L16 Antidiabetic Drugs

一、The Pancreas

An organ that makes insulin and enzymes for digestion (excorine function).

Both endocrine system and digestive system (exocrine)

Pancreatic islet cells and their secretory products

Insulin: the storage and anabolic hormone of the body (glycometabolism)
Amylin: modulates appetite, gastric emptying, and glucagon and insulin secretion
Glucagon: the hyperglycemic factor that mobilizes glycogen stores

Disorders of the Pancreas: Diabetes Mellitus

Caused by:

Insufficient secretion of insulin
Resistance of body cells to the effects of insulin

One model of control of insulin release from the pancreatic B cell

Insulin-induces glucose uptake in muscle, fat, liver, and brain

Insulin induces glucose transporter (Glut) surface relocation

Glucose transporters (GLUT)

Insulin promotes glycogen synthesis and storage

1. Endocrine effects of insulin

Effect on liver:

Inhibits glycogenolysis
Inhibits conversion of fatty acids and amino acids to Acetyl-CoA

Anabolic action

Promotes glucose storage as glycogen (induces glucokinase and glycogen synthase, inhibits phosphorylase)
Increases triglyceride synthesis and very-low-density lipoprotein formation

Effect on muscle:

Increased protein synthesis
Increases amino acid transport
Increases ribosomal protein synthesis
Increased glycogen synthesis
Increases glucose transport
Induces glycogen synthase and inhibits phosphorylase

Effect on adipose tissue:

Increased triglyceride storage
Glucose transport into cell provides glycerol phosphate to permit esterification of fatty acids supplied by lipoprotein transport
Intracellular lipase is inhibited by insulin

二、Diabetes Mellitus

Types

1. TypeⅠ Diabetes

develops suddenly, usually before age 15

results in insulin dependence
severe or absolute insulin deficiency

Type I diabetes occurs when insulin producing cells are destroyed by the body’s own immune system

2. Treatment of Type Ⅰ Diabetes

Injection of insulin

Surgery: replacing the pancreas or just the beta cells

pancreas-kidney transplant
Stem cell research

3. Type Ⅲ Diabetes – GDM

Gestational diabetes mellitus (GDM, 妊娠期糖尿病) is a condition in which women without previously diagnosed diabetes exhibit high blood glucose levels during pregnancy

Most patients are treated only with diet modification and moderate exercise but some take anti-diabetic drugs, including insulin therapy.

4. Type Ⅳ Diabetes

Other specific types

Drug-induced diabetes :

1992, anti-hypertensive vasodilator diazoxide, and corticosteroids in high doses could cause diabetes.
2006, antipsychotic drugs： Olanzapine: induces hyperinsulinemia. dozens of those patients died from diabetes-related complications.

5. Type Ⅱ Diabetes

adult onset, usually occurs after age 40

Etiology: Insulin resistance; relative deficiency in insulin secretion (late stage).

blood glucose levels rise due to :

Lack of insulin production
Insufficient insulin action (resistant cells)

6. Treatment of TypeⅡ Diabetes

Drugs

Oral hypoglycemic agent = OHA

OHA s + Insulin therapy

Surgery

Surgery: Type 2 diabetes can be cured gastric bypass surgery in 80-100% of Severely obese patients

Treatment

Antidiabetic Drugs

Insulin
Insulin Secretagogues: Sulfonylureas; Meglitinides
Insulin Sensitisers: Biguanides; Thiazolidinediones
Alpha-glucosidase inhibitors
Peptide analogs:
- Glucagon-like peptide (GLP) analogs
- DPP-4 inhibitors
- Amylin analogues

1. Insulin

Application

Diabetes mellitus type 1 is a disease caused by the lack of insulin

Insulin must be used in Type I, which must be injected or inhaled.

Pharmacological effects of insulin

Decrease the blood glucose concentration (BGC)

Insulin preparation

Rapid-acting, Short-acting, Intermediate-acting, Long-acting

Delivery

Insulin Delivery System

Regular injections (Subcutaneous)
Portable pen injections
Continuous subcutaneous insulin infusion devices (CSII, insulin pumps)
Inhaled insulin

Portable pen injections

It is an insulin injection tool that resembles a pen.
This is great for people who need to give themselves an insulin injection when out in public but do not like it to be noticeable.
The Insulin Pen also contains memory of your last 16 injections

Continuous Subcutaneous Insulin Infusion CSII

Continuous infusion of a short-acting insulin driven by mechanical force and delivered via a needle or soft cannula under the skin.

Inhaled insulin

Inhaled insulin is a powdered form of insulin absorbed by the lungs through use of a hand-held inhaler.
Inhaled insulin is the first noninjectable option.

Complications of Insulin Therapy

Hypoglycemia

Immunopathology: Insulin allergy; Immune insulin resistance (potential vicious cycle)

Lipodystrophy (abnormal accumulation of fat tissue) at injection sites

Treatment of Hypoglycemia

Glucagon
- A hormone produced by the alpha cells in the pancreas.
- It raises blood glucose.
- An injectable form of glucagon

2. Oral hypoglycemic agents

Insulin Secretagogues

Insulin Secretagogues: agents which increase the amount of insulin secreted

(1) Sulfonylureas (SU)

Sulfonylureas were the first widely used oral hypoglycemic medications

Mechanism of Action

trigger insulin release by direct action on the K channel of the pancreatic beta cells.

Therapeutic uses

Only useful in Type II diabetes

They work best with patients over 40 years old, who have had diabetes mellitus for under ten years

Diabetes insipidus (large amount of urine)

Chlorpropamide has also an antidiuretic effect and may be used to treat diabetes insipidus.

Adverse reactions

Serious adverse reaction is hypoglycemia

Common adverse effects: gastrointestinal reactions such as nausea and vomiting

(2) Meglitinides

Uses

Meglitinides help the pancreas produce insulin and are often called “short-acting secretagogues.”

Their mode of action is original, affecting potassium channels

By closing the potassium channels of the pancreatic beta cells, they open the calcium channels, hence enhancing insulin secretion.

They are taken with meals to boost the insulin response to each meal.

repaglinide (Prandin) The maximum dosage is 16 mg/day, taken 0 to 30 minutes before meals. If a meal is skipped, the medication is also skipped.

nateglinide (Starlix) The maximum dosage is 360 mg/day, usually 120 mg three times a day (TID).

Adverse reactions

weight gain

hypoglycemia

Insulin Sensitisers

Insulin Sensitisers: agents which increase the sensitivity of target to insulin

(1) Biguanides

Mechanism of action

Direct stimulation of glycolysis in tissues, with increased glucose removal from blood
inhibiting gluconeogenesis
reducing the absorption of glucose from the intestine (influence on gut microbiota)

Therapeutic uses

Metformin is usually the first-line medication used for treatment of type-2 diabetes.

Adverse reactions

The main adverse reactions of Phenformin are lactic acidosis (due to high glycolysis)
The most frequent toxic effects of Metformin are gastrointestinal symptoms including nausea, vomiting, and diarrhea.

(2) Thiazolidinediones (TZDs)

Drugs

Pioglitazone
Rosiglitazone
Ciglitazone
Englitazone
Troglitazone

Mechanism of action

Enhance the target tissue’s sensitivity to insulin through PPARγ pathway

PPAR-γ is a type of nuclear regulatory proteins involved in transcription of genes regulating glucose and fat metabolism. These PPARs act on Peroxysome Proliferator Responsive Elements (PPRE). The PPREs influence insulin sensitive genes, which enhance production of mRNAs of insulin dependent enzymes. The final result is better use of glucose by the cells.

α-Glucosidase Inhibitors

Alpha-glucosidase inhibitors: agents which decrease the rate at which glucose is absorbed from the gastrointestinal tract.

(1) Acarbose

Mechanism of action

Reduces intestinal absorption of starch and dextrin by inhibiting the action of α-glucosidase in intestinal brush border.

Clinical use

The agents are effective by themselves only in the earliest stages of impaired glucose tolerance, but can be helpful in combination with other agents in type 2 diabetes

They do have the potential to cause weight loss by lowering the amount of sugar metabolized

Peptide analogs

Overview of insulin secretion

Incretin mimetics

Incretins like GLP1 are insulin secretagogues
The main candidate molecules that fulfill criteria for being an incretin are Glucagon-like peptide-1 (GLP-1)
GLP-1 is rapidly inactivated by the enzyme dipeptidyl peptidase-4 (DPP-4).

(1) Glucagon-like peptide (GLP) analogs

GLP agonists bind to a membrane GLP receptor.
As a consequence of this, insulin release from the pancreatic beta cells is increased.

Exenatide (also Exendin-4, marketed as Byetta) is the first GLP agonist approved for the treatment of type 2 diabetes

It is an injectable medication. (liraglutide)

These agents may also cause a decrease in gastric motility, responsible for the common side effect of nausea, and is probably the mechanism by which weight loss occurs

(2) DPP-4 inhibitors

Sitagliptin

an inhibitor of dipeptidyl peptidase-4 (DPP4), the enzyme that degrades incretin and other GLP-l-like molecules.
increase blood concentration of the incretin GLP-1
This drug appears likely to be approved for use in type 2 diabetes.