philalethes
Member
Glucagon is the key factor in the development of diabetes
The authors of this paper make some interesting assertions about the role of glucagon in the development of diabetes:
“Glucagon excess, rather than insulin deficiency, is essential for the development of diabetes for several reasons. Glucagon increases hepatic glucose and ketone production, the catabolic features of insulin deficiency. Hyperglucagonaemia is present in every form of diabetes. Beta cell destruction in glucagon receptor null mice does not cause diabetes unless mice are administered adenovirus encoding the glucagon receptor. In rodent studies the glucagon suppressors leptin and glucagon receptor antibody suppressed all catabolic manifestations of diabetes during insulin deficiency. Insulin prevents hyperglycaemia; however, insulin monotherapy cannot cure diabetes such that non-diabetic glucose homeostasis is achieved. Glucose-responsive beta cells normally regulate alpha cells, and diminished insulin action on alpha cells will favour hypersecretion of glucagon by the alpha cells, thus altering the insulin:glucagon ratio. Treating diabetes by suppression of glucagon, with leptin or antibody against the glucagon receptor, normalised glucose level (without glycaemic volatility) and HbA1c. Glucagon suppression also improved insulin sensitivity and glucose tolerance.”
I don't think artificially suppressing glucagon is going to fix the underlying problems at work here. The first thing to note is how glucagon and insulin typically have opposite roles, with the former promoting release of energy substrates and catabolism, and the latter promoting their absorption and anabolism.
Thus under circumstances of insulin resistance, I believe what happens is that the cells are lacking energy, and even with blood sugar being high and insulin being present, the insulin resistance leads to the sugar not being shuttled into the cells as one would want. This would lead to continued catabolism and release of glucose from the liver to hopelessly attempt to feed the cells, but to little avail. Thus you get the chronically catabolic hyperglucagonemic state described.
Suppressing glucagon in that situation would certainly be helpful, there's no denying that, since it's not achieving what it's supposed to at all, but the underlying problem of insulin resistance remains to be solved, even if it is somewhat mitigated by the all the glycative stress from the hyperglucagonemic state.