Glucose regulation in diabetics

Diabetes is one of the most common diseases in the world. An essential feature of the disease is the loss of insulin-controlled sugar removal from the blood. Type I diabetes is caused by immune system targeting of pan-creatic beta cells (the body’s source of insulin), killing them and thereby eliminating insulin production. On the other hand, in type II diabetes, cells around the body be-come resistant to the effects of insulin; beta cells produce more and more insulin and eventually die from the added stress. In both cases, blood sugar levels in the blood-stream rise to dangerous levels, resulting in complications such as vision loss, kidney disease, stroke and heart disease.

Counteracting the effects of insulin is the hormone glucagon, produced by the pancreatic alpha cells. This acts to stimulate glucose release from the liver. Thus, a ying/yang situation exists, with each hormone’s release being stimulated by the action of the other.

Previous research in mice showed that a synthetic antibody that blocks glucagon receptors in the membranes of liver cells could restore normal blood glucose levels, but the mechanism was unclear. Now, a new study has revealed that blocking glucagon receptors has the surprising indirect effect of transform-ing pancreatic alpha (glucagon-secreting) cells into beta (insulin-secreting) cells, thereby restoring a source of insulin in the pancreas that successfully reg-ulates blood glucose.

Glucose regulation in diabetics who have significant loss of pancreatic beta cells is a very tricky business. Insulin injection and drug intervention is nev-er as effective as the real thing. Transforming alpha cells into beta cells may be a particularly promising treatment for type I diabetes. Even after decades of an autoimmune attack on their beta cells, type I diabetics still have plentiful amounts of alpha cells that are not susceptible to such immune attack.

To get a better handle on the mechanism by which alpha cell conver-sion occurs, researchers designed experiments in three different mouse mod-els. In the first, a genetic mutation induced cell suicide in beta cells in response to a particular chemical treatment, leading to a diabetic state. The resulting dia-betes was successfully reversed by weekly injections of glucagon receptor anti-bodies that increased beta cell numbers sevenfold.

But they didn’t know if this result would hold up under a sustained im-mune attack, so they used another model where the animals’ immune systems depleted pancreatic beta cells. Treated with antibodies, beta cell numbers re-bounded despite continued immune attacks.

A third model tested whether the treatment would work in human pan-creas cells. Human pancreatic tissue with alpha and beta cells was grafted into diabetic mice, but in numbers ensuring the mice remained mildly diabetic. When these mice were treated with the antibodies, the human beta cells proliferated, helping to restore blood glucose regulation.

The researchers concluded that these results provide hope that a one-weekly injection of a human antibody against the glucagon receptors can en-hance functional beta cell mass!