Insulin Resistance Labs – Adiponectin

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Adiponectin is a hormone that is excreted exclusively from adipose (fat) cell and helps regulate several metabolic processes including the oxidation of fatty acids and glucose regulation. Levels are inversely correlated to the amount of body fat. Adiponectin plays a role in suppressing the metabolic dysfunction that often leads to metabolic syndrome, Diabetes (type 2), non-alcoholic fatty liver disease (NAFLD), obesity, and atherosclerosis. To underscore its role in regulating metabolism, adiponectin in conjunction with leptin was able to completely reverse insulin resistance in mice.

Adiponectin levels are generally higher in females than in males. Weight (body fat) reduction greatly increases serum levels of adiponectin. Diabetics have lower levels of adiponectin than non-diabetics. Obesity and TNF-a both decrease adiponectin levels. Low levels of adiponectin is an independent risk factor for developing diabetes and metabolic syndrome.

Molecules of adiponectin tend to join together to form polymers of adiponectin. These larger molecules seem to be the most active in regards to appropriate maintenance of glucose but this form is also associated with an increased risk of cardiovascular disease (CVD). At least some of the weight reduction effects of  adiponectin occur in the brain and seems to work synergistically with Leptin in this regard.

Adiponectin has the following effects:

  • It causes a decrease in the production of glucose (gluconeogenesis)
  • It increases the uptake of glucose
  • It increases the metabolism of fatty acids in the mitochondria (beta-oxidation)
  • It decreases triglycerides by increasing their clearance from the blood
  • It protects blood vessels from endothelial dysfunction
  • It increases insulin sensitivity
  • It promotes weight loss
  • It helps regulate energy metabolism
  • It upregulates uncoupling proteins – these are proteins that increase metabolism by utilizing energy sources but convert them to heat as opposed to energy

Interestingly, levels of adiponectin were disproportionately elevated in the blood of patients who went on to develop Alzheimer’s Disease (AD) as noted in the Framingham Heart Study. This information suggests that elevated levels of adiponectin could cause Alzheimer’s Disease. However, while we don’t know the answer to this piece, there are other potential explanations such as adiponectin resistance. For example, elevated insulin levels do not cause diabetes but are the result of insulin resistance that accompanies diabetes. This could be the same explanation for the development of AD in the setting of increased adiponectin levels.

How do you increase adiponectin? Berberine, EPA, & DHA have all been shown to increase the genetic expression of adiponectin. Curcumin, Resveratrol, astaxanthin, exercise, and Vitamin D (possibly) have been shown to increase adiponectin. The best options for improving adiponectin are supplements as listed above as well as optimizing body composition, decreasing body fat, exercising, and eating right.

 

References:

  1. http://www.huffingtonpost.com/scott-mendelson-md/alzheimers-_b_1187919.html
  2. http://en.wikipedia.org/wiki/Adiponectin
  3. http://www.wellnessresources.com/weight/articles/fiber_fish_oil_exercise_boost_adiponectin/
  4. http://www.shape.com/weight-loss/weight-loss-strategies/8-essential-fat-loss-hormones?page=3
  5. http://care.diabetesjournals.org/content/27/2/629.full
  6. http://www.hindawi.com/journals/jnume/2012/148729/
  7. http://www.ncbi.nlm.nih.gov/pubmed/18601853
  8. http://www.ncbi.nlm.nih.gov/pubmed/20980258
  9. http://www.ncbi.nlm.nih.gov/pubmed/19892350

Test Description

Adipose (fat) tissue has a number of functions. In addition to its role as a storage form of energy, adipose tissue is a highly active endocrine organ that coordinates multiple hormonal, metabolic, inflammatory, and neurohumoral activities.1,2 Adipocytes produce and secrete a variety of bioactive proteins into the bloodstream, collectively called adipocytokines, including leptin, tumor necrosis factor (TNF)-α and other cytokines, plasminogen-activator inhibitor type 1 (PAI-1), resistin, apelin, retinol binding protein 4 (RBP4), and adiponectin.2

Adiponectin is a 247-amino-acid protein produced almost exclusively by adipocytes, although low level expression can also be detected in skeletal muscle, cardiac muscle, and liver.3,4 It belongs to the collagen superfamily and exists either as a full-length 30 kDa protein or as smaller globular fragments, with the full-length monomer produced primarily by adipocytes.2,3

Circulating adiponectin monomers assemble to form several multimeric forms, including high-molecular weight (MW) oligomers, a medium-MW hexamer, and low-MW trimer. The different multimeric forms individually range in concentration from 2-30 μg/mL in the bloodstream, and may exert different biological actions.5-7 Adiponectin plays an important role in both insulin action and cardiovascular health. Cellular actions of adiponectin are mediated via specific receptors AdipoR1 and AdipoR2.8

AdipoR1 are expressed ubiquitously, with particularly high levels in skeletal muscle, while AdipoR2 expression occurs predominantly in liver.8 Both receptors are expressed in cardiac tissue.9 Both AdipoR1 and AdipoR2 activate the APPL1-AMP kinase signaling cassette in different tissues.

Adiponectin-mediated AMPK activation leads to suppression of gluconeogenic enzymes in liver and enhances fatty acid β-oxidation in both liver and muscle, counteracting the lipotoxic effects of obesity and type-2 diabetes that lead to insulin resistance in those tissues.10 Adiponectin may also directly enhance GLUT4 translocation in muscle via APPL1 signaling.11,12

In addition, adiponectin exerts protective cardiovascular effects by enhancing endothelial function and inhibiting atherogenesis through multiple mechanisms.13,14 In the heart, adiponectin helps to prevent left ventricular hypertrophy and ischemia-reperfusion injury, and enhances healthy myocardial remodeling in the post-MI period. Recent evidence suggests that adiponectin may also support the function and longevity of pancreatic β cells.15

Adiponectin testing is performed by enzyme-linked immunosorbent assay (ELISA), with risk ranges:

  • High risk < 10 μg/mL
  • Intermediate risk 10-14 μg/mL
  • Optimal > 14 μg/mL.

Clinical Interpretation

Clinical and experimental studies show that low concentrations of adiponectin (hypoadiponectinemia) may contribute to type-2 diabetes mellitus (T2DM) and cardiovascular disease. Decreased plasma adiponectin levels occur in genetic and diet-induced rodent models of obesity, as well as in human diseases associated with insulin resistance.16-19 This is in contrast to most other adipocytokines, whose levels are increased in these conditions, often in proportion to increased fat mass.

In cross-sectional studies, adiponectin has consistently been correlated with elements of the metabolic syndrome: plasma levels decrease as abdominal adiposity, plasma glucose, HbA1C, and measurements of insulin resistance increase.6 Recent studies have demonstrated that adiponectin may be one of most consistently reliable indicators of risk for incident type 2 diabetes among nondiabetic individuals. Importantly, the association of adiponectin with type-2 diabetes risk is independent of most other traditional risks, including age, family history of type-2 diabetes, height, waist circumference, resting heart rate, hypertension, HDL cholesterol, triglycerides, fasting glucose and serum uric acid.20

Euglycemic-hyperinsulinemic clamp studies in both humans and rats demonstrate that insulin itself can exert an acute effect to suppress adiponectin production by adipocytes; therefore chronic hyperinsulinemia may be an important factor leading to reduced adiponectin production in insulin-resistant states.21 In addition, certain genetic polymorphisms of the adiponectin gene that affect protein expression may contribute to reduced adiponectin levels and increased risk for type-2 diabetes.22,23 Men generally have lower adiponectin levels than women, possibly due to androgen effects21,24,25 and levels are also influenced by ethnicity.25

Recent large trials demonstrate that adiponectin levels are also an important indicator of risk for major adverse cardiovascular events and all-cause mortality.26 Low adiponectin adds risk that is independent of all other traditional cardiovascular risk factors (e.g., Framingham and Reynolds-type risk) and quantitative in nature: one study demonstrated a step-wise 20% increase in cardiovascular events/death for every 5 ug/mL reduction in plasma adiponectin levels.

These findings confirm an extensive prior body of knowledge from smaller studies in which adiponectin has been associated with different aspects of increased cardiovascular risk. Plasma adiponectin levels are lower in diabetic patients who also have coronary artery disease (CAD) than in those without CAD, indicating that adiponectin may have anti-atherogenic properties.27 The incidence of cardiovascular death has also been found to be higher in patients with renal failure who have low adiponectin levels, indicating that the relationship remains valid even when renal function may be impaired.24,28

Adiponectin inhibits proliferation of vascular smooth cells and is abundant in the vascular intima of catheter injured vessels.29,30 Adiponectin decreases the surface expression of vascular adhesion molecules that modulate endothelial inflammatory responses and suppresses macrophage-foam cell transformation in vitro.29,31

Consistent with its anti-inflammatory actions, adiponectin concentrations are inversely correlated to high-sensitivity C-reactive protein (hs-CRP; a marker of inflammation) and coronary atherosclerosis.20 Importantly, adiponectin appears to protect against myocardial infarction, independently of CRP or glycemic status in patients with atherosclerosis.32,33

In other clinical studies, low adiponectin levels have been associated with essential hypertension and an atherogenic lipid profile.27,34,35 Adiponectin influences plasma lipoprotein profiles by altering the levels and activity of key enzymes (lipoprotein lipase and hepatic lipase) responsible for the catabolism of triglyceride-rich lipoproteins and high-density lipoprotein (HDL), thus influencing atherosclerosis by affecting the balance of atherogenic and anti-atherogenic lipoproteins in plasma. Several studies have reported a significant negative correlation between circulating adiponectin and triglyceride levels, and a positive correlation between adiponectin and HDL cholesterol (HDL-C), in both diabetic and non-diabetic individuals.6,27,34

Treatment Considerations

There is increasing evidence to support the notion that adiponectin not only has diagnostic/prognostic value but should also be considered a therapeutic target.36-38 Since a decrease in adiponectin levels may precede development of other markers of insulin resistance, early initiation of therapy could potentially halt or reverse the progression of metabolic or cardiovascular disease associated with low adiponectin. Lifestyle modification, visceral fat reduction, and certain medications can both increase serum adiponectin levels and improve insulin sensitivity, thus helping to prevent both type 2 diabetes and cardiovascular disease.2 Certain lipid-lowering drugs, such as niacin and fibrates— which primarily lower triglycerides and increase HDL-C level— also increase adiponectin levels, typically in proportion to the extent of change in HDL-C and triglycerides. In general, thiazolidinedione peroxisome proliferator-activated receptor (PPAR) gamma agonists (e.g., pioglitazone or Actos) increase adipocyte adiponectin production and circulating adiponectin levels. However, it is not known whether this benefit outweighs some of the cardiac risks associated with thiazolidinediones. Specific agonists of adiponectin receptors are currently in preclinical phases of development.6,39,40

If FPG and HbA1c are abnormal, follow therapeutic guidelines of the American Diabetes Association. The following lifestyle recommendations and medications can be used to reduce insulin resistance and improve β-cell function, personalized to the individual patient’s clinical needs.

Lifestyle:41-47

  • Limit carbohydrates (especially simple sugars and processed carbohydrates) while maintaining moderate fat intake
  • Weight loss (as appropriate)
  • Regular exercise (150 minutes/week combining cardiovascular activity at a moderate-to-vigorous pace with resistance training)

Medication choices may include:

  • Metformin (e.g., Glucophage®, Glumetza®)
  • Pioglitazone (Actos®)
  • Incretin mimetics (GLP-1 agonists)
  • DPP-4 inhibitors
  • Quick-release bromocriptine mesylate (Cycloset®)
  • Alpha-glucosidase inhibitors (acarbose)

NOTE: No medications are currently FDA approved for the treatment of insulin resistance or β-cell dysfunction. Insulin may be considered for the treatment of hyperglycemia meeting ADA criteria for diabetes but should NOT be used in the setting of insulin resistance without diabetes or in prediabetes due to the potential for hypoglycemia.48 Patients who are taking metformin are at increased risk for vitamin B12 deficiency and may benefit from sublingual vitamin B12 supplementation.49

References

1. Kershaw EE, Flier JS. Adipose tissue as an endocrine organ. J Clin Endocrinol Metab 2004;89(6):2548-56.

2. Chandran M, Phillips SA, et al. Adiponectin: more than just another fat cell hormone? Diabetes Care 2003;26(8):2442-50.

3. Kadowaki T, Yamauchi T. Adiponectin and adiponectin receptors. Endocr Rev 2005;26(3):439-51.

4. Pineiro R, Iglesias MJ, et al. Adiponectin is synthesized and secreted by human and murine cardiomyocytes. FEBS Lett 2005;579(23):5163-9.

5. Yamauchi T, Kamon J, et al. Adiponectin stimulates glucose utilization and fatty-acid oxidation by activating AMP-activated protein kinase. Nat Med 2002;8(11):1288-95.

6. Yamauchi T, Kamon J, et al. Cloning of adiponectin receptors that mediate antidiabetic metabolic effects. Nature 2003;423(6941):762-9.

7. Schraw T, Wang ZV, et al. Plasma adiponectin complexes have distinct biochemical characteristics. Endocrinology 2008;149(5):2270-82.

8. Giannessi D, Maltinti M, et al. Adiponectin circulating levels: a new emerging biomarker of cardiovascular risk. Pharmacol Res 2007;56(6):459-67.

9. Lara-Castro C, Fu Y, et al. Adiponectin and the metabolic syndrome: mechanisms mediating risk for metabolic and cardiovascular disease. Curr Opin Lipidol 2007;18(3):263-70.

10. Fujioka D, Kawabata K, et al. Role of adiponectin receptors in endothelin-induced cellular hypertrophy in cultured cardiomyocytes and their expression in infarcted heart. Am J Physiol Heart Circ Physiol 2006;290(6):H2409-16.

11. Cheng KK, Lam KS, et al. Adiponectin-induced endothelial nitric oxide synthase activation and nitric oxide production are mediated by APPL1 in endothelial cells. Diabetes 2007;56(5):1387-94.

12. Mao X, Kikani CK, et al. APPL1 binds to adiponectin receptors and mediates adiponectin signalling and function. Nat Cell Biol 2006;8(5):516-23.

13. Nanayakkara G, Kariharan T, et al. The cardio-protective signaling and mechanisms of adiponectin. Am J Cardiovasc Dis 2012;2(4):253-66.

14. Villarreal-Molina MT, Antuna-Puente B. Adiponectin: anti-inflammatory and cardioprotective effects. Biochimie 2012;94(10):2143-9.

15. Dunmore SJ, Brown JE. The role of adipokines in beta-cell failure of type 2 diabetes. J Endocrinol 2013;216(1):T37-45.

16. Yamauchi T, Kamon J, et al. The fat-derived hormone adiponectin reverses insulin resistance associated with both lipoatrophy and obesity. Nat Med 2001;7(8):941-6.

17. Arita Y, Kihara S, et al. Paradoxical decrease of an adipose-specific protein, adiponectin, in obesity. Biochem Biophys Res Commun 1999;257(1):79-83.

18. Weyer C, Funahashi T, et al. Hypoadiponectinemia in obesity and type 2 diabetes: close association with insulin resistance and hyperinsulinemia. J Clin Endocrinol Metab 2001;86(5):1930-5.

19. Lilja M, Rolandsson O, et al. The impact of leptin and adiponectin on incident type 2 diabetes is modified by sex and insulin resistance. Metab Syndr Relat Disord 2012;10(2):143-51.

20. Marques-Vidal P, Schmid R, et al. Adipocytokines, hepatic and inflammatory biomarkers and incidence of type 2 diabetes. the CoLaus study. PLoS ONE 2012;7(12):e51768.

21. Hotta K, Funahashi T, et al. Plasma concentrations of a novel, adipose-specific protein, adiponectin, in type 2 diabetic patients. Arterioscler Thromb Vasc Biol 2000;20(6):1595-9.

22. Westphal S, Borucki K, et al. Adipokines and treatment with niacin. Metabolism 2006;55(10):1283-5.

23. Nakamura T, Kodama Y, et al. Increase in circulating levels of adiponectin after treatment with statin and fibrate in patients with coronary artery disease and hyperlipidemia. Atherosclerosis 2007;193(2):449-51.

24. Arita Y, Kihara S, et al. Adipocyte-derived plasma protein adiponectin acts as a platelet-derived growth factor-BB-binding protein and regulates growth factor-induced common postreceptor signal in vascular smooth muscle cell. Circulation 2002;105(24):2893-8.

25. Spranger J, Kroke A, et al. Adiponectin and protection against type 2 diabetes mellitus. Lancet 2003;361(9353):226-8.

26. Lindberg S, Mogelvang R, et al. Relation of serum adiponectin levels to number of traditional atherosclerotic risk factors and all-cause mortality and major adverse cardiovascular events (from the Copenhagen City Heart Study). Am J Cardiol 2013;111(8):1139-45.

27. Ouchi N, Kihara S, et al. Novel modulator for endothelial adhesion molecules: adipocyte-derived plasma protein adiponectin. Circulation 1999;100(25):2473-6.

28. Adamczak M, Wiecek A, et al. Decreased plasma adiponectin concentration in patients with essential hypertension. Am J Hypertens 2003;16(1):72-5.

29. Matsubara M, Maruoka S, et al. Decreased plasma adiponectin concentrations in women with dyslipidemia. J Clin Endocrinol Metab 2002;87(6):2764-9.

30. Zoccali C, Mallamaci F, et al. Adiponectin, metabolic risk factors, and cardiovascular events among patients with end-stage renal disease. J Am Soc Nephrol 2002;13(1):134-41.

31. Okamoto Y, Arita Y, et al. An adipocyte-derived plasma protein, adiponectin, adheres to injured vascular walls. Horm Metab Res 2000;32(2):47-50.

32. Valsamakis G, Chetty R, et al. Fasting serum adiponectin concentration is reduced in Indo-Asian subjects and is related to HDL cholesterol. Diabetes Obes Metab 2003;5(2):131-5.

33. Yu JG, Javorschi S, et al. The effect of thiazolidinediones on plasma adiponectin levels in normal, obese, and type 2 diabetic subjects. Diabetes 2002;51(10):2968-74.

34. Matsuda M, Shimomura I, et al. Role of adiponectin in preventing vascular stenosis. The missing link of adipo-vascular axis. J Biol Chem 2002;277(40):37487-91.

35. Vasseur F, Meyre D, et al. Adiponectin, type 2 diabetes and the metabolic syndrome: lessons from human genetic studies. Expert Rev Mol Med 2006;8(27):1-12.

36. Pischon T, Girman CJ, et al. Plasma adiponectin levels and risk of myocardial infarction in men. JAMA 2004;291(14):1730-7.

37. Persson J, Lindberg K, et al. Low plasma adiponectin concentration is associated with myocardial infarction in young individuals. J Intern Med 2010;268(2):194-205.

38. Pischon T, Rimm EB. Adiponectin: a promising marker for cardiovascular disease. Clin Chem 2006;52(5):797-9.

39. Mangge H, Almer G, et al. Inflammation, adiponectin, obesity and cardiovascular risk. Curr Med Chem 2010;17(36):4511-20.

40. Smith CC, Yellon DM. Adipocytokines, cardiovascular pathophysiology and myocardial protection. Pharmacol Ther 2011;129(2):206-19.

41. Mirza NM, Palmer MG, et al. Effects of a low glycemic load or a low-fat dietary intervention on body weight in obese Hispanic American children and adolescents: a randomized controlled trial. Am J Clin Nutr 2013;97(2):276-85.

42. Yki-Jarvinen H. Nutritional modulation of nonalcoholic fatty liver disease and insulin resistance: human data. Curr Opin Clin Nutr Metab Care 2010;13(6):709-14.

43. Bradley U, Spence M, et al. Low-fat versus low-carbohydrate weight reduction diets: effects on weight loss, insulin resistance, and cardiovascular risk: a randomized control trial. Diabetes 2009;58(12):2741-8.

44. Ross R, Janssen I, et al. Exercise-induced reduction in obesity and insulin resistance in women: a randomized controlled trial. Obes Res 2004;12(5):789-98.

45. O’Hagan C, De Vito G, et al. Exercise prescription in the treatment of type 2 diabetes mellitus : current practices, existing guidelines and future directions. Sports Med 2013;43(1):39-49.

46. Davidson LE, Hudson R, et al. Effects of exercise modality on insulin resistance and functional limitation in older adults: a randomized controlled trial. Arch Intern Med 2009;169(2):122-31.

47. Williams MA, Haskell WL, et al. Resistance exercise in individuals with and without cardiovascular disease: 2007 update: a scientific statement from the American Heart Association Council on Clinical Cardiology and Council on Nutrition, Physical Activity, and Metabolism. Circulation 2007;116(5):572-84.

48. Aguilar RB. Evaluating treatment algorithms for the management of patients with type 2 diabetes mellitus: a perspective on the definition of treatment success. Clin Ther 2011;33(4):408-24.

49. Moore EM, Mander AG, et al. Increased risk of cognitive impairment in patients with diabetes is associated with metformin. Diabetes Care 2013;36(10):2981-7.