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🔥+ reverses diabetes type 2 04 Jun 2020 Type 2 diabetes can have bad effects on health in the long term (diabetic complications), such as severe eye or kidney disease or 'diabetic feet' ...

reverses diabetes type 2 Excluding gestational diabetes — diabetes that develops during pregnancy — there are two main types: type 1 and type 2. In type 1 diabetes, ...

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Animal Models of Type 1 and Type 2 Diabetes Mellitus

Aileen King, Amazon Austin, in Animal Models for the Study of Human Disease (Second Edition), 2017

4 Diabetic Complications

Diabetic complications, such as neuropathy, nephropathy, retinopathy, and cardiovascular disease arise in both Type 1 and Type 2 diabetes. In humans, these complications develop for 1 last update 04 Jun 2020 after chronic hyperglycemia and thus many rodent models do not develop complications due to the relatively short periods of hyperglycemia. STZ is often used in diabetes induction when studying complications, but the possibility of direct effects of the STZ on the specific organ should be considered. An example of this is in the study of neuropathies, where it has been shown that STZ directly stimulates the TRPA1 channels, which could complicate the interpretation of results (Andersson et al., 2015). The Akita mouse is an STZ-free alternative that has been used to study diabetic neuropathy (Islam, 2013), although many of the Type 2 models are also suitable for this purpose.Diabetic complications, such as neuropathy, nephropathy, retinopathy, and cardiovascular disease arise in both Type 1 and Type 2 diabetes. In humans, these complications develop after chronic hyperglycemia and thus many rodent models do not develop complications due to the relatively short periods of hyperglycemia. STZ is often used in diabetes induction when studying complications, but the possibility of direct effects of the STZ on the specific organ should be considered. An example of this is in the study of neuropathies, where it has been shown that STZ directly stimulates the TRPA1 channels, which could complicate the interpretation of results (Andersson et al., 2015). The Akita mouse is an STZ-free alternative that has been used to study diabetic neuropathy (Islam, 2013), although many of the Type 2 models are also suitable for this purpose.

Models of retinopathy include STZ-induced models of hyperglycemia, as well as spontaneous Type 1 and Type 2 models, such as Akita mice, NOD mice, and Lepdb/db mice (Lai and Lo, 2013). The pathogenesis of retinopathy can also be investigated by using normoglycemic models of proliferative retinopathy, such as oxygen-induced retinopathy.

A variety of different animal strains have been used to model nephropathy including OLETF rats, Lepob/b mice, Lepdb/db mice, Zucker fatty rats (Betz and Conway, 2016). STZ-induced diabetes has also been used, but possiblereverses diabetes type 2 song (🔥 with mellitus) | reverses diabetes type 2 in hindihow to reverses diabetes type 2 for direct effects of STZ on the kidneys should be controlled for. Akita mice have also been used but the disease progression is limited so may not be the best model for late stage experiments (Alpers and Hudkins, 2011). It should be noted that susceptibility to diabetic nephropathy is strain dependent with the C57Bl/6 relatively resistant (Betz and Conway, 2016).

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Carbohydrate Metabolism, Diabetes, and Hypoglycemia

reverses diabetes type 2 case study (👍 korean) | reverses diabetes type 2 treatment guidelineshow to reverses diabetes type 2 for Amitava Dasgupta PhD, DABCC, Amer Wahed MD, in Clinical Chemistry, Immunology and Laboratory Quality Control, 2014Amitava Dasgupta PhD, DABCC, Amer Wahed MD, in Clinical Chemistry, Immunology and Laboratory Quality Control, 2014

reverses diabetes type 2 in youth (⭐️ teens) | reverses diabetes type 2 eventshow to reverses diabetes type 2 for 7.8 Complications of Diabetes

Diabetic complications can be divided into two broad categories: acute and chronic complications. Acute complications include diabetic ketoacidosis (DKA), hyperosmolar non-ketosis, and lactic acidosis. Chronic complications could be either macrovascular (stroke, myocardial infarction, gangrene, etc.) or microvascular (such as diabetic retinopathy, diabetic eye diseases, and diabetic neuropathy).

Diabetic ketoacidosis may be the presenting feature of type 1 diabetes mellitus, or it may occur in a diabetic individual managed on insulin who does not take insulin or whose insulin requirement has been increased due to infection, myocardial infarction, or other causes. Diabetic ketoacidosis is a medical emergency, and, if not treated on time, can be fatal. In typical diabetic ketoacidosis, absolute insulin deficiency, along with increased secretion of glucagon and other counter regulatory hormones, results in decreased uptake of glucose into cells with increased glycogenolysis and gluconeogenesis. This produces more sugars, which are released in the circulation. As a result, marked hyperglycemia, glycosuria, and osmotic diuresis may result, causing water and salt loss through the kidneys. Reduction in plasma volume may cause renal hypoperfusion and eventually acute renal failure. Absence of insulin also leads to release of fatty acids, mostly from adipose tissue (lipolysis), causing generation of excess fatty acids that result in the formation of ketone bodies, including acetoacetic acid, beta hydroxybutyric acid, and acetone. Acetoacetic acid and beta-hydroxybutyric acid contribute to the acidosis. The body attempts to neutralize such excess acid by bicarbonate compensatory mechanisms. As bicarbonate is depleted, the body attempts other mechanisms of compensation, such as hyperventilation, and, in some patients, extreme forms of hyperventilation (Kussmaul respiration). Acetone is volatile and responsible for the typical ketone odor present in patients with diabetic ketoacidosis. Typically, in patients with diabetic ketoacidosis, blood glucose is above 250 mg/dL, arterial blood pH<7.3, and bicarbonate is between 15 and 18 mmol/L (but may be lower than 10 mmol/L in severe cases). In addition, ketone bodies are present in urine. Diabetic ketoacidosis is more commonly encountered in patients with type 1 diabetes, although under certain circumstances (e.g. trauma, surgery, infection) severe stress diabetic ketoacidosis may also be observed in patients with type 2 diabetes. Other than diabetes, ketoacidosis may be observed in patients with alcoholism (alcoholic ketoacidosis), starvation, and also may be drug-induced (e.g. salicylate poisoning).

Hyperosmolar non-ketosis is typically seen in patients with type 2 diabetes mellitus. Insulin deficiency is not absolute and as a result ketosis is not significant. There is also minimal acidosis. Characteristic clinical features include significant hyperglycemia with high plasma osmolality and dehydration. Lactic acidosis is an uncommon situation with diabetics. It may be seen in patients on biguanide therapy (e.g. on phenformin) with liver or renal impairment.

Macrovascular complications of diabetes mellitus are related to atherosclerosis, and diabetes is a major risk factor for cardiovascular diseases. There are multiple reasons for this. Diabetic individuals have abnormal lipid metabolism with increased low density lipoprotein cholesterol (LDL), and decreased high density lipoprotein cholesterol (HDL). Triglyceride levels are typically increased in patients with diabetes mellitus. In addition, glycation of lipoproteins may lead to altered functions of these lipoproteins.

Microvascular complications are for 1 last update 04 Jun 2020 related to the following mechanisms:Microvascular complications are related to the following mechanisms:

Non-enzymatic glycosylation of proteins.

Activation of protein kinase C.

Disturbance in the polyol the 1 last update 04 Jun 2020 pathway.Disturbance in the polyol pathway.

The degree of non-enzymatic glycosylation is related to the blood glucose level and measurement of glycosylated hemoglobin, and, less frequently, the glycosylated fructosamine level in blood is measured on a regular basis in patients with diabetes. Hyperglycemia-induced activation of protein kinase C results in the production of pro-angiogenic molecules that can cause neovascularization and also the formation of pro-fibrogenic molecules that lead to the deposition of extracellular matrix and basement membrane material. An increase in intracellular glucose leads to increased production of sorbitol by the enzyme aldose reductase. Sorbitol is a polyol, which is converted to fructose. Increased accumulation of sorbitol and fructose can cause cellular injury.

Case Report

reverses diabetes type 2 numbers (👍 urine) | reverses diabetes type 2 would be consideredhow to reverses diabetes type 2 for A 15-year-old female with known type 1 diabetes mellitus was admitted to the hospital with complaints of abdominal pain and fatigue for the past 24 h. Her glycemic control in the morning showed hypoglycemia (glucose: 61 mg/dL) and she omitted her morning insulin dose due to low glucose level and poor appetite. On admission, she was alert but showed marked Kussmaul breathing and the smell of ketones on her breath. She also showed severe hyperglycemia (glucose: 414 mg/dL) and blood gas analysis revealed severe metabolic acidosis (pH 6.99); her bicarbonate level was 5.0 mmol/L. She also showed an elevated anion gap of 29.8 mmol/L and increased base excess. However, blood urea, electrolytes, and liver enzymes were within normal limits. At the sixth hour of treatment with intravenous fluid and insulin, the patient became delirious. A brain image study did not reveal any edema or abnormal intracranial pathology. At the 18th hour of treatment, the patient developed a high fever and further laboratory investigation indicated that the patient had vulvovaginitis. Treatment with fluconazole was initiated. At the 24th hour of therapy, her acidosis was resolved completely, but she was still unconscious with little response to verbal stimuli. Finally, at the 36th hour, the patient was able to respond to commands and sit up. She was discharged a few days later and recovered completely. The authors established the diagnosis as severe diabetic ketoacidosis associated with infection [6].

Case Report

A 26-year-old-African-American man presented to the emergency department with a three-week history of increased urination, thirst, fatigue, mild nausea, and weight loss. On admission, his random glucose level was 615 mg/dL, hemoglobin A1c was 15.8%, C-peptide was 0.4 ng/mL, and he had an elevated anion gap of 25 mmol/L. His venous blood gas showed a pH of 7.19, bicarbonate of 13.9 mmol/L, and pCO2 of 38 mmHg. A urine dipstick analysis showed a small amount of ketones. A diagnosis of type 1 diabetes mellitus was established and the patient was given insulin. On discharge he was advised to stop taking ephedra and to start eating a balanced diet. He returned to the clinic after eight weeks and stated that he was not suffering from diabetes. His hemoglobin A1c was 6.2% and his blood glucose was 120 mg/dL, and he also said that he had discontinued the insulin. He was advised to continue monitoring his blood glucose. He returned to the clinic three months later with casual glucose between 90 and 140 mg/dL and continued to do well. At that time antibodies to islet cell and anti-glutamic acid decarboxylase antibody tests were ordered and both were negative. Lack of antibodies and his blood glucose levels raised suspicions regarding the initial diagnosis of type 1 diabetes mellitus. Finally the patient was managed with metformin, an oral hypoglycemic agent, and insulin was discontinued. The most likely diagnosis for this patient was ketosis prone diabetes, a disease most commonly encountered in African-Americans, but also observed in Hispanics, Asians, and sometimes in the Caucasian population [7].

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FGFs in Injury Repair and for 1 last update 04 Jun 2020 RegenerationFGFs in Injury Repair and Regeneration

Xiaokun Li, ... Xiaokun the 1 last update 04 Jun 2020 Li, in Xiaokun Li, ... Xiaokun Li, in Fibroblast Growth Factors, 2018

1 Introduction

Diabetic complications have become a serious issue for public health. One of these complications is the impaired wound healing for diabetic patients. Lack of cellular and molecular signals required for normal wound healing process such as angiogenesis, granulation tissue formation, epithelialization, and remodeling may be the reason for the poor healing of diabetic wound.

Although multiple factors including hyperglycemia, hyperlipidemia, and inflammation all contribute pathogenic effects to various vascular complications in diabetes, hyperglycemia plays a critical role in the widespread cellular damage since endothelial cells poorly regulate intracellular glucose and are particularly vulnerable to hyperglycemia-derived oxidative damage. Furthermore, these pathogens also inhibit angiogenic pathways, leading to inadequate blood vessel growth and consequently delaying diabetic wound healing process.

Cytokines, especially various growth factors, provide the cellular and molecular signals necessary for normal healing process, but are deficient in diabetic wounds. Topical application of several growth factors to stimulate fibroblast and endothelial cell proliferation to heal the impaired wound may enhance successful rate of wound healing. Under appropriate pathophysiological conditions, growth factors, such as vascular endothelial growth factor (VEGF) and fibroblast growth factor (FGF), are released to initiate angiogenesis. Impaired wound healing is a common condition in diabetes associated with a delay in progression beyond the inflammatory and proliferative phases of normal wound healing. For example, FGF is secreted by fibroblasts, macrophages, and in particular endothelial cells in response to tissue injury and plays an important role in angiogenesis. Hyperglycemia-derived glycation significantly reduces FGF's binding capacity to the tyrosine kinase receptor and activates signal transduction pathways responsible for both mitogenesis and capillary formation. Therefore, significant acceleration of wound healing by topical application of various exogenous growth factors including FGF has been observed in diabetic animal models and a few diabetic patients. However, only application of a single growth factor remains unable to obtain the the 1 last update 04 Jun 2020 maximal therapeutic purpose. These studies suggest multiple mechanisms contributing to diabetes-impaired wound healing.

reverses diabetes type 2 home remedie (👍 coronavirus risk) | reverses diabetes type 2 diet plan lose weighthow to reverses diabetes type 2 for Indeed other alterations in wound local tissue except for the defect of growth factors also significantly affect the healing. Zinc (Zn) is an essential trace element for cell growth, proliferation, and cellular repair and signaling. Diabetes significantly impairs Zn homeostasis, leading to systemic Zn deficiency, which is proposed to be associated with the impaired wound healing. Significant benefit of topical application of Zn with or without other components on diabetic or nondiabetic wound healing was observed. The beneficial effects of topical application of Zn include not only the correction of wound tissue's Zn deficiency but also the enhancement of angiogenesis, decrease of inflammatory response and bacterial growth, and increase of antioxidants against diabetes-caused dermal and further vessel damage. More important, Zn is also able to amplify FGF functions.

Systemic abnormalities also play important roles in the delay of diabetic wound healing. Recent study shows that dysfunction of endothelial progenitor cells (EPCs) is a critical cause of the impairment of diabetic wound healing. Administration of circulating CD34+ cells, which can function as EPCs, accelerates the revascularization and healing in the skin wound of streptozotocin (STZ)-induced diabetic mice. An early study also showed that administration of stem-cell stimulating factor improved diabetic wound healing. A recent study with topical use of VEGF also showed that the significantly improved diabetic wound healing was also mediated by systemic mobilization of bone marrow hematopoietic progenitor cells (BM-HPCs), including a population that contributes to blood vessel formation, as one of the multiple possible mechanisms.

Granulocyte colony-stimulating factor (G-CSF) is a colony-stimulating factor, which is produced by a number of different tissues to stimulate the bone marrow to produce granulocytes and stem cells and then mobilize these cells into the blood and wound tissue for participating in the new blood vessel generation. Therefore, in vivo application of G-CSF stimulated wound healing under nondiabetic conditions.

The beneficial effects of these different approaches, such as topical application of FGF or Zn and/or systemic application of G-CSF imply that there may be a significant synergistic stimulation of the wound healing when these multiple approaches are applied together. A few studies have preliminarily explored the combined therapeutic effects with two growth factors. However, these studies focused on the improvement of wound tissue growth factor defect without much consideration of wound tissue antioxidant and micronutrient improvement and systemic upregulation of stem cell mobilization. Therefore, the purpose of the present study was to assess the curative effect on the healing-impaired ulcer in STZ-induced diabetic rats with a combined protocol, including topical application of recombinant human acid fibroblast growth factor (aFGF) and nutrient (Zn) to correct wound local defect of both tissue growth factors and Zn homeostasis, and systemic application of G-CSF to peripherally mobilize the endogenous BM-HPCs. Although this hypothesis may be easily imaged to produce a more efficient therapeutic effect, its feasibility remains very interesting and it is urgent to test this approach preclinically in an animal model. We demonstrated that diabetic ulcer healing was found to be significantly improved by aFGF/G-CSF/ZnSO4, as compared to other treatment combinations, suggesting the potential of aFGF/G-CSF/ZnSO4 as a new diabetic ulcer treatment strategy for clinical application.

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Perturbations of Energy Metabolism

N.V. Bhagavan, Chung-Eun Ha, in reverses diabetes type 2 pancreas (🔴 high blood sugar symptoms) | reverses diabetes type 2 cause high blood pressurehow to reverses diabetes type 2 for Essentials of Medical Biochemistry (Second Edition), 2015

Chronic Complications of Diabetes Mellitus

Chronic complications of diabetes mellitus stem from elevated plasma glucose levels and involve tissues that do not require insulin (e.g., lens, retina, peripheral nerve) for the uptake and metabolism of glucose. In these tissues, the intracellular level of glucose parallels that in plasma. The chronic complications, which cause considerable morbidity and mortality, are atherosclerosis, microangiopathy, retinopathy, nephropathy, neuropathy, and cataracts. The biochemical basis of these abnormalities may be attributed to increased tissue ambient glucose concentration and may involve the following mechanisms: nonenzymatic protein glycation increased production of sorbitol, and decreased levels of myo-inositol.

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reverses diabetes type 2 in children (⭐️ reversal) | reverses diabetes type 2 naturehow to reverses diabetes type 2 for Pulmonary Manifestations of Systemic Disorders

Laura S. Inselman, in Pediatric Respiratory Medicine (Second Edition), 2008

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Pulmonary complications of diabetes mellitus are diagnosed by the history, physical examination, radiography, and laboratory studies. The presence of ketoacidosis and/or uncontrolled hyperglycemia in an individual with diabetes and pneumonia should suggest the possibility of a fungal or mycobacterial infection. Pulmonary mucormycosis should be considered in the presence of rhinocerebral disease with a characteristic black eschar.reverses diabetes type 2 treatment diet (👍 example) | reverses diabetes type 2 exhaustionhow to reverses diabetes type 2 for 122 ARDS can develop rapidly in diabetics in the presence of only mild hypoxemia without crackles or radiographic changes initially.141 Stains and cultures of respiratory secretions and blood for bacteria, fungi, mycobacteria, and viruses; immunologic studies for specific viral antigens and antibodies; anteroposterior and lateral chest radiographs; and when indicated, CT scans are important in the diagnosis of these disorders.

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Diabetes mellitus

Stanley F. Malamed DDS, ... Daniel L. OrrII DDS, MS (ANES), PHD, JD, MD, in Medical Emergencies in the Dental Office (Seventh Edition), 2015

Acute Complications

Acute complications of for 1 last update 04 Jun 2020 diabetes mellituscomplications of diabetes mellitus include hypoglycemia, diabetic ketoacidosis, and hyperglycemic hyperosmolar nonketotic coma.reverses diabetes type 2 in young children (👍 ribbon) | reverses diabetes type 2 diethow to reverses diabetes type 2 for 1 Hyperglycemia, or high blood sugar, and its sequelae represent one of two clinically significant complications for the doctor who is called on to manage the dental needs of the diabetic patient. The second and more acutely life-threatening complication is hypoglycemia, or low blood sugar. Hypoglycemia may be present in diabetic and nondiabetic individuals. Blood glucose levels below 50 mg per 100 mL (venous blood) usually indicate hypoglycemia in adults, whereas blood glucose values less than 40 mg per 100 mL indicate hypoglycemia in children.9 The estimated incidence of hypoglycemia in diabetic patients is 9 to 120 episodes per 100 patient-years.10–12 Signs and symptoms of hypoglycemia may become evident within minutes, leading rapidly to the loss of consciousness, or, more commonly, they may develop gradually, leading to progressive alterations in consciousness.

Hyperglycemia may also result ultimately in the loss of consciousness (diabetic coma), but this usually represents the end of a much longer process. (The time elapsed from the onset of symptoms to the loss of consciousness is usually at least 48 hours.) Loss of consciousness due to hyperglycemia is an extremely unlikely occurrence in the dental office. Conversely, low blood sugar is significantly more likely to lead to profound changes in levels of consciousness or to the loss of consciousness. Regardless of cause, the doctor must be able to recognize the clinical problem and initiate the proper management protocol. To aid in the differential diagnosis of diabetic complications, this chapter stresses the differences between hyperglycemia and hypoglycemia.

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Diabetes and the Nervous System

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Cognitive Dysfunction

A complication of diabetes mellitus that is frequently overlooked or under-reported is cognitive decline, which was first reported almost a century ago and can occur with type 1 or type 2 diabetes.46–49 An elevated risk of dementia, cerebral atrophy, and presence of white matter abnormalities have been shown in multiple studies. Cognitive dysfunction may be apparent during childhood50,51 or in late stages of life52 when neurodegeneration may predominate.reverses diabetes type 2 lawsuit (🔴 genetic link) | reverses diabetes type 2 high blood sugarhow to reverses diabetes type 2 for 47,50–52 Patients with diabetes also have an increased risk of development of Alzheimer disease (AD) as compared with subjects without diabetes.53 A substantial number of AD patients have either glucose intolerance or diabetes.54

Children with type 1 diabetes have lower intelligence scores, lowered mental efficiency, and poor school performance compared to children without diabetes.50 The younger the age of onset of the diabetes, the greater the cognitive impact.55 Once present, early-onset cognitive dysfunction persists into adulthood, associated with impaired cognitive performance and significant cerebral atrophy.56,57 Chronic hyperglycemia may possibly accelerate neurodegeneration. for 1 last update 04 Jun 2020 5858 Thus, some reports have speculated on the association between acute hypoglycemic episodes and cognitive impairment; a large meta-analysis failed to demonstrate such an association.59,60 A longer duration of diabetes also appears to increase cognitive dysfunction. for 1 last update 04 Jun 2020 6161

In type 2 diabetes mellitus, there are several other confounding factors that may influence cognition such as obesity, dyslipidemia, hypertension, and stroke.62–64 Patients with prediabetes or impaired glucose tolerance may also have cognitive impairment to a lesser degree. the 1 last update 04 Jun 2020 65,6665,66 Another important comorbidity is depression in some patients with diabetes, although its impact appears to be less than the impact of diabetes itself.67,68

Particular domains of cognition may be impacted more than others in diabetes, including attention and executive function, processing speed, perception, and memory.69 Language and visuospatial abilities tend to be preserved.70 In both cross-sectional and longitudinal studies, there is mild-to-moderate impairment of working memory in patients with type 2 diabetes.71,72 Mental flexibility and planning is also impaired in these patients, along with verbal memory. the 1 last update 04 Jun 2020 73–7573–75

Many patients with type 2 diabetes have mild cognitive impairment rather than frank dementia.76,77 However, like all patients with mild cognitive impairment, there is an increased risk of developing dementia.78 Diabetes has been shown to be a risk factor for vascular dementia and AD.79–81 Despite limitations of intensive glycemic management, hyperinsulinemia may be the basis of this increased risk.72

Changes present in the diabetic brain over time can be described pathologically as diabetic leukoencephalopathy.46,82 The main hallmarks include cerebral atrophy and periventricular, subcortical white matter abnormalities (Fig. 19-3).reverses diabetes type 2 young adults (☑ rise) | reverses diabetes type 2 japanhow to reverses diabetes type 2 for 82,83

Figure 19-3. Magnetic resonance imaging (MRI) of the brain from a 62-year-old woman with type 2 diabetes mellitus for 12 years, who presented with mild ataxia of gait and polyneuropathy. These axial T2-weighted fluid-attenuated inversion recovery (FLAIR) sequences progress from caudal to rostral cuts (A to D) and show nonenhancing bilateral white matter hyperintensities (arrows in A), also termed diabetic leukoencephalopathy.

Studies examining cognitive function in diabetic females or males demonstrate similar patterns of cognitive impairment.84,85 Longer durations of diabetes and poor glycemic control are associated with greater microvascular end-organ complications and greater cognitive dysfunction that parallel elevated glycosylated hemoglobin (HbA1c) levels.27,74,86–89 It is possible that cognitive dysfunction is partially reversible with improvements in glycemic control,90,91 although optimal target levels have not yet been established.90,91

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Medical Conditions

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Complications

reverses diabetes type 2 journal (🔥 nice) | reverses diabetes type 2 home remediehow to reverses diabetes type 2 for The complications of diabetes mellitus can be divided into acute and chronic categories. Acute complications primarily include diabetic ketoacidosis (discussed in the section, Diabetic Ketoacidosis), nonketotic hyperosmolar syndrome, and hypoglycemia. Chronic complications are predominantly related to the long-term effects of hyperglycemia on the vasculature and can be divided into microvascular retinopathy (nonproliferative, also known as preproliferative, and proliferative), nephropathy, neuropathy (peripheral distal symmetric polyneuropathy, autonomic neuropathy, proximal painful motor the 1 last update 04 Jun 2020 neuropathy, and cranial mononeuropathy), and macrovascular disease (accelerated atherosclerosis, coronary artery disease, myocardial infarction, and peripheral vascular disease). Although tight glycemic control has been shown to improve microvascular disease (Diabetic Clinical Control Trial), its role in macrovascular disease remains controversial. The United Kingdom Prospective Diabetes Study (UKPDS) indicated no benefits, but a follow-up study showed some improvement. There is no doubt that macrovascular disease may be improved with control of lipid levels and blood pressure, smoking cessation, and aspirin therapy.The complications of diabetes mellitus can be divided into acute and chronic categories. Acute complications primarily include diabetic ketoacidosis (discussed in the section, Diabetic Ketoacidosis), nonketotic hyperosmolar syndrome, and hypoglycemia. Chronic complications are predominantly related to the long-term effects of hyperglycemia on the vasculature and can be divided into microvascular retinopathy (nonproliferative, also known as preproliferative, and proliferative), nephropathy, neuropathy (peripheral distal symmetric polyneuropathy, autonomic neuropathy, proximal painful motor neuropathy, and cranial mononeuropathy), and macrovascular disease (accelerated atherosclerosis, coronary artery disease, myocardial infarction, and peripheral vascular disease). Although tight glycemic control has been shown to improve microvascular disease (Diabetic Clinical Control Trial), its role in macrovascular disease remains controversial. The United Kingdom Prospective Diabetes Study (UKPDS) indicated no benefits, but a follow-up study showed some improvement. There is no doubt that macrovascular disease may be improved with control of lipid levels and blood pressure, smoking cessation, and aspirin therapy.

The symptoms of hypoglycemia may be confused with those of cerebrovascular events, vasovagal syndrome, or a variety of disorders considered in the differential diagnosis of a delirious patient (hypoxia, infection, metabolic abnormalities, myocardial infarction, and medication overdose and withdrawal). Hypoglycemia is defined as a blood glucose level below 60 mg/dl. The symptoms may be divided into those that are neurologic and those that are secondary to increased adrenergic (sympathetic) outflow. Neurologic symptoms consist of visual disturbances, paresthesias, lethargy, irritability, delirium, confusion, seizures, and coma. Adrenergic symptoms consist of nausea, anxiety, weakness, sweating, and tremors. In a previously undiagnosed patient, the differential diagnosis should include primary or secondary hyperinsulinemia (insulinoma). Other important considerations include sepsis, malnutrition, and liver failure. The most common reason for hypoglycemia in a diabetic patient is insulin mismanagement. Patients with renal failure are more prone to hypoglycemia, because a small fraction of gluconeogenesis is conducted by the kidneys. Treatment of hypoglycemia in an awake patient consists of oral glucose administration (e.g., orange juice). If intravenous access is available, dextrose 10% or 50% in water (D10W or D50W) is acceptable. In the unconscious patient with no intravenous access, 1 mg of glucagon IM/SC can be administered. Diazoxide, octreotide, and hydrocortisone are other alternatives. Diabetic ketoacidosis and nonketotic hyperosmolar coma are discussed elsewhere in this book. It is important to treat any suspicion of hypoglycemia rapidly, because hyperglycemia in a misdiagnosed patient does not have any immediate emergent complications; however, untreated undiagnosed hypoglycemia may be devastating.

It is commonly known that patients with diabetes mellitus are more susceptible to infections. It is thought that various steps in neutrophil function are altered, including leukocyte adherence, chemotaxis, and phagocytosis. The antioxidants, which are involved in the bactericidal activity, may also be altered. The defects in neutrophil function are at least partially reversible by strict glycemic control (blood glucose between 80 and 110 mg/dl). However, it is hypothesized that the pathophysiology of the immunologic defects in diabetes mellitus is not exclusively related to glycemic control.

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Diabetic Neuropathy

H.C. Powell, A.P. Mizisin, in Encyclopedia of Neuroscience, 2009

Metabolic Consequences of Hyperglycemia

In diabetic complications, mechanisms of hyperglycemia-induced damage include polyol pathway flux, advanced glycation end product (AGE) formation, activation of protein kinase C (PKC), and hexosamine pathway activity. During hyperglycemia, reduction of intracellular glucose by aldose reductase results in the formation of sorbitol and concomitant oxidation of nicotinamide adenine dinucleotide phosphate (NADPH). The sorbitol formed is subsequently oxidized to fructose by sorbitol dehydrogenase with the reduction of NAD+. Proposed detrimental effects of increased polyol pathway flux include sorbitol-induced osmotic stress, decreased Na+-K+-ATPase activity, increased cytosolic NADH/NAD+ and consequent inhibition of glyceraldehydes-3-phosphate dehydrogenase (GAPDH), and decreased cytosolic NADPH. In nerve, aldose reductase has been localized to myelinated fiber Schwann cell cytoplasm. Extraneural sites of aldose reductase localization include skeletal muscle and endothelial cells of blood vessels. Although an unequivocal role for polyol flux in the development of diabetic neuropathy has not been established, accumulation of sorbitol and changes in cofactor levels may compromise Schwann cell metabolism, initiate reduction of Schwann cell-derived neurotrophic factors, and ultimately promote the destruction of this cell. Other consequences include nerve conduction defects, increased triose phosphate concentrations, and decreased reduced glutathione levels.

The primary initiating event in the formation of intracellular and extracellular AGEs is thought to be the generation of glucose-derived carbonyl precursors by auto-oxidation of glucose to glyoxyl, decomposition of Amadori product to 3-deoxyglucosone, and fragmentation of triose phosphates to methylglyoxal. Potential detrimental effects of AGE production are wide ranging. Proteins modified by AGE formation have altered function and structure, with negative consequences for enzyme function, and interaction of extracellular matrix ligands and receptors. Activation of AGE receptors on endothelial cells and macrophages also induces receptor-mediated production of reactive oxygen species.

PKC is a family of 11 isoforms, the majority of which are activated by the triose phosphate lipid second messenger diacylglycerol (DAG). In diabetes, the β and δ isoforms of PKC are activated by hyperglycemia-induced increases in DAG, which are thought to be the consequence of the cytosolic NADH/NAD+ imbalance and consequent inhibition of GAPDH that results in elevated triose phosphate levels. Many of the proposed effects of PKC activation in diabetes are vascular and include blood flow abnormalities resulting from altered expression of endothelial nitric oxide synthase and endothelin-1; changes in vascular permeability and angiogenesis mediated by enhanced vascular endothelial growth factor expression; capillary and vascular occlusion resulting from increased collagen and fibronectin expression; and decreased fibrinolysis due to altered expression of transforming growth factor (TGF)-β⋅ and plasminogen activator inhibitor-1, respectively.

Aside from increases in triose phosphates, another consequence of hyperglycemia and hyperglycemia-induced inhibition of GAPDH is increased activity of the hexosamine pathway. Shunting excess intracellular glucose into the hexosamine pathway results in conversion of fructose-6-phosphate diverted from glycolysis into glucosamine-6-phosphate via the rate-limiting enzyme, glutamine:fructose-6-phosphate amidotransferase. The glucosamine-6-phosphate is subsequently converted into UDP-N-acetylglucosamine, which is believed to modulate transcription factors responsible for the production of TGF-β and plasminogen activator inhibitor-1 implicated in the vascular abnormalities alluded to previously.

Specific inhibitors of polyol pathway activity, AGE formation, PKC activation, and hexosamine flux have been shown to ameliorate early hyperglycemia-induced biochemical the 1 last update 04 Jun 2020 and functional nerve disorders, emphasizing the potential role of these mechanisms in the pathogenesis of diabetic neuropathy. Studies have implicated oxidative stress as an element common to these mechanisms and emphasized their interrelationship. Others have suggested that oxidative stress is the common element linking these mechanisms of hyperglycemia-induced damage, with each of the four mechanisms reflecting overproduction of superoxide by mitochondrial electron-transport chains. However, despite these contentions, there is little direct evidence supporting an oxidative stress-mediated link between early metabolic events and subsequent structural injury characteristic of diabetic neuropathy. Such evidence is critical for evaluating the overall importance of oxidative stress in the pathogenesis of diabetic neuropathy.Specific inhibitors of polyol pathway activity, AGE formation, PKC activation, and hexosamine flux have been shown to ameliorate early hyperglycemia-induced biochemical and functional nerve disorders, emphasizing the potential role of these mechanisms in the pathogenesis of diabetic neuropathy. Studies have implicated oxidative stress as an element common to these mechanisms and emphasized their interrelationship. Others have suggested that oxidative stress is the common element linking these mechanisms of hyperglycemia-induced damage, with each of the four mechanisms reflecting overproduction of superoxide by mitochondrial electron-transport chains. However, despite these contentions, there is little direct evidence supporting an oxidative stress-mediated link between early metabolic events and subsequent structural injury characteristic of diabetic neuropathy. Such evidence is critical for evaluating the overall importance of oxidative stress in the pathogenesis of diabetic neuropathy.

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