2 diabetes mellitus in adults: pathogenesis, prevention and therapy | Signal Transduction and Targeted Therapy

  https://www.nature.com/articles/s41392-024-01951-9

  The metabolites of chronic overnutrition, such as high glucose and non-esterified fatty acids (NEFAs), interfere with the activation of insulin receptor and its subsequent IRS-1/PI3K/Akt2 pathways, leading to the development of chronic inflammation in adipose tissue and ectopic lipid deposition in the liver and muscles, along with ERS and oxidative stress, etc. These alterations in target organs interact with each other to aggravate metabolic disorders, ultimately leading to IR. […] Continuous insulin production and secretion in cells under chronic hyperglycemia and IR result in the overload of protein folding machinery and the accumulation of excessive misfolded or unfolded proteins in the ER, therefore triggering UPR and the ERS. […] Hyperglycemia can induce target organ damage (TOD) by increasing the risk of panvascular disease, including microvascular disease (such as diabetic retinopathy, nephropathy and neuropathy), and atherosclerotic macrovascular disease (cardiovascular, cerebrovascular, and other peripheral vascular diseases). […] The used term chronic diabetic complications is misleading for both doctors and patients, leading to the blood glucose-focused management, while ignoring the development of TOD related to other metabolic disorders in the MDS.

• #43 Hyperglycemia in diabetes – Symptoms & causes – Mayo Clinic

  https://www.mayoclinic.org/diseases-conditions/hyperglycemia/symptoms-causes/syc-20373631

  High blood sugar, also called hyperglycemia, affects people who have diabetes. Several factors can play a role in hyperglycemia in people with diabetes. They include food and physical activity, illness, and medications not related to diabetes. Skipping doses or not taking enough insulin or other medication to lower blood sugar also can lead to hyperglycemia. […] Diabetes drastically reduces insulin’s effects on the body. This may be because your pancreas is unable to produce insulin, as in type 1 diabetes. Or it may be because your body is resistant to the effects of insulin, or it doesn’t make enough insulin to keep a normal glucose level, as in type 2 diabetes. […] In people who have diabetes, glucose tends to build up in the bloodstream. This condition is called hyperglycemia. It may reach dangerously high levels if it is not treated properly. Insulin and other drugs are used to lower blood sugar levels.

• #44 Type 1 diabetes: MedlinePlus Medical EncyclopediaLock

  https://medlineplus.gov/ency/article/000305.htm

  Type 1 diabetes is a lifelong (chronic) disease in which there is a high level of sugar (glucose) in the blood. […] Without enough insulin, glucose builds up in the bloodstream instead of going into the cells. This buildup of glucose in the blood is called hyperglycemia. The body is unable to use the glucose for energy. This leads to the symptoms of type 1 diabetes. […] Insulin lowers blood sugar by allowing it to leave the bloodstream and enter cells. […] Most people with type 1 diabetes need to take two kinds of insulin. Basal insulin is long-lasting and controls how much sugar your own body makes when you are not eating. Meal-time (bolus or prandial) insulin is rapid acting and is taken with every meal, usually a few minutes before you start eating. It lasts only long enough to help move the sugar absorbed from a meal into muscle and fat cells for storage. […] High blood sugar and other problems can lead to kidney damage. The kidneys may not work as well as they used to. They may even stop working, so that you would need dialysis or a kidney transplant.

• #45 Diabetes Mellitus (DM) – Endocrine and Metabolic Disorders – Merck Manual Professional Edition

  https://www.merckmanuals.com/professional/endocrine-and-metabolic-disorders/diabetes-mellitus-and-disorders-of-carbohydrate-metabolism/diabetes-mellitus-dm

  Hyperglycemia itself may impair insulin secretion, because high glucose levels desensitize beta cells, cause beta-cell dysfunction (glucose toxicity), or both. […] Obesity and weight gain are important determinants of insulin resistance in type 2 diabetes. […] The pathogenesis of the autoimmune beta-cell destruction involves incompletely understood interactions between susceptibility genes, autoantigens, and environmental factors. […] The disease generally develops in adults and becomes more common with increasing age; up to one third of adults age 65 years have impaired glucose tolerance. […] The most common symptoms of diabetes mellitus are those of hyperglycemia. […] More significant hyperglycemia causes glycosuria and thus an osmotic diuresis, leading to urinary frequency, polyuria, and polydipsia that may progress to orthostatic hypotension and dehydration. […] Hyperglycemia can also cause weight loss, nausea and vomiting, and blurred vision, and it may predispose to bacterial or fungal infections. […] Hyperglycemia responds to non-insulin antihyperglycemic medications.

• #46 Type 2 diabetes mellitus in adults: pathogenesis, prevention and therapy | Signal Transduction and Targeted Therapy

  https://www.nature.com/articles/s41392-024-01951-9

  Type 2 diabetes (T2D) is a disease characterized by heterogeneously progressive loss of islet cell insulin secretion usually occurring after the presence of insulin resistance (IR) and it is one component of metabolic syndrome (MS), and we named it metabolic dysfunction syndrome (MDS). The pathogenesis of T2D is not fully understood, with IR and cell dysfunction playing central roles in its pathophysiology. Dyslipidemia, hyperglycemia, along with other metabolic disorders, results in IR and/or islet cell dysfunction via some shared pathways, such as inflammation, endoplasmic reticulum stress (ERS), oxidative stress, and ectopic lipid deposition. […] The realization of T2D as downstream disease of MDS suggests that metabolic complications or MDS-related TOD may be more reasonable instead of so-called chronic diabetic complications. This updated philosophy is crucial for the management of T2D, emphasizing that TOD is not only caused by hyperglycemia.

• #47 Type 2 diabetes mellitus in adults: pathogenesis, prevention and therapy | Signal Transduction and Targeted Therapy

  https://www.nature.com/articles/s41392-024-01951-9

  Type 2 diabetes (T2D) is a disease characterized by heterogeneously progressive loss of islet cell insulin secretion usually occurring after the presence of insulin resistance (IR) and it is one component of metabolic syndrome (MS), and we named it metabolic dysfunction syndrome (MDS). The pathogenesis of T2D is not fully understood, with IR and cell dysfunction playing central roles in its pathophysiology. Dyslipidemia, hyperglycemia, along with other metabolic disorders, results in IR and/or islet cell dysfunction via some shared pathways, such as inflammation, endoplasmic reticulum stress (ERS), oxidative stress, and ectopic lipid deposition. […] The realization of T2D as downstream disease of MDS suggests that metabolic complications or MDS-related TOD may be more reasonable instead of so-called chronic diabetic complications. This updated philosophy is crucial for the management of T2D, emphasizing that TOD is not only caused by hyperglycemia.

• #48 Type 2 diabetes mellitus in adults: pathogenesis, prevention and therapy | Signal Transduction and Targeted Therapy

  https://www.nature.com/articles/s41392-024-01951-9

  The metabolites of chronic overnutrition, such as high glucose and non-esterified fatty acids (NEFAs), interfere with the activation of insulin receptor and its subsequent IRS-1/PI3K/Akt2 pathways, leading to the development of chronic inflammation in adipose tissue and ectopic lipid deposition in the liver and muscles, along with ERS and oxidative stress, etc. These alterations in target organs interact with each other to aggravate metabolic disorders, ultimately leading to IR. […] Continuous insulin production and secretion in cells under chronic hyperglycemia and IR result in the overload of protein folding machinery and the accumulation of excessive misfolded or unfolded proteins in the ER, therefore triggering UPR and the ERS. […] Hyperglycemia can induce target organ damage (TOD) by increasing the risk of panvascular disease, including microvascular disease (such as diabetic retinopathy, nephropathy and neuropathy), and atherosclerotic macrovascular disease (cardiovascular, cerebrovascular, and other peripheral vascular diseases). […] The used term chronic diabetic complications is misleading for both doctors and patients, leading to the blood glucose-focused management, while ignoring the development of TOD related to other metabolic disorders in the MDS.

• #49 Medication-induced hyperglycemia: pediatric perspective | BMJ Open Diabetes Research & Care

  https://drc.bmj.com/content/8/1/e000801

  Medication-induced hyperglycemia is a frequently encountered clinical problem in children. […] The mechanisms of hyperglycemia may involve cell destruction, decreased insulin secretion and/or sensitivity, and excessive glucose influx. […] Mechanisms involved in medication-induced hyperglycemia include cell destruction, decreased insulin secretion and/or sensitivity, and excessive glucose influx. […] The majority of drugs associated with hyperglycemia affect insulin production, secretion, or action, leading to an imbalance in insulin and glucose homeostasis. […] The pathophysiology of glucocorticoid-induced hyperglycemia involves multiple mechanisms: increased insulin resistance, increased gluconeogenesis, and decreased insulin production. […] Hyperglycemia does not occur in all individuals exposed to diabetogenic drugs but it is more common when several factors are involved, including: (1) Host-specific factors such as obesity, insulin resistance or cell autoimmunity. (2) High doses of diabetogenic medications or multiple medications that affect glucose metabolism (ie, additive effect). (3) Environmental influences (eg, diet, stress, illness, lack of physical activity). […] Medication-induced hyperglycemia usually originates from insulin resistance and/or decreased insulin secretion. […] Many of the molecular mechanisms for the changes in insulin secretion/action as well as the basis for the variability between patients are poorly understood.

• #50 Medication-induced hyperglycemia: pediatric perspective | BMJ Open Diabetes Research & Care

  https://drc.bmj.com/content/8/1/e000801

  Medication-induced hyperglycemia is a frequently encountered clinical problem in children. […] The mechanisms of hyperglycemia may involve cell destruction, decreased insulin secretion and/or sensitivity, and excessive glucose influx. […] Mechanisms involved in medication-induced hyperglycemia include cell destruction, decreased insulin secretion and/or sensitivity, and excessive glucose influx. […] The majority of drugs associated with hyperglycemia affect insulin production, secretion, or action, leading to an imbalance in insulin and glucose homeostasis. […] The pathophysiology of glucocorticoid-induced hyperglycemia involves multiple mechanisms: increased insulin resistance, increased gluconeogenesis, and decreased insulin production. […] Hyperglycemia does not occur in all individuals exposed to diabetogenic drugs but it is more common when several factors are involved, including: (1) Host-specific factors such as obesity, insulin resistance or cell autoimmunity. (2) High doses of diabetogenic medications or multiple medications that affect glucose metabolism (ie, additive effect). (3) Environmental influences (eg, diet, stress, illness, lack of physical activity). […] Medication-induced hyperglycemia usually originates from insulin resistance and/or decreased insulin secretion. […] Many of the molecular mechanisms for the changes in insulin secretion/action as well as the basis for the variability between patients are poorly understood.

• #51 Medication-induced hyperglycemia: pediatric perspective | BMJ Open Diabetes Research & Care

  https://drc.bmj.com/content/8/1/e000801

  Medication-induced hyperglycemia is a frequently encountered clinical problem in children. […] The mechanisms of hyperglycemia may involve cell destruction, decreased insulin secretion and/or sensitivity, and excessive glucose influx. […] Mechanisms involved in medication-induced hyperglycemia include cell destruction, decreased insulin secretion and/or sensitivity, and excessive glucose influx. […] The majority of drugs associated with hyperglycemia affect insulin production, secretion, or action, leading to an imbalance in insulin and glucose homeostasis. […] The pathophysiology of glucocorticoid-induced hyperglycemia involves multiple mechanisms: increased insulin resistance, increased gluconeogenesis, and decreased insulin production. […] Hyperglycemia does not occur in all individuals exposed to diabetogenic drugs but it is more common when several factors are involved, including: (1) Host-specific factors such as obesity, insulin resistance or cell autoimmunity. (2) High doses of diabetogenic medications or multiple medications that affect glucose metabolism (ie, additive effect). (3) Environmental influences (eg, diet, stress, illness, lack of physical activity). […] Medication-induced hyperglycemia usually originates from insulin resistance and/or decreased insulin secretion. […] Many of the molecular mechanisms for the changes in insulin secretion/action as well as the basis for the variability between patients are poorly understood.

• #52 Medication-induced hyperglycemia: pediatric perspective | BMJ Open Diabetes Research & Care

  https://drc.bmj.com/content/8/1/e000801

  Medication-induced hyperglycemia is a frequently encountered clinical problem in children. […] The mechanisms of hyperglycemia may involve cell destruction, decreased insulin secretion and/or sensitivity, and excessive glucose influx. […] Mechanisms involved in medication-induced hyperglycemia include cell destruction, decreased insulin secretion and/or sensitivity, and excessive glucose influx. […] The majority of drugs associated with hyperglycemia affect insulin production, secretion, or action, leading to an imbalance in insulin and glucose homeostasis. […] The pathophysiology of glucocorticoid-induced hyperglycemia involves multiple mechanisms: increased insulin resistance, increased gluconeogenesis, and decreased insulin production. […] Hyperglycemia does not occur in all individuals exposed to diabetogenic drugs but it is more common when several factors are involved, including: (1) Host-specific factors such as obesity, insulin resistance or cell autoimmunity. (2) High doses of diabetogenic medications or multiple medications that affect glucose metabolism (ie, additive effect). (3) Environmental influences (eg, diet, stress, illness, lack of physical activity). […] Medication-induced hyperglycemia usually originates from insulin resistance and/or decreased insulin secretion. […] Many of the molecular mechanisms for the changes in insulin secretion/action as well as the basis for the variability between patients are poorly understood.

• #53 Hyperglycemia (High Blood Sugar): Symptoms & Treatment

  https://my.clevelandclinic.org/health/diseases/9815-hyperglycemia-high-blood-sugar

  Hyperglycemia (high blood sugar) is common in people who have diabetes. If its left untreated, chronic hyperglycemia can lead to diabetes complications, such as nerve damage, eye disease and kidney damage. […] Hyperglycemia usually means you have diabetes, and people with diabetes can experience hyperglycemia episodes frequently. […] If you have hyperglycemia thats untreated for long periods of time, it can damage your nerves, blood vessels, tissues and organs. […] Severe hyperglycemia can also lead to an acute (sudden and severe) life-threatening complication called diabetes-related ketoacidosis (DKA), especially in people with diabetes who take insulin or people with undiagnosed Type 1 diabetes. This requires immediate medical treatment. […] Hyperglycemia most often results from a lack of insulin. This can happen due to insulin resistance and/or issues with your pancreas the organ that makes insulin.

• #54 Diabetes Mellitus (DM) – Endocrine and Metabolic Disorders – Merck Manual Professional Edition

  https://www.merckmanuals.com/professional/endocrine-and-metabolic-disorders/diabetes-mellitus-and-disorders-of-carbohydrate-metabolism/diabetes-mellitus-dm

  Hyperglycemia itself may impair insulin secretion, because high glucose levels desensitize beta cells, cause beta-cell dysfunction (glucose toxicity), or both. […] Obesity and weight gain are important determinants of insulin resistance in type 2 diabetes. […] The pathogenesis of the autoimmune beta-cell destruction involves incompletely understood interactions between susceptibility genes, autoantigens, and environmental factors. […] The disease generally develops in adults and becomes more common with increasing age; up to one third of adults age 65 years have impaired glucose tolerance. […] The most common symptoms of diabetes mellitus are those of hyperglycemia. […] More significant hyperglycemia causes glycosuria and thus an osmotic diuresis, leading to urinary frequency, polyuria, and polydipsia that may progress to orthostatic hypotension and dehydration. […] Hyperglycemia can also cause weight loss, nausea and vomiting, and blurred vision, and it may predispose to bacterial or fungal infections. […] Hyperglycemia responds to non-insulin antihyperglycemic medications.

• #55 Diabetes Mellitus (DM) – Endocrine and Metabolic Disorders – Merck Manual Professional Edition

  https://www.merckmanuals.com/professional/endocrine-and-metabolic-disorders/diabetes-mellitus-and-disorders-of-carbohydrate-metabolism/diabetes-mellitus-dm

  Hyperglycemia itself may impair insulin secretion, because high glucose levels desensitize beta cells, cause beta-cell dysfunction (glucose toxicity), or both. […] Obesity and weight gain are important determinants of insulin resistance in type 2 diabetes. […] The pathogenesis of the autoimmune beta-cell destruction involves incompletely understood interactions between susceptibility genes, autoantigens, and environmental factors. […] The disease generally develops in adults and becomes more common with increasing age; up to one third of adults age 65 years have impaired glucose tolerance. […] The most common symptoms of diabetes mellitus are those of hyperglycemia. […] More significant hyperglycemia causes glycosuria and thus an osmotic diuresis, leading to urinary frequency, polyuria, and polydipsia that may progress to orthostatic hypotension and dehydration. […] Hyperglycemia can also cause weight loss, nausea and vomiting, and blurred vision, and it may predispose to bacterial or fungal infections. […] Hyperglycemia responds to non-insulin antihyperglycemic medications.

• #56 Hyperglycemia in diabetes – Symptoms & causes – Mayo Clinic

  https://www.mayoclinic.org/diseases-conditions/hyperglycemia/symptoms-causes/syc-20373631

  High blood sugar, also called hyperglycemia, affects people who have diabetes. Several factors can play a role in hyperglycemia in people with diabetes. They include food and physical activity, illness, and medications not related to diabetes. Skipping doses or not taking enough insulin or other medication to lower blood sugar also can lead to hyperglycemia. […] Diabetes drastically reduces insulin’s effects on the body. This may be because your pancreas is unable to produce insulin, as in type 1 diabetes. Or it may be because your body is resistant to the effects of insulin, or it doesn’t make enough insulin to keep a normal glucose level, as in type 2 diabetes. […] In people who have diabetes, glucose tends to build up in the bloodstream. This condition is called hyperglycemia. It may reach dangerously high levels if it is not treated properly. Insulin and other drugs are used to lower blood sugar levels.

• #57 Figure 1. [Pathogenesis of hyperglycemia. Hyperglycemia results…]. – Endotext – NCBI Bookshelf

  https://www.ncbi.nlm.nih.gov/books/NBK279093/figure/mgmt-diab-hosp-patnt.F1/

  Pathogenesis of hyperglycemia. Hyperglycemia results from increased hepatic glucose production and impaired glucose utilization in peripheral tissues. Reduced insulin and excess counter-regulatory hormones (glucagon, cortisol, catecholamines, and growth hormone) increase lipolysis and protein breakdown (proteolysis) and impair glucose uptake by peripheral tissues. Hyperglycemia causes osmotic diuresis, leading to volume depletion, decreasing glomerular filtration rate, and worsening hyperglycemia. At the cellular level, increased blood glucose concentrations result in mitochondrial injury by generating reactive oxygen species and endothelial dysfunction by inhibiting nitric oxide production. Hyperglycemia increases levels of pro-inflammatory cytokines such as tumor necrosis factor- (TNF-) and interleukin [IL]-6, leading to immune system dysfunction. These changes can eventually lead to an increased risk of infection, impaired wound healing, multiple organ failure, prolonged hospital stay, and death. […] Figure 1. [Pathogenesis of hyperglycemia. Hyperglycemia results…].

• #58 Hyperglycemia (High Blood Sugar): Symptoms & Treatment

  https://my.clevelandclinic.org/health/diseases/9815-hyperglycemia-high-blood-sugar

  Hyperglycemia (high blood sugar) is common in people who have diabetes. If its left untreated, chronic hyperglycemia can lead to diabetes complications, such as nerve damage, eye disease and kidney damage. […] Hyperglycemia usually means you have diabetes, and people with diabetes can experience hyperglycemia episodes frequently. […] If you have hyperglycemia thats untreated for long periods of time, it can damage your nerves, blood vessels, tissues and organs. […] Severe hyperglycemia can also lead to an acute (sudden and severe) life-threatening complication called diabetes-related ketoacidosis (DKA), especially in people with diabetes who take insulin or people with undiagnosed Type 1 diabetes. This requires immediate medical treatment. […] Hyperglycemia most often results from a lack of insulin. This can happen due to insulin resistance and/or issues with your pancreas the organ that makes insulin.

• #59 Diabetic Ketoacidosis (DKA): Practice Essentials, Background, Pathophysiology

  https://emedicine.medscape.com/article/118361-overview

  Diabetic ketoacidosis (DKA) is an acute, major, life-threatening complication of diabetes characterized by hyperglycemia, ketoacidosis, and ketonuria. […] DKA is defined clinically as an acute state of severe uncontrolled diabetes associated with ketoacidosis that requires emergency treatment with insulin and intravenous fluids. […] DKA usually occurs as a consequence of absolute or relative insulin deficiency that is accompanied by an increase in counter-regulatory hormones (ie, glucagon, cortisol, growth hormone, epinephrine). This type of hormonal imbalance enhances hepatic gluconeogenesis, glycogenolysis, and lipolysis. […] Hepatic gluconeogenesis, glycogenolysis secondary to insulin deficiency, and counter-regulatory hormone excess result in severe hyperglycemia, while lipolysis increases serum free fatty acids.

• #60 Figure 1. [Pathogenesis of hyperglycemia. Hyperglycemia results…]. – Endotext – NCBI Bookshelf

  https://www.ncbi.nlm.nih.gov/books/NBK279093/figure/mgmt-diab-hosp-patnt.F1/

  Pathogenesis of hyperglycemia. Hyperglycemia results from increased hepatic glucose production and impaired glucose utilization in peripheral tissues. Reduced insulin and excess counter-regulatory hormones (glucagon, cortisol, catecholamines, and growth hormone) increase lipolysis and protein breakdown (proteolysis) and impair glucose uptake by peripheral tissues. Hyperglycemia causes osmotic diuresis, leading to volume depletion, decreasing glomerular filtration rate, and worsening hyperglycemia. At the cellular level, increased blood glucose concentrations result in mitochondrial injury by generating reactive oxygen species and endothelial dysfunction by inhibiting nitric oxide production. Hyperglycemia increases levels of pro-inflammatory cytokines such as tumor necrosis factor- (TNF-) and interleukin [IL]-6, leading to immune system dysfunction. These changes can eventually lead to an increased risk of infection, impaired wound healing, multiple organ failure, prolonged hospital stay, and death. […] Figure 1. [Pathogenesis of hyperglycemia. Hyperglycemia results…].

• #61 Figure 1. [Pathogenesis of hyperglycemia. Hyperglycemia results…]. – Endotext – NCBI Bookshelf

  https://www.ncbi.nlm.nih.gov/sites/books/NBK279093/figure/mgmt-diab-hosp-patnt.F1/?report=objectonly

  Hyperglycemia results from increased hepatic glucose production and impaired glucose utilization in peripheral tissues. […] Reduced insulin and excess counter-regulatory hormones (glucagon, cortisol, catecholamines, and growth hormone) increase lipolysis and protein breakdown (proteolysis) and impair glucose uptake by peripheral tissues. […] At the cellular level, increased blood glucose concentrations result in mitochondrial injury by generating reactive oxygen species and endothelial dysfunction by inhibiting nitric oxide production. […] Hyperglycemia increases levels of pro-inflammatory cytokines such as tumor necrosis factor- (TNF-) and interleukin [IL]-6, leading to immune system dysfunction. […] These changes can eventually lead to an increased risk of infection, impaired wound healing, multiple organ failure, prolonged hospital stay, and death.

• #62 Hyperglycemia (High Blood Sugar): Symptoms & Treatment

  https://my.clevelandclinic.org/health/diseases/9815-hyperglycemia-high-blood-sugar

  Prolonged (chronic) hyperglycemia over the years can damage blood vessels and tissues in your body. This can lead to a variety of complications, including the following: Retinopathy, Nephropathy, Neuropathy, Gastroparesis, Heart disease, Stroke. […] Acute (sudden and severe) hyperglycemia can lead to DKA, which is life-threatening. […] Chronic hyperglycemia can cause severe complications, and the complications are usually irreversible. Several studies have shown that untreated chronic hyperglycemia shortens lifespans and worsens the quality of life.

• #63 Hyperglycemia (High Blood Sugar): Symptoms & Treatment

  https://my.clevelandclinic.org/health/diseases/9815-hyperglycemia-high-blood-sugar

  Prolonged (chronic) hyperglycemia over the years can damage blood vessels and tissues in your body. This can lead to a variety of complications, including the following: Retinopathy, Nephropathy, Neuropathy, Gastroparesis, Heart disease, Stroke. […] Acute (sudden and severe) hyperglycemia can lead to DKA, which is life-threatening. […] Chronic hyperglycemia can cause severe complications, and the complications are usually irreversible. Several studies have shown that untreated chronic hyperglycemia shortens lifespans and worsens the quality of life.

• #64 Diabetes Mellitus (DM) – Endocrine and Metabolic Disorders – Merck Manual Professional Edition

  https://www.merckmanuals.com/professional/endocrine-and-metabolic-disorders/diabetes-mellitus-and-disorders-of-carbohydrate-metabolism/diabetes-mellitus-dm

  Diabetes mellitus is impaired insulin secretion and variable degrees of peripheral insulin resistance leading to hyperglycemia. […] Years of poorly controlled hyperglycemia lead to multiple, primarily vascular complications that affect small vessels (microvascular), large vessels (macrovascular), or both. […] In type 2 diabetes mellitus (previously called adult-onset or noninsulin-dependent), insulin secretion is inadequate because patients have developed resistance to insulin. Hepatic insulin resistance leads to an inability to suppress hepatic glucose production, and peripheral insulin resistance impairs peripheral glucose uptake. This combination gives rise to fasting and postprandial hyperglycemia. […] Pathogenesis is complex and incompletely understood. Hyperglycemia develops when insulin secretion can no longer compensate for insulin resistance.

• #65 Hyperglycemia – Wikipedia

  https://en.wikipedia.org/wiki/Hyperglycemia

  Hyperglycemia also creates microbiological changes within the body: hyperglycemia can lead to rapid changes in blood pH and cell viscosity, weakening the cells and making it more conducive for infectious agents to thrive and dampen inflammatory responses. […] Due to neutrophil changes, microbiological changes, and chronic inflammation, patients with hyperglycemia are thus more prone to severe respiratory infections. […] Hyperglycemia and risk of severe infectious outcomes can even further be complicated by physiological stress.

• #66 Hyperglycemia – Wikipedia

  https://en.wikipedia.org/wiki/Hyperglycemia

  Hyperglycemia also creates microbiological changes within the body: hyperglycemia can lead to rapid changes in blood pH and cell viscosity, weakening the cells and making it more conducive for infectious agents to thrive and dampen inflammatory responses. […] Due to neutrophil changes, microbiological changes, and chronic inflammation, patients with hyperglycemia are thus more prone to severe respiratory infections. […] Hyperglycemia and risk of severe infectious outcomes can even further be complicated by physiological stress.

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