antidiabetic agents1dated

Anti-diabetic Agents

Florencia D. Munsayac, MD, FPSECP, MBA, RMT

The Endocrine Pancreas1 million islets of Langerhans

• The islets are endocrine tissue containing four types of cells. In order of abundance, they are:

• beta cells, which secrete insulin and amylin;

• alpha cells, which secrete glucagon;

• delta cells, which secrete somatostatin

• gamma cells, which secrete a polypeptide.

Diabetes Mellitus Type 1 Diabetes

- cells that produce insulin are destroyed

- results in insulin dependence

- commonly detected before 30

Type 2 Diabetes- blood glucose levels rise due to 1) Lack of insulin production2) Insufficient insulin action (resistant cells)- commonly detected after 40

- eventually leads to β-cell failure (resulting in insulin dependence)

Type 3 Diabetes-Refers to multiple other specific causes of an elevated blood glucose

Type 4 Diabetes (Gestational Diabetes) 3-5% of pregnant women in the US develop gestational diabetes

Diabetes Mellitus

• Incidence: 171 M worldwide (WHO 2006)

• Greatest prevalence: Asia & Africa

• Top 5 of the most significant diseases in developed world

• ADA: 18.3% (8.6M) of Americans age 60

Diabetes – Insulin(synthesis, storage, secretion)

This light micrograph of a section of the human pancreas shows one of the islets of Langerhans, center, a group of modified glandular cells. These cells secrete insulin, a hormone that helps the body metabolize sugars, fats, and starches. The blue and white lines in the islets of Langerhans are blood vessels that carry the insulin to the rest of the body.


Insulin is a small protein consisting of an A chain of 21 amino acids linked by two disulfide (S—S) bridges to a B chain of 30 amino acids.

Beta cells have channels in their plasma membrane that serve as glucose detectors. Beta cells secrete insulin in response to a rising level of circulatingglucose.


Chemistry:• a small protein with molecular weight of 5808

• contains 51 amino acids

• arranged in 2 chains ( A & B ) linked by disulfide bonds/bridges

• stored crystals consisting of 2 atoms of zinc & 6 molecules of insulin

• contain 8mg of insulin/human pancreas (=200

units)


Regulation of Insulin Release• Stimulants of insulin release

– Glucose, mannose– Leucine– Vagal stimulation– sulfonylureas

• Amplifiers of glucose-induced insulin release– Enteric hormones

• Glucagon-like peptide• Gastrin inhibitory peptide• Cholecystokinin• Secretin, gastrin

– Neural amplifiers• Beta receptor stimulation

– Amino acids• arginine

• Inhibitors of insulin release– Neural: alpha sympathetic effect of cathecolamines– Humoral: somatostatin, amylin– Drugs: diazoxide, phenytoin, vinblastine, colchicine

Diabetes – Insulin• Insulin Degradation:

- 2 main organs: liver – 60% kidney – 35-40%

- hydrolysis of the disulfide bonds glutathione insulin transhydrogenase (insulinase )- half-life: 3-5 minutes

• Measurement of Circulating Insulin:

- radioimmunoassay permits detection of insulin in picomolar quantities- basal insulin values: 5-15uU/ml (30-90pmol/L)- peak rise: 60-90uU/ml (360-540pmol/L)

Diabetes – Insulin(Biochemical Role)

Tyrosine kinase receptors are the locks

in which the insulin key fits

Involved in signal transduction

(insulin hormone being 1st messenger)

Effects of Insulin on its Targets

Insulin affects many organs:

• It stimulates skeletal muscle fibers.

• It stimulates liver cells.

• It acts on fat cells

• It inhibits production of certain enzyme.

In each case, insulin triggers these effects by binding to the insulin receptor.

protein synthesis

amino acids uptake

glucoseuptake

glycogen synthesis

enzymeproduction

glycogenbreaking

fat synthesis

Effects of Insulin on its Targets

Transporters

Tissues GlucoseKm (Mmo/L)

Function

GLUT 1 All tissues, esp.red cells, brain

1-2 Basal uptake of glucose;Transport across the BBB

GLUT 2 B cells of pancreas;Liver; kidney; gut

15-20 Regulation of insulin release, other aspects of glucose homeostasis

GLUT 3 Brain, kidney, placenta, other tissues

< 1 Uptake into neurons, other tissues

GLUT 4 Muscle, adipose 5 Insulin-mediated uptake of glucose

GLUT 5 Gut, kidney 1-2 Absorption of fructose

Diabetes - Insulin Receptor

The insulin receptor (IR) is a transmembrane glycoprotein, composed of 2α and 2β domains.

Its intracellular tyrosine

kinase domain is activated by binding of insulin, leading to a cascade of signaling events.

Principal Types and Duration of Action

1. Rapid-acting insulins:- Dispensed as clear solutions at neutral pH- Contain small amount of zinc to improve

stability & shelf-life- Preferred for use in continuous SC infusion

devices• Insulin lispro, • Insulin aspart, • insulin glulysine,

- Available in powder form for alveolar absorption

• human insulin recombinant inhaled


• Pharmacokinetics:

Rapid-acting insulin

Onset Peak Duration

Insulin lispro 5-15 min 1 hr 3-5 hrs

Insulin aspart 5-15 min 1 hr 3-5 hrs

Insulin glulysine

5-15 min 1hr 3-5 hrs

HIRI 10-20 min 2 hrs 6-7 hrs


2. Short-acting insulin• Regular insulin

– A soluble crystalline zinc– Made by recombinant DNA techniques– Onset: 30 minutes– Peak: 2-3 hours– Duration: 5-8 hours– Administered intravenously

• Useful in diabetic ketoacidosis, surgery or during acute infection, and when the insulin requirement is changing rapidly


3. Intermediate-acting & Long-acting insulins

a. LENTE INSULIN (insulin zinc suspension)– mixture of 30% semilente with 70% ultralente insulin

provide a combination of relatively rapid absorption with sustained long action

b. NEUTRAL PROTAMINE HAGEDORN or

Isophane Insulin– absorption & onset of action is delayed by combining

appropriate amounts of insulin & protamine– 6 molecules of insulin per molecule of protamine


c. INSULIN GLARGINE– soluble, “peakless, ultra-long-acting insulin analog

– designed to provide reproducible, convenient, background insulin replacement

– Onset: 1-1.5 hours

– maximum effect: 4-5 hours

– Duration: 11-24 hours or longer

– given once a day


d. INSULIN DETEMIR– Injected SC

– Binds to albumin via its fatty acid chain

– Administered b.i.d.

– Onset: 1-2 hours

– Duration: > 24 hours

Species of Insulin

• Beef and pork insulin– The beef insulin differs by 3 amino

acids, pork differs by 1 amino acid– The beef hormone is most antigenic

• Human insulin

– Less expensive, less immunogenic– Production by recombinant DNA

techniques

• Purity of Insulin– chromatography

• Concentrations:– 100 units– 500 units

Insulin Delivery Systems A. Portable Pen Injectors

- to facilitate multiple SQ injections

B. Continuous Subcutaneous Insulin Infusion Devices (CSII, Insulin Pumps)

- encouraged for individuals who are unable to obtain target control while on multiple injection regimens & where excellent glycemic control is desired, such as during pregnancy

- velosulin (reg. insulin) & insulin aspart and lispro

C. Inhaled Insulin- have a rapid route and a relatively short duration of action- used to cover mealtime insulin requirements - to correct high glucose levels

Factors that Affect Insulin Absorption:- site of injection: abdomen, buttock, anterior thigh, or dorsal

arm

- type of insulin

- subcutaneous blood flow: massage, hot baths, or exercise

- smoking

- regional muscular activity at the site of the injection

- volume & concentration of injected insulin

- depth of injection

Complications of Insulin Therapy

A. Hypoglycemia• Mechanisms and diagnosis

– result from a delay in taking a meal– unusual physical exertion– dosage error

• CM: tachycardia, palpitations, sweating, tremulousness, hunger, nausea, convulsion, coma

• Treatment: glucose administration Glucagons 1 mg SQ or IM Honey or syrup

Complications of Insulin Therapy

B. Immunopathology of Insulin Therapy 1. Insulin allergy

– an immediate type of hypersensitivity (IgE-antibodies)– Tx: antihistamines, corticosteroids & desensitization

2. Immune insulin resistance (IgG antibodies)

– + circulating antibodies that neutralize the action of insulin to a small extent

– Tx: switching to a lesser antigenic purified insulin

C. Lipodystrophy at injection sites– corrected by avoidance of that specific injection site or with liposuction

– hypertrophy

Oral Anti-diabetic Agents 4 Categories: a. Insulin secretagogues (sulfonylureas,

meglitinides, D-phenylalanine derivatives)

b. Biguanides

c. Thiazolidinediones

d. Alpha-glucosidase inhibitors

Insulin Secretagogues:

A. Sulfonylureas

• Mechanism of Action:– to increase insulin release from pancreatic B cells

– Sulfonylureas bind to S receptor inhibits efflux of K+

depolarization opens a voltage-gated Ca++ channel results in Ca++ influx and the release of preformed insulin

– reduction of serum glucagon concentrations

• Chronic administration of sulfonylureas to type 2 diabetics reduces serum glucagon levels

– potentiation of insulin action on target tissues


Sulfonylureas:

• 1st generation

– tolbutamide

– tolazamide

– chlorpropamide

– acetohexamide

• 2nd generation

– glipizide

– glyburide

• 3rd generation

– glimepiride


• Tolbutamide: – well absorbed but rapidly metabolized in the liver

– duration of action: 6-12 hours

– elimination half-life: 4-5 hours

– toxic reactions: skin rash hypoglycemia

– drug interactions: dicumarol, phenylbutazone, sulfonamides


• Chlorpropamide:– duration of action: up to 60 hours

– half-life: 32 hours

– slowly metabolized in the liver

– 20-30% is excreted unchanged in the urine

– SE: hypoglycemia, hyperemic flush, dilutional hyponatremia, transient leukopenia, thrombocytopenia, jaundice

– CI: hepatic & renal insufficiency

– Dosage: 250mg daily


• Tolazamide:– duration of action: 10-14 hours

– more slowly absorbed


– SE: hypoglycemia


• Glyburide:– metabolized in the liver

– short plasma half-life


– SE: flushing, hypoglycemia

– Contraindication: hepatic & renal insufficiency

– Dosage: 5-10mg as single morning dose


• Glipizide:– has the shortest half-life: 2-4 hours


– 90% is metabolized in the liver

– 10% excreted unchanged in the urine

– SE: hypoglycemia

– Contraindication: renal & hepatic insufficiency

– Dosage: 5-20mg as a single dose, 30 minutes before breakfast


• Glimepiride:– duration of action: 12-24 hours


– available as once-daily dosing

– completely metabolized by the liver

– dosage: 1 mg daily


B. Meglitinides – Repaglinide:

• modulate B cell insulin release by regulating K+ efflux through the K+ channels

• no direct effect on insulin exocytosis

• peak concentration & peak effect: within 1 hour

• fast onset & duration of action (5-8 hrs.)

O

OHO

NH

N

O

2-Ethoxy-4-{[3-methyl-1-(2-piperidin-1-yl-phenyl)-butylcarbamoyl]-methyl}-benzoic acid


B. Meglitinides– Repaglinide:

• hepatically cleared by CYP3A4

• half-life: 1 hour

• indication: controlling postprandial glucose excursions

• Dosage: 0.25-4 mg

• SE: hypoglycemia

• Caution: hepatic & renal impairment


C. D-phenylalanine derivative

Nateglinide:• stimulates very rapid and transient

release of insulin from B cells through the closure of ATP-sensitive K+ channel

• may suppress glucagon release early in the meal and result in less endogenous or hepatic glucose production

• has minimal effect on overnight or fasting blood glucose levels

• ingested just prior to meals

O

OH

NH

O

2-[(4-Isopropyl-cyclohexanecarbonyl)-amino]-3-phenyl-propionic acid


C. D-phenylalanine derivativeNateglinide:• absorbed within 20 minutes after oral administration

• time to peak concentration: < 1 hour

• hepatically metabolized by CYP2C9 & CYP3A4

• half-life: 1.5 hours

• duration of action: < 4 hours

• SE: hypoglycemia but lowest of all the secretagogues

Biguanides• Mechanisms of action:

– direct stimulation of glycolysis in tissues, with increased glucose removal from blood

– reduced hepatic & renal gluconeogenesis

– slowing of glucose absorption from the GIT, with increased glucose to lactate conversion by enterocytes

– reduction of plasma glucagon levels

Biguanides• Metabolism & Excretion:

– Metformin:• half-life: 1.5-3 hours

• duration of action: 10-12 hours

• not bound to plasma proteins

• not metabolized

• excreted by the kidneys as active compound

• may impair the hepatic metabolism of lactic acid

N N

N

N

N

H

H

H

H H

+ HCl

Biguanides

Clinical Uses:• refractory obesity whose BS is due to

ineffective insulin action (insulin resistance syndrome) - only anti-diabetic drug that has been

proven to reduce the complications of diabetes, as evidenced in a large study of overweight patients with diabetes (UKPDS 1998).

• use as in combination with sulfonylureas or thiazolidinediones in type 2 diabetics in whom oral monotherapy is inadequate

• dosage: 500mg TID

Biguanides

Toxic Effects:• anorexia, nausea, vomiting,

abdominal discomfort, diarrhea

• absorption of B12 appears to be reduced during long-term therapy

Biguanides

Contraindications:• renal disease, alcoholism• hepatic disease• chronic cardiopulmonary dysfunction

Thiazolidinediones

• Increase the sensitivity of muscle, fat & liver to endogenous & exogenous insulin (“insulin sensitizers”)

• Binds to and activates the gamma isoform of the peroxisome proliferator-activated receptor (PPARγ) - PPARγ is a member of the steroid hormone nuclear receptor superfamily, and is found in adipose tissue, cardiac and skeletal muscle, liver and placenta

• Major site of action: adipose tissue → promotes glucose uptake and utilization and modulate synthesis of lipid hormones or cytokines and other proteins involved in energy regulation

• Considered “euglycemics”

• Have a slow onset and offset of activity

Thiazolidinediones

• Side Effects:– Hypoglycemia in combination

– Drop in triglyceride levels

– Slight rise in HDL & LDL cholesterol values

– Edema – fluid retention

– Anemia

– Dose-related weight gain (1-3 kg)

Thiazolidinediones

• CI: – pregnancy– Significant liver disease– Heart failure

Thiazolidinediones

• Pioglitazone:– may have PPAR-alpha as well as PPAR-gamma activity

– absorbed within 2 hours of ingestion

– metabolized by CYP2C8 and CYP3A4 to active metabolites

– DI: estrogen-containing oral contraceptives

– Taken once daily

– Dosage: 15-30mg

– Approved as monotherapy or in combination with metformin, sulfonylureas, and insulin

S

NH

O

O

ON

5-{4-[2-(5-Ethyl-pyridin-2-yl)-ethoxy]-benzyl}-thiazolidine-2,4-dione

Thiazolidinediones

• Rosiglitazone:– rapidly absorbed and highly protein bound

– metabolized in the liver by CYP2C8 & CYP2C9

– administered once or twice daily

– dosage: 4-8 mg

– approved as monotherapy or in combination with biguanides & sulfonylureas

Alpha-Glucosidase Inhibitors

• are competitive inhibitors of the intestinal alpha-glucosidases and reduce the postprandial digestion and absorption of starch and disaccharides--> lowering post-meal glycemic excursions (45-60mg/dl) and creating an insulin-sparing effect

• members: acarbose

miglitol

N

OO

OO

O

H

H H

H H

1-(2-Hydroxy-ethyl)-2-hydroxymethyl-piperidine-3,4,5-triol

Alpha-Glucosidase Inhibitors

• taken in doses of 25-100 mg just prior to ingesting the first portion of each meal

• both are absorbed from the gut

• SE: flatulence, Diarrhea, Abdominal pain

• CI: Chronic or inflammatory bowel disease, Renal impairment, Hepatic disease (acarbose)

Pathophysiology of Type 2 Diabetes

• Insulin resistance.

• Beta cell dysfunction.


Insulin Resistance

• Insulin Resistance starts very early in the course of the disease.

• insulin resistance alone will not produce diabetes. If beta-cell function is normal, one can compensate for insulin resistance by increasing insulin secretion.


Beta cell defect• all type 2 patients have at least a relative defect in both

beta-cell function and mass. • Function: in the (UKPDS), newly diagnosed people with

diabetes had, on average, only about 50% of normal beta-cell function. [Diabetes. 1995;44:1249-1258 , Diab Res Clin Pract. 1998;40(suppl):S21-S25.]

• Mass: Autopsy studies comparing the volume of beta

cells in non-diabetic individuals with that of people with diabetes found a 41% decrease in beta-cell mass among people with type 2 diabetes


Other Factors

• Two other factors:

- Glucagon.

- Gastric emptying.


The Glucagon Factor

• In response to a carbohydrate-containing meal, individuals without diabetes not only increase insulin secretion but also simultaneously decrease pancreatic alpha-cell glucagon secretion.

• The decrease in glucagon is associated with a decrease in hepatic glucose production, and along with the insulin response, results in a very modest increase in postprandial glucose.

N Engl J Med. 1971;285:443-449.


The Glucagon Factor• In contrast, the glucagon secretion in type 2 diabetics is

not decreased, and may even be paradoxically increased.

• These insulin and glucagon abnormalities produce an excessive postprandial glucose excursion.

• more than 35 years ago, Roger Unger presciently stated, "One wonders if the development of a pharmacologic means of suppressing glucagon to appropriate levels would increase the effectiveness of available treatments for diabetes”.

N Engl J Med. 1971;285:443-449.


The Gastric Emptying Factor

• Many factors can affect the rate of gastric emptying.

• studies suggest that all other factors being equal, most people with type 1 and type 2 diabetes have accelerated gastric emptying compared to those without diabetes.Gastroenterology. 1990;98:A378.


One last observation

• In 1930 La Barre described a greater effect of oral rather parenteral glucose in increasing insulin secretion.

• In 1986 Nauck demonstrated that a glucose infusion graded to achieve plasma glucose levels identical of those achieved with oral glucose led to an insulin response that was only one quarter as great.

J Clin Endocrinol Metab. 1986;63:492-498.

• Incretin hormones were discovered during researchers trials to find out interpretation to this phenomenon which has been called the incretin effect.

What are incretins?

• Hormones produced by the gastrointestinal tract in response to incoming nutrients, and have important actions that contribute to glucose homeostasis.

• Two hormones: - Gastric inhibitory polypeptide (GIP)

. - Glucagon-like peptide-1 (GLP-1).

What are incretins?

Gastric Inhibitory Polypeptide (GIP)

• Secreted by the K cells of the proximal gut. However, type 2 diabetes patients are resistant to its action (high blood level), making it a less attractive therapeutic target.

What are incretins? Glucagon-like peptide-1 (GLP-1)

• a 30-amino acid peptide secreted in response to the oral ingestion of nutrients by L cells, primarily in the ileum and colon.

• There are GLP-1 receptors in islet cells and in the central nervous system, among other places.

• GLP-1 is metabolized by the enzyme dipeptidyl peptidase-IV (DPP-IV) .

Actions of GLP-1

• It enhances glucose-dependent insulin secretion.

• Inhibits glucagon secretion and therefore hepatic glucose production.

• Slows gastric emptying.

• Increases satiety resulting in less food intake.

• Appears to stimulate insulin gene transcription and insulin synthesis.

Actions of GLP-1

• In animal studies it increases beta-cell mass by:

- Decreasing beta cell apoptosis. - Stimulating the growth of new beta

cells. Diabetes Care. 2003;26:2929-2940.

???... Long term benefit in reversing the progressive insulin deficiency.

Actions of GLP-1

• Important, as glucose levels approach the normal range, the GLP-1 effects on insulin stimulation and glucagon inhibition declined (glucose dependence - reduction of hypoglycemia. - therapeutic advantage) Diabetologia. 1993;36:741-744

Actions of GLP-1 The Problem

• Unfortunately, GLP-1 is rapidly broken down by the DPP-IV enzyme (very short half-life in plasma - requires continuous IV infusion).

The Solution

Two options:

• Incretin mimetics are glucagon-like peptide-1 (GLP-1) agonists.

• Dipeptidyl peptidase-IV (DPP-IV) antagonists - inhibit the breakdown of GLP-1.

Incretin mimetics

Exenatide

• The first incretin-related therapy available for patients with type 2 diabetes.

• Naturally occurring peptide from the saliva of the Gila Monster.

• Has an approximate 50% amino acid homology with GLP-1.

• Binds to GLP-1 receptors and behaves as GLP-1.

Incretin mimetics

Exenatide

• Resistant to DPP-IV inactivation.

• Following injection, it is measurably present in plasma for up to 10 hours.

• Suitable for twice a day administration by subcutaneous injection.Regul Pept. 2004;117:77-88.

Am J Health Syst Pharm. 2005;62:173-181.

Weight Loss With Exenatide

After adding exenatide:• the group that was on metformin alone lost about 3 kg of body weight at 30

weeks,

• while the sulfonylurea group experienced a 1.5- to 2-kg weight reduction.

• Patients receiving metformin and a sulfonylurea in combination along with exenatide lost an average of 2 kg.

• Weight loss of up to 10 kg has been documented, but it varies from person to person.

• recently published findings have shown progressive weight loss continuing for 82 weeks. Patients convenience

Diabetes Care. 2004;27:2628-2635, 2005;28:1092-1100, 2005;28:1083-1091. Diabetes, Obesity and Metabolism. 2006; 8(4):436; ISSN: 4.

Nausea With Exenatide

• was seen uniformly across the clinical trials, although most episodes were mild-to-moderate in intensity and generally intermittent.

• more frequent at the initiation of treatment and decreased over the course of several weeks.

Incretin mimetics Recent Advances

• Liraglutide: Another GLP-1 analog with longer half-life, similar to exenatide with once-daily injection. Diabetes Care. 2007;30:1608-1610

• Long acting exenatide: Highly effective with once weekly injection. Diabetes Care. 2007;30:1487-1493

Dipeptidyl Peptidase-IV Antagonists

• The concept is to allow the endogenous GLP-1 to remain in circulation for a longer period.

• DPP-IV inhibitors are oral, rather than injectable. • Weight neutral.

• associated with a low incidence of hypoglycemia or gastrointestinal side effects. Diabetes Care. 2004;27:2874-2880.

• Preliminary long-term studies suggest a durable effect on glycemia and improvement in some parameters of beta-cell function. (www.glucagon.com).

Dipeptidyl Peptidase-IV Antagonists Sitagliptin and Vildagliptin

• Sitagliptin and vildagliptin are the first agents in this class to have received FDA approval.

• Incidence of adverse reactions was reported to be very low in a pooled safety data from 5141 patients. ADA

meeting, Chicago, June 2007.

• They are indicated as monotherapy and in combination with metformin, thiazolidinediones and insulin.

• They look to be at least weight neutral.

Dipeptidyl Peptidase-IV Antagonists Recent Advances

• During the last ADA meeting in Chicago, Illinois, 22-26 June 2007, fifty-five presentations addressed 12 different DPP-IV inhibitors and “… more will be seen during the coming months…”

• Some members seem particularly interesting as saxagliptin (? potent) and alogliptin (long acting… ? Better affecting fasting glucose).

Newer Agent

• Pramlintide– Synthetic analog of amylin

– Suppresses glucagon release, delays gastric emptying & has CNS-mediated anorectic effects

– An injectable antihyperglycemic, administered in addition to insulin

– Rapidly absorbed after SC administration, before eating

Newer Agent

• Pramlintide– Peak level: 20 minutes

– Duration: not more than 150 minutes

– Metabolized & excreted renally

– Modulates postprandial glucose levels in type 1 & 2 DM

– SE: hypoglycemia, N/V, & anorexia

Summary

• Insulin resistance and relative insulin secretory defect are key elements of the pathogenesis of type 2 diabetes.

• GLP-1 deficiency is another key component in diabetic pathophysiology contributing to:

- insulin secretory deficit.

- excess of plasma glucagon.

- postprandial hyperglycemia.

Summary

• Incretin mimetics offer a new approach in the management of type 2 diabetes.

• Exenatide is the first agent in this class and is administered via injection twice a day.

• In addition to improving glycemic control, exenatide has the unique benefit of causing weight loss that appears to be prolonged based on initial studies.

Summary

• DPP-IV inhibitors raise GLP-1 levels 2- to 3-fold. • They appear to be weight neutral and have a remarkable

low incidence of adverse reactions.

• Sitagliptin ad vildagliptin are the first of the DPP-IV inhibitors to receive FDA approval.

• these promising new therapies should be undertaken in combination not only with existing oral anti-diabetes medications as indicated, but also with other proven cardiovascular risk-reduction strategies, including lifestyle reduction and pharmacologic therapy, as needed.

THANK YOU

Insulin Drug Evolution

• Stage 1 Insulin was extracted from the glands of cows and pigs. (1920s)

• Stage 2 Convert pig insulin into human insulin by removing the one amino acid that distinguishes them and replacing it with the human version.

Insulin Drug Evolution

• Stage 3 Insert the human insulin gene into E. coli and culture the recombinant E.coli to produce insulin (trade name = Humulin®). Yeast is also used to produce insulin (trade name = Novolin®) (1987).

Recombinant DNA technology has also made it possible to manufacture slightly-modified forms of human insulin that work faster (Humalog® and NovoLog®) or slower (Lantus®) than regular human insulin.

antidiabetic agents1dated

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