Endocrine Abstracts

JOINT1448

Relative insulin deficiency and high Glucagon level are the hallmark of DKA. What is the exact mechanism? When does exactly the cascade begin? How we can prevent it? Is there a cascade of events that begins days before overt clinical presentation and can we stop it?

Aim: Finding molecular pathogenesis of ketoacidosis

Methods: In a 6 years research we used immune modulatory drugs to stop type I DM. Cox multivariate analysis on 1700 patients was done. Many combinations were used and those without response were omitted. Earlier combinations included Nicotinic acid but our triumphant combination with significant c-Peptide increase did not.

Results: Although socioeconomic status, omission of Insulin and infection were the three strongest risk factors, patients (763) on Nicotinic acid showed almost no case of DKA in the first year and only 6 in the second year that was later found to be due to Nicotinic acid discontinuation. The protocol without Nicotinic acid showed 26 cases of DKA in almost 650 patients. A proportional hazard study showed very indirectly that the DKA process begins at least 2 weeks before overt clinical presentation and can be prevented by pharmacological intervention. Some patients showed deterioration of well being with urinary ketone of 1+ that seemed not to need treatment.

Conclusion: Increased activity of ATGL, HSL augmented by loss of inhibition of Perilipin-1 causes high load of Acetyl-CoA within the mitochondria that overrides its clearing potential. Acids leak out of it and the cytoplasm has no enzymatic weapon to counteract it. Extrusion of acid into the circulation re-established cytoplasmic milieu at the expense of generalized acidity. This can be blocked by anti-lipolysis agents such as Nicotinic acid or Acipimox. Increased incidence of DKA coincident with DDP-4 or SGLT-2 inhibitors is not a per se phenomenon but due to less insulin use and lower energy expenditure. Many data shows that Insulin concentrations less than 72ng/dl in mice can cause ketoacidosis.