We will now go over the diabetes drug classes from a
functional perspective, following the path of glucose through the body. We must leave out Metformin, the only Biguanide diabetic drug, since we do not currently
understand exactly how it mediates its effects, which are always euglycemic,
decreasing gluconeogenesis, increasing glycolysis and insulin sensitivity in
the body’s peripheral cells, but never to the point of hypoglycemia.
Our story begins with Pramlintide,
which mimics the body’s natural amylin, secreted from the pancreas beta cells
along with insulin at 100 times the concentration of amylin. In addition to
decreasing gastric emptying, thereby depriving the body of immediate sugar, the
body’s natural amylin decreases glucagon secretion from alpha cells, as does
Pramlintide, thus decreasing blood glucose and magnifying the effect of endogenous insulin.
After leaving the stomach, polysaccharide sugars need to be
broken down into glucose by Alpha-glucosidase in the gut before they are
absorbed into the blood stream by the brush border. The alpha-glucosidase
inhibitors Acarbose and Miglitol imitate sugars, thereby
competitively inhibiting alpha-glucosidase, so less glucose is taken up and
more excreted.
Glucose actually stimulates insulin release by entering the
beta-cell from the bloodstream. Its metabolism creates ATP which closes
ATP-dependent potassium gates on the cell membrane. The intracellular build-up
of potassium depolarizes the cell, leading to the opening of voltage-gated
calcium gates. The inflowing calcium activates receptors on granules in
beta-cells filled with insulin, triggering insulin’s release from the
beta-cell.
Obviously, the different types of polygenic insulin analogs
directly replace insulin and are used for DM1, DM2 and Gestational Diabetes
Mellitus (GDM). The ultra-short acting insulins are Lispro, Aspart, and Glusine. Regular Insulin is short acting, and is used to combat
Diabetic Ketoacidosis (DKA) in DM1 patients and Hyperglycemic Hyperosmolar Syndrome (HHS) in DM2 patients. NPH Insulin
has an intermediate half-life, while Glargine
and Detemir are long-acting and
can cover an entire day.
We have to take a break from following the path of glucose
now, because most other drugs (except 3 drugs from 2 classes we’ll cover at the
end to return to the glucose story) modify insulin levels in the blood in order
to increase removal of glucose from the blood stream. The potassium gates mentioned above can
be artificially closed using sulfonylurea drugs, while glucagon-like protein-1 (GLP-1) can both close the potassium gates and open the usually-voltage-dependent
calcium channels on the beta cell membrane.
The sulfonylurea drugs come in two generations. The first
gen drugs are Tolbutamide and Chlorpropamide. Tolbutamide is safest
for elderly patients; and both drugs have low potency, which is why the more
commonly used second gen drugs, Glyburide,
Glimepiride, Glipizide (Useful note: all second gens start with G, but none
of the first gens do.) All of the sulfonylureas have the potential for
hypoglycemia, but because of their potency this is especially true of second
gens.
GLP-1 Analogs Exenatide
and Lyraglutide mimic GLP-1,
which has the effects of the sulfonylureas plus calcium-channel-opening effects,
thereby decreasing glucagon and increasing insulin release. GLP-1 is released
by cells in the distal gut when excess food is detected. It also induces
satiety in the hypothalamus.
One step back from this, DPP-4 inhibitors Linagliptin, Saxaglyptin and Sitaglyptin, inhibit an inhibitor of
GLP-1, DPP-4, secreted by most somatic cells in the body, released when they are "hungry". Unfortunately, these drugs also degrade many of the body's proteins and enzymes and so can lead to urinary and respiratory infections.
Returning back to the glucose pathway, glucose is taken up
by GLUT-4 transporters on all body cell membranes except in the Brain, RBCs, Intestine, Cornea, Kidney and Liver (BRICKL). Physiologically, insulin upregulates this transporter by binding to
the alpha subunit of insulin receptors on body cells. The beta subunit then
phosphorylates tyrosine residues that end up upregulating the GLUT-4
transporter on the cell surface until the insulin receptor is endocytosed.
Insulin receptor transcription along with other catabolic
activities is increased by the diabetes drug class known as Glitazones or Thiazoledinediones.
They include Pioglitazone and Rosiglitazone and increase PPAR-gamma
transcription. Rosiglitazone can have cardiac side effects, while pioglitazone
induces Cytochrome P450 and so can have negative drug interactions.
Glucose is small enough that it slips through the podocytes
in the glomerulus and has to be reabsorbed by GLUT-2 transporters. But the
GLUT-2 transporter can be inhibited by Canagliflozin
in patients with functioning kidneys, which is not always the case with
diabetics (Think Kimmelsteil-Wilson lesions).
Using this method of accounting for DM drugs creates a
natural memory hook in the path of glucose through the body, all the way from
considering to eat (GLP-1 induces hypothalamic satiety) to the excretion of
glucose in the kidneys (Canagliflozin).
HSV1 & HSV2 Negative.
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