Tuesday, February 7, 2017

Diabetes Mellitus Drugs: A logical account from start to finish.



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).






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