Can a lizard's hormone treat diabetes?

The lizard Heloderma species, including H. horridum and H. suspectum are native to several American states and are poisonous.  Lizard venom contains a number of highly bioactive peptides including the peptides exendin-3 and exendin-4. These peptides were named exendins by Eng and Raufman in that they were isolated from an exocrine gland and were subsequently shown to have endocrine actions. Exendin-4 was initially isolated from the venom found in the saliva of a poisonous  lizard found in South America, known as the Gila monster. This lizard eats four times a year. When it eats, exendin-4 secreted in the saliva causes it’s pancreas to ‘switch on’.

Structure

Molecular formula: C184H282N50O60S.C2H4O2

Molecular structure of Exenatide Acetate

Mechanism of Action

Exenatide is a potent 39-amino acid peptide that exhibits several anti-diabetic, or glucose lowering actions. The effects on glucose control seen with exenatide treatment are thought to be due to several properties that are similar to those of the naturally occurring incretin hormone GLP-1. These actions include stimulating the insulin response in response to glucose and preventing glucagon (a hormone which raises blood sugar) release after meals.

It is the first member of a new class of therapeutic medications known as incretin mimetic agents. Exenatide (synthetic exendin-4) is being investigated for its potential to address important unmet medical needs of many people with type 2 diabetes. Clinical trials suggest that exenatide treatment decreases blood glucose toward target levels and is associated with weight loss. The effects on glucose control seen with exenatide treatment are likely due to several actions that are similar to those of the naturally occurring incretin hormone GLP-1. These actions include stimulating the body’s ability to produce insulin in response to elevated levels of blood glucose, inhibiting the release of glucagon following meals and slowing the rate at which nutrients are absorbed into the bloodstream. In animal studies exenatide administration resulted in preservation and formation of new beta cells, the insulin-producing cells in the pancreas, which fail as type 2 diabetes progresses.

How effective is it?

Unlike most other oral hypoglycaemic drugs which work by a single mechanism, exendin-4 works by several mechanisms: it stimulates insulin secretion, slows emptying of the stomach and inhibits production of glucose by the liver. It also appears to suppress appetite and helps weight loss. This would be a particular advantage with type 2 diabetes.

Side effects

In these clinical trials, exenatide was well tolerated. Most of the reported side effects were mild or moderate. Nausea was the most common reported effect.

Use

People with type 2 diabetes who are not well controlled on diet and oral agents i.e. those not achieving target HbA1c levels on sulphonylureas, metformin or thiazolidenediones.

Prodcut available in market GENERIC NAME: exenatide      BRAND NAME: Byetta 

DRUG CLASS AND MECHANISM: Exenatide is an injectable drug that reduces the level of sugar in the blood. It is used for treating type 2 diabetes. Exenatide belongs in a class of drugs called incretin mimetics because these drugs mimic the effects of incretins. Incretins, such as human-glucagon-like peptide-1 (GLP-1), are hormones that are produced and released into the blood by the intestine in response to food. GLP-1 increases the secretion of insulin from the pancreas, slows absorption of glucose from the gut, and reduces the action of glucagon (Glucagon is a hormone that increases glucose production by the liver.) All three of these actions reduce levels of glucose in the blood. In addition, GLP-1 reduces appetite. Exenatide is a synthetic (man-made) hormone that resembles and acts like GLP-1. In studies, exenatide-treated patients achieved lower blood glucose levels and experienced weight loss. Exenatide was approved by the FDA in May, 2005. 

DRUG INTERACTIONS: Exenatide slows down transit of food and drugs through the intestine and, therefore, can reduce the absorption of drugs that are taken orally. To avoid this interaction, administer oral medications one hour before exenatide is administered. Orally administered drugs that need to be administered with food should be given with a light meal or snack when exenatide is not administered. 

Advantages and disadvantages of exenatide compared with other drugs

Exenatide is unique among currently marketed drugs in its broad effects to normalize postprandial physiology. In some ways, it can be thought of as having some of the same benefits of a secretagogue plus a biguanide plus an alpha-glucosidase inhibitor, without the baggage of hypoglycemia, lactic acidosis, or flatulence. Exenatide will fundamentally transform our thinking of how to approach the patient failing one or more oral agents and broaden the options beyond adding another pill or insulin to include an option that is associated with weight loss and sustained efficacy.

Drawing a conclusion from previously proven research and trials, Exenatide is indicated as adjunctive therapy to improve glycemic control in patients with type 2 diabetes mellitus who are taking metformin, a sulfonylurea, a thiazolidinedione, a combination of metformin and a sulfonylurea, or a combination of metformin and a thiazolidinedione, but have not achieved adequate glycemic control.

References:

1. Michael A. Nauck and Juris J. Meier. Glucagon-like peptide 1 and its derivatives in the treatment of diabetes, , Pubmed [MEDLINE]

2. Exendin-4 stimulates both beta-cell replication and neogenesis, resulting in increased beta-cell mass and improved glucose tolerance in diabetic rats. Diabetes. 1999 Dec;48(12):2270-6

3. Insulinotropic glucagon-like peptide 1 agonists stimulate expression of homeodomain protein IDX-1 and increase islet size in mouse pancreas Diabetes 49:741–748, 2000

4. Exendin-4 decelerates food intake, weight gain, and fat deposition in Zucker rats. Endocrinology. 2000 Jun;141(6):1936-41

5. Insulinotropic actions of exendin-4 and glucagon-like peptide-1 in vivo and in vitro. Metabolism. 2001 May;50(5):583-9

6. Glucagon-like peptide-1 and exendin-4 stimulate beta-cell neogenesis in streptozotocin-treated newborn rats resulting in persistently improved glucose homeostasis at adult age. Diabetes. 2001 Jul;50(7):1562-70

7. Synergistic insulinotropic effects of succinic acid dimethyl ester and exendin-4 in anaesthetized rats. Int J Mol Med. 2001 Sep;8(3):269-71

8. Persistent improvement of type 2 diabetes in the Goto-Kakizaki rat model by expansion of the beta-cell mass during the prediabetic period with glucagon-like peptide-1 or exendin-4. Diabetes. 2002 May;51(5):1443-52.

9. Glucagon-like peptide-1 treatment delays the onset of diabetes in 8 week-old db/db mice. Diabetologia. 2002 Sep;45(9):1263-73

10. Glucagon-like peptide-1 receptor signaling modulates beta cell apoptosis. J Biol Chem. 2003 Jan 3;278(1):471-8

11. Role of Endogenous Glucagon-Like Peptide-1 in Islet Regeneration After Partial Pancreatectomy. Diabetes. 2003 Feb;52(2):365-371

12. Exendin-4 Prevents the Development of Diabetes in the Intrauterine Growth Retarded Rat. Diabetes. 2003 Mar;52(3):734-740.