16th World Congress on Insulin Resistance, Diabetes & Cardiovascular Disease :

Metformin May Lessen Diabetes Complications, Improve Cognitive Decline

With Derek LeRoith, MD, PhD

Statistics reflect an increasing prevalence of diabetes with age. While 2.2% of the adults, 18 to 44 years of age, have been diagnosed with diabetes, more than 25% of those 65 years of age and older are living with this disease,1 according to the Centers for Disease and Prevention.

“And that number is expected to grow as time goes on," said Derek LeRoith, MD, PhD, professor of medicine and director of research in the division of endocrinology at Mount Sinai Hospital and Icahn School of Medicine in New York City. 

This is noteworthy because these aging patients face a higher mortality rate, functional limitations, and greater comorbidities.3 With that as an introduction, Dr. LeRoith addressed the causality, associated complications, and potential therapeutics that are most beneficial to patients who are facing greater health challenges with advancing age, 2 in a presentation at the 16th World Congress on Insulin Resistance Diabetes & Cardiovascular Disease in Los Angeles, California.

Aging is met with many physiological changes, including weight gain, decreased glucose tolerance, increased insulin resistance, and declining beta cell function, regardless of diabetes status.3

Dr. LeRoith listed the following factors as the primary drivers that predispose the elderly to develop type 2 diabetes (T2D):2

  • Coexisting illness
  • Genetics influences
  • Certain medications
  • Decreased physical activity
  • Rising adiposity
  • Declining insulin secretion
  • Increasing insulin resistance

Concomitant Medical Issues that Arise in Older Patients with Diabetes

Older adults diagnosed with diabetes face major issues, including cognitive problems, sarcopenia, falls, hypoglycemia and polypharmacy, 2 Dr. LeRoith said.

Of particular concern to many, cognitive decline is exacerbated by the effect of diabetes with aging, he said. Hypoglycemia, hyperglycemia, insulin resistance, and insulin insufficiency, all have an adverse effect on cognitive function.3,4

Type 2 diabetes, in particular, has been linked with impaired insulin signaling, vascular damage, neuroinflammation, tau hyperphosphorylation, and amyloid-beta accumulation,2 he continued.

"It's not just the insulin resistance per se, but also defects in beta cell activity," Dr. LeRoith told EndocrineWeb, likely due to the effects of long-standing diabetes over many years.

Citing his own research,4 he indicated that trajectories in glycemic control over time have been linked with cognitive performance in the elderly with T2D. In a study of 835 adults with type 2 diabetes, those with stable hemoglobin A1c (HbA1c), had the lowest levels at entry (at 6% or 6.8%) and performed best in cognitive tests.

"Glycemic control may modulate cognitive performance," he said, "So those in the highest tertile of HbA1c, experienced the greatest decline in cognition."

Effect of Diet, More Specifically the Adverse Effects of High Heat Cooking 

Over time, insulin, in combination with other diabetes medicines, has been shown to lessen the neuropathology of Alzheimer’s disease,6 he said citing research published in Diabetes Care.

In addition, diet has played a notable role, too with a high intake of dietary advanced glycation end products (AGEs) associated with poorer spatial learning and accelerated amyloid beta deposition in an Alzheimer mouse model.AGEs are formed when protein or fat are combined with sugar in a process known as glycation, or when foods are exposed to high temperatures during food preparation most commonly: grilling (searing), frying, roasting, and toasting.

Animal foods that are naturally high in fat and protein, for example, red meat, cheese, and butter, form high levels of AGEs when blackened (charred) or burnt. The same is try for fried foods, which tend to form AGEs.

Based on growing evidence,7 it appears that people who consume diets high in AGEs may face greater neurotoxicity, which is accelerated in people who have diabetes. On the other end of the continuum, consumption of diets low in AGE-forming foods may decrease the risk of dementia,2 he said.

Studies underway are looking at the effect of intranasal insulin on improved cognition and effects on Alzheimer's; one trial is due to be done this year, he says.

Practical Solutions to Pass Along to Patients 

Lifestyle definitely counts, he said. The role of physical performance is clearly linked to cognitive fitness. "Encourage your patients to engage in physical activity most days of the week, especially those with T2D," he said. "It's also good for warding off sarcopenia, and perhaps in the process, reducing the risk of falls and fractures."

Coffee and caffeine from other sources may be beneficial too. According to research led by Dr. LeRoith and others, consuming caffeine may have a positive effect on cognitive functioning in those with type 2 diabetes, perhaps through mechanisms underlying greater gray matter volume.

While it needs more study, ''I starting drinking more coffee nonetheless," Dr. LeRoith says. How much are we talking about? That's unclear, but Dr. LeRoith told EndocrineWeb he keeps his own intake to about three cups daily. More research is expected to come up with more definitive answers.

What else might help the downward spiral? While studies in the past have looked at human growth hormone to increase muscle mass, Dr. LeRoith says that ''we would rather advise exercise and lifestyle changes."

Metformin may prove valuable, too. It's being studied in the Taming Aging with Metformin (TAME) trial as a way to prevent aging, diabetes, even cancer.8 After researchers showed it has age-delaying effects on nematodes and on mice, they also showed it delays type 2 diabetes, is associated with less cancer in type 2 patients and may delay cognitive decline and Alzheimer's in both those with and without type 2 diabetes.

Take Home Message for Clinicians

The take-home message for clinicians is to promote exercise both to help improve the management of diabetes and to reduce cognitive decline, said Dr. LeRoith.

"Metformin may turn out to be an important medication to arrest the aging process as well as to slow development of type 2 diabetes and cardiovascular disease, he said, even lessen the risk of certain cancers," he said. That's a stay-tuned situation.

Dr. LeRoith is on the scientific advisory board of AstraZeneca, Merck & Co and Oramed Pharmaceuticals.



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