Insulin resistance and childhood diabetes (healthy under the skin your in)

Background Information

There is an increasing trend in the incidence of type-2 diabetes in children and adolescents in many populations around the world including Australia. The increase in type-2 diabetes is often paralleled by an increase in body mass in the same population, but this is not predictive. The reason for this association is not yet completely understood but appears to be linked with decreased production of an important molecule called adiponectin by white adipose tissue (i.e. fat cells or adipocytes).

White adipose tissue (WAT) stores energy in the form of triglycerides during nutritional abundance and releases energy as free fatty acids during nutritional deprivation.¹ This has advantages for times of starvation but disadvantages during times of nutritional plenty. WAT is also a major endocrine organ producing a range of biologically active molecules called adipocytokines. These molecules appear to influence the function as well as the structural integrity of other tissues.² Included in these are adiponectin, leptin and resistin.

Leptin and resistin concentrations both positively correlate with obesity and insulin resistance (IR) while adiponectin is inversely correlated. Importantly, while serum adiponectin levels are inversely related to adiposity amongst adults³ and children⁴ the differences are more marked amongst women compared to men.⁵

Despite this difference, serum adiponectin levels are associated with adiposity, type 2 diabetes and cardiovascular disease in both genders.⁶ Adiponectin is negatively regulated in obesity and negatively correlated with serum leptin concentration, fasting insulin, insulin resistance,⁷ body mass index, systolic and diastolic blood pressure, fasting plasma glucose, total and low-density lipoprotein-cholesterol, triglycerides and uric acid but positively correlated with high-density lipoprotein-cholesterol.⁵ This suggests a positive role for adiponectin in the maintenance of cardiovascular health.

Adiponectin appears to exert its effect in reducing insulin resistance by decreasing plasma fatty acid and triglyceride levels in muscle and liver cells.^8-9

Chronic inflammation is also a hallmark of obesity, and inflammatory changes correlate with adverse health outcomes. As the adipocytes enlarge, cell metabolism is altered promoting the recruitment of macrophages and production of proinflammatory cytokines such as TNF-. In addition to its positive contribution to markers of both diabetes type 2 and vascular health adiponectin has also been shown to down-regulate mediators of inflammation such as TNF- and induce anti-inflammatory cytokines such as IL-10.¹⁰

While adiponectin can promote vascular health, reduce markers of inflammation and promote insulin sensitivity in humans, little is known about the mechanisms controlling production of this important adipokine.

Weight loss amongst obese¹¹ and insulin-resistant⁶ individuals as well as treatment with insulin-sensitizing drugs such as thiazolidinediones¹² has been shown to increase adiponectin levels. The control of adiponectin release by adipocytes is not currently well understood, but is likely to involve peroxisome proliferator-activated receptor gamma (PPAR-γ) receptor activity, which is the master regulator of adipocyte differentiation and controls many adipocyte genes.

One study examined the role of caloric intake in adiponectin production and found that an intensive lifestyle modification program with caloric restriction and structured exercise amongst obese subjects with insulin resistance resulted in increased adiponectin levels.¹³ While studies on the effect of selected dietary components are essentially absent in humans, the effect of diet has been more extensively examined in rodents. Neschen et al¹⁴ have reported that fish oils will increase adiponectin secretion from adipocytes through a PPARγ-dependant mechanism.

In mice fed a high-fat diet plasma adiponectin levels decreased significantly resulting in insulin resistance and hypertriglyceridemia.⁹ Furthermore, adiponectin-deficient mice developed mild insulin sensitivity on a standard diet¹⁵ but severe insulin resistance when fed a high-fat, high sucrose diet.¹⁶ No studies have correlated serum adiponectin levels to consumption of specific food groups or lifestyle patterns. Our group has previously identified an apparent reduction in insulin resistance in adolescents who consume nuts regularly (publication in progress), and is currently studying the association between vegetable rich diets and adiponectin levels in an adult female population. This present study will examine the effect of specific food groups and exercise patters on serum adiponectin levels in an adolescent female population.

Research in this area will contribute to the identification of healthy food choices, allowing health promotion to concentrate not so much on the reduction of weight, but rather more importantly, on including those foods in the diet that will keep adiponectin production high, (i.e. what foods keep the fat cells healthy?).

Study Aims

• To quantitate serum adiponectin levels and other recognised measures of metabolic syndrome (associated with type-2 diabetes) in adolescent females.
• To correlate adiponectin levels to consumption of selected foods (including nuts, vegetables, fruits, whole grains, oils, fish, meat, dairy etc) and average degree of physical activity.

References

1. Kadowaki, T. et al. J Clin Invest 116, 1784-1792 (2006)
2. Diez, J.J. et al. Europ J Endocrin 148, 293-300 (2003)
3. Arita, Y. et al. Biochem Biophys Res Comm 257, 79-83 (1999)
4. Stefan, N. et al. J Clin Endocr Met 87, 4652-4656 (2002)
5. Yamamoto, Y. et al. Clinical Sci 103, 137-142 (2002)
6. Hotta, K. et al. Arterioscl Throm Vas Biol 20, 1595-1599 (2000)
7. Matsubara, M. et al. Europ J Endocrin 147, 173-180 (2002)
8. Fruebis, J. et al. Proc Natl Acad Sci 98, 2005-2010 (2001)
9. Yamauchi, T. et al. Nat Med 7, 941-946 (2001)
10. Tilg, H. et al. Exp Opin Ther Targets 9, 245-251 (2005)
11. Yang, W.S. et al. J Clin Endocr Met 86, 3815-3819 (2001)
12. Combs, T.P. et al. Endocrinology 143, 998-1007 (2002)
13. Monzillo, L.U. et al. Obes Res 11, 1048-1054 (2003)
14. Neschen, S. et al. Diabetes 55, 924-928 (2006)
15. Kubota, N et al. J Biol Chem 277, 25863-25866 (2002)
16. Maeda, K. et al. Biochem Biophys Res Comm 221, 286-289 (1996)