Blockade of glucagon signaling prevents or reverses diabetes onset only if residual β-cells persist

Abstract

Glucagon secretion dysregulation in diabetes fosters hyperglycemia. Recent studies report that mice lacking glucagon receptor ( Gcgr ^-/- ) do not develop diabetes following streptozotocin (STZ)-mediated ablation of insulin-producing β-cells. Here, we show that diabetes prevention in STZ-treated Gcgr ^-/- animals requires remnant insulin action originating from spared residual β-cells: these mice indeed became hyperglycemic after insulin receptor blockade. Accordingly, Gcgr ^-/- mice developed hyperglycemia after induction of a more complete, diphtheria toxin (DT)-induced β-cell loss, a situation of near-absolute insulin deficiency similar to type 1 diabetes. In addition, glucagon deficiency did not impair the natural capacity of α-cells to reprogram into insulin production after extreme β-cell loss. α-to-β-cell conversion was improved in Gcgr ^-/- mice as a consequence of α-cell hyperplasia. Collectively, these results indicate that glucagon antagonism could i) be a useful adjuvant therapy in diabetes only when residual insulin action persists, and ii) help devising future β-cell regeneration therapies relying upon α-cell reprogramming.

DOI: http://dx.doi.org/10.7554/eLife.13828.001

eLife digest

After meals, digested food causes sugar to accumulate in the blood. This triggers the release of the hormone insulin from beta cells in the pancreas, which allows liver cells, muscle cells and fat cells to use and store the sugar for energy. Other cells in the pancreas, called alpha cells, release a hormone called glucagon that counteracts the effects of insulin by telling the liver to release sugar into the bloodstream. The balance between the activity of insulin and glucagon keeps blood sugar levels steady.

Diabetes results from the body being unable to produce enough insulin or respond to the insulin that is produced, which results in sugar accumulating in the blood. Diabetes also increases the production of glucagon, which further increases blood sugar levels. Recently, some researchers have reported that mice that lack the receptor proteins through which glucagon works do not develop diabetes, even when they are treated with a drug called streptozotocin that wipes out most of their beta cells. This suggests that the high blood sugar levels seen in diabetes result from an excess of glucagon, and not a lack of insulin.

Drugs that block the action of glucagon have been found to reduce the symptoms of mild diabetes in mice and are now being tested in humans. However, it is less clear whether this treatment has any benefits in animals with more severe diabetes.

Streptozotocin destroys most of a mouse’s beta cells but a significant fraction of them persist, while a different system relying on diphtheria toxin destroys more than 99% of these cells. Damond et al. have now found that treating mice that lack glucagon receptors with diphtheria toxin causes the mice to develop severe diabetes. Mice that lacked glucagon receptors that had been treated with streptozotocin also developed diabetes after they had been treated with an insulin-blocking drug. Further experiments showed that blocking glucagon receptors in typical mice with diabetes reduces blood sugar, but only if there is some insulin left in their bodies.

Damond et al. also found that the glucagon receptor-lacking mice have more alpha cells, which have the ability to convert into insulin-producing cells after the widespread destruction of beta cells. Together, the experiments suggest that blocking glucagon could be a useful treatment for diabetes, but only in individuals who still have some insulin-producing cells. Such treatment would help reduce the release of sugar from the liver and increase the production of insulin in converted alpha cells in the pancreas. Damond et al. are now investigating how alpha cells convert into beta cells, with the aim of learning how to make beta cells regenerate more efficiently.

DOI: http://dx.doi.org/10.7554/eLife.13828.002