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Which Tissues Are Insulin Dependent For Glucose Uptake? Is The Brain One Of Them?

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[1]. There’s a section titled ‘Sites of Insulin Action and Manifestations of Insulin Resistance’ that I would encourage the Continue reading >>

New Insulins And Newer Insulin Regimens: A Review Of Their Role In Improving Glycaemic Control In Patients With Diabetes

New Insulins And Newer Insulin Regimens: A Review Of Their Role In Improving Glycaemic Control In Patients With Diabetes

The legacy effect of early good glycaemic control in people with diabetes shows it is associated with reduction of microvascular and macrovascular complications. Insulin therapy is essential and lifesaving in individuals with type 1 diabetes and beneficial for those with type 2 diabetes who fail to achieve optimal glycaemic targets with other classes of glucose-lowering therapies. Since the introduction of insulin analogues, insulin management has changed. This follow-up review attempts to update our earlier publication from 2009 and discusses the role of new insulin analogues and newer insulin regimens. Recognising the advent of new quality and economic initiatives both in the UK and worldwide, this paper reviews current insulin prescribing and the pros and cons of prescribing analogues in comparison to the human insulins that are now gaining more acceptance in everyday clinical practice. Continue reading >>

Is It True That Insulin Makes You Age Faster Or Is It Just More Dieting Mumbo Jumbo?

Is It True That Insulin Makes You Age Faster Or Is It Just More Dieting Mumbo Jumbo?

Yes. In fact, calorie restriction induces a reduction in the insulin signalling pathways (both through IGF-I and insulin), and this reduction in insulin signalling pathways is thought to be one of the primary mechanisms through which calorie restriction acts to increase lifespan. High blood insulin levels are usually the result of high blood glucose levels. So high levels of insulin signalling are a signal of high "nutritional state", and shift a cell's internal state towards increased levels of growth and decreased levels of repair. Increases in growth and decreases in repair = increases in waste products that accumulate within a cell and that ultimately cause aging at the cellular level. An increase in insulin levels usually causes an increases in protein synthesis and decreases in both proteolysis and autophagy through the pathway diagrammed below [1]. This is bad, as this will effectively increase the number of misfolded proteins that fail to degrade (one major factor in aging rate). In fact, decreased protein synthesis and increased autophagy are both associated with increased lifespan (Page on Nih, Protein translation, 2007. ). (figure from ) For a summary of its physiological effects, see Insulin stimulates mTOR, and inhibition of mTOR by rapamycin is associated with the anti-aging effects of rapamycin (see Mammalian target of rapamycin and mTOR is a key modulator of ageing and age-related disease ). As a secondary pathway (see pathway below), insulin also inhibits FOXO1, and FOXO1 is involved in cellular stress resistance. Increased activity of the C. elegans homologue of FOXO1 (daf-16) is required for the 2x life extension caused by reducing IGF1 signalling through mutation of daf-2 (the C. elegans analogue of the IGF1 receptor - see Publications ). (figure fro Continue reading >>

Insulin And Insulin Resistance

Insulin And Insulin Resistance

Go to: Abstract As obesity and diabetes reach epidemic proportions in the developed world, the role of insulin resistance and its consequences are gaining prominence. Understanding the role of insulin in wide-ranging physiological processes and the influences on its synthesis and secretion, alongside its actions from the molecular to the whole body level, has significant implications for much chronic disease seen in Westernised populations today. This review provides an overview of insulin, its history, structure, synthesis, secretion, actions and interactions followed by a discussion of insulin resistance and its associated clinical manifestations. Specific areas of focus include the actions of insulin and manifestations of insulin resistance in specific organs and tissues, physiological, environmental and pharmacological influences on insulin action and insulin resistance as well as clinical syndromes associated with insulin resistance. Clinical and functional measures of insulin resistance are also covered. Despite our incomplete understanding of the compl Continue reading >>

Advances In Insulin Therapy: A Review Of New Insulin Glargine 300 Units/ml In The Management Of Diabetes

Advances In Insulin Therapy: A Review Of New Insulin Glargine 300 Units/ml In The Management Of Diabetes

In Brief New insulin glargine 300 units/mL (Gla-300) is a formulation of insulin glargine that has a more constant pharmacokinetic profile with a prolonged duration of action. The EDITION clinical trial program showed that the use of Gla-300 leads to glycemic control comparable to that of insulin glargine 100 units/mL in a wide range of populations of people with diabetes. It is associated with comparable to less nocturnal confirmed or severe hypoglycemia and less weight gain, despite requiring a somewhat higher insulin dose than U-100. The distinct pharmacokinetic/pharmacodynamic and clinical profiles of Gla-300 may benefit a range of people with type 1 or type 2 diabetes. The use of long-acting basal insulin analogs has contributed significantly to improvements in diabetes management over the past decade. Their longer duration of action, with a less distinct peak of action compared to NPH insulin, results in improved glycemic control and an associated reduction in hypoglycemia (1–6). The reduction in hypoglycemia seen with the long-acting basal insulins is important both in terms of clinical outcomes and in addressing patients’ and clinicians’ fears of hypoglycemia, which may affect both willingness to initiate or titrate insulin therapy and patient adherence to treatment (7). The long-term safety of long-acting insulin glargine 100 units/mL (Gla-100) is also well established (8), and this formulation has been shown to have a neutral effect on cardiovascular outcomes and cancer (9,10). Recently, newer basal insulins have been developed that have an even longer duration of action with less variation in blood glucose control, and with these there has been a trend toward a reduction in nocturnal hypoglycemia. These new basal insulins include insulin degludec (11– Continue reading >>

Is There Any Scientific Basis To Suggest That The Paleo Diet Is Actually Healthy?

Is There Any Scientific Basis To Suggest That The Paleo Diet Is Actually Healthy?

The paleo diet is actually one of the few diets that is based on science. Few (if any) paleo adherents are preaching a literal, "live like a caveman" type of dogma. The paleo lifestyle is about living in a way that is optimal for the modern human animal, viewed through the lens of evolution. The "caveman" thing is the straw-man that haters use to throw the baby out with the bathwater. Over the past few years, there has been an increasing amount of studies. If you search for "paleo" or "ancestral" in pub-med you will find a large number of recent studies linking paleo diets with reduced inflammation, blood pressure, lipid profile and glucose tolerance, non-alcoholic fatty liver disease, weight loss, etc. Gary Taubes and Dr. Peter Attia have created NuSci.org, a non-profit to conduct even more studies on the subject. Part of the caveman straw-man is that "because much of the food our ancestors ate doesn't exist anymore, its impossible to REALLY eat a paleo diet." Nobody argues that the animals and plants in existence now are the same as they were 10,000 years ago. In fact, most of the plants and animals available now aren't the same as they were 50 years ago due to factory farming and mono-crop agriculture. This is why the paleo lifestyle encourages finding the highest quality, most nutritious food you can. Grass-fed meats, wild-caught fish, organic fruits and vegetables, etc. And if you can't afford, or can't find it, that's OK. Don't let perfect be the enemy of the good. I think the cartoon that Craig posted as part of his "answer" says more about his ignorance than it does the Paleo Diet. To think that prehistoric humans dropped dead at 30 is preposterous. That's the AVERAGE age of prehistoric man, which was abnormally low due to high rates of infant mortality and the Continue reading >>

A Review Of Insulin Errors

A Review Of Insulin Errors

This week we have a review adapted from information provided by Novo Nordisk of the most common insulin errors which include: Clinician errors Self-administration errors Self-monitoring errors Improper insertion techniques Bad drawing-up procedure Insulin timing Using the wrong insulin Miscalculating insulin sensitivity factor Using an incorrect carbohydrate ratio Not checking blood glucose 2hrs after injection Beware: half of all dosage errors are among the age 60 and older population. The U.S. Pharmacopeia Medication Errors Reporting Program states that approximately 50 percent of all medication errors involve insulin. As the incidence of diabetes increases, insulin use can reasonably be expected to increase and the mistakes will no doubt increase as well. Insulin is a very powerful medication, and some of these mistakes will require the ambulance, the hospital, or worse. Insulin manufacturer Novo Nordisk (the source of much of this information) estimates that morbidity and mortality rates resulting from medication errors add an estimated $1,900 per patient to total U.S. health care costs and remember, about half of that is mistakes with insulin. Divided among all insulin-using diabetics, rather than "all patients," the figure will be far higher. What kind of mistakes do we see? There are clinician errors, self-administration errors, and self-monitoring errors. Insulin is the single most frequently mis-prescribed medication — everything from ill-written orders, poorly labeled vials, to incorrect rates programmed into an insulin pump. But if the doctor errs, the patient isn’t far behind. What about maintaining dose accuracy? A "grave error," defined as a deviation of more than 15 percent above or below the intended dose, can result from confusing instructions, inad Continue reading >>

Clinical Considerations For Insulin Pharmacotherapy In Ambulatory Care, Part Two: Review Of Primary Literature And An Evidence-based Approach For Treatment

Clinical Considerations For Insulin Pharmacotherapy In Ambulatory Care, Part Two: Review Of Primary Literature And An Evidence-based Approach For Treatment

IN BRIEF This article reinforces the dosing guidance from the package inserts of available insulin products and supplemental information provided by the manufacturers of insulin products. It reviews and evaluates pertinent primary literature detailing algorithms for the initiation and titration of insulin therapy that have helped to shape current clinical practice guidelines. The article discusses the clinical applicability of the evidence on insulin pharmacotherapy and offers recommendations for initiation and titration of various insulin products for insulin-requiring people with type 2 diabetes in the ambulatory care setting. EDITOR’S NOTE: This is the second of a two-article series. The first, “Clinical Considerations for Insulin Pharmacotherapy in Ambulatory Care, Part One: Introduction and Review of Current Products and Guidelines,” was published in an earlier issue (Clinical Diabetes 2014;32:66–75). As discussed in part one of this series, the majority of current treatment guidelines for type 2 diabetes lack prescriptive recommendations for insulin titration beyond the weeks after insulin initiation; the exception is the 2013 American Association of Clinical Endocrinologists (AACE) algorithm and consensus statement (1–5). Furthermore, package inserts for available products offer little guidance with regard to insulin titration (6–21), and, although dosing information is available for some insulin preparations based on clinical trial data, it is not universally implemented in practice. However, a comprehensive review of insulin therapy published in the Journal of the American Medical Association in June 2014 reviewed the available literature and proposed an algorithm for insulin dosing (22). Although an individualized, patient-centered approach is esse Continue reading >>

A Review Of Insulin For The Treatment Of Diabetes Mellitus.

A Review Of Insulin For The Treatment Of Diabetes Mellitus.

Abstract Insulin is commonly used in the treatment of diabetes in the home care setting. Understanding the wide variety of insulin preparations available will assist the clinician in guiding people with diabetes and their caregivers through the complexities of self-care and promote safe and optimal glucose control. The purpose of this article is to review the various available insulin preparations and discuss their use in the treatment of diabetes mellitus. Continue reading >>

Does The Body Generate Insulin In Response To Artificial Sweeteners? In The Event That It Does, What Happens To The Insulin?

Does The Body Generate Insulin In Response To Artificial Sweeteners? In The Event That It Does, What Happens To The Insulin?

'Does the body generate insulin in response to artificial sweeteners? In the event that it does, what happens to the insulin?'. This answer summarizes Key takeaways from some human observational studies and clinical trials on insulin response to artificial sweeteners (AS). Caveats to nutrition science data: In general as well as particulars that apply to human AS studies. Key Takeaways from some Human Observational Studies and Clinical Trials on Insulin Response to AS Responses tend to be different between healthy lean adults compared to obese and/or diabetic individuals. Caveat: many studies examined different groups of individuals, some only lean and healthy, others only obese or diabetic, etc. Responses tend to be different between type I and type II diabetics. Caveat: few studies examined both type I and II diabetes. Compared to lean and healthy, those prone to weight gain and/or diabetes tend to regularly consume AS to minimize calorie intake. Chicken and egg problem: Do observed differences ensue from underlying health issues or does regular AS consumption precipitate and/or exacerbate underlying health issues? Considering such daunting hurdles, a systematic 2016 review still cautiously concluded AS had some effect on glucose metabolism (See below from 1, emphasis mine). 18 of 28 clinical trials included in the review assessed AS effect on insulin and 8 (44%) found statistically significant (+/-) effects. Clearly, AS aren't 'inert' as they were long presumed. 'Twenty-eight clinical trials studying different effects of NNS [non-nutritive sweetener] were identified. Of these studies, 10 found significant effects on some or all the studied variables. All of these studies have analyzed glucose and most of them have measured insulin concentrations, 11 quantified GLP-1 Continue reading >>

Who Is Managing Type 1 Diabetes Holistically Without Medication?

Who Is Managing Type 1 Diabetes Holistically Without Medication?

When I was diagnosed with type 1 diabetes at the age of 22, I asked that exact same question. The year was 2002, and no matter where I turned, all signs pointed towards eating a low-carbohydrate diet as the only solution to managing blood glucose and insulin use in type 1 diabetes. So began my journey into understanding the optimal diet for people living with type 1 diabetes, type 1.5 diabetes, pre diabetes, type 2 diabetes and gestational diabetes. At the age of 22, I was the first to admit that I didn’t know anything about diabetes, only that it had something to do with old people and chocolate cake. For the first time in my life, I was faced with a series of challenging questions for which I had no answers: How do I inject insulin? How much insulin do I need? How often should I inject insulin? What is an appropriate amount of insulin? What are the dangers of too much insulin? What are the dangers of too little insulin? What should I eat to control my blood glucose? What should I NOT eat? When should I eat? Can I still exercise? How much should I exercise? What happens if I don't eat? What's going to happen to me in 5 years? 10 years? 20 years? Am I destined for a heart attack? Am I going to gain weight on a low-carbohydrate diet? Plagued with chronically high blood glucose, excessive thirst, low energy, bad breath and constant anxiety, I listened to everything that my doctors and nutritionist told me at the time. Without reservation, they recommended that I eat a low-carbohydrate diet, because that was “the only way to manage blood glucose.” So I did. I minimized my carbohydrate intake, and did my best to avoid fruits, breads, cereals, pastas and rice. Instead, I increased my intake of foods containing fat and protein, including peanut butter, cheese, milk, fis Continue reading >>

Review Of Basal-plus Insulin Regimen Options For Simpler Insulin Intensification In People With Type 2 Diabetes Mellitus

Review Of Basal-plus Insulin Regimen Options For Simpler Insulin Intensification In People With Type 2 Diabetes Mellitus

Abstract To identify simple insulin regimens for people with Type 2 diabetes mellitus that can be accepted and implemented earlier in primary and specialist care, taking into consideration each individual's needs and capabilities. Methods Using randomized clinical trials identified by a search of the PubMed database, as well as systematic reviews, meta-analyses and proof-of-concept studies, this review addresses topics of interest related to the progressive intensification of a basal insulin regimen to a basal-plus regimen (one basal insulin injection plus stepwise addition of one to three preprandial short-acting insulin injections/day) vs a basal-bolus regimen (basal insulin plus three short-acting insulin injections per day) in people with Type 2 diabetes. The review explores approaches that can be used to define the meal for first prandial injection with basal-plus regimens, differences among insulin titration algorithms, and the importance of self-motivation and autonomy in achieving optimum glycaemic control. A basal-plus regimen can provide glycaemic control equivalent to that obtained with a full basal-bolus regimen, with fewer injections of prandial insulin. The first critical step is to optimize basal insulin dosing to reach a fasting glucose concentration of ~6.7 mmol/l; this allows ~40% of patients with baseline HbA1c >75 mmol/mol (9%) to be controlled with only one basal insulin injection per day. Compared with a basal-bolus regimen, a basal-plus insulin regimen is as effective but more practical, and has the best chance of acceptance and success in the real world. Continue reading >>

How Do I Know If I Have Insulin Resistance Using My Glucose Curve Results?

How Do I Know If I Have Insulin Resistance Using My Glucose Curve Results?

From the values you have, it appears that you don’t have significant insulin resistance. Several indices can be calculated which look at the relationship between glucose levels and the amount of insulin in your blood. Insulin resistance is said to exist when your body needs to produce more insulin than usual to bring down your blood glucose. By comparing these indices with known normal values, we can tell whether your body has normal insulin sensitivity(a measure of how well your insulin does its job). It is important to note that insulin resistance is not an all or none phenomenon - think of it as a spectrum from good insulin sensitivity to poor insulin sensitivity (aka insulin resistance). Some important IR indices calculated from your blood glucose and insulin values are HOMA -1R = 1.96 (less than 2.5 is normal) Matsuda index - 6.62 ( whole body insulin resistance if less than 2.5) QUICKI index -0.35 Insulinogenic index - 1.9 ( defect in insulin secretion if less than 0.4) Several web based calculators are available for calculating these indices and for health professionals downloading the excel file may be useful. A couple of such online calculators can be accessed at For a more detailed review of how insulin resistance is assessed,( for health care professionals), you can see my presentation below. Continue reading >>

What Is The Mechanism Of Action In The Treatment Of Diabetes?

What Is The Mechanism Of Action In The Treatment Of Diabetes?

Insulin therapy is necessary for type 1 diabetics because they have an absolute insulin deficiency due to the autoimmune destruction of the pancreatic beta cells. Insulin therapy is also used in treating type 2 diabetes. As the disease advances, many type 2 diabetics will require insulin therapy, because the beta cells are damaged by hyperglycemia, and patients develop significant defects in insulin secretion. These drugs bind to and block the ATP-sensitive K+ channel on pancreatic beta cells, causing depolarization and increased insulin secretion (review Humoral Regulation). These drugs improve glycemic control, but patients taking them tend to gain weight. Sulfonylureas (glyburide, glimepiride) are older drugs and less expensive. A potential problem is that they can induce too much insulin secretion and hypoglycemia can result. The meglitinides (repaglinide, nateglinide) are newer drugs that are designed to avoid this problem. They have a shorter half-life, and are taken at mealtimes to enhance insulin secretion and prevent postprandial hyperglycemia. Incretins are gastrointestinal hormones that increase insulin secretion (review Incretins). GLP-1 agonists are peptide drugs with a longer half-life than the native hormone because they are resistant to digestion by the protease DPP-4. DPP-4 inhibitors (“gliptins”) prolong the action of native incretins. DPP-4 inhibitors are less effective at lowering HbA1c than GLP-1 agonists, but an advantage is that they are oral drugs. GLP-1 agonists have the added benefit of inducing weight loss (several kilograms, depending upon the length of treatment). The mechanism is thought to be that GLP-1 delays stomach emptying into the small intestine, causing patients to eat less because they feel full sooner. These drugs improve insu Continue reading >>

Pursuit Of A Perfect Insulin

Pursuit Of A Perfect Insulin

Insulin remains indispensable in the treatment of diabetes, but its use is hampered by its narrow therapeutic index. Although advances in peptide chemistry and recombinant DNA-based macromolecule synthesis have enabled the synthesis of structurally optimized insulin analogues, the growing epidemics of obesity and diabetes have emphasized the need for diabetes therapies that are more efficacious, safe and convenient. Accordingly, a broad set of drug candidates, targeting hyperglycaemia plus other disease abnormalities, is now progressing through the clinic. The development of an insulin therapy that is responsive to glucose concentration remains an ultimate goal, with initial prototypes now reaching the proof-of-concept stage. Simultaneously, the first alternatives to injectable delivery have progressed to registration. Home, P. et al. Insulin therapy in people with type 2 diabetes: opportunities and challenges? Diabetes Care 37, 1499–1508 (2014). A panel of specialists provides guidelines to initiating insulin therapy in the context of recent findings and novel treatment options. Gough, S. C. et al. One-year efficacy and safety of a fixed combination of insulin degludec and liraglutide in patients with type 2 diabetes: results of a 26-week extension to a 26-week main trial. Diabetes Obes. Metab. 17, 965–973 (2015). This extended clinical study underscores the benefits of combination therapy of insulin with GLP1 analogues. Vora, J. & Heise, T. Variability of glucose cowering effect as a limiting factor in optimizing basal insulin therapy: a review. Diabetes Obes. Metab. 15, 701–712 (2013). The identification of inter-and intra-patient variability as the major issue of the current insulin therapies and establishing it as a primary consideration for future treatments Continue reading >>

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