Kerintangan insulin

Daripada Wikipedia, ensiklopedia bebas.
Lompat ke: pandu arah, cari
Kerintangan insulin
Pengelasan dan sumber luaran
eMedicine med/1173
MeSH C18.452.394.968.500
Wikipedia tidak memberikan nasihat perubatan Penafian perubatan

Kerintangan insulin (insulin resistance, IR) ialah keadaan di mana jumlah insulin normal tidak lagi mencukupi bagi menghasilkan tindak balas insulin normal terhadap sel lemak, otot, dan hati. Kerintangan insulin pada sel lemak mengurangkan keberkesanan insulin dan mengakibatkan peningkatan hidrolisis trigliserida yang tersimpan dengan kecuali berlaku tindakan sama ada meningkatkan kesensitifan insulin atau dengan insulin tambahan. Peningkatan pergerakan lipid tersimpan dalam sel ini meningkatkan asid lemak bebas dalam plasma darah. Kerintangan insulin pada otot mengurangkan pengambilan glukosa (dengan itu menyimpan glukosa tempatan sebagai glikogen), sementara kerintangan insulin pada sel hati mengakibatkan kecacatan penghasilan glikogen dan kegagalan mengekang penghasilan glukosa. Peningkatan kepekatan asid lemak dalam darah (dikaitkan dengan kerintangan insulin dan diabetes melitus jenis 2), mengurangkan pengambilan glukosa otot, dan peningkatan penghasilan glukosa hati kesemuanya menyumbang kepada peningkatan kepekatan glukosa darah. Tahap plasma tinggi bagi insulin dan glukosa akibat kerintangan insulin dipercayai punca sindrom metabolik dan diabetes melitus jenis 2, termasuk komplikasi berkait dengannya.

Tanda dan simptom[sunting | sunting sumber]

  1. Lesu.
  2. Bingung dan tidak dapat memberi penumpuan. Kadang kala kelesuan adalah fizikal,tetapi sering kali ia adalah kelesuan mental.
  3. Usus kecil kembang. Kebanyakan gas perut terhasil dari karbohidrat dalam permakanan. Pengidap kerintangan Insulin yang makan karbohidrat kadang kala berhadapan dengan gas.
  4. Mengantuk. Kebanyakan pengidap kerintangan insulin menjadi mengantuk selepas makan makanan yang mengandungi lebih 20% atau 30% karbohidrat.
  5. Peningkatan berat badan, penyimpanan lemak, sukar menurunkan berat badan. Bagi kebanyakan orang, terlalu berat adalah kerana terlalu banyak lemak. Lemak bagi Kerintangan Insulin IR biasanya tersimpan pada dan sekitar organ perut bagi kedua-dua lelaki dan wanita. Pada masa kini is disyaki akibat kesan hormon dari lemak sedemikian adalah punca awalkerintangan insulin.
  6. Peningkatan tahap triglyceride darah.
  7. Peningkatan tekanan darah. kebanyakan orang dengan hipertensi samaada kending manis atau pra-kencing manis dan memiliki tahap insulin tinggi disebabkan kerintangan insulin. Satu daripada kesan insulin adalah pada dinding arteri diseluruh badan.
  8. Kemurungan. Ini disebabkan metabolis berubah akibat kerintangan insulin, kesan psikologi adalah perkara biasa. Kemurungan dikatakan merupakan simptim psikologi meluas.


Pathophysiology[sunting | sunting sumber]

Any eating or drinking will cause a person's blood glucose level to increase. In a person with normal metabolism, the elevated blood glucose level will cause the beta (β) cells of the Islets of Langerhans located in the pancreas to release insulin ("postprandial"). The insulin in turn causes insulin-sensitive tissues in the body (e.g., muscle, adipose) to absorb glucose and thereby to lower the blood glucose level. The beta cells reduce insulin output as the blood glucose level 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. The elevated insulin levels have additional effects (see insulin) which cause further biological effects throughout the body.

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 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). 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 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.

Elevated blood levels of glucose — regardless of cause — leads 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 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, 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 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. A great deal of attention into the 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 uncommon.

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 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 the 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[sunting | sunting sumber]

Fasting insulin levels[sunting | sunting sumber]

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)[sunting | sunting sumber]

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[sunting | sunting sumber]

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 will be 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.

Pilihan lain[sunting | sunting sumber]

Disebabkan sifat rumit bagi teknik "clamp" (dan kemungkinan bahaya hipoglycemia bagi sesetengah pesakit), pilihan lain telah dicari bagi memudahkan pengukuran kerintangan insulin. Yag pertama adalah Penilaian Model Homeostatik (HOMA), dan kaedah yang paling terkini adalah Quantitative insulin sensitivity check index (QUICKI). Kedua-dua kaedah menggunakan puasa insulin dan tahap glukos bagi mengira kerintangan insulin, dan kedua-dua selaras dengan memuaskan dengan hasil dari kajian clamping. Wallace et al. menunjukkan bahawa QUICKI merupakan nilai logarithm dari salah satu persamaan HOMA.[5]

Causes[sunting | sunting sumber]

Terdapat beberapa tahap punca kerintangan insulin termasuk permakanan, genetik dan penyakit.

Permakanan[sunting | sunting sumber]

Asas bagi mengaitkan kerintangan insulin dengan permakanan karbohidrat tinggi oleh kajian Amerika Syarikat yang menunjukkan glucosamine (sering kali diberikan bagi masaalah sendi) mungkin menyebabkan kerintangan insulin.[6] Kerintangan Insulin juga telah dikaitkan dengan PCOS (polycystic ovary syndrome) sebagai punca atau menyebabkannya. Kajian lanjut sedang dilakukan. Kajian lain pula turut mengaitkan jumlah fruktose (contoh., pada HFCShigh fructose corn syrup, kini pemanis berzat paling murah digunakan dalam jumlah perindustrian); pada manusia, fruktose menyebabkan pertukaran pada profil lipid darah, antara lain, kebanyakannya disebabkan kesannya pada fungsi hati. 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.[petikan diperlukan] 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[sunting | sunting sumber]

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. 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[sunting | sunting sumber]

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]

Genetik[sunting | sunting sumber]

Perbezaan individual merupaka punca komponen diwarisi, kerana peningkatan kadar kerintangan insulin dan kencing manis Type 2 didapati dikalangan saudara rapat kepada pesakit kencing manis Type 2.

Disease[sunting | sunting sumber]

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 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[sunting | sunting sumber]

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[sunting | sunting sumber]

The primary treatment for insulin resistance is exercise and weight loss. Low-glycemic index or low-carbohydrate diets have also been shown to help.[13] 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.[14] 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.[15] One 2009 study has found that carbohydrate deficit after exercise, but not energy deficit, contributed to insulin sensitivity increase.[16]

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 (Cinnamomum aromaticum), which also contains anticoagulants; whereas "true cinnamon" (Cinnamomum zeylanicum or sp. verum) does not.[petikan diperlukan]

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.[17][18][19]

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.[20]

One study found that chromium is necessary for maintaining normal glucose tolerance.[21]

Sejarah[sunting | sunting sumber]

Konsep bahawa kerintangan insulin mungkin merupakan punca diabetes mellitus type 2 pertama kali dicadangkan oleh Prof. Wilhelm Falta dan diterbitkan di Vienna pada 1931,[22] dan disahkan oleh Sir Harold Percival Himsworth dari University College Hospital Medical Centre di London pada 1936.[23]

See also[sunting | sunting sumber]

References[sunting | sunting sumber]

  • Symptoms list was quoted in part from various websites that are trying to educate the public about the illness, but were edited for accuracy.
  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. PMC 45693. 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. Diperoleh pada 2007-11-11. 
  7. Jeff Unger. "Intensive Management of Type 2 Diabetes". Emergency Medicine. Diperoleh pada 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. Diperoleh pada 2008-01-11. 
  9. "UCSD Researchers Discover Inflammation, Not Obesity, Cause of Insulin Resistance". Diperoleh pada 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. 
  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. 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. 
  14. 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. 
  15. 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. PMC 1370926. PMID 11832527. 
  16. doi:10.1152/japplphysiol.01106.2009
    Petikan ini akan disiapkan secara automatik dalam beberapa minit. Anda boleh memotong barisan atau mengembangkannya sendiri
  17. 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. 
  18. 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. 
  19. 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. 
  20. 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. 
  21. Article: Chromium Critical for Glucose Tolerance by Judy McBride, USDA 1999
  22. Falta W, Boller R (1931). "Insularer und insulinresistenter Diabetes". Klin Wochenschr 10: 438–443. doi:10.1007/BF01736348. 
  23. 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. 

Pautan luar[sunting | sunting sumber]