Why do these drugs cause EKA?

With the introduction of *Gliflozins as a strategy to target hyperglycaema, and insulin resistance, there has been for the first time real promise that perhaps, we can reverse Type 2 Diabetes.

These drugs (like all) have costs and benefits. They cause increased incidence of UTI as now, sugary urine is a virtual fertiliser for bladder bacteria.  They also cause a rare ketoacidosis where the blood sugar isn’t elevated- euglycaemic KetoAcidosis.  Why??......read on.

Unlike the older sulphonylureas, Metformin, and even incretin mimics, Januvia and it’s DPP4 inhibitor cousins, the Gliflozins are novel.  These drugs (empagliflozin, dapagliflozin) shut off a protein in your kidneys (SGLT2) responsible for reabsorbing glucose back into the blood.  Block SGLT2, and you pee your glucose out, dropping your blood sugar, and subsequently your insulin secretion.  Less sugar = less insulin = improved insulin sensitivity.... T2 diabetes fixed (... ok not that simple, but treating Insulin Resistance (IR) is the goal in T2DM.

So ... remember that insulin reduction in blood results from blood glucose reduction.

Now insulin.   To fully understand insulin, you need to rearrange what you previously knew about this little hormone.

Insulin is a growth hormone.  It grows fat.  The more insulin a person has, the better they grow fat.

Insulin takes glucose and offers it to cells.  When fat cells are offered glucose, they say “Yes please!!!”, and takes in glucose in to convert it with free fatty acids, to fat.  Now if there is lots of insulin,there is lots of storage.

The FAT house - think of a house with an open doorway where glucose is streaming in.  Insulin keeps that door open, and glucose flushing in.  If insulin is absent or low, then instead of glucose flooding into fat cells, fatty acids flood out.  Low insulin = free fatty acids (FFA) released into blood.

Are you with me?

Insulin = fat cells grow
No insulin = fat cells melt

Now, when this happens, the FFA, circulated to the liver which converts these FFAs into a group of acids called Ketone Bodies, or just, Ketones.  An accumulation of ketones can only happen when - Fatty acids are converted to ketones, and this can only happen when insulin is too low.

Summary: low insulin - fat melts - ketones produced.

Now - back to the side effect of Gliflozins...Euglycaemic KetoAcidosis.

Work it back...

The blood is acidotic because too many ketone acids in the blood.
Ketones are made because fat cells are melting FFA into blood.
Fat is melting because insulin levels fell.
Insulin levels fell because glucose levels fell.
Glucose fell because Kidneys pee all the glucose out (glucosuria)
Glucosuria occurs because
The Gliflozins block glucose reabsorption back to blood.

Less glucose = less insulin = fat melt = ketones and acidosis (Ketoacidodis).

I need a chocolate!