Treatment of Diabetes Mellitus*

By: Iyas Yaser Mustafa

* The mechanism of action of the hypoglycemic drugs.

Note: Treatment options of

diabetes need to be made on

individual basis !

Type 1 Diabetes Mellitus

Type 1 Diabetes Mellitus

● Type 1 DM = Insulin-Dependent DM

● The only treatment of hypoglycemia in DM 1 is insulin

injections (subcutaneously) because the pancreatic beta

cells can't produce insulin at all.

● Why not orally? intravenously?

Insulin

Mechanism

of

Action:

Type 2 Diabetes Mellitus

Type 2 Diabetes Mellitus

● Type 2 DM = Insulin-Independent DM

● The pancreatic beta cells can't produce enough insulin or

insulin resistance. (or both)

● Diet, Exercise, and Weight loss are the 1st line of treatment

!

● There are many choices for the treatment of

hyperglycemia in DM 2

● If the oral hypoglycemic drugs can't work or the pancreatic

cells are too exhausted that can't produce insulin any

more, insulin injections are required.

Biguanides

● Metformin is the only drug of the biguanide class

● Actions:

- Reduce hepatic gluconeogenesis, “which is markedly

increased in type 2 diabetes” - by AMPK activation.

- Increase glucose uptake and utilisation in skeletal

muscle (i.e. they reduce insulin resistance)

- Reduce carbohydrate absorption

- Increase fatty acid oxidation

- Reduce circulating LDL and VLDL

Sulfonylureas

● E.G.: Tolbutamide, Chlorpropamide, Glibenclamide,

Glipizide

● Mechanism of action:

* They stimulate insulin secretion and thus reducing

plasma glucose.

High-affinity receptors for sulfonylureas are present on the

KATP channels in B-cell plasma membranes.

Block KATP channel activation depolarization, Ca 2+

entry and insulin secretion.

Thiazolidinediones (glitazones)

● E.G.: Pioglitazone.

● The effect of thiazolidinediones on blood glucose is slow in

onset, the maximum effect being achieved only after 1–2

months of treatment.

● Actions:

- Reduce hepatic glucose output.

- Increase glucose uptake into muscle, by enhancing the

effectiveness of endogenous insulin.

They reduce the amount of exogenous insulin needed to

maintain a given level of blood glucose by approximately

30%.

Thiazolidinediones (glitazones) ~ cont.

● Mechanism of Action:

- Thiazolidinediones bind to a nuclear receptor called the

peroxisome proliferator-activated receptor-γ (PPARγ),

which is complexed with retinoid X receptor (RXR)

“mainly in adipose tissue, but also in muscle and liver”.

- It causes differentiation of adipocytes, increases

lipogenesis and enhances uptake of fatty acids and

glucose.

- Thiazolidinediones cause the PPARγ–RXR complex to

bind to DNA, promoting transcription of several genes

with products that are important in insulin signalling.

α-Glucosidase inhibitors

● E.G.: Acarbose.

● Mechanism of action:

It delays carbohydrate absorption, reducing the

postprandial increase in blood glucose.

Incretin mimetics and related drugs

● E.G.: Exenatide.

● Mechanism of action:

It mimics the effects of GLP-1, but is longer acting.

It lowers blood glucose after a meal by:

- increasing insulin secretion.

- suppressing glucagon secretion.

- slowing gastric emptying.

It reduces food intake (by an effect on satiety) and is

associated with modest weight loss. It reduces hepatic

fat accumulation.

Gliptins

● E.G.: Sitagliptin, Vildagliptin

● Mechanism of action:

Inhibit dipeptidylpeptidase-4 (DPP-4), thereby lowering

blood glucose by potentiating endogenous incretins

(GLP-1 and GIP).

SGLT-2 Inhibitors

• E.g. Dapagliflozin, Canagliflozin, Empagliflozin.

• SGLT (sodium-glucose linked transporter): a family of glucose transporter found in the intestinal mucosa (enterocytes) of the small intestine (SGLT1) and the proximal tubule of the nephron (SGLT2 in PCT and SGLT1 in PST). They contribute to renal glucose reabsorption.

• Mechanism of action of SGLT-2 inhibitors:

Reducing the amount of glucose being absorbed in the kidneys so that it is passed out in the urine Reducing the amount of glucose in blood.

Sources

● Rang and Dale’s Pharmacology, 7th Ed – Chapter 30

● http://en.wikipedia.org/wiki/Sodium-

glucose_transport_proteins

● http://www.diabetes.org.uk/Guide-to-diabetes/What-is-

diabetes/Diabetes-treatments/SGLT2-inhibitors/