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Insulin Resistance and Heart Disease

See also Carahealth Blood Sugar

Insulin resistance (IR) is the condition in which normal amounts of insulin are inadequate to produce a normal insulin response from fat, muscle, and liver cells.

  • Insulin resistance in fat cells results in elevated hydrolysis (breakdown) of stored triglycerides. These results in increased triglycerides in the blood know as hypertriglycerydaemia, which is a risk factor for heart disease.
  • Insulin resistance in muscle cells reduces glucose uptake by the muscles to be stored as glycogen.
  • Insulin resistance in liver cells results in impaired glycogen synthesis also.
  • All these factors lead to elevated blood glucose levels known as hyperglycaemia which is linked to metabolic syndrome and type 2 diabetes, a global pandemic.

Symptoms of Insulin Resistance

1. Fatigue. Many people with insulin resistance get sleepy immediately after eating a meal containing more than 20% or 30% carbohydrates

2. Brain Fag. Sometimes the fatigue is physical, but often it is mental.

3. High blood sugar.

4. Intestinal bloating. Most intestinal gas is produced from carbohydrates in the diet.

5. Decreased synthesis of hydrochloric acid by the stomach (hypochlorydria).

6. Weight gain, fat storage, and difficulty losing weight. Central obesity.

7. Increased blood triglyceride levels.

8. Increased blood pressure.Many people with hypertension are either diabetic or pre-diabetic. Insulin forces arterial wall muscle to relax (vasodilation) so in insulin resistance, the arterial wall muscles to contract (vasodilation)

9. Depression. Because of the deranged metabolism resulting from insulin resistance, psychological effects are not uncommon. Depression is said to be the prevalent psychological symptom.

Pathophysiology

In a person with normal metabolism, insulin is released from the beta (β) cells of the Islets of Langerhans located in the pancreas after eating ("postprandial"), which signals insulin-sensitive tissues in the body (e.g., muscle, adipose (fat cells)) to absorb glucose. This lowers blood glucose levels. The beta cells reduce their insulin output as blood glucose levels fall, with the result that blood glucose is maintained at approximately 5 mmol/L (mM) (90 mg/dL). In an insulin-resistant person, normal levels of insulin do not have the same effect on muscle and adipose cells, with the result that glucose levels stay higher than normal. To compensate for this, the pancreas in an insulin-resistant individual is stimulated to release more insulin.

When Insulin resistance leads to Type 2 Diabetes

The most common type of insulin resistance is associated with a collection of symptoms known as metabolic syndrome. Insulin resistance can progress to full type 2 diabetes. This is often seen when hyperglycaemia develops after a meal, when pancreatic β-cells are unable to produce sufficient insulin to maintain normal blood sugar levels (euglycaemia). The inability of the β-cells to produce sufficient insulin in a condition of hyperglycaemia is what characterises the transition from insulin resistance to type 2 diabetes.[1]

Other Contributing Factors

Various disease states make the body tissues more resistant to the actions of insulin. Examples include infection (mediated by the cytokine TNFα) and acidosis. Recent research is investigating the roles of adipokines (the cytokines produced by adipose tissue) in insulin resistance. Certain drugs may also be associated with insulin resistance (e.g., glucocorticoids). Insulin itself can lead to insulin resistance; every time a cell is exposed to insulin, the production of GLUT4 (type four glucose receptors) on the cell's membrane is decreased.[2] This leads to a greater need for insulin, which again leads to fewer glucose receptors. Exercise reverses this process in muscle tissue,[3] but if left unchecked, it can spiral into insulin resistance. Insulin resistance is often found in people with visceral adiposity (i.e., a high degree of fatty tissue underneath the abdominal muscle wall - as distinct from subcutaneous adiposity or fat between the skin and the muscle wall, especially elsewhere on the body, such as hips or thighs), hypertension, hyperglycaemia and dyslipidaemia involving elevated triglycerides, small dense low-density lipoprotein (sdLDL) particles, and decreased HDL cholesterol levels.

Visceral adiposity and insulin resistance

With respect to visceral adiposity, a great deal of evidence suggests two strong links with insulin resistance. Firstly, unlike subcutaneous adipose tissue, visceral adipose cells produce significant amounts of proinflammatory cytokines such as tumour necrosis factor-alpha (TNF-a), and Interleukins-1 and -6, etc. In numerous experimental models, these proinfammatory cytokines profoundly disrupt normal insulin action in fat and muscle cells, and may be a major factor in causing the whole-body insulin resistance observed in patients with visceral adiposity.

Secondly, visceral adiposity is related to an accumulation of fat in the liver, a condition known as nonalcoholic fatty liver disease (NAFLD). The result of NAFLD is an excessive release of free fatty acids into the bloodstream (due to increased lipolysis, the breakdown of fats), and an increase in hepatic glucose production, both of which have the effect of exacerbating peripheral insulin resistance and increasing the likelihood of type-2 diabetes. Insulin resistance is also often associated with a hypercoagulable state (impaired fibrinolysis) and increased inflammatory cytokine levels.

Insulin and Magnesium

Magnesium (Mg) is present in living cells and its plasma concentration is remarkably constant in healthy subjects. Plasma and intracellular Mg concentrations are tightly regulated by several factors. Among them, insulin seems to be one of the most important. In vitro and in vivo studies have demonstrated that insulin may modulate the shift of Mg from extracellular to intracellular space. Intracellular Mg concentration has also been shown to be effective in modulating insulin action (mainly oxidative glucose metabolism), offset calcium-related excitation-contraction coupling, and decrease smooth cell responsiveness to depolarising stimuli.

A poor intracellular Mg concentration, as found in noninsulin-dependent diabetes mellitus (NIDDM) and in hypertensive patients, may result in a defective tyrosine-kinase activity at the insulin receptor level and exaggerated intracellular calcium concentration. Both events are responsible for the impairment in insulin action and a worsening of insulin resistance in noninsulin-dependent diabetic and hypertensive patients.

By contrast, in NIDDM patients daily Mg administration, restoring a more appropriate intracellular Mg concentration, contributes to improve insulin-mediated glucose uptake. The benefits deriving- from daily Mg supplementation in NIDDM patients are further supported by epidemiological studies showing that high daily Mg intake are predictive of a lower incidence of NIDDM. A fasting serum insulin level of greater than the upper limit of normal for the assay used (approximately 60 pmol/L) is considered evidence of insulin resistance.

Measuring Insulin Resistance

Glucose tolerance testing (GTT)

During a glucose tolerance test, which may be used to diagnose diabetes mellitus, a fasted patient takes a 75 gram oral dose of glucose. Blood glucose levels are then measured over the following 2 hours. Interpretation is based on WHO guidelines. After 2 hours a Glycemia less than 7.8 mmol/L is considered normal, a glycaemia of between 7.8 to 11.0 is considered as Impaired Glucose Tolerance (IGT) and a glycaemia of greater than or equal to 11.1 is considered Diabetes Mellitus. An OGTT can be normal or mildly abnormal in simple insulin resistance. Often, there are raised glucose levels in the early measurements, reflecting the loss of a postprandial (after the meal) peak in insulin production. Extension of the testing (for several more hours) may reveal a hypoglycemic "dip," which is a result of an overshoot in insulin production after the failure of the physiologic postprandial insulin response.

Hyperinsulinemic euglycaemic clamp

The gold standard for investigating and quantifying insulin resistance is the "hyperinsulinemic euglycemic clamp," so-called because it measures the amount of glucose necessary to compensate for an increased insulin level without causing hypoglycemia.[4] The test is rarely performed in clinical care, but is used in medical research, for example, to assess the effects of different medications. The rate of glucose infusion is commonly referred to in diabetes literature as the GINF value. The procedure takes about 2 hours. Through a peripheral vein, insulin is infused at 10-120 mU per m2 per minute. In order to compensate for the insulin infusion, glucose 20% is infused to maintain blood sugar levels between 5 and 5.5 mmol/l. The rate of glucose infusion is determined by checking the blood sugar levels every 5 to 10 minutes. Low-dose insulin infusions are more useful for assessing the response of the liver, whereas high-dose insulin infusions are useful for assessing peripheral (i.e., muscle and fat) insulin action. The rate of glucose infusion during the last 30 minutes of the test determines insulin sensitivity. If high levels (7.5 mg/min or higher) are required, the patient is insulin-sensitive. Very low levels (4.0 mg/min or lower) indicate that the body is resistant to insulin action. Levels between 4.0 and 7.5 mg/min are not definitive and suggest "impaired glucose tolerance," an early sign of insulin resistance.

Causes of insulin resistance

The cause of the vast majority of cases of insulin resistance remains unknown. There is clearly an inherited component, as sharply increased rates of insulin resistance and Type 2 diabetes are found in those with close relatives who have developed Type 2 diabetes. However, there are some grounds for suspecting that insulin resistance is related to a high-carbohydrate diet. Insulin resistance has also been linked to PCOS (polycystic ovary syndrome) as either causing it or being caused by it. Further studies are in progress.

Insulin Resistance and Sugar

Other studies have also linked to the increased amounts of fructose (e.g., in HFCS - high fructose corn syrup, currently the least expensive nutritive sweetener available in industrial quantities); in humans, fructose causes changes in blood lipid profiles, among other things, mostly due to its effects on liver function. The high amounts of ordinary sucrose (i.e., table sugar) in the typical developed-world diet is also suspected of having some causative effect on the development of insulin resistance (sucrose is 1/2 fructose, which may account for the effect, if any). Insulin resistance has certainly risen in step with the increase in sugar consumption and the substantial commercial usage of HFCS since its introduction to the food trades.

Hyperinsulinaemia and Insulin Resistance

At the cellular level, excessive circulating insulin appears to be a contributor to insulin resistance via down-regulation of insulin receptors. This occurs due to prolonged and repeated elevations of circulating insulin.[7] Since the usual instances of Type 2 insulin resistance are distinct from pathological over production of insulin, this does not seem to be the typical cause of the insulin resistance leading to Type 2 diabetes mellitus, the largest clinical issue connected with insulin resistance. The presence of insulin resistance typically precedes the diagnosis of Types 2 diabetes mellitus, however, and as elevated blood glucose levels are the primary stimulus for insulin secretion and production, habitually excessive carbohydrate intake is a likely contributor.

Inflammation and Insulin Resistance

Inflammation also seems to be implicated in causing insulin resistance. Mice without JNK1-signaling do not develop insulin resistance under dietary conditions that normally produce it.[8][9] Vitamin D deficiency is also associated with insulin resistance.[10] Some research has shed light on a complex interaction between elevated free fatty acids and inflammatory cytokines seen in obesity activating Protein Kinase C isoform theta. PKC Theta inhibits Insulin Receptor Substrate (IRS) activation and hence prevents glucose up-take in response to insulin.

Future Research Potential

Recent research and experimentation has uncovered a non-obesity related connection to insulin resistance and Type 2 diabetes. It has long been observed that patients who have had some kinds of bariatric surgery have increased insulin sensitivity and even remission of Type 2 diabetes. It was discovered that diabetic / insulin resistant non obese rats whose proximal small intestine and duodenum has been surgically removed also experienced increased insulin sensitivity and remission of Type 2 diabetes. This suggested similar surgery in humans, and early reports in prominent medical journals (January 08) are that the same effect is seen in humans, at least the small number who have participated in the experimental surgical program. The speculation is that some substance is produced in that portion of the small intestine which signals body cells to become insulin resistant. If the producing tissue is removed, the signal ceases and body cells revert to normal insulin sensitivity. No such substance has been found as yet, so its existence remains speculation.

Associated Conditions

Several associated conditions include

* Abnormally Sedentary Lifestyle, whether the result of the effects of aging on the body or lack of physical exercise (both of which can also produce obesity)

* Haemochromatosis

* Polycystic ovarian syndrome(PCOS)

* Hypercortisolism (e.g., steroid use or Cushing's disease)

* Drugs (e.g., rifampicin, isoniazid, olanzapin, risperidone, progestogens, many antiretrovirals, possibly alcohol[11], methadone)

* Genetic causes

o Insulin receptor mutations (Donohue Syndrome)

o LMNA mutations (Familial Partial Lipodystrophy) Insulin resistance may also be caused by the damage of liver cells having undergone a defect of insulin receptors in hepatocytes.

Treatment

The primary treatment for insulin resistance is exercise and weight loss. Low-glycemic index or low-carbohydrate diets have also been shown to help.[12] Both metformin and the thiazolidinediones improve insulin resistance, but are only approved therapies for type 2 diabetes, not insulin resistance, per se. By contrast, growth hormone replacement therapy may be associated with increased insulin resistance.[13] Metformin has become one of the more commonly prescribed medications for insulin resistance, and currently a newer drug, exenatide (marketed as Byetta), is being used. Exenatide has not been approved except for use in diabetics, but often improves insulin resistance by the same mechanism as it does diabetes. It also has been used to aid in weight loss for diabetics and those with insulin resistance, and is being studied for this use as well as for weight loss in people who have gained weight while on antidepressants.

The Diabetes Prevention Program showed that exercise and diet were nearly twice as effective as metformin at reducing the risk of progressing to type 2 diabetes.[14]

Many people with insulin resistance currently follow the lead of some diabetics, and add cinnamon in therapeutic doses to their diet to help control blood sugar. This has the danger of increasing the risk of bleeding, since most commercial cinnamon preparations are actually from cassia, which also has anticoagulants, though true cinnamon cinnamomum sp. zeylonicum, or sp. verum, does not.

Some types of Monounsaturated fatty acids and saturated fats appear to promote insulin resistance, whereas some types of polyunsaturated fatty acids (omega-3 can increase insulin sensitivity.[15][16][17] There are scientific studies showing that vanadium (e.g., as vanadyl sulfate) and chromium (e.g., in chromium picolinate and GTF formulations) in reasonable doses have reportedly also shown some efficacy in improving IR sensitivity, but these effects are controversial.

Naturopathic approaches to insulin resistance have been advocated including supplementation of vanadium (but see preceding paragraph), bitter melon (Momordica, but reportedly dangerous if not used with care), and Gymnema sylvestre.[18]

One study found that chromium is necessary for maintaining normal glucose tolerance.[19]

Daily Mg administration, restoring an appropriate intracellular Mg concentration, contributes to improve insulin-mediated glucose uptake. High daily Mg intake are predictive of a lower incidence of NIDDM.

Herbal Medicine

Herbal medicine is effective in reducing blood sugar and imroving insulin sensitivity without side effects.

 

For a full explanation of herbal medicines to treat blood sugar imbalace please see Carahealth Blood Sugar.

For a full naturopathic approach to treat metabolic syndrome please see also Natural Alternatives to the Antidiabetic Drug Avandia

1. McGarry J (2002). "Banting lecture 2001: dysregulation of fatty acid metabolism in the etiology of type 2 diabetes". Diabetes 51 (1): 7-18. doi:10.2337/diabetes.51.1.7. PMID 11756317

2. J R Flores-Riveros (1993). Insulin down-regulates expression of the insulin-responsive glucose transporter (GLUT4) gene: effects on transcription and mRNA turnover. 90. pp. 512-516.

3. Paul S. MacLean_2002 (2002). "Exercise-Induced Transcription of the Muscle Glucose Transporter (GLUT 4) Gene". Biochemical and Biophysical Research Communications 292 (2): 409-414. doi:10.1006/bbrc.2002.6654.

4. DeFronzo R, Tobin J, Andres R (1979). "Glucose clamp technique: a method for quantifying insulin secretion and resistance". Am J Physiol 237 (3): E214-23. PMID 382871

5. Wallace T, Levy J, Matthews D (2004). "Use and abuse of HOMA modeling". Diabetes Care 27 (6): 1487-95. doi:10.2337/diacare.27.6.1487 PMID 15161807.

6. Pham, T; Cornea A; Blick KE; Jenkins A; Scofield RHMD (2007). "Oral Glucosamine in Doses Used to Treat Osteoarthritis Worsens Insulin Resistance".. The American Journal of the Medical Sciences 333 (6): 333-339. doi:10.1097/MAJ.0b013e318065bdbe. PMID 17570985 http://www.amjmedsci.com/pt/re/ajms/fulltext.00000441-200706000-00003.htm. Retrieved on 2007-11-11.

7. Jeff Unger. "Intensive Management of Type 2 Diabetes", Emergency Medicine. http://www.emedmag.com/html/pre/fea/features/101501.asp. Retrieved on 2008-01-13.

8. Solinas Giovanni et al (2007-11-07). "JNK1 in Hematopoietically Derived Cells Contributes to Diet-Induced Inflammation and Insulin Resistance without Affecting Obesity",. Cell Metabolism, 6: 386-397. doi:10.1016/j.cmet.2007.09.011.http://www.cellmetabolism.org/content/article/abstract?uid=PIIS1550413107002926 Retrieved on 2008-01-11.

9. "UCSD Researchers Discover Inflammation, Not Obesity, Cause of Insulin Resistance". http://www.dlife.com/diabetes-news/2007/11/ucsd_researchers_discover_infl.html. Retrieved on 2008-01-12.

10. Chiu KC, Chu A, Go VL, Saad MF (2004). "Hypovitaminosis D is associated with insulin resistance and beta cell dysfunction". American Journal of Clinical Nutrition 79 (5): 820-825. PMID 15113720 http://www.ncbi.nlm.nih.gov/pubmed/15113720.

11. J Hong1, R R Smith, A E Harvey and N P Núñez Alcohol consumption promotes insulin sensitivity without affecting body fat levels International Journal of Obesity (2009) 33, 197-203; doi:10.1038/ijo.2008.266

12. Boden G, Sargrad K, Homko C, Mozzoli M, Stein TP (2005). "Effect of a low-carbohydrate diet on appetite, blood glucose levels, and insulin resistance in obese patients with type 2 diabetes" . Annals of Internal Medicine 142 (6): 403-411. PMID 15767618. http://www.ncbi.nlm.nih.gov/pubmed/15767618.

13. Bramnert M, Segerlantz M, Laurila E, Daugaard JR, Manhem P, Groop L (2003). "Growth hormone replacement therapy induces insulin resistance by activating the glucose-fatty acid cycle". The Journal Of Clinical Endocrinology & Metabolism 88 (4): 1455-1463. doi:10.1210/jc.2002-020542. PMID 12679422. http://jcem.endojournals.org/cgi/content/full/88/4/1455.

14. Knowler WC, Barrett-Connor E, Fowler SE, Hamman RF, Lachin JM, Walker EA, Nathan DM; Diabetes Prevention Program Research Group (2002). "Reduction in the incidence of type 2 diabetes with lifestyle intervention or metformin". New England Journal of Medicine, 346 (6): 393-403. doi:10.1056/NEJMoa012512. PMID 11832527. http://content.nejm.org/cgi/content/abstract/346/6/393

15. Lovejoy, JC (2002). "The influence of dietary fat on insulin resistance". Current Diabetes Reports 2 (5): 435-440. doi:10.1007/s11892-002-0098-y. PMID 12643169.

16. Fukuchi S (2004). "Role of Fatty Acid Composition in the Development of Metabolic Disorders in Sucrose-Induced Obese Rats". Experimental Biology and Medicine 229 (6): 486-493. PMID 15169967. http://www.ebmonline.org/cgi/content/full/229/6/486

17. Storlien LH (1996). "Dietary fats and insulin action". Diabetologica 39 (6): 621-631. doi:10.1007/BF00418533. PMID 8781757.

18. Harinantenaina L (2006). "Momordica charantia constituents and antidiabetic screening of the isolated major compounds". Chemical & Pharmaceutical Bulletin (Tokyo) 54 (7): 1017-21. doi:10.1248/cpb.54.1017. PMID 16819222. http://www.jstage.jst.go.jp/article/cpb/54/7/54_1017/_article.

19. Article: Chromium Critical for Glucose Tolerance by Judy McBride, USDA 1999 Adapted from Wikipedia

Carina is available to lecture for your group or institution on this subject

Carina Harkin BHSc.Nat.BHSc.Hom.BHSc.Acu. is a practitioner of 11 years, complementary medicine lecturer of 4 years and mother of six in Galway, Ireland who practices what she teaches.

For an appointment call Carina directly on 083 34 66 333.

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Carahealth Galway Ireland. Acupuncture, Naturopathy, Homeopathy, Herbal Medicine, Nutrition, Nutritional therapy, Flower essences, Iridology, Short Courses

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