The present article highlights the role of Glucagon excess in the pathogenesis of Insulin-dependent diabetes.
Glucagon is a hormone produced by alpha-cells in the pancreas, as well as from cells in the stomach and intestine. Insulin is a well-known hormone produced by beta-cells in the pancreas, which reduces blood sugar by trafficking it into cells.
The opposing roles of Glucagon and Insulin is known since 1921. However, the importance of Glucagon in normal blood sugar metabolism and in diabetes remains controversial.
The development of new lab techniques exposed the reciprocal behavior of the two hormones: Insulin levels fall when sugar intake is low and rise during sugar administration, whereas Glucagon registered the exact opposite responses. Another clue of this bi-hormonal relationship was the demonstration that when Insulin rises after sugar feeding, the inhibition of Glucagon secretion is not caused by the high sugar levels, but by high Insulin levels. In other words, Insulin not only counteracts Glucagon, but also directly inhibits its release from alpha-cells in the pancreas. It is therefore not surprising to find that high levels of Glucagon are present in untreated patients with type 1diabetes (T1DM), due to a deficiency in Insulin. Studies proved that the suppression of Glucagon reduces the manifestations of Insulin deficiency seen in diabetes.
If Glucagon hyper-secretion is in fact the direct cause of the major metabolic alterations in diabetes, Glucagon inhibition could become an important treatment strategy. However, administering high levels of Insulin may put the patient in risk of hypoglycemia (drop in blood sugar) and yet not inhibit completely Glucagon excess. Glucagon inhibition can be achieved using non-Insulin agents as Amylin or Leptin (hormones with a key role in regulating energy).
Amylin (Pramlitinide) was already used in patients with T1DM combined with Insulin, leading to a decrease in blood sugar levels its fluctuations. It also decreased Insulin requirements.
As for Leptin, for the moment it was only tested on mice with promising results, that seem to support the concept of Glucagon inhibition.
In conclusion, it is well known that in T1DM, Insulin alone cannot control blood sugar levels for long. Also, several studies have demonstrated the importance of Glucagon in this condition. However, to this end, no clinical trials have been attempted to put this theory into test.
Published By :
The Journal of Clinical Investigation
Date :
Jan 03, 2012
