Glucagon-Blocking Drugs May Prevent or Reverse Diabetes If Some Beta Cells Remain Interview with:

Pedro L. Herrera, PhD Professor Dept. Genetic Medicine & Development, room #F09.2770 Faculty of Medicine, University of Geneva Geneva, Switzerland

Dr. Pedro Herrera

Pedro L. Herrera, PhD
Dept. Genetic Medicine & Development, room #F09.2770
Faculty of Medicine, University of Geneva
Geneva, Switzerland What is the background for this study? What are the main findings?

Dr. Herrera: After meals, the digestion of food leads to an accumulation of sugar (glucose) in the blood (hyperglycemia). This triggers the release of the hormone insulin from the pancreas (beta-cells), which allows the tissues (liver, muscle and fat) to use and store it.

Another pancreatic hormone, glucagon, is released by alpha-cells during fasting or exercising, and opposes the action of insulin: it tells the liver to release glucose, which increases blood sugar levels. The balance between insulin and glucagon keeps blood sugar levels steady. Persistent hyperglycemia due to insulin deficiency is diabetes.

Glucagon production is exacerbated in diabetes, which aggravates hyperglycemia. What should clinicians and patients take away from your report?

Dr. Herrera: Recent controversial publications report that mice lacking the receptor for glucagon (KO) do not become diabetic, even if a majority of insulin-producing beta-cells are ablated using a drug named streptozotocin (STZ). The authors suggested that blocking glucagon action would prevent hyperglycemia despite a complete absence of insulin, and thus that hyperglycemia in diabetes is caused by glucagon excess, not by insulin deficiency.

We challenged this hypothesis.

Drugs that block the action of glucagon have a beneficial effect in mildly diabetic animals, and are now in clinical trials. Yet the benefits of blocking glucagon action in severely diabetic animals are less clear.

We used transgenic mice in which nearly all insulin-producing cells can be efficiently ablated with diphtheria toxin (DT) administration: ablation efficiency is much higher than in the previously used STZ model. This time, the mice became severely diabetic despite the fact they lacked glucagon receptors.

Glucagon receptor-KO mice also became diabetic after STZ when we treated them with a drug inhibiting insulin action.

In another experiment we showed that administration of antibodies blocking glucagon receptors reduce hyperglycemia in wild-type diabetic mice, yet only when some amount of residual insulin persists in the body.

In parallel, we had previously shown that after massive insulin-cell death some glucagon-producing alpha-cells convert into insulin producers in mice. It was also known that the absence of glucagon signaling triggers alpha-cell proliferation. In addition to the results mentioned above, we found in the current study that because of the higher number of alpha-cells in mice lacking glucagon receptors, the total number of alpha-cells that start making insulin was also higher. What recommendations do you have for future research as a result of this study?

Dr. Herrera: Our results indicate that glucagon action blockade could be beneficial as adjuvant diabetes treatment, but only in patients that have some remaining/surviving pancreatic insulin-producing cells.

Blocking glucagon action may therefore represent a double advantage in diabetes: reduction of glucose output in the liver and increase of insulin production in the pancreas. We are now trying to better understand the mechanisms of alpha-to-beta-cell conversion to make beta-cell regeneration more efficient.


Nicolas Damond, Fabrizio Thorel, Julie S Moyers, Maureen J Charron, Patricia M Vuguin, Alvin C Powers, Pedro L Herrera. Blockade of glucagon signaling prevents or reverses diabetes onset only if residual β-cells persist. eLife, 2016; 5 DOI: 10.7554/eLife.13828

Note: Content is Not intended as medical advice. Please consult your health care provider regarding your specific medical condition and questions.

More Medical Research Interviews on


Last Updated on April 21, 2016 by Marie Benz MD FAAD