Question

How have alterations in metabolic and signalling pathways produces Diabetic Ketoacidosis ,and the symptoms of it?

Answer 1

As insulin levels are insufficient to meet the body’s basic metabolic requirements diabetic ketoacidosis occurs. DKA occurs in type 1 diabetes mellitus (DM). Major symptoms are nausea, vomiting, and abdominal pain and can progress to cerebral edema, coma, and death.

insulin deficiency is the most important regulator of ketogenesis. Lipolysis – the breakdown of triglycerides – is mediated by hormone‐sensitive lipase in adipose tissue. Hormone‐sensitive lipase is activated by both insulin deficiency and the rise in counter‐regulatory hormones, the precise hormonal milieu that characterizes DKA. This same hormonal milieu inhibits lipid synthesis and re‐esterification in the adipocytes. The net impact of these events on adipose tissue is the release into the circulation of large quantities of free fatty acids (FFA).

Circulating FFA are both the principal substrate for ketogenesis and the major stimulant for this process to occur. In the liver of patients with active DKA, the effective lack of insulin and the high levels of counter‐regulatory hormones combine to impair the re‐esterification of FFA (that is, to impair hepatic lipid synthesis) and to catalyze the processes by which FFA are transported into mitochondria73, 74 and subsequently converted into ketone bodies. FFA transport into hepatic mitochondria is enhanced by glucagon‐mediated reductions in the cytosolic malonyl‐CoA, which removes inhibition of carnitine palmitoyltransferase 1 (CPT1). Malonyl‐CoA competitively inhibits CPT1, the enzyme that transports fatty acyl CoA across hepatic mitochondrial membranes. Within the mitochondria, fatty acyl CoA normally undergoes β‐oxidation to acetyl CoA, and acetyl CoA is in turn shunted into the tricarboxylic acid cycle. In DKA, however, the enormous supply of fatty acyl CoA and deficiency in oxaloacetate overwhelm these normal biochemical pathways. When this occurs, excessive amounts of fatty acyl CoA derivatives are oxidized to form ketone bodies, and large quantities of 3HB and AcAc are released into the blood.