The Neuropeptide Cyclo(His-Pro) Levels are Increased in Diabetic Ketoacidosis and Fall with Treatment in Parallel with Levels of Glucagon

The importance of insulin deficiency and glucagon excess is recognized as critical in the pathogenesis of diabetic ketoacidosis (DKA). The finding of elevated levels of another gut peptide in DKA with potential relevant physiological effects might renew discussion of the pathogenesis of this disorder. Cyclo(His-Pro) is a gut-brain peptide found in gut of rat and man. In pancreas it is localized to alpha cells. A stereospecific hepatic bonding site has been found. We have shown that cyclo(His-Pro) augments the insulin response to oral glucose in rat by decreasing hepatic insulin clearance. In view of cyclo(His-Pro)'s location in alpha cells, the hepatic binding site and action described, we wondered if levels of cyclo(His-Pro) might be elevated in a hyperglucagonemic state such as DKA and whether these levels might correlate with those of glucagon and other commonly followed parameters in DKA.

Plasma was collected from 7 nondiabetic controls and 9 patients in DKA before and after 4, 8, 12, and 24 h of therapy and assayed for glucose, HCO₃, anion gap, glucagon and cyclo(His-Pro). Cyclo(His-Pro) levels were higher in DKA patients before therapy than controls (15.6 ± 3.2 vs. 8.0 ± 0.2 pmol/ml; p =0.023) as were glucagon levels (201 ± 4 vs. 56 ± 5ng/L; p = 0.006). Cyclo(His-Pro) levels fell significantly with treatment (15.6 ± 3.2 vs 8.1 ± 1.1; p = 0.024) and in parallel with those of glucagon. We conclude that cyclo(His-Pro) levels are increased in patients with DKA before therapy and fall in parallel with those of glucagon. This represents the first report of altered levels of this peptide in a disease state.