Insulin, Obesity, and Exercise Relationships to Type-2 Diabetes

Introduction
People with type-2 diabetes are characterized by insulin resistance. Their bodies produce enough insulin but they have an impaired ability to move glucose into their cells. Exercise is commonly prescribed as a treatment for those suffering from type-2 diabetes. In addition to the cardiovascular benefits associated with exercise, blood glucose levels are lowered in type-2 diabetics with chronic exercise as their cells are better able to take up glucose. But did you ever wonder why this occurs? After all, if type-2 diabetics are considered "insulin resistant", then why does exercise help lower blood glucose levels? This article will go over the pathology of type-2 diabetes as well as provide a short summary on how and why exercise is beneficial for type-2 diabetics.

Pathology and Physiology
Your skeletal muscle and liver are the two primary organs responsible for maintaining normal blood glucose (1). In a normal person, high blood glucose (primarily from a high carbohydrate or sugary meal) stimulate insulin to be secreted from the pancreas. Insulin then stimulates the movement of glucose transporters, known as GLUT4 transporters, to the surface of their cells to move glucose from the blood into their cells, thus reducing blood glucose levels.

Type-2 diabetics exhibit insulin resistance. Insulin is not able to stimulate as many GLUT4 transporters to the surface of their cells, especially muscle cells (2). This prevents their cells from taking in more glucose and leads them to a chronic state of hyperglycemia, or a constant elevated blood glucose level. Type-2 diabetics are also hyperinsulinemic, meaning their bodies keep producing insulin in response to hyperglycemia in an effort to remove glucose from their blood. But because of insulin's limited effect on GLUT4 transporters, this is only marginally effective and blood glucose levels remain high.

Chances are a type-2 diabetic is also obese, which further exacerbates the problem because obesity has been linked to a decrease in fatty acid oxidation (5, 6), the use of fats to generate energy. This leads to a buildup of fats in cells (especially muscles) and this is thought to inhibit insulin from stimulating GLUT4 transporters to move to the cell surface to take up glucose (1). Research has shown fat content within muscle is negatively related to insulin and whole-body glucose uptake (3).

Furthermore, type-2 diabetics have a reduced amount of a protein known as mitochondrial uncoupling-protein 3 (UCP-3) in their cells (4). UCP-3 protects the mitochondria (energy producing centers of a cell) from damage by accumulated fatty acids (4). Mitochondria play a crucial role in fatty acid oxidation and the conversion of fats to energy. Damage to mitochondria will lead to fewer fats able to be converted to energy, and more available to inhibit insulin's effect on GLUT4.

Some may point out high performance endurance athletes, such as marathon runners and cyclists, also have a high fat content in their muscle cells and this has been linked to an increase in insulin sensitivity and glucose uptake within these individuals (7). However, insulin resistance is linked to the location of fat in the body, especially in the abdominal region (4). And it is unlikely high performance endurance athletes will have a significant amount of abdominal fat. Thus the locations of fat, as well as the accumulation of fat, have a detrimental effect on the action of insulin to mobilize GLUT4 transporters and lower blood glucose levels.

Effects of Exercise
So how does exercise affect diabetes? The first reason is exercise increases fatty acid oxidation and subsequently decreases the amount of fatty acids available to inhibit insulin's action on GLUT4. This allows more GLUT4 to migrate to the surface of the cell and reduce blood glucose levels. We know fatty acid oxidation increases regardless if an individual is type-2 diabetic or not (5,8). This implies more fats are going to the mitochondria for conversion to energy, which reduces the inhibitory action of fats on insulin and GLUT4 mobilization. In addition, this probably reduces the effect of accumulated fats on mitochondrial damage in type-2 diabetics, allowing them to have a slightly improved ability for fatty acid oxidation.

Not to mention, exercise over time will reduce the amount of abdominal fat in the body. And since abdominal fat is linked to type-2 diabetes (4), reduction of abdominal fat will significantly improve their insulin sensitivity and their ability to lower blood glucose levels.

The second, and recently theorized reason, is that active muscle contraction through exercise increases expression of the gene regulating GLUT4 transporters (9). What this means is as you conduct exercise, the movement and activity of your muscles causes them to produce more and more GLUT4 transporters. These newly created transporters then migrate to the cell surface and promote glucose uptake, again lowering blood glucose levels. However, this is a relatively new theory and it looks like this mechanism of action is independent of insulin. More research is needed in this area to either support, or debunk this theory.

Summary
Insulin resistance in type-2 diabetics is due to their inability to mobilize GLUT4 transporters from their cell interior to the cell surface. However, with continuous exercise, type-2 diabetics can improve their overall health. Exercise promotes the mobilization of GLUT4 transporters through muscle contraction and increases use of fats for energy, which leads to a decrease in high blood glucose levels in type-2 diabetics and improving their overall well-being.

References

1. Lowell, B. B., Shulman, G.I., Mitochondrial Dysfunction and Type 2 Diabetes, Science, Vol. 307, pg. 384-387, 2005

2. Kelley, D.E., Mintun, M.A., Watkins, S.C., Simoneau, J.-Aime, Fayegh, J., Fredrickson, A., Beattie, J., Theriault, R. The Effect of Non-Insulin-dependent Diabetes Mellitus and Obesity on Glucose Transport and Phosphorylation in Skeletal Muscle, The Journal of Clinical Investigation, Vol. 97, pg. 2705-2713, 1996

3. Krssak, M., Petersen, F., Dresner, A., DiPietro, S., Vogel, S.M., Rothman, D.L, Shulman, G.I., Roden, M., Intramyocellular Lipid Concentrations are Correlated with Insulin Sensitivity in Humans: A ¹H NMR Spectroscopy Study, Diabetologia, Volume 42, pg 113-116, 1999

4. Rattarasarn, C., Physiological and Pathophysiological Regulation of Regional Adipose Tissue in the Development of Insulin Resistance and Type-2 Diabetes, Acta Physiologica, Vol. 186, pg 87-101, 2006

5. Thyfault, J.P., Kraus, R.M., Hickner, R.C., Howell, A.W., Wolfe, R.R., Dohm, G.L., Imparied Plasma Fatty Acid Oxidation in Extremely Obese Women, American Journal of Physiology. Endocrinology and Metabolism, Vol. 287, pg 1076-1081, 2004

6. Mensink, M., Blaak, E.E., Baak, M.A., Wagenmakers, A.J.M., Saris, W.H.M., Plasma Free Fatty Acid Uptake and Oxidation Are Already Diminished in Subjects at High Risk for Developing Type 2 Diabetes, Diabetes, Vol. 50, pg. 2548-2554, 2001

7. Van Loon, L.J.C., Koopman, R., Manders, R., Van der Weegen, W., Van Kranenberg, G.P., Keizer, H.A, Intramyocellular Lipid Content in Type 2 Diabetes Patients Compared with Overnight Sedentary Men and Highly Trained Endurance Athletes, American Journal of Physiology. Endocrinology and Metabolism, Vol. 287, pg 558-565, 2004

8. Borghouts, L. B., Wagenmakers, A. J. M., Goyens, P. L. L., Keizer, H. A., Substrate utilization in non -obese Type II diabetic patients at rest and during exercise, Clincal Science, Vol. 103, pg. 559-556, 2002

9. Holmes, B., Dohm, G. Lynis, Regulation of GLUT4 Gene Expression during Exercise. Medicine & Science in Sports & Exercise, Vol. 36, pg. 1202-1206, 2004