Insulin resistance

Insulin resistance
Classification and external resources
eMedicine med/1173
MeSH C18.452.394.968.500

Insulin resistance (IR) is a physiological condition where the natural hormone, insulin, becomes less effective at lowering blood sugars. The resulting increase in blood glucose may raise levels outside the normal range and cause adverse health effects. Certain cell types such as fat and muscle cells require insulin to absorb glucose. When these cells fail to respond adequately to circulating insulin, blood glucose levels rise. The liver helps regulate glucose levels by reducing its secretion of glucose in the presence of insulin. This normal reduction in the liver’s glucose production may not occur in people with insulin resistance.

Insulin resistance in muscle and fat cells reduces glucose uptake (and so local storage of glucose as glycogen and triglycerides, respectively), whereas insulin resistance in liver cells results in reduced glycogen synthesis and storage and a failure to suppress glucose production and release into the blood. Insulin resistance normally refers to reduced glucose-lowering effects of insulin. However, other functions of insulin can also be affected. For example, insulin resistance in fat cells reduces the normal effects of insulin on lipids and results in reduced uptake of circulating lipids and increased hydrolysis of stored triglycerides. Increased mobilization of stored lipids in these cells elevates free fatty acids in the blood plasma. Elevated blood fatty-acid concentrations (associated with insulin resistance and diabetes mellitus Type 2), reduced muscle glucose uptake, and increased liver glucose production all contribute to elevated blood glucose levels. High plasma levels of insulin and glucose due to insulin resistance are a major component of the metabolic syndrome. If insulin resistance exists, more insulin needs to be secreted by the pancreas. If this compensatory increase does not occur, blood glucose concentrations increase and type 2 diabetes occurs.

Contents

Signs and symptoms

These depend on poorly understood variations in individual biology and so are not found in all with insulin resistance.

  1. Fatigue.
  2. Brain fogginess and inability to focus, sometimes physical(???), but often mental.
  3. High blood sugar.
  4. Intestinal bloating—most intestinal gas is produced from carbohydrates in the diet, mostly those that humans cannot digest and absorb.
  5. Sleepiness, especially after meals.
  6. Weight gain, fat storage, difficulty losing weight—for most people, excess weight is from high fat storage; the fat in IR is generally stored in and around abdominal organs in both males and females. It is currently suspected that hormone production in that fat are a precipitating cause of insulin resistance.
  7. Increased blood triglyceride levels.
  8. Increased blood pressure. Many people with hypertension are either diabetic or pre-diabetic and have elevated insulin levels due to insulin resistance. One of insulin's effects is to control arterial wall tension throughout the body.
  9. Depression. Due to the deranged metabolism resulting from insulin resistance, psychological effects, including depression, are not uncommon.
  10. Acanthosis nigricans.

Pathophysiology

Any food or drink containing glucose (or the digestible carbohydrates that contain it, such as sucrose, starch, etc.) causes blood glucose levels to increase. In a normal metabolism, the elevated blood glucose level makes beta (β) cells in the Islets of Langerhans, located in the pancreas, release insulin into the blood. The insulin, in turn, makes insulin-sensitive tissues in the body (e.g., muscle, adipose) absorb glucose, and thereby lower the blood glucose level. The beta cells reduce insulin output as the blood glucose level falls, allowing blood glucose to settle at a constant of approximately 5 mmol/L (mM) (90 mg/dL). In an insulin-resistant person, normal levels of insulin do not have the same effect in controlling blood glucose levels. During the compensated phase on insulin resistance insulin levels are higher, and blood glucose levels are still maintained. If compensatory insulin secretion fails, then either fasting (impaired fasting glucose) or postprandial (impaired glucose tolerance) glucose concentrations increase. Eventually, type 2 diabetes occurs when glucose levels become higher throughout the day as the resistance increases and compensatory insulin secretion fails. The elevated insulin levels have additional effects (see insulin) that cause further abnormal biological effects throughout the body.

The most common type of insulin resistance is associated with overweight and obesity in a condition known as metabolic syndrome. Insulin resistance often progresses to full Type 2 diabetes mellitus (T2DM). This is often seen when hyperglycemia develops after a meal, when pancreatic β-cells are unable to produce sufficient insulin to maintain normal blood sugar levels (euglycemia) in the face of insulin resistance. The inability of the β-cells to produce sufficient insulin in a condition of hyperglycemia is what characterizes the transition from insulin resistance to Type 2 diabetes mellitus.[1]

Various disease states make 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 leads to a kind of insulin resistance; every time a cell is exposed to insulin, the production of GLUT4 (type four glucose receptors) on the cell's membrane decreases somewhat.[2] In the presence of a higher than usual level of insulin (generally caused by insulin resistance), this down-regulation acts as a kind of positive feedback, increasing the need for insulin. Exercise reverses this process in muscle tissue,[3] but if it is left unchecked, it can contribute to insulin resistance.

Elevated blood levels of glucose — regardless of cause — lead to increased glycation of proteins with changes, only a few of which are understood in any detail, in protein function throughout the body.

Insulin resistance is often found in people with visceral adiposity (i.e., a high degree of fatty tissue within the abdomen - 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, hyperglycemia and dyslipidemia involving elevated triglycerides, small dense low-density lipoprotein (sdLDL) particles, and decreased HDL cholesterol levels. With respect to visceral adiposity, a great deal of evidence suggests two strong links with insulin resistance. First, unlike subcutaneous adipose tissue, visceral adipose cells produce significant amounts of proinflammatory cytokines such as tumor necrosis factor-alpha (TNF-a), and Interleukins-1 and -6, etc. In numerous experimental models, these proinflammatory cytokines 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. Much of the attention on production of proinflammatory cytokines has focused on the IKK-beta/NF-kappa-B pathway, a protein network that enhances transcription of cytokine genes. Second, 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), 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 mellitus.

Insulin resistance is also often associated with a hypercoagulable state (impaired fibrinolysis) and increased inflammatory cytokine levels.

Insulin resistance is also occasionally found in patients who use insulin. In this case, the production of antibodies against insulin leads to lower-than-expected glucose level reductions (glycemia) after a specific dose of insulin. With the development of human insulin and analogues in the 1980s and the decline in the use of animal insulins (e.g., pork, beef), this type of insulin resistance has become less common. This form of insulin resistance is not what is being referred to in the metabolic syndrome.

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. Among the controlling mechanisms, 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 depolarizing stimuli. Poor intracellular Mg concentrations, as found in Type 2 diabetes mellitus 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 impairment in insulin action, and a worsening of insulin resistance in noninsulin-dependent diabetic and hypertensive patients. By contrast, in T2DM 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 T2DM patients are further supported by epidemiological studies showing that high daily Mg intake are predictive of a lower incidence of T2DM.

Diagnosis

Fasting insulin levels

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.

Glucose tolerance testing (GTT)

During a glucose tolerance test, which may be used to diagnose diabetes mellitus, a fasting 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 (140 mg/dl) is considered normal, a glycemia of between 7.8 to 11.0 mmol/dl (140 to 197 mg/dl) is considered as Impaired Glucose Tolerance (IGT) and a glycemia of greater than or equal to 11.1 mmol/dl (200 mg/dl) 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.

Measuring insulin resistance

Hyperinsulinemic euglycemic 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] It is a type of glucose clamp technique. 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.

This basic technique can be significantly enhanced by the use of glucose tracers. Glucose can be labeled with either stable or radioactive atoms. Commonly-used tracers are 3-3H glucose (radioactive), 6,6 2H-glucose (stable) and 1-13C Glucose (stable). Prior to beginning the hyperinsulinemic period, a 3h tracer infusion enables one to determine the basal rate of glucose production. During the clamp, the plasma tracer concentrations enable the calculation of whole-body insulin-stimulated glucose metabolism, as well as the production of glucose by the body (i.e., endogenous glucose production).

Modified Insulin Suppression Test

Another measure of insulin resistance is the modified insulin suppression test developed by Gerald Reaven at Stanford University. The test correlates well with the euglycemic clamp with less operator-dependent error. This test has been used to advance the large body of research relating to the metabolic syndrome.

Patients initially receive 25 mcg of octreotide (Sandostatin) in 5 ml of normal saline over 3 to 5 min IV as an initial bolus, and then are infused continuously with an intravenous infusion of somatostatin (0.27 μgm/m2/min) to suppress endogenous insulin and glucose secretion. Insulin and 20% glucose is then infused at rates of 32 and 267 mg/m2/min, respectively. Blood glucose is checked at zero, 30, 60, 90, and 120 minutes, and then every 10 minutes for the last half-hour of the test. These last 4 values are averaged to determine the steady-state plasma glucose level. Subjects with an SSPG greater than 150 mg/dl are considered to be insulin-resistant.

Alternatives

Given the complicated nature of the "clamp" technique (and the potential dangers of hypoglycemia in some patients), alternatives have been sought to simplify the measurement of insulin resistance. The first was the Homeostatic Model Assessment (HOMA), and a more recent method is the Quantitative insulin sensitivity check index (QUICKI). Both employ fasting insulin and glucose levels to calculate insulin resistance, and both correlate reasonably with the results of clamping studies. Wallace et al. point out that QUICKI is the logarithm of the value from one of the HOMA equations.[5]

Causes

There are several levels of insulin resistance causation including diet, cellular, molecular, genetic, and disease.

Diet

Grounds exist for linking insulin resistance to a high-carbohydrate diet. An American study has shown that glucosamine (often prescribed for joint problems) may cause insulin resistance.[6] 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. 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. 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; the effect may also be due to other parallel diet changes however. Further research may distinguish between candidate causes.

Cellular

At the cellular level, excessive circulating insulin appears to be a contributor to insulin resistance via down-regulation of insulin receptors. This down-regulation occurs due to prolonged and repeated elevations of circulating insulin.[7] As the pathological over-production of insulin is relatively rare, a more likely cause of the insulin resistance associated with Type 2 diabetes mellitus is repeated and sustained increases in blood glucose. The presence of insulin resistance typically precedes the diagnosis of Types 2 diabetes mellitus, and as elevated blood glucose levels are the primary stimulus for insulin secretion and production, habitually excessive carbohydrate intake is a likely contributor. Additionally, some Type 2 cases require so much external insulin that this down-regulation contributes to total 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.

Molecular

Insulin resistance has been proposed at a molecular level to be a reaction to excess nutrition by superoxide dismutase in cell mitochondria that acts as a antioxidant defense mechanism. This link seems to exist under diverse causes of insulin resistance. It is also based on the finding that insulin resistance can be rapidly reversed by exposing cells to mitochondrial uncouplers, electron transport chain inhibitors, or mitochondrial superoxide dismutase mimetics.[11]

Genetic

Individual variability is a cause with 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. The trait for insulin resistance can be passed down through generations, from a family member who has Type 2 diabetes.

Disease

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 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 8) 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 that 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.

HCV and Insulin Resistance

A recent study was published about Hepatitis C (HCV) and insulin resistance, "Chronic Hepatitis C Is Associated With Peripheral Rather Than Hepatic Insulin Resistance," which confirms that Hepatitis C also makes people three to four times more likely to develop Type 2 diabetes and insulin resistance. In addition, "people with Hepatitis C who develop diabetes probably have susceptible insulin-producing cells, and would probably get it anyway -- but much later in life. The extra insulin resistance caused by Hepatitis C apparently brings on diabetes at 35 or 40, instead of 65 or 70."

Associated conditions

Several associated conditions include:

Insulin resistance may also be caused by the damage of liver cells having undergone a defect of insulin receptors in hepatocytes.

Management

The primary treatment for insulin resistance is exercise and weight loss. Low-glycemic index or low-carbohydrate diets have also been shown to help.[14] 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.[15] 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 in healthy individuals by the same mechanism as it does in diabetics. 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.[16] One 2009 study has found that carbohydrate deficit after exercise, but not energy deficit, contributed to insulin sensitivity increase.[17]

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.[18][19][20]

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.[21]

As for people that have genetically inherited insulin resistance, since the trait controls the way sugar is stored, it can be nearly impossible to find a way around it. The body stores glucose rapidly, causing weight gain over the years. Exercise and weight loss can be troublesome for people who have genetically inherited insulin resistance, and most people who have been diagnosed are recommended to eat healthier and exercise regularly, although effects of a healthy diet and regular exercise may not be visible in the physical characteristics of someone who has inherited this condition.

One study found that chromium is necessary for maintaining normal glucose tolerance.[22]

History

The concept that insulin resistance may be the underlying cause of diabetes mellitus type 2 was first advanced by Prof. Wilhelm Falta and published in Vienna in 1931,[23] and confirmed by Sir Harold Percival Himsworth of the University College Hospital Medical Centre in London in 1936.[24]

See also

References

  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; McLenithan, JC; Ezaki, O; Lane, MD (1993). "Insulin down-regulates expression of the insulin-responsive glucose transporter (GLUT4) gene: effects on transcription and mRNA turnover". PNAS 90 (2): 512–516. doi:10.1073/pnas.90.2.512. PMID 8421683. 
  3. ↑ Paul S. MacLean_2002; Zheng, D; Jones, JP; Olson, AL; Dohm, GL (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. PMID 11906177. 
  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 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 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 (5): 386–397. doi:10.1016/j.cmet.2007.09.011. PMID 17983584. http://www.cellmetabolism.org/content/article/abstract?uid=PIIS1550413107002926. Retrieved 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 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. ↑ Hoehn KL, Salmon AB, Hohnen-Behrens C, Turner N, Hoy AJ, Maghzal GJ, Stocker R, Van Remmen H, Kraegen EW, Cooney GJ, Richardson AR, James DE. (2009). Insulin resistance is a cellular antioxidant defense mechanism. Proc Natl Acad Sci U S A. 106:17787–17792. doi:10.1073/pnas.0902380106 PMID 19805130
  12. ↑ 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
  13. ↑ Kerry–Lee Milner, David van der Poorten, Michael Trenell, Arthur B. Jenkins, Aimin Xu, George Smythe, Gregory J. Dore , Amany Zekry , Martin Weltman, Vincent Fragomeli, Jacob George, Donald J. Chisholm Chronic Hepatitis C Is Associated With Peripheral Rather Than Hepatic Insulin Resistance
  14. ↑ 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. 
  15. ↑ 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. 
  16. ↑ 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. PMC 1370926. http://content.nejm.org/cgi/content/abstract/346/6/393. 
  17. ↑ doi:10.1152/japplphysiol.01106.2009
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  18. ↑ 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. 
  19. ↑ Fukuchi S; Hamaguchi, K; Seike, M; Himeno, K; Sakata, T; Yoshimatsu, H (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. 
  20. ↑ Storlien LH; Baur, LA; Kriketos, AD; Pan, DA; Cooney, GJ; Jenkins, AB; Calvert, GD; Campbell, LV (1996). "Dietary fats and insulin action". Diabetologica 39 (6): 621–631. doi:10.1007/BF00418533. PMID 8781757. 
  21. ↑ Harinantenaina L; Tanaka, M; Takaoka, S; Oda, M; Mogami, O; Uchida, M; Asakawa, Y (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. 
  22. ↑ Article: Chromium Critical for Glucose Tolerance by Judy McBride, USDA 1999
  23. ↑ Falta W, Boller R (1931). "Insularer und insulinresistenter Diabetes". Klin Wochenschr 10: 438–443. doi:10.1007/BF01736348. 
  24. ↑ Himsworth HP (1936). "Diabetes mellitus: its differentiation into insulin-sensitive and insulin-insensitive types". Lancet 1: 127–130. doi:10.1016/S0140-6736(01)36134-2. 

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