Review Article How Does Brain Insulin Resistance Develop In Alzheimer's Disease?
Abstract Compelling preclinical and clinical evidence supports a pathophysiological connection between Alzheimer's disease (AD) and diabetes. Altered metabolism, inflammation, and insulin resistance are key pathological features of both diseases. For many years, it was generally considered that the brain was insensitive to insulin, but it is now accepted that this hormone has central neuromodulatory functions, including roles in learning and memory, that are impaired in AD. However, until recently, the molecular mechanisms accounting for brain insulin resistance in AD have remained elusive. Here, we review recent evidence that sheds light on how brain insulin dysfunction is initiated at a molecular level and why abnormal insulin signaling culminates in synaptic failure and memory decline. We also discuss the cellular basis underlying the beneficial effects of stimulation of brain insulin signaling on cognition. Discoveries summarized here provide pathophysiological background for identification of novel molecular targets and for development of alternative therapeutic approaches in AD. Continue reading >>
Insulin In The Brain: Its Pathophysiological Implications For States Related With Central Insulin Resistance, Type 2 Diabetes And Alzheimers Disease
Insulin in the Brain: Its Pathophysiological Implications for States Related with Central Insulin Resistance, Type 2 Diabetes and Alzheimers Disease We are experimenting with display styles that make it easier to read articles in PMC. The ePub format uses eBook readers, which have several "ease of reading" features already built in. The ePub format is best viewed in the iBooks reader. You may notice problems with the display of certain parts of an article in other eReaders. Generating an ePub file may take a long time, please be patient. Insulin in the Brain: Its Pathophysiological Implications for States Related with Central Insulin Resistance, Type 2 Diabetes and Alzheimers Disease Enrique Blzquez, Esther Velzquez, [...], and Juan Miguel Ruiz-Albusac Although the brain has been considered an insulin-insensitive organ, recent reports on the location of insulin and its receptors in the brain have introduced new ways of considering this hormone responsible for several functions. The origin of insulin in the brain has been explained from peripheral or central sources, or both. Regardless of whether insulin is of peripheral origin or produced in the brain, this hormone may act through its own receptors present in the brain. The molecular events through which insulin functions in the brain are the same as those operating in the periphery. However, certain insulin actions are different in the central nervous system, such as hormone-induced glucose uptake due to a low insulin-sensitive GLUT-4 activity, and because of the predominant presence of GLUT-1 and GLUT-3. In addition, insulin in the brain contributes to the control of nutrient homeostasis, reproduction, cognition, and memory, as well as to neurotrophic, neuromodulatory, and neuroprotective effects. Alterations of the Continue reading >>
Insulin In Central Nervous System: More Than Just A Peripheral Hormone
Journal of Aging Research Volume 2012 (2012), Article ID 384017, 21 pages 1CNC, Center for Neuroscience and Cell Biology, University of Coimbra, 3004-517 Coimbra, Portugal 2Institute of Physiology, Faculty of Medicine, University of Coimbra, 3000-354 Coimbra, Portugal 3Institute of Biochemistry, Faculty of Medicine, University of Coimbra, 3000-354 Coimbra, Portugal Academic Editor: Barbara Shukitt-Hale Copyright © 2012 Ana I. Continue reading >>
Insulin Regulates Brain Function, But How Does It Get There?
Insulin Regulates Brain Function, but How Does It Get There? Division of Endocrinology, Department of Medicine, University of Virginia, School of Medicine, Charlottesville, VA Author information Article notes Copyright and License information Disclaimer Received 2014 Feb 26; Accepted 2014 Jul 12. Copyright 2014 by the American Diabetes Association. Readers may use this article as long as the work is properly cited, the use is educational and not for profit, and the work is not altered. This article has been cited by other articles in PMC. We have learned over the last several decades that the brain is an important target for insulin action. Insulin in the central nervous system (CNS) affects feeding behavior and body energy stores, the metabolism of glucose and fats in the liver and adipose, and various aspects of memory and cognition. Insulin may even influence the development or progression of Alzheimer disease. Yet, a number of seemingly simple questions (e.g., What is the pathway for delivery of insulin to the brain? Is insulins delivery to the brain mediated by the insulin receptor and is it a regulated process? Is brain insulin delivery affected by insulin resistance?) are unanswered. Here we briefly review accumulated findings affirming the importance of insulin as a CNS regulatory peptide, examine the current understanding of how peripheral insulin is delivered to the brain, and identify key gaps in the current understanding of this process. Accumulating information suggests several significant roles for insulin action in the brain. Here, we briefly review selected studies that provoke exploration of this emerging field. More pointedly, we highlight seemingly serious deficiencies in our understanding of how insulin from the systemic circulation might actually g Continue reading >>
Which Tissues Are Insulin Dependent For Glucose Uptake? Is The Brain One Of Them?
In brief, Skeletal muscle accounts for approximately 70% of insulin mediated glucose uptake. Adipose tissue accounts for about 10% of insulin dependent glucose uptake. While intracellular glucose uptake in the liver is not insulin dependent, insulin does modulate key metabolic processes in the liver through signalling cascades. The vascular endothelium does not depend on insulin mediated glucose uptake, but insulin signalling does mediate endothelial function through nitric oxide production. The brain also does not depend on insulin for intracellular glucose uptake. However, the insulin receptor is expressed in the brain in the hippocampus, hypothalamus, vessels of the choroid plexus, the striatum, and cerebral cortex. Similar to other tissues that are responsive to insulin, but don’t depend on it for glucose uptake, insulin signalling modulates key metabolic processes and serves to indicate the state of systemic glucose homeostasis. A few other insulin receptor expressing tissues that don’t depend on insulin for glucose uptake include: the pancreas, the anterior pituitary gland, the kidneys, the gonads, and osteoblasts and osteoclasts in bone. It is also worth noting that many tissues that take up glucose in response to insulin have alternate glucose uptake pathways that are insulin independent. An example of this is exercise induced glucose uptake in skeletal muscle. A specific mechanism is not known, but is of great interest to researchers studying type II diabetes and insulin resistance. This very nice review article has just about everything you might want to know about insulin . It’s not the newest review, but it is very inclusive. There’s a section titled ‘Sites of Insulin Action and Manifestations of Insulin Resistance’ that I would encourage the Continue reading >>
Brain May Play Key Role In Blood Sugar Metabolism And Diabetes Development
Brain may play key role in blood sugar metabolism and diabetes development A growing body of evidence suggests that the brain plays a key role in glucose regulation and the development of type 2 diabetes, researchers write in the Nov. 7 ssue of the journal Nature. If the hypothesis is correct, it may open the door to entirely new ways to prevent and treat this disease, which is projected to affect one in three adults in the United States by 2050. A laboratory procedure taking place in the diabetes research lab of Dr. Michael SchwartzClare McLean In the paper, lead author Dr. Michael W. Schwartz, UW professor of medicine and director of the Diabetes and Obesity Center of Excellence, and his colleagues from the universities of Cincinnati, Michigan, and Munich, note that the brain was originally thought to play an important role in maintaining normal glucose metabolism With the discovery of insulin in the 1920s, the focus of research and diabetes care shifted to almost exclusively to insulin. Today, almost all treatments for diabetes seek to either increase insulin levels or increase the bodys sensitivity to insulin. These drugs, the researchers write, enjoy wide use and are effective in controlling hyperglycemia [high blood sugar levels], the hallmark of type 2 diabetes, but they address the consequence of diabetes more than the underlying causes, and thus control rather than cure the disease. New research, they write, suggests that normal glucose regulation depends on a partnership between the insulin-producing cells of the pancreas, the pancreatic islet cells, and neuronal circuits in the hypothalamus and other brain areas that are intimately involved in maintaining normal glucose levels. The development of diabetes type 2, the authors argue, requires a failure of both Continue reading >>
Insulin Regulates Brain Function, But How Does It Get There?
We have learned over the last several decades that the brain is an important target for insulin action. Insulin in the central nervous system (CNS) affects feeding behavior and body energy stores, the metabolism of glucose and fats in the liver and adipose, and various aspects of memory and cognition. Insulin may even influence the development or progression of Alzheimer disease. Yet, a number of seemingly simple questions (e.g., What is the pathway for delivery of insulin to the brain? Is insulin’s delivery to the brain mediated by the insulin receptor and is it a regulated process? Is brain insulin delivery affected by insulin resistance?) are unanswered. Here we briefly review accumulated findings affirming the importance of insulin as a CNS regulatory peptide, examine the current understanding of how peripheral insulin is delivered to the brain, and identify key gaps in the current understanding of this process. Introduction Accumulating information suggests several significant roles for insulin action in the brain. Here, we briefly review selected studies that provoke exploration of this emerging field. More pointedly, we highlight seemingly serious deficiencies in our understanding of how insulin from the systemic circulation might actually get to the brain parenchyma, and suggest that addressing these deficiencies is requisite to both a basic understanding of insulin physiology and a rational consideration of therapeutics involving the delivery of insulin to the brain. Brain Insulin Action Because bulk brain glucose uptake is not affected by insulin in either rats (1) or humans (2,3), the brain had long been considered “insulin insensitive.” While there is evidence for the expression and activity of glucose transport with the insulin-sensitive GLUT4 in a fe Continue reading >>
Fgf19 Action In The Brain Induces Insulin-independent Glucose Lowering
Insulin-independent glucose disposal (referred to as glucose effectiveness [GE]) is crucial for glucose homeostasis and, until recently, was thought to be invariable. However, GE is reduced in type 2 diabetes and markedly decreased in leptin-deficient ob/ob mice. Strategies aimed at increasing GE should therefore be capable of improving glucose tolerance in these animals. The gut-derived hormone FGF19 has previously been shown to exert potent antidiabetic effects in ob/ob mice. In ob/ob mice, we found that systemic FGF19 administration improved glucose tolerance through its action in the brain and that a single, low-dose i.c.v. injection of FGF19 dramatically improved glucose intolerance within 2 hours. Minimal model analysis of glucose and insulin data obtained during a frequently sampled i.v. glucose tolerance test showed that the antidiabetic effect of i.c.v. FGF19 was solely due to increased GE and not to changes of either insulin secretion or insulin sensitivity. The mechanism underlying this effect appears to involve increased metabolism of glucose to lactate. Together, these findings implicate the brain in the antidiabetic action of systemic FGF19 and establish the brain’s capacity to rapidly, potently, and selectively increase insulin-independent glucose disposal. Continue reading >>
Brain Glucose Metabolism
The brain is an obligate glucose consumer, although it can utilize other metabolites in special situations such as fasting. It has very high energy consumption for its size, mainly due to the energy expenditure needed to maintain the potential difference across nerve cell membranes, as well as axonal and dendritic transport and tissue repair. Hence it consumes ~100 g/day of glucose in a 70 kg individual. Glucose enters the brain by insulin-insensitive facilitated diffusion across the blood-brain barrier, and enters brain cells mainly via a range of insulin-insensitive glucose transporters. Within the cell, glucose is phosphorylated by hexokinase, an enzyme of such high affinity towards glucose that the rate of glucose phosphorylation approximates the enzyme’s maximum reaction rate. Blood-brain glucose transfer obeys Michaelis-Menten kinetics, such that the glucose extraction fraction rises in hypoglycaemia and falls during hyperglycaemia. Insulin also crosses the blood brain barrier and binds to receptors on neurons and glial cells. There is controversy as to whether insulin resistance is present in the CNS, but emerging data suggests that insulin insensitivity may play an important role in the pathogenesis of obesity, type 2 diabetes, and Alzheimer’s disease. GLP-1 may also modulate cerebral glucose metabolism with neuroprotective effects in the presence of hyperglycaemia. Cerebral glucose metabolism Figure 1: [Click to enlarge] The Michaelis-Menten Meter is a graphical rendition of the Michaelis-Menten equation applied to transport across the blood-brain barrier in both directions, the difference between the fluxes being equal to the rate of glucose phosphorylation. In the three panels, the abscissa is the apparent permeability-surface area product or clearance of Continue reading >>
Fgf19 Action In The Brain Induces Insulin-independent Glucose Lowering. | Diabetes Research Centers
Animals, Brain, Diabetes Mellitus, Type 2, Fibroblast Growth Factors, Glucose, Glucose Tolerance Test, Injections, Intraventricular, Insulin, Male, Mice, Mice, Inbred C57BL, Mice, Obese, Mice, Transgenic, Models, Biological, Pro-Opiomelanocortin, Signal Transduction Insulin-independent glucose disposal (referred to as glucose effectiveness [GE]) is crucial for glucose homeostasis and, until recently, was thought to be invariable. However, GE is reduced in type 2 diabetes and markedly decreased in leptin-deficient ob/ob mice. Strategies aimed at increasing GE should therefore be capable of improving glucose tolerance in these animals. The gut-derived hormone FGF19 has previously been shown to exert potent antidiabetic effects in ob/ob mice. In ob/ob mice, we found that systemic FGF19 administration improved glucose tolerance through its action in the brain and that a single, low-dose i.c.v. injection of FGF19 dramatically improved glucose intolerance within 2 hours. Minimal model analysis of glucose and insulin data obtained during a frequently sampled i.v. glucose tolerance test showed that the antidiabetic effect of i.c.v. FGF19 was solely due to increased GE and not to changes of either insulin secretion or insulin sensitivity. The mechanism underlying this effect appears to involve increased metabolism of glucose to lactate. Together, these findings implicate the brain in the antidiabetic action of systemic FGF19 and establish the brains capacity to rapidly, potently, and selectively increase insulin-independent glucose disposal. Continue reading >>
Neuronal Control Of Peripheral Insulin Sensitivity And Glucose Metabolism
Neuronal control of peripheral insulin sensitivity and glucose metabolism Nature Communications volume 8, Articlenumber:15259 (2017) The central nervous system (CNS) has an important role in the regulation of peripheral insulin sensitivity and glucose homeostasis. Research in this dynamically developing field has progressed rapidly due to techniques allowing targeted transgenesis and neurocircuitry mapping, which have defined the primary responsive neurons, associated molecular mechanisms and downstream neurocircuitries and processes involved. Here we review the brain regions, neurons and molecular mechanisms by which the CNS controls peripheral glucose metabolism, particularly via regulation of liver, brown adipose tissue and pancreatic function, and highlight the potential implications of these regulatory pathways in type 2 diabetes and obesity. More than one third of the adult population is obese in many countries, including newly industrialized states, making obesity a global human health problem 1 . Obesity is often accompanied by insulin resistance (the condition when cells fail to respond to insulin) and glucose intolerance (the inability of cells to clear glucose from the blood stream after a glucose load), the prevalence of which are estimated to advance as the number of obese individuals continues to increase 2 . Obesity constitutes an important risk factor not only for the development of type 2 diabetes (T2D), but also for cardiovascular disease and even certain types of cancer, all of which ultimately reduce life expectancy 3 , 4 . Insulin resistance and glucose intolerance result in a disturbed glucose homeostasis, a state that describes the inability to maintain stable glucose levels (euglycemia). Maintenance of euglycemia is controlled via the tightly ba Continue reading >>
- Effects of resveratrol on glucose control and insulin sensitivity in subjects with type 2 diabetes: systematic review and meta-analysis
- Effects of resveratrol on glucose control and insulin sensitivity in subjects with type 2 diabetes: systematic review and meta-analysis
- Diagnostic accuracy of resting systolic toe pressure for diagnosis of peripheral arterial disease in people with and without diabetes: a cross-sectional retrospective case-control study
Insulin Resistance In Brain And Possible Therapeutic Approaches
Insulin Resistance in Brain and Possible Therapeutic Approaches Author(s): Sevki Cetinkalp , Ilgin Y. Simsir , Sibel Ertek . Department of Endocrinology and Metabolic Diseases, Ege University Medical School, 35100 Bornova- IZMIR- TURKEY. Journal Name: Current Vascular Pharmacology Although the brain has long been considered an insulin-independent organ, recent research has shown that insulinhas significant effects on the brain, where it plays a role in maintaining glucose and energy homeostasis. To avoid peripheralinsulin resistance, the brain may act via hypoinsulinemic responses, maintaining glucose metabolism and insulinsensitivity within its own confines; however, brain insulin resistance may develop due to environmental factors. Insulinhas two important functions in the brain: controlling food intake and regulating cognitive functions, particularly memory.Notably, defects in insulin signaling in the brain may contribute to neurodegenerative disorders. Insulin resistance maydamage the cognitive system and lead to dementia states. Furthermore, inflammatory processes in the hypothalamus,where insulin receptors are expressed at high density, impair local signaling systems and cause glucose and energymetabolism disorders. Excessive caloric intake and high-fat diets initiate insulin and leptin resistance by inducing mitochondrialdysfunction and endoplasmic reticulum stress in the hypothalamus. This may lead to obesity and diabetes mellitus(DM). Exercise can enhance brain and hypothalamic insulin sensitivity, but it is the option least preferred and/or continuouslypracticed by the general population. Pharmacological treatments that increase brain and hypothalamic insulinsensitivity may provide new insights into the prevention of dementia disorders, obesity, and type 2 DM Continue reading >>
Physiologic Effects Of Insulin
Stand on a streetcorner and ask people if they know what insulin is, and many will reply, "Doesn't it have something to do with blood sugar?" Indeed, that is correct, but such a response is a bit like saying "Mozart? Wasn't he some kind of a musician?" Insulin is a key player in the control of intermediary metabolism, and the big picture is that it organizes the use of fuels for either storage or oxidation. Through these activities, insulin has profound effects on both carbohydrate and lipid metabolism, and significant influences on protein and mineral metabolism. Consequently, derangements in insulin signalling have widespread and devastating effects on many organs and tissues. The Insulin Receptor and Mechanism of Action Like the receptors for other protein hormones, the receptor for insulin is embedded in the plasma membrane. The insulin receptor is composed of two alpha subunits and two beta subunits linked by disulfide bonds. The alpha chains are entirely extracellular and house insulin binding domains, while the linked beta chains penetrate through the plasma membrane. The insulin receptor is a tyrosine kinase. In other words, it functions as an enzyme that transfers phosphate groups from ATP to tyrosine residues on intracellular target proteins. Binding of insulin to the alpha subunits causes the beta subunits to phosphorylate themselves (autophosphorylation), thus activating the catalytic activity of the receptor. The activated receptor then phosphorylates a number of intracellular proteins, which in turn alters their activity, thereby generating a biological response. Several intracellular proteins have been identified as phosphorylation substrates for the insulin receptor, the best-studied of which is insulin receptor substrate 1 or IRS-1. When IRS-1 is activa Continue reading >>
Insulin And The Brain
In the Paleo world, we talk a lot about insulin and insulin resistance, and how diet affects metabolic health, diabetes, and other related diseases. But all that talk tends to be really focused on insulin in the bloodstream, and it ignores insulin in the brain. Insulin is one of the few chemicals that can cross the blood-brain barrier, and it’s important for appetite regulation, learning, and memory. Your brain can get insulin resistant just like your muscles or fat tissue, and insulin resistance in the brain is associated with weight gain and also degenerative brain diseases (like Alzheimer’s Disease). Insulin and the Brain Insulin is best-known as a carbohydrate storage hormone. If you eat something containing digestible carbohydrates, you’ll end up with higher blood sugar: more carbohydrates (glucose) in your bloodstream. In the long term, high blood sugar is dangerous. That glucose needs to get out of the bloodstream and preferably sooner rather than later. Enter insulin, which shuttles it off to muscle and/or fat cells as needed. It shouldn’t be surprising that insulin is important for your brain – the brain is the biggest glucose hog in your whole body. It’s the only organ that actually requires glucose. Everything else can run on fat if it has to, but for the brain, it’s glucose or bust. Even if you don’t eat any carbohydrate, your liver will turn protein into glucose (through a process called gluconeogenesis) to make sure your brain gets enough. Even if you don’t eat anything at all, your liver will break down your own muscle tissue to get protein to make glucose for your brain. This review goes over some of the major points about insulin and the brain. Unlike most substances, insulin can pass fairly easily between the bloodstream and the brain Continue reading >>
Is The Brain Affected In Diabetes Mellitus?
Didi....This is a very good question because the impact of diabetes on the brain is actually overlooked. Theoretically, one can say that since diabetes affects so many organs in the body, therefore, it might affect the brain as well. Practically speaking, it has been shown that chronic hyperglycemia leads to the release of mediators that cause chronic brain inflammation, reduce blood flow and damage the cells. In fact hyperglycemia raises the risk of having dementia and depression. The chances of becoming depressed or getting dementia increases when diabetes complications develop and decreases in diabetic people with good blood sugar control. Besides, cardiovascular complications could contribute to stroke by blocking the blood flow to the brain. Another way in which diabetes can affect the brain is ketoacidosis, that occurs most likely in Type I diabetes, where the brain cannot handle the excessive amounts of ketone bodies. We must not forget that hypoglycemia, resulting from an overdose of antidiabetic drugs, leads to hypoglycemic coma. Continue reading >>