Is Brain Insulin Important for Whole-Body Metabolism?

Martin Heni, MD; Mark Harmel, MPH, CDCES


October 17, 2022

This transcript has been edited for clarity.

Data from animal models showed that animals who didn't have any insulin in their brain developed a type 2 diabetes–like phenotype. We wondered if this is true in humans. Can it be that insulin acts in the human brain? Is this important for metabolism in the entire body? This is how I became interested in studying how insulin acts in the human brain.

What we've learned so far is that, indeed, insulin acts in the human brain. This happens in many persons, but there's a substantial number of persons who are insulin resistant in their brain. In these individuals, the brain no longer responds to insulin.

We've learned that proper insulin action in the brain is important to coordinate your metabolism after food intake. It suppresses glucose production from the liver and stimulates glucose uptake in the periphery. Over time, these processes contribute to the regulation of body fat distribution. This determines where in the body fat and energy are stored.

If insulin action in the brain is good, your body stores energy in the subcutaneous compartment. In the case of brain insulin resistance, these processes are disturbed. The brain can't control peripheral metabolism, and in the long run, this leads to an accumulation of visceral fat.

This is where you don't want to have fat because visceral fat is a risk factor for not only type 2 diabetes but also cardiovascular diseases and even some types of cancer. Insulin resistance of the brain leads to a phenotype that's very unfavorable. You don't want this.

What we've done over the last couple of years was to try to find out if brain insulin resistance is something that can be treated or if it is fixed forever.

Our first treatment approach was with the sodium-glucose cotransporter 2 (SGLT2) inhibitor empagliflozin. We studied persons with prediabetes who were overweight or obese and treated them with the SGLT2 inhibitor over 8 weeks. These 8 weeks of SGLT2 inhibition were sufficient to totally restore insulin responsiveness of the hypothalamus. This was the first study to show that brain insulin resistance is something that you can treat in humans.

Interestingly, this improvement in hypothalamic insulin action in response to SGLT2 inhibition was closely linked to improvements of peripheral metabolism and to a reduction of liver fat content. That's speculation, but I believe that improved hypothalamic insulin action could contribute to the clinical benefits that we know of this substance class that are present after a long time and really hard clinical endpoints.

The second treatment approach that we tested was exercise. Here, we included sedentary persons who were overweight or obese, and we had them exercise quite heavily over 8 weeks. After 8 weeks of exercise, they didn't lose weight, but it was sufficient to normalize their brain response to a level we normally see in lean persons.

Again, this improved insulin action of the brain after exercise was closely linked to metabolic benefits, underlying that the brain can contribute to metabolic regulation in the body and that this is something that can be restored.

Our next steps will be to better understand how these treatments work, to see what approaches work best, and to determine the mechanisms.

I hope treatment approaches that will improve insulin sensitivity of the brain will not only be beneficial for metabolism, diabetes, and overweight and obesity, but also have beneficial effects on diseases of the brain that are much more frequent in our patients with type 2 diabetes, such as depression and dementia.

I hope we'll learn much more about this in the upcoming years.

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