Diabetes in the Elderly: The Power of the Mitochondria

The Mighty Mitochondria

Mitochondria create energy from fats and sugar so our cells and our bodies can do their work. In essence, the food we eat is broken down by our bodies into small constituent parts, such as glucose from sugar, and fatty acids from fats. Unlike some other molecules, glucose and fatty acids are small enough to pass directly into individual cells. Once in the cell, they are transported to the mitochondria. The mitochondria then metabolize them through a series of chemical steps. These steps are very complicated, involving many proteins, enzymes, and signaling triggers. When the body does not need all the energy it receives, the glucose and fatty acids are stored as fat.

Insulin Resistance

Diabetes investigators, however, believe that stored fat in the body may lead to a condition known as insulin resistance, which is the first step towards the development of type 2 diabetes . When someone has insulin resistance they feel well and their blood sugars typically remain below the levels at which diabetes can be diagnosed. In normal cells, insulin helps to regulate glucose transport, whereas in insulin resistant cells, glucose transport is impaired. Even if normal while fasting, the blood sugar of persons with insulin resistance may rise excessively following a meal.

Insulin resistance often also leads to serious metabolic abnormalities including elevation of blood fats (triglycerides) and lowering of heart-protecting forms of cholesterol (HDL). All of these metabolic changes occur because the body’s cells fail to respond completely to the normal (or often high levels) of insulin produced in response to food intake. Insulin resistance can exist for many years before progressing to type 2 diabetes, which is characterized by high blood sugars and complications like heart disease, stroke , and kidney disease. Many of these complications may be “incubating” during the long period of insulin resistance before diabetes is diagnosed. There are many risk factors for developing diabetes from insulin resistance including older age, obesity, a sedentary lifestyle, and genetic predisposition.

In most cases, insulin resistance is caused by fat tissue accumulating around the waist. There is, as yet, little certainty about precisely how this fat accumulation leads to the development of insulin resistance. Recently some scientists have come to believe that fat stored within cells is importantly linked to the development of insulin resistance.

The Mitochondria and Insulin Resistance

Since the mitochondria are the headquarters of glucose and fatty acid metabolism, current research has honed in on the mitochondria as the potential seat of the problem of insulin resistance. Gerald Shulman, MD, PhD, a professor at Yale University School of Medicine, has been studying mitochondria for over a decade. Some of his work looks at the association of stored fat and insulin resistance in cells. More recently, he and colleagues looked at mitochondrial function in older people. “The real question we had,” says Shulman, “was 'what’s happening to us as we age?'”

Shulman and colleagues decided to compare thin, healthy young people to thin, healthy older people to see if there were differences in mitochondrial activity related to aging alone. They found that the 70-year olds, even though they appeared as fit and trim as the younger people, had more fat stored in their cells and more insulin resistance. “The question then became ‘why is the fat building up in the cell?’” he says.

Further chemical analyses showed that the mitochondria in the 70-year olds were not nearly as active as the mitochondria in the younger people. Putting all the data together, Shulman and colleagues surmised that we lose mitochondrial activity as we age. And, as we lose mitochondrial activity, fat stores may increase, triggering insulin resistance—perhaps even in people who are not judged to be overweight. Although Shulman says this decreased mitochondrial activity appears to be part of the aging process, we don’t have to despair that insulin resistance and diabetes is our unalterable fate. The link between mitochondrial activity and insulin resistance is likely only one step on the road to diabetes.

Exercise and the Mitochondria

Looking at the role of mitochondrial activity also lends hope of finding factors that may reduce the risk of developing diabetes. Recent data shows that many mitochondrial enzymes actually become more active after exercise. For example, Shulman and others have been studying an enzyme called AMP kinase. When they tested animals after exercise, they found increased AMP kinase levels. Increased AMP kinase in cells causes more fatty acids to be metabolized by the mitochondria. With more fatty acids metabolized, there is less stored fat, which should yield less insulin resistance.

Further, the association between exercise and increased mitochondrial activity may involve more than just revving up certain enzymes. “It is quite clear,” says Shulman, “that when you biopsy young marathon runners, they have more mitochondria than someone who doesn’t run marathons.” However, why this happens is not yet known. Many researchers are studying how exercise affects mitochondrial activity and how exercise may reduce the risk of developing diabetes. It is likely that the effects of exercise occur through many pathways including increased mitochondrial activity.

In sum, the role of mitochondria in the development of diabetes is still being worked out, but every new insight brings us closer to understanding this complicated disease and its prevention. Maintaining normal weight, a good diet with plenty of fruits and vegetables, and a life-long program of fitness and exercise should reduce your risk of developing both insulin resistance and diabetes. Your health should benefit greatly from these choices, and so—if current research is any indication—will your mitochondria.

RESOURCES:

American Diabetes Association
http://www.diabetes.org

National Institutes of Diabetes and Digestive and Kidney Diseases
http://www.niddk.nih.gov

References:

Conquering diabetes: highlights of program efforts, research, advances, and opportunities. National Institutes of Health, National Institute of Diabetes and Digestive and Kidney Diseases. 2002. No. 02-5137.

Diabetes in America. 2nd ed. National Diabetes Data Group. National Institutes of Health, National Institute of Diabetes and Digestive and Kidney Diseases. 1995. No. 95-1468.

Petersen KF, Befroy D, Dufour S, et al. Mitochondrial dysfunction in the elderly: possible role in insulin resistance. Science. 2003;300:1140-1142.

Recent Advances and Emerging Opportunities: Diabetes, Endocrinology, and Metabolic Diseases. National Institutes of Health, National Institute of Diabetes and Digestive and Kidney Diseases. 2003.

Ruderman NB, Cacicedo JM, Itani S, et al. Malonyl-CoA and AMP-activated protein kinase (AMPK): possible links between insulin resistance in muscle and early endothelial cell damage in diabetes. Biochem Soc Trans. 2003;31:202-206.

Short KR, Vittone JL, Bigelow ML, et al. Impact of aerobic exercise training on age-related changes in insulin sensitivity and muscle oxidative capacity. Diabetes. 2003;52:1888-1896.

Womack C. Diabetes, obesity, and fatty acid metabolism. Academy eBriefings. New York Academy of Sciences website. Available at: http://www.nyas.org/publications/ebrief.cfm. Accessed January 6, 2004.

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