Insulin resistance

Insulin resistance (IR) is a pathological condition in which cells fail to respond normally to the hormone insulin.

Insulin resistance
SpecialtyEndocrinology

Insulin is a hormone that allows glucose to enter cells which also reduces blood glucose (blood sugar). Insulin is released by the pancreas in response to carbohydrates consumed in the diet. In states of insulin resistance, the same amount of insulin does not have the same effect on glucose transport and blood sugar levels. There are many causes of insulin resistance and the underlying process is still not completely understood, but sulfate depletion may be the important factor. Risk factors for insulin resistance include obesity, sedentary lifestyle, family history of diabetes, various health conditions, and certain medications. Insulin resistance is considered a component of the metabolic syndrome. There are multiple ways to measure insulin resistance such as fasting insulin levels or glucose tolerance tests, but these are not often used in clinical practice. Insulin resistance can be improved or reversed with lifestyle approaches, such as exercise and dietary changes.

Cause

Risk factors

There are a number of risk factors for insulin resistance, including being overweight or obese or having a sedentary lifestyle.[1] Various genetic factors can increase risk, such as a family history of diabetes, and there are some specific medical conditions associated with insulin resistance, such as polycystic ovary syndrome.[1]

The National Institute of Diabetes and Digestive and Kidney Diseases states that specific risks that may predispose an individual to insulin resistance can include:

  • being aged 45 or older
  • having African American, Alaska Native, American Indian, Asian American, Hispanic/Latino, Native Hawaiian, or Pacific Islander American ethnicity
  • having health conditions such as high blood pressure and abnormal cholesterol levels
  • having a history of gestational diabetes
  • having a history of heart disease or stroke.[1]

In addition some medications and other health conditions can raise the risk.[1]

Lifestyle factors

Dietary factors likely contribute to insulin resistance, however, causative foods are difficult to determine given the limitations of nutrition research. Foods that have independently been linked to insulin resistance include those high in sugar with high glycemic indices, high in dietary fat and fructose, low in omega-3 and fiber, and which are hyper-palatable which increases risk of overeating.[2] Overconsumption of fat- and sugar-rich meals and beverages have been proposed as a fundamental factor behind the metabolic syndrome epidemic.

Diet also has the potential to change the ratio of polyunsaturated to saturated phospholipids in cell membranes. The percentage of polyunsaturated fatty acids (PUFAs) is inversely correlated with insulin resistance.[3] It is hypothesized that increasing cell membrane fluidity by increasing PUFA concentration might result in an enhanced number of insulin receptors, an increased affinity of insulin to its receptors, and reduced insulin resistance.[4]

Vitamin D deficiency has also been associated with insulin resistance.[5]

Sedentary lifestyle increases the likelihood of development of insulin resistance.[6] In epidemiological studies, higher levels of physical activity (more than 90 minutes per day) reduce the risk of diabetes by 28%.[7]

Studies have consistently shown that there is a link between insulin resistance and circadian rhythm, with insulin sensitivity being higher in the morning and lower in the evening. A mismatch between the circadian rhythm and the meals schedule, such as in circadian rhythm disorders, may increase insulin resistance.[8] [9][10]

Medications

Some medications are associated with insulin resistance including corticosteroids, protease inhibitors (type of HIV medication),[11] and atypical antipsychotics.[12]

Hormones

Many hormones can induce insulin resistance including cortisol,[13] growth hormone, and human placental lactogen.[14]

Cortisol counteracts insulin and can lead to increased hepatic gluconeogenesis, reduced peripheral utilization of glucose, and increased insulin resistance.[15] It does this by decreasing the translocation of glucose transporters (especially GLUT4) to the cell membrane.[16][17]

Based on the significant improvement in insulin sensitivity in humans after bariatric surgery and rats with surgical removal of the duodenum,[18][19] it has been proposed that some substance is produced in the mucosa of that initial 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, and the existence of such a substance remains speculative.

Leptin is a hormone produced from the ob gene and adipocytes.[20] Its physiological role is to regulate hunger by alerting the body when it is full.[21] Studies show that lack of leptin causes severe obesity and is strongly linked with insulin resistance.[22]

Diseases

Polycystic ovary syndrome[23] and non-alcoholic fatty liver disease (NAFLD) are associated with insulin resistance. Hepatitis C also makes people three to four times more likely to develop type 2 diabetes and insulin resistance.[24]

Inflammation

Acute or chronic inflammation, such as in infections, can cause insulin resistance. TNF-α is a cytokine that may promote insulin resistance by promoting lipolysis, disrupting insulin signaling, and reducing the expression of GLUT4.[25]

Genetics

Several genetic loci have been determined to be associated with insulin insensitivity. This includes variation in loci near the NAT2, GCKR, and IGFI genes associated with insulin resistance. Further research has shown that loci near the genes are linked to insulin resistance. However, these loci are estimated to only account for 25-44% of the genetic component of insulin resistance.[26]

Pathophysiology

In normal metabolism, the elevated blood glucose instructs beta (β) cells in the Islets of Langerhans, located in the pancreas, to release insulin into the blood. The insulin makes insulin-sensitive tissues in the body (primarily skeletal muscle cells, adipose tissue, and liver) absorb glucose which provides energy as well as lowers blood glucose.[27] 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 (90 mg/dL). In an insulin-resistant person, normal levels of insulin do not have the same effect in controlling blood glucose levels.

When the body produces insulin under conditions of insulin resistance, the cells are unable to absorb or use it as effectively and it stays in the bloodstream. Certain cell types such as fat and muscle cells require insulin to absorb glucose and when these cells fail to respond adequately to circulating insulin, blood glucose levels rise. The liver normally helps regulate glucose levels by reducing its secretion of glucose in the presence of insulin. However, in insulin resistance, this normal reduction in the liver's glucose production may not occur, further contributing to elevated blood glucose.[28]

Insulin resistance in fat cells results in reduced uptake of circulating lipids and increased hydrolysis of stored triglycerides. This leads to elevated free fatty acids in the blood plasma and can further worsen insulin resistance.[29][30][31] Since insulin is the primary hormonal signal for energy storage into fat cells, which tend to retain their sensitivity in the face of hepatic and skeletal muscle resistance, insulin resistance stimulates the formation of new fatty tissue and accelerates weight gain.[2]

In states of insulin resistance, beta cells in the pancreas increase their production of insulin. This causes high blood insulin (hyperinsulinemia) to compensate for the high blood glucose. During this compensated phase of 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 as the resistance increases and compensatory insulin secretion fails.[32][33] 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.

Insulin resistance is strongly associated with intestinal-derived apoB-48 production rate in insulin-resistant subjects and type 2 diabetic patients.[34] Insulin resistance often is found in people with visceral adiposity, hypertension, hyperglycemia, and dyslipidemia involving elevated triglycerides, small dense low-density lipoprotein (sdLDL) particles, and decreased high-density lipoprotein (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 inflammatory markers and mediators that may cause insulin resistance. Second, visceral adiposity is related to an accumulation of fat in the liver, a condition known as non-alcoholic 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 breakdown of glycogen stores into glucose (glycogenolysis), both of which have the effect of exacerbating peripheral insulin resistance and increasing the likelihood of Type 2 diabetes mellitus.

The excessive expansion of adipose tissue that tends to occur under sustainedly positive energy balance (as in overeating) has been postulated by Vidal-Puig to induce lipotoxic and inflammatory effects that may contribute to causing insulin resistance and its accompanying disease states.[35]

Also, insulin resistance often is associated with a hypercoagulable state (impaired fibrinolysis) and increased inflammatory cytokine levels.[36]

Molecular mechanism

At the molecular level, a cell senses insulin through insulin receptors, with the signal propagating through a signaling cascade collectively known as PI3K/Akt/mTOR signaling pathway.[37] Recent studies suggested that the pathway may operate as a bistable switch under physiologic conditions for certain types of cells, and insulin response may well be a threshold phenomenon.[38][37][39] The pathway's sensitivity to insulin may be blunted by many factors such as lipolysis of free fatty acids,[40] causing insulin resistance. From a broader perspective, however, sensitivity tuning (including sensitivity reduction) is a common practice for an organism to adapt to the changing environment or metabolic conditions.[41] Pregnancy, for example, is a prominent change of metabolic conditions, under which the mother has to reduce her muscles' insulin sensitivity to spare more glucose for the brains (the mother's brain and the fetal brain). This can be achieved through raising the response threshold (i.e., postponing the onset of sensitivity) by secreting placental growth factor to interfere with the interaction between insulin receptor substrate (IRS) and PI3K, which is the essence of the so-called adjustable threshold hypothesis of insulin resistance.[38]

Insulin resistance has been proposed to be a reaction to excess nutrition by superoxide dismutase in cell mitochondria that acts as an antioxidant defense mechanism. This link seems to exist under diverse causes of insulin resistance. It also is based on the finding that insulin resistance may be reversed rapidly by exposing cells to mitochondrial uncouplers, electron transport chain inhibitors, or mitochondrial superoxide dismutase mimetics.[42]

Diagnosis

Fasting insulin levels

A fasting serum insulin level greater than 125 mg/dl or 174 pmol/L indicates insulin resistance. The same levels apply three hours after the last meal.[43]

Glucose tolerance testing

During a glucose tolerance test (GTT), which may be used to diagnose diabetes mellitus, a fasting patient takes a 75 gram oral dose of glucose. Then blood glucose levels are measured over the following two hours.

Interpretation is based on WHO guidelines. After two hours a glycemia less than 7.8 mmol/L (140 mg/dL) is considered normal, a glycemia of between 7.8 and 11.0 mmol/L (140 to 197 mg/dL) is considered as impaired glucose tolerance (IGT), and a glycemia of greater than or equal to 11.1 mmol/L (200 mg/dL) is considered diabetes mellitus.

An oral glucose tolerance test (OGTT) may 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 peak (after the meal) in insulin production. Extension of the testing (for several more hours) may reveal a hypoglycemic "dip," that is a result of an overshoot in insulin production after the failure of the physiologic postprandial insulin response.

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.[44] 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 commonly is referred to in diabetes literature as the GINF value.[45]

The procedure takes about two 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 five to ten minutes.[45]

The rate of glucose infusion during the last thirty 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.[45]

This basic technique may be enhanced significantly by the use of glucose tracers. Glucose may 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).[45]

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.[45]

Patients initially receive 25 μg of octreotide (Sandostatin) in 5 mL of normal saline over 3 to 5 minutes via intravenous infusion (IV) as an initial bolus, and then, are infused continuously with an intravenous infusion of somatostatin (0.27 μg/m2/min) to suppress endogenous insulin and glucose secretion. Next, insulin and 20% glucose are infused at rates of 32 and 267 mg/m2/min, respectively. Blood glucose is checked at zero, 30, 60, 90, and 120 minutes, and thereafter, every 10 minutes for the last half-hour of the test. These last four values are averaged to determine the steady-state plasma glucose level (SSPG). Subjects with an SSPG greater than 150 mg/dL are considered to be insulin-resistant.[45]

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),[46] and more recent methods include the Quantitative insulin sensitivity check index (QUICKI)[47] and SPINA-GR, a measure for insulin sensitivity.[48] All of these calculated markers employ fasting insulin and glucose levels to calculate insulin resistance, and all correlate reasonably with the results of clamping studies.

Prevention and management

Maintaining a healthy body weight and being physically active can help reduce the risk of developing insulin resistance.[1]

The primary treatment for insulin resistance is exercise and weight loss.[49] Both metformin and thiazolidinediones improve insulin sensitivity. Metformin is approved for prediabetes and type 2 diabetes and has become one of the more commonly prescribed medications for insulin resistance.[50]

The Diabetes Prevention Program (DPP) showed that exercise and diet were nearly twice as effective as metformin at reducing the risk of progressing to type 2 diabetes.[51] However, the participants in the DPP trial regained about 40% of the weight that they had lost at the end of 2.8 years, resulting in a similar incidence of diabetes development in both the lifestyle intervention and the control arms of the trial.[52] In epidemiological studies, higher levels of physical activity (more than 90 minutes per day) reduce the risk of diabetes by 28%.[53]

Furthermore, physical training has also generally been seen to be an effective antagonist of insulin resistance in obese or overweight children and adolescents (under the age of 19).[54] As per the 2016 systematic review and meta-analysis conducted by Marson et al., aerobic exercise is associated with fasting insulin reduction; however, resistance and combined exercise are not.[54] The authors caution against demeaning the importance of resistance and combined exercise, as this type of training is generally less researched than aerobic training.[54] Overall, physical training can be used in both adolescents and adults to prevent the progression of insulin resistance and future possible metabolic and cardiovascular disease.

Resistant starch from high-amylose corn, amylomaize, has been shown to reduce insulin resistance in healthy individuals, in individuals with insulin resistance, and in individuals with type 2 diabetes.[55]

Some types of polyunsaturated fatty acids (omega-3) may moderate the progression of insulin resistance into type 2 diabetes,[56][57][58] however, omega-3 fatty acids appear to have limited ability to reverse insulin resistance, and they cease to be efficacious once type 2 diabetes is established.[59]

History

The concept that insulin resistance may be the underlying cause of diabetes mellitus type 2 was first advanced by Professor Wilhelm Falta and published in Vienna in 1931,[60] and confirmed as contributory by Sir Harold Percival Himsworth of the University College Hospital Medical Centre in London in 1936;[61] however, type 2 diabetes does not occur unless there is concurrent failure of compensatory insulin secretion.[62]

Adaptive explanations

Some scholars go as far as to claim that neither insulin resistance, nor obesity really are metabolic disorders per se, but simply adaptive responses to sustained caloric surplus, intended to protect bodily organs from lipotoxicity (unsafe levels of lipids in the bloodstream and tissues): "Obesity should therefore not be regarded as a pathology or disease, but rather as the normal, physiologic response to sustained caloric surplus... As a consequence of the high level of lipid accumulation in insulin target tissues including skeletal muscle and liver, it has been suggested that exclusion of glucose from lipid-laden cells is a compensatory defense against further accumulation of lipogenic substrate."[63]

Other prevailing thoughts that insulin resistance can be an evolutionary adaptation include the thrifty gene hypothesis. This hypothesis raises the point that if there is a genetic component to insulin resistance and Type 2 diabetes, these phenotypes should be selected against.[64] Yet, there has been an increase in mean insulin resistance in both the normoglycemic population as well as the diabetic population.[65]

J.V. Neel postulates that originally in times of increased famine in ancient humans' ancestors, genes conferring a mechanism for increased glucose storage would be advantageous. In the modern environment today, however, this is not the case.[64]

Evidence is contradictory to Neel in studies of the Pima Indians, which indicate that the people with higher insulin sensitives tended to weigh the most and conversely people with insulin resistance tended to weigh less on average in this demographic.[66]

Modern hypotheses suggest that insulin metabolism is a socio-ecological adaptation with insulin being the means for differentiating energy allocation to various components of the body and insulin sensitivity an adaptation to manipulate where the energy is diverted to. The Behavioral Switch Hypothesis posits that insulin resistance results in two methods to alter reproductive strategies and behavioral methods. The two strategies are coined as “r to K” and “soldier to diplomat.” The r to K strategy involves diverting insulin via placenta to the fetus. This has demonstrated weight gain in the fetus, but not the mother indicating a method of increased parental investment (K strategy). In the “soldier to diplomat” the insensitivity of skeletal muscle to insulin could divert the glucose to the brain, which doesn't require insulin receptors. This has shown increases in cognitive development across various studies.[67]

See also

References
  1. "Insulin Resistance & Prediabetes". National Institute of Diabetes and Digestive and Kidney Diseases. May 2018.
  2. Isganaitis E, Lustig RH (December 2005). "Fast food, central nervous system insulin resistance, and obesity". Arteriosclerosis, Thrombosis, and Vascular Biology. 25 (12): 2451–62. doi:10.1161/01.ATV.0000186208.06964.91. PMID 16166564.
  3. Haugaard SB, Madsbad S, Høy CE, Vaag A (February 2006). "Dietary intervention increases n-3 long-chain polyunsaturated fatty acids in skeletal muscle membrane phospholipids of obese subjects. Implications for insulin sensitivity". Clinical Endocrinology. 64 (2): 169–78. doi:10.1111/j.1365-2265.2006.02444.x. PMID 16430716. S2CID 22878943.
  4. Russo GL (March 2009). "Dietary n-6 and n-3 polyunsaturated fatty acids: from biochemistry to clinical implications in cardiovascular prevention". Biochemical Pharmacology. 77 (6): 937–46. doi:10.1016/j.bcp.2008.10.020. PMID 19022225.
  5. Chiu KC, Chu A, Go VL, Saad MF (May 2004). "Hypovitaminosis D is associated with insulin resistance and beta cell dysfunction". The American Journal of Clinical Nutrition. 79 (5): 820–5. doi:10.1093/ajcn/79.5.820. PMID 15113720.
  6. Ivy JL (November 1997). "Role of exercise training in the prevention and treatment of insulin resistance and non-insulin-dependent diabetes mellitus". Sports Medicine. Auckland, NZ. 24 (5): 321–36. doi:10.2165/00007256-199724050-00004. PMID 9368278. S2CID 29053249.
  7. Kyu HH, Bachman VF, Alexander LT, Mumford JE, Afshin A, Estep K, Veerman JL, Delwiche K, Iannarone ML, Moyer ML, Cercy K, Vos T, Murray CJ, Forouzanfar MH (August 2016). "Physical activity and risk of breast cancer, colon cancer, diabetes, ischemic heart disease, and ischemic stroke events: systematic review and dose-response meta-analysis for the Global Burden of Disease Study 2013". BMJ. 354: i3857. doi:10.1136/bmj.i3857. PMC 4979358. PMID 27510511.
  8. Stenvers DJ, Scheer FA, Schrauwen P, la Fleur SE, Kalsbeek A (February 2019). "Circadian clocks and insulin resistance" (PDF). Nature Reviews. Endocrinology. 15 (2): 75–89. doi:10.1038/s41574-018-0122-1. hdl:20.500.11755/fdb8d77a-70e3-4ab7-a041-20b2303b418b. PMID 30531917. S2CID 54449238.
  9. Reutrakul S, Van Cauter E (July 2018). "Sleep influences on obesity, insulin resistance, and risk of type 2 diabetes". Metabolism. 84: 56–66. doi:10.1016/j.metabol.2018.02.010. PMID 29510179.
  10. Mesarwi O, Polak J, Jun J, Polotsky VY (September 2013). "Sleep disorders and the development of insulin resistance and obesity". Endocrinology and Metabolism Clinics of North America. 42 (3): 617–34. doi:10.1016/j.ecl.2013.05.001. PMC 3767932. PMID 24011890.
  11. Fantry LE (March 2003). "Protease inhibitor-associated diabetes mellitus: a potential cause of morbidity and mortality". J Acquir Immune Defic Syndr. 32 (3): 243–4. doi:10.1097/00126334-200303010-00001. PMID 12626882.
  12. Burghardt KJ, Seyoum B, Mallisho A, Burghardt PR, Kowluru RA, Yi Z (April 2018). "Atypical antipsychotics, insulin resistance and weight; a meta-analysis of healthy volunteer studies". Progress in Neuro-Psychopharmacology & Biological Psychiatry. 83: 55–63. doi:10.1016/j.pnpbp.2018.01.004. PMC 5817633. PMID 29325867.
  13. Joseph JJ, Golden SH (March 2017). "Cortisol dysregulation: the bidirectional link between stress, depression, and type 2 diabetes mellitus". Annals of the New York Academy of Sciences. 1391 (1): 20–34. Bibcode:2017NYASA1391...20J. doi:10.1111/nyas.13217. PMC 5334212. PMID 27750377.
  14. Newbern D, Freemark M (December 2011). "Placental hormones and the control of maternal metabolism and fetal growth". Current Opinion in Endocrinology, Diabetes and Obesity. 18 (6): 409–16. doi:10.1097/MED.0b013e32834c800d. PMID 21986512. S2CID 24095227.
  15. Brown DD (2003). USMLE Step 1 Secrets. p. 63.
  16. King MW (2005). Lange Q&A USMLE Step 1 (6th ed.). New York: McGraw-Hill Medical. p. 82. ISBN 978-0-07-144578-8.
  17. Piroli GG, Grillo CA, Reznikov LR, Adams S, McEwen BS, Charron MJ, Reagan LP (2007). "Corticosterone impairs insulin-stimulated translocation of GLUT4 in the rat hippocampus". Neuroendocrinology. 85 (2): 71–80. doi:10.1159/000101694. PMID 17426391. S2CID 38081413.
  18. Garrido-Sanchez L, Murri M, Rivas-Becerra J, Ocaña-Wilhelmi L, Cohen RV, Garcia-Fuentes E, Tinahones FJ (2012). "Bypass of the duodenum improves insulin resistance much more rapidly than sleeve gastrectomy". Surgery for Obesity and Related Diseases. 8 (2): 145–50. doi:10.1016/j.soard.2011.03.010. PMID 21570362.
  19. Goodman A (June 1, 2016). "Duodenal resurfacing achieves metabolic benefits in type 2 diabetes". Family Practice News. Retrieved 12 March 2017.
  20. Friedman JM (April 2000). "Obesity in the new millennium". Nature. 404 (6778): 632–4. doi:10.1038/35007504. PMID 10766249. S2CID 4406498.
  21. Flier JS (May 1998). "Clinical review 94: What's in a name? In search of leptin's physiologic role". The Journal of Clinical Endocrinology and Metabolism. 83 (5): 1407–13. doi:10.1210/jcem.83.5.4779. PMID 9589630.
  22. Elmquist JK, Maratos-Flier E, Saper CB, Flier JS (October 1998). "Unraveling the central nervous system pathways underlying responses to leptin". Nature Neuroscience. 1 (6): 445–50. doi:10.1038/2164. PMID 10196541. S2CID 7474447.
  23. Nafiye Y, Sevtap K, Muammer D, Emre O, Senol K, Leyla M (April 2010). "The effect of serum and intrafollicular insulin resistance parameters and homocysteine levels of nonobese, nonhyperandrogenemic polycystic ovary syndrome patients on in vitro fertilization outcome". Fertility and Sterility. 93 (6): 1864–9. doi:10.1016/j.fertnstert.2008.12.024. PMID 19171332.
  24. Milner KL, van der Poorten D, Trenell M, Jenkins AB, Xu A, Smythe G, et al. (March 2010). "Chronic hepatitis C is associated with peripheral rather than hepatic insulin resistance". Gastroenterology. 138 (3): 932–41.e1–3. doi:10.1053/j.gastro.2009.11.050. PMID 19962985.
  25. Peraldi P, Spiegelman B (May 1998). "TNF-alpha and insulin resistance: summary and future prospects". Molecular and Cellular Biochemistry. 182 (1–2): 169–75. doi:10.1023/A:1006865715292. PMID 9609126. S2CID 32740002.
  26. Brown AE, Walker M (August 2016). "Genetics of Insulin Resistance and the Metabolic Syndrome". Current Cardiology Reports. 18 (8): 75. doi:10.1007/s11886-016-0755-4. PMC 4911377. PMID 27312935.
  27. "A heavy burden". The Economist. December 15, 2012. Retrieved 10 January 2013.
  28. "Science daily". Jun 2009.
  29. Schinner S, Scherbaum WA, Bornstein SR, Barthel A (June 2005). "Molecular mechanisms of insulin resistance". Diabetic Medicine. 22 (6): 674–82. doi:10.1111/j.1464-5491.2005.01566.x. PMID 15910615. S2CID 10680747.
  30. Koyama K, Chen G, Lee Y, Unger RH (October 1997). "Tissue triglycerides, insulin resistance, and insulin production: implications for hyperinsulinemia of obesity". The American Journal of Physiology. 273 (4): E708-13. doi:10.1152/ajpendo.1997.273.4.E708. PMID 9357799.
  31. Roden M, Price TB, Perseghin G, Petersen KF, Rothman DL, Cline GW, Shulman GI (June 1996). "Mechanism of free fatty acid-induced insulin resistance in humans". The Journal of Clinical Investigation. 97 (12): 2859–65. doi:10.1172/JCI118742. PMC 507380. PMID 8675698.
  32. "Insulin resistance". Medicine net.
  33. Insulin Resistance Leads to LADA (Report). Diabetes Health. Retrieved Feb 21, 2015.
  34. "Chylomicrons: Advances in biology, pathology, laboratory testing, and therapeutics". ResearchGate.
  35. Caprio S, Pierpont B, Kursawe R (March 2018). "The "adipose tissue expandability" hypothesis: a potential mechanism for insulin resistance in obese youth". Horm Mol Biol Clin Investig. 33 (2). doi:10.1515/hmbci-2018-0005. PMID 29596053. S2CID 4515780.
  36. Nagaev I, Bokarewa M, Tarkowski A, Smith U (December 2006). "Human resistin is a systemic immune-derived proinflammatory cytokine targeting both leukocytes and adipocytes". PLOS ONE. 1: e31. doi:10.1371/journal.pone.0000031. PMC 1762367. PMID 17183659.
  37. Wang G (December 2010). "Singularity analysis of the AKT signaling pathway reveals connections between cancer and metabolic diseases". Physical Biology. 7 (4): 046015. Bibcode:2010PhBio...7d6015W. doi:10.1088/1478-3975/7/4/046015. PMID 21178243.
  38. Wang G (December 2014). "Raison d'être of insulin resistance: the adjustable threshold hypothesis". Journal of the Royal Society, Interface. 11 (101): 20140892. doi:10.1098/rsif.2014.0892. PMC 4223910. PMID 25320065.
  39. Wang G (October 2012). "Optimal homeostasis necessitates bistable control". Journal of the Royal Society, Interface. 9 (75): 2723–34. doi:10.1098/rsif.2012.0244. PMC 3427521. PMID 22535698.
  40. Lucidi P, Rossetti P, Porcellati F, Pampanelli S, Candeloro P, Andreoli AM, et al. (June 2010). "Mechanisms of insulin resistance after insulin-induced hypoglycemia in humans: the role of lipolysis". Diabetes. 59 (6): 1349–57. doi:10.2337/db09-0745. PMC 2874695. PMID 20299466.
  41. Wang G, Zhang M (February 2016). "Tunable ultrasensitivity: functional decoupling and biological insights". Scientific Reports. 6: 20345. Bibcode:2016NatSR...620345W. doi:10.1038/srep20345. PMC 4742884. PMID 26847155.
  42. Hoehn KL, Salmon AB, Hohnen-Behrens C, Turner N, Hoy AJ, Maghzal GJ, et al. (October 2009). "Insulin resistance is a cellular antioxidant defense mechanism". Proceedings of the National Academy of Sciences of the United States of America. 106 (42): 17787–92. Bibcode:2009PNAS..10617787H. doi:10.1073/pnas.0902380106. PMC 2764908. PMID 19805130.
  43. {https://www.healthline.com/health/diabetes/insulin-resistance-symptoms#symptoms}
  44. DeFronzo RA, Tobin JD, Andres R (September 1979). "Glucose clamp technique: a method for quantifying insulin secretion and resistance". The American Journal of Physiology. 237 (3): E214-23. doi:10.1152/ajpendo.1979.237.3.e214. PMID 382871. S2CID 7192984.
  45. Muniyappa R, Lee S, Chen H, Quon MJ (January 2008). "Current approaches for assessing insulin sensitivity and resistance in vivo: advantages, limitations, and appropriate usage". American Journal of Physiology. Endocrinology and Metabolism. 294 (1): E15-26. doi:10.1152/ajpendo.00645.2007. PMID 17957034. S2CID 848540.
  46. Matthews, DR; Hosker, JP; Rudenski, AS; Naylor, BA; Treacher, DF; Turner, RC (July 1985). "Homeostasis model assessment: insulin resistance and beta-cell function from fasting plasma glucose and insulin concentrations in man". Diabetologia. 28 (7): 412–9. doi:10.1007/BF00280883. PMID 3899825.
  47. Katz, A; Nambi, SS; Mather, K; Baron, AD; Follmann, DA; Sullivan, G; Quon, MJ (July 2000). "Quantitative insulin sensitivity check index: a simple, accurate method for assessing insulin sensitivity in humans". The Journal of clinical endocrinology and metabolism. 85 (7): 2402–10. doi:10.1210/jcem.85.7.6661. PMID 10902785.
  48. Dietrich, Johannes W.; Dasgupta, Riddhi; Anoop, Shajith; Jebasingh, Felix; Kurian, Mathews E.; Inbakumari, Mercy; Boehm, Bernhard O.; Thomas, Nihal (21 October 2022). "SPINA Carb: a simple mathematical model supporting fast in-vivo estimation of insulin sensitivity and beta cell function". Scientific Reports. 12 (1): 17659. doi:10.1038/s41598-022-22531-3. PMID 36271244.
  49. Davidson LE, Hudson R, Kilpatrick K (Jan 2009). "Effects of Exercise Modality on Insulin Resistance and Functional Limitation in Older Adults". Archives of Internal Medicine. JAMA. 169 (2): 122–131. doi:10.1001/archinternmed.2008.558. PMID 19171808. Retrieved 17 Sep 2020.
  50. Giannarelli R, Aragona M, Coppelli A, Del Prato S (September 2003). "Reducing insulin resistance with metformin: the evidence today". Diabetes & Metabolism. 29 (4 Pt 2): 6S28–35. doi:10.1016/s1262-3636(03)72785-2. PMID 14502098.
  51. Knowler WC, Barrett-Connor E, Fowler SE, Hamman RF, Lachin JM, Walker EA, Nathan DM (February 2002). "Reduction in the incidence of type 2 diabetes with lifestyle intervention or metformin". The New England Journal of Medicine. 346 (6): 393–403. doi:10.1056/NEJMoa012512. PMC 1370926. PMID 11832527.
  52. Kahn R (January 2012). "Reducing the impact of diabetes: is prevention feasible today, or should we aim for better treatment?". Health Affairs. 31 (1): 76–83. doi:10.1377/hlthaff.2011.1075. PMID 22232097.
  53. Kyu HH, Bachman VF, Alexander LT, Mumford JE, Afshin A, Estep K, Veerman JL, Delwiche K, Iannarone ML, Moyer ML, Cercy K, Vos T, Murray CJ, Forouzanfar MH (August 2016). "Physical activity and risk of breast cancer, colon cancer, diabetes, ischemic heart disease, and ischemic stroke events: systematic review and dose-response meta-analysis for the Global Burden of Disease Study 2013". BMJ. 354: i3857. doi:10.1136/bmj.i3857. PMC 4979358. PMID 27510511.
  54. Marson EC, Delevatti RS, Prado AK, Netto N, Kruel LF (December 2016). "Effects of aerobic, resistance, and combined exercise training on insulin resistance markers in overweight or obese children and adolescents: A systematic review and meta-analysis". Prev Med. 93: 211–218. doi:10.1016/j.ypmed.2016.10.020. PMID 27773709.
  55. Keenan MJ, Zhou J, Hegsted M, Pelkman C, Durham HA, Coulon DB, Martin RJ (March 2015). "Role of resistant starch in improving gut health, adiposity, and insulin resistance". Advances in Nutrition. 6 (2): 198–205. doi:10.3945/an.114.007419. PMC 4352178. PMID 25770258.
  56. Lovejoy JC (October 2002). "The influence of dietary fat on insulin resistance". Current Diabetes Reports. 2 (5): 435–40. doi:10.1007/s11892-002-0098-y. PMID 12643169. S2CID 31329463.
  57. Fukuchi S, Hamaguchi K, Seike M, Himeno K, Sakata T, Yoshimatsu H (June 2004). "Role of fatty acid composition in the development of metabolic disorders in sucrose-induced obese rats". Experimental Biology and Medicine. 229 (6): 486–93. doi:10.1177/153537020422900606. PMID 15169967. S2CID 20966659.
  58. Storlien LH, Baur LA, Kriketos AD, Pan DA, Cooney GJ, Jenkins AB, et al. (June 1996). "Dietary fats and insulin action". Diabetologia. 39 (6): 621–31. doi:10.1007/BF00418533. PMID 8781757. S2CID 33171616.
  59. Delarue J, LeFoll C, Corporeau C, Lucas D (2004). "N-3 long chain polyunsaturated fatty acids: a nutritional tool to prevent insulin resistance associated to type 2 diabetes and obesity?". Reproduction, Nutrition, Development. 44 (3): 289–99. doi:10.1051/rnd:2004033. PMID 15460168.
  60. Falta W, Boller R (1931). "Insulärer und Insulinresistenter Diabetes". Klinische Wochenschrift. 10 (10): 438–43. doi:10.1007/BF01736348. S2CID 32359074.
  61. Himsworth H (1936). "Diabetes mellitus: its differentiation into insulin-sensitive and insulin insensitive types". The Lancet. 227 (5864): 127–30. doi:10.1016/S0140-6736(01)36134-2.
  62. Nolan CJ (October 2010). "Failure of islet β-cell compensation for insulin resistance causes type 2 diabetes: what causes non-alcoholic fatty liver disease and non-alcoholic steatohepatitis?". Journal of Gastroenterology and Hepatology. 25 (10): 1594–7. doi:10.1111/j.1440-1746.2010.06473.x. PMID 20880166.
  63. Unger RH, Scherer PE (June 2010). "Gluttony, sloth and the metabolic syndrome: a roadmap to lipotoxicity". Trends in Endocrinology and Metabolism. 21 (6): 345–52. doi:10.1016/j.tem.2010.01.009. PMC 2880185. PMID 20223680.
  64. Neel JV (December 1962). "Diabetes mellitus: a "thrifty" genotype rendered detrimental by "progress"?". American Journal of Human Genetics. 14 (4): 353–62. PMC 1932342. PMID 13937884.
  65. Ioannou GN, Bryson CL, Boyko EJ (2007-11-01). "Prevalence and trends of insulin resistance, impaired fasting glucose, and diabetes". Journal of Diabetes and Its Complications. 21 (6): 363–70. doi:10.1016/j.jdiacomp.2006.07.005. PMID 17967708.
  66. Swinburn BA, Nyomba BL, Saad MF, Zurlo F, Raz I, Knowler WC, et al. (July 1991). "Insulin resistance associated with lower rates of weight gain in Pima Indians". The Journal of Clinical Investigation. 88 (1): 168–73. doi:10.1172/JCI115274. PMC 296017. PMID 2056116.
  67. Watve MG, Yajnik CS (April 2007). "Evolutionary origins of insulin resistance: a behavioral switch hypothesis". BMC Evolutionary Biology. 7: 61. doi:10.1186/1471-2148-7-61. PMC 1868084. PMID 17437648.

Further reading
This article is issued from Wikipedia. The text is licensed under Creative Commons - Attribution - Sharealike. Additional terms may apply for the media files.