Diabetes Mellitus

Overview and Treatments

Diabetes - a growing threat There are currently more than 230 million people with

diabetes worldwide.  If nothing is done to slow the epidemic, the number will exceed 350 million by 2025.

In 2003, the five countries with the largest numbers of persons with diabetes were

India (35.5 million) China (23.8 million) the United States (16 million)  Russia (9.7 million) Japan (6.7 million). 

By 2025, the number of people with diabetes is expected to more than double in Africa, the Eastern Mediterranean, the Middle East, and South-East Asia.

Diabetes Mellitus : a group of diseases characterized by high levels of blood glucose resulting from defects in insulin production, insulin action, or both

Criteria of diagnosis of DM:

- Polyuria, polydipsia and unexplained weight loss

- Random plasma glucose level of greater than 200 mg/dl (11.1 mmol/L)

- Fasting plasma glucose level of more than 126 mg/dl (7 mmol/L)

- Plasma glucose level of more than 200 mg/dl 2 hours after ingestion of an oral glucose load.

¨ Complications :- Stroke- Heart attack- Kidney disease- Eye Disease- Nerve Damage

Consists of 3 types:1. Type 1 diabetes2. Type 2 diabetes3. Gestational diabetes

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 production

2) Insufficient insulin action (resistant cells)

- commonly detected after 40 although it is being increasingly being detected in younger people

- effects > 90%

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

Gestational Diabetes Gestational diabetes (GDM) is defined as any abnormality in glucose levels noted for the first time during pregnancy.

Testing :

Fasting Plasma Glucose Test (FPG) - (cheap, fast)

*fasting B.G.L. 100-125 mg/dl signals pre-diabetes*>126 mg/dl signals diabetes

Oral Glucose Tolerance Test (OGTT)

*tested for 2 hrs after glucose- rich drink*140-199 mg/dl signals pre-diabetes*>200 mg/dl signals diabetes

¨ 80 to 90 mg per 100 ml, is the normal fasting blood glucose concentration in humans and most mammals which is associated with very low levels of insulin secretion.

A.K.A.: Glycated Hemoglobin tests A1C

PancreasKidneys

Stomach

Pancreas

The bulk of the pancreas is an exocrine gland secreting pancreatic fluid into the duodenum after a meal.

Inside the pancreas are millions of clusters of cells called 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 somatostatingamma cells, which secrete a polypeptide.

Diabetes - Insulin

Discovered in 1921 by Banting and Best

Consist of A & B chains linked by 2 disulfide bonds

(plus additional disulfide in A)~ ~ ~ ~ ¨ A = 21amino acids B = 30 amino acids

Diabetes – Insulin(synthesis, storage, secretion) Produced within the pancreas by β

cells islets of Langerhans insulin mRNA is translated as a single

chain precursor called preproinsulin(110 aa)

removal of signal peptide during insertion into the endoplasmic reticulum generates proinsulin(86 aa)

Within the endoplasmic reticulum, proinsulin is exposed to several specific endopeptidases which excise the C peptide, thereby generating the mature form of insulin(51 aa)

Stored as β granulesThis 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.

Zn

B chain

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.

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.

A chain

Insulin secration is a tightly regulated process. The regulation is achieved by coordinated interplay of various factors.

• Food stuffs stimulate insulin secretion Glucose: Orally ingested glucose has a greater capacity to stimulate insulin secretion than intravenous glucose administration. amino acids (Arg, Lys) fatty acids and ketones

• Several GI hormone promote secretion of insulin: The most potent of these GIP, GLP-1. Beside these sectetin, gastrin, cholecystokinine, VIP, gastrin-releasing peptide, enteroglucagon.

Other Hormones: Insulin release is under reciprocal control by glucagon (α cells). Glucagon stimulates insulin secretion: Insulin inhibits the release of glucagon.

• Autonomic Mechanisms: Autonomic regulation of insulin release is regulated by the ventrolateral (vagal) and the ventromedial (sympathetic) hypothalamus. Stimulation of a2 adrenergic receptors inhibit insulin release, where as 2 and vagal nerve stimulation enhance release.

Secretion of Insulin

• The majority of insulin in the blood circulates unbound. The volume of distribution approximates the volume of extracellular fluid.

• Pancreas secretes about 40 mg of insulin/hour in portal vein resulting 0.5 ng/ml in peripheral circulation.

• The half-life of insulin in plasma about 5-6 minute for both normal and diabetics.

• Degradation of insulin occurs primarily in liver, kidney and muscle. 50% of insulin reaching the liver is destroyed by thiol metalloproteinase in a single pass. Insulin is filtered by the glomerulus and reabsorbed by the tubular epithelial cells which degrade it.

• Degradation of insulin in the liver and other target tissues occurs primarily through insulin-receptor internalization which results in proteolytic degradation of insulin and return of the receptor to the cell surface.

Distribution and Degradation of Insulin

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.

glucoseuptake

glycogen synthesis

protein synthesis

amino acids uptake

enzymeproduction

glycogenbreaking

fat synthesis

Insulin affects many organs

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)

Diabetes – Insulin(Biochemical Role)

In the case of type 1 diabetes, insulin levels are grossly deficient. Thus type 1 diabetes is invariably treated with insulinType 2 diabetes is frequently associated with obesity. Serum insulin levels are normal or elevated, so this is a disease of insulin resistance.

Insulin and diabetes

This leads to an increase in the amount of glucose in the blood. This high concentration of glucose or ’high blood sugar’ is termed hyperglycaemia.

¨ Chronic elevation of blood glucose eventually leads to tissue damage.

¨ The kidneys, eyes, peripheral nerves and vascular tree manifest the most significant diabetic complications.

¨ The mechanism for this is complex and not yet fully understood. It involves:

• The direct toxic effects of high glucose levels

• The impact of elevated blood pressure

• Abnormal lipid levels• Functional and structural

abnormalities of small blood vessels

Tissue damage

¨ Out-of-control diabetes, when severe, leads to the body using stored fat for energy and a subsequent build-up of acids (ketone bodies) in the blood. This is known as ketoacidosis and is associated with very high glucose levels. It requires emergency treatment and can lead to coma and even death.

¨ Recurrent or persistent infections (including tuberculosis).

¨ Both hyperglycaemia and hypoglycaemia (abnormally low blood glucose resulting from treatment) may cause coma and, if untreated, may be fatal.

The short term effects of diabetes

The long term effects of diabetes can be divided into– macrovascular complications – microvascular complications.

¨ Macrovascular complications affect the larger blood vessels, such as those supplying blood to the heart, brain and legs. The most common macrovascular fatal complication is coronary artery disease. Strokes are also a common cause of disability and death in people with diabetes.

¨ Microvascular complications affect the small blood vessels, such as those supplying blood to the eyes and kidneys. The microvascular complications of diabetes are retinopathy, nephropathy and neuropathy.

The long term effects of diabetes

Visual impairment:diabetic retinopathy,

cataract and glaucoma

Kidney disease(diabetic nephropathy)

Sexual dysfunction

Sensory impairment(peripheral neuropathy)

Ulceration

Stroke(cerebrovascular disease)

Heart disease(cardiovascular disease)

Severe hardening of the arteries (atherosclerosis) Autonomic neuropathy

(including slow emptyingof the stomach and diarrhea)

Necrobiosis lipidoica

Gangrene

Poor blood supply to lower limbs (peripheral vascular disease)

The major diabetic complications

Bacterial and fungalinfections of the skin

The close association of type 2 diabetes with cardiovascular disease has led to the hypothesis that they both share a common antecedent. This concept has been labeled ‘The Metabolic Syndrome’ by the World Health Organization and others.

The metabolic syndrome reflects the clustering of central obesity with several other major cardiovascular disease risk factors commonly found in those with type 2 diabetes.

Central obesity

Dyslipidaemia

Hypertension

Impaired glucose regulation or diabetes

Insulin resistance

The metabolic syndrome

Increased levels of procoagulant factors

Insulin resistance: A state in which a given level of insulin produces a less than expected biological effect.

Diabetic Emergencies

D iabetic K etoacidosisH yperg lycem ia

Acidosis w ith anion gapE lectro lyte D isturbances

H yperg lycem ic H yperosm olar S tateH yperg lycem ia

N o acidosisH ypernatrem ia and others

H ypoglycem ia

D iabetes

Diabetic ketoacidosis is a serious complication of diabetes. Diabetic ketoacidosis develops when there is too little insulin in body. Without enough insulin, sugar (glucose) can't enter cells. Blood sugar level rises, and body begins to break down fat for energy. This produces toxic acids known as ketones. Left untreated, diabetic ketoacidosis may cause one to lose consciousness. Eventually, untreated diabetic ketoacidosis can be fatal. Diabetic ketoacidosis is most common in people who have type 1 diabetes, but people who have type 2 diabetes may develop diabetic ketoacidosis, too. In fact, in a few cases diabetic ketoacidosis is the first sign that a person has diabetes.

Diabetic Ketoacidosis

Diabetic Ketoacidosis: Symptom

Diabetic ketoacidosis symptoms often develop quickly, sometimes within 24 hours. Symptoms includes:

Excessive thirst Frequent urination Nausea and vomiting Abdominal pain Loss of appetite Weakness or fatigue Shortness of breath Fruity-scented breath Confusion

More specific signs of diabetic ketoacidosis — which can be detected through home blood and urine testing kits — include:

High blood sugar level High ketone level in your urine

Treatment is usually a three-prong approach: • Fluid replacement. either orally or through a vein

(intravenously) — until rehydrated. The fluids will replace fluid lost through excessive urination, as well as help dilute the excess sugar in blood.

• Electrolyte replacement. Electrolytes are minerals in blood that carry an electric charge, such as sodium, potassium and chloride. The absence of insulin can lower the level of several electrolytes in our blood. Electrolytes should be administered through veins to help keep heart, muscles and nerve cells functioning normally.

• Insulin therapy. Insulin reverses the processes that cause diabetic ketoacidosis. Along with fluids and electrolytes, IV insulin therapy should be started. When blood sugar level falls below 250 mg/dL (14 mmol/L) and blood is no longer acidic, intravenous insulin therapy may be stop and conventional therapy should be started.

Diabetic Ketoacidosis: Treatment

Hyperglycemic Hyperosmolar State

This second most common form of hyperglycemic

coma is characterized by severe hyperglycemia in the

absence of significant ketosis, with hyperosmolality

and dehydration. It occurs in patients with mild or

occult diabetes, and most patients are at least middle-

aged to elderly. Lethargy and confusion develop as

serum osmolality exceeds 310 mosm/kg, and coma

can occur if osmolality exceeds 320-330 mosm/kg.

Weeks of symptoms Polyuria Weight loss Decreased PO intake

Elderly patient Confusion Altered mental status Lethargy Profound dehydration Hypotension Tachycardia

Hyperglycemic Hyperosmolar State: Clinical Features

Hyperglycemic Hyperosmolar State: Treatment

Significant fluid and electrolyte replacement

Insulin treatment started via IV but not aggressive

Hypoglycemia DefinedFall in blood glucose concentrations that elicits symptoms of glucose deprivation in the central nervous system.

• Sudden (Adrenergic sx)• Diaphoresis, pallor

• Tremulousness

• Tachycardia, palpitations

• Visual distubances

• Mental confusion, weakness,

• Gradual• Fatigue

• Confusion

• Headach

• Memory loss

• Seizures, coma

Hypoglycemia

Hypoglycemia

A lterations in consc iousness ;S e izures ; H ead ache ;

U nusua l B ehav ior

B ra in lack s ad eq uate g lucose

P a le; C ool sk in;S w eating; T achycard ia ;Increased B P ; N ausea

A d renal G land s re lease E p inep hr ine

B lood S ugar F alls

Pale, cool skin; sweating; nausea; tachycardia

Is that why hypoglycemia sometimes is called “Insulin Shock?”

¨ Prehospital Management of Diabetic Emergencies1. ABC’s/O22. Determine BGL (Normal range 60-120

mg/Dl)3. Oral Glucose if BGL <60 and patient

conscious.4. If unable to take orally, est. IV and

administer 25 g D50/W Child 0.5 g/kg5. If unable to eat. IV or orals, Glucagon 1 mg

SC/IM6. Repeat glucoscan after glucose

administration

Transport all patients on oral anti-hypoglycemic agents who develop

hypoglycemia

In general, give IV D50/W for any hypoglycemia <50 even if oral glucose

given

Hypoglycemia: treatment

Who need insulin

Type I (insulin dependent) diabetes patients whose body produces no insulin.

Type 2 diabetes patients that do not always produce enough insulin.

Treatment

subcutaneous injection

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.

Rapid-acting: Lispro, Aspart, Glulisine

Short-acting: Regular Formulation

Intermediate-acting: NPH Humulin

Long-acting: Insuline detemer, Insuline glargine

Insulin formulation: Type

Depending on Source

• Human

• Procaine

• Bovine

Human peptide sequence Pig and beef insulin differ by 1 (AlaB30Thr) and 2 (ThrA8Ala, ileA10Val) amino acids respectively.

Types of insulin

• Regular insulins

• Insulin analogs

• Pre-mixed insulin

• Short peptide mimics

Regular insulins:

¨ Human insulin: Humulin® (from E.coli), Novalin® (from yeast)¨ NPH - neutral protamine Hagedorn (NPH),

protamine mixed.¨ Lente® insulin / Ultralente® insullin- zinc added

Types of insulin

• Regular insulins

• Insulin analogs

• Pre-mixed insulin

Short peptide mimics

Insulin Analogs:

Fatty Acid Acylated insulins Insulin Lispro (Humalog®) (1996)

Insulin Aspart (NovoLog®) (2000) Insulin Glargine (Lantus®) (2002) Insulin Detemir (Levemir®) (Jun.,2005) Insulin Glulisine (Apidra®) (Jan., 2006)

Amino Acid SubstitutonsA-

chain

Position

B- chain Position

Source/Type

A21 B3 B28 B29 B30 B31 AndB32

Human Asn Asn Pro Lys Thr

Aspart Asn Asparticacid

Lys Thr

Lispro Asn Lys Pro ThrGlulisine Asn Lys Pro Glu Thr

Glargine Gly Pro Lys Thr Arg

Detemir Lys Myristicacid

rapid-acting

long-acting

Extent and duration of action of various types of Insulin

Unitage: One unit of insuline is equal to the amount required to reduce the concentration of blood glucose in a fasting rabbit to 45 mg/dl (2.50mM).Homogeneous preparations of insuline contain between 25 and 30 units/mg

CHOICE OF INSULIN PREPARATION

There are two types of regimen for patients requiring insulin: Intensive/flexible therapy. This uses pens (or pumps)

to administer multiple injections of short-acting insulin during the day to mimic prandial secretion of insulin by the pancreas, and a single night-time dose of long-acting insulin.

Conventional therapy. This involves two injections a day of biphasic insulin. Soluble insulin or one of the rapid-acting analogues is given subcutaneously three times a day. Soluble insulin is given 30 min before meals whilst the analogues have the advantage of being given immediately before, during or after the meal. Risk of hypoglycaemic reaction is lower with the analogues.

NPH insulin or one of the long-acting analogues is given at night. This mimics basal pancreatic insulin release. The long-acting analogues do this more effectively over 24 h than NPH insulin, and avoid risk of nocturnal hypoglycaemia. Biphasic insulins are a mixture of variable proportions of soluble insulin with NPH insulin, or of short-acting analogue with protamine insulin. The available mixtures are listed in. The most commonly used is 30 : 70 (soluble:NPH). All of the above are normally administered subcutaneously. Soluble insulin may also be administered by intravenous infusion. This is the preferred method of delivery in diabetic ketoacidosis, in other critically ill patients, and in perioperative management of diabetes.

CHOICE OF INSULIN PREPARATION

Complication of Insulin Therapy

• Hypoglycemia:

• Most common cmplication of insulin therapy

• Symptoms of hypoglycemia appears at plasma glucose level of 60-80 mg/dl

• Sweating, hunger, paresthesias, palpitations, tremor and anxiety first appears

• Difficulty in concentrating, confusion, weakness, dizziness blurred vision and loss of cnsciousness.

• Insulin allergy and resistant:

• Lipoatrophy and lipohypertropy:

• Insuline edema

Diabetes – Oral Medications

Sulfonylureas Biguanides Thiazolidinediones Alpha-glycosidase inhibitors Meglitinides

5 Classes :

Sulfonylureas : stimulate β cells to produce more insulin

1st generation (1) tolbutamide (3) tolazamide (6) chlorpropamide

¨ 2nd generation– (75) glipizide– (150) glipizide)– (150) glyburide– (250) micronized glyburide

¨ 3rd generation– (350) glimepiride

2-(p-aminobenzenesulfonamido)-5-isopropyl -thiadiazole (IPTD) was used in treatment of typhoid fever in 1940’s hypoglycemia

Currently > 12,000

Rel

. Pot

ency

bind

to p

rote

in

may become dislodged delayed activity

*Hydroxylation of the aromatic ring appears to be the most favored metabolic pathway*Hydroxylated derivatives have much lower hypoglycemic activity

Mechanism of Action Sulfonylureas interact with receptors on

pancreatic -cells to block ATP-sensitive potassium channels

This, in turn, leads to opening of calcium channels

Which leads to the production of insulin

Oral Hypoglycemic agents: Sulfonylureas

Adverse effects:

• infrequent, occurring in about 4% patients

• It can cause hypoglycemic reaction, including coma

• Other adverse effect include

• GIT disturbances: nausea, vomiting, cholestatic jaundice

• Blood diorder: agranulocytosis, aplastic anemia and hemolytic anemia

• Hypersensitivity reaction: transient rashes, which rarely progress to erythema multiforme and exfoliative dermatitis, fever and ajundice

• Others-headache, photosensitivity, weight gain

Biguanides : improves insulin’s ability to move glucose into cells (esp. muscle)

Metformin- Glucophage®, Fortamet®, Riomet®

*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).

NN

NN

N

RR R

R

RR

R

N N

N

N

N

H

H

H

H H

+ HCl

Mechanism of action:Metformin mechanism of action is complex and incompletely

understood. Currently proposed mechanisms of action include

• reduced hepatic and renal gluconeogenesis; • lowering of glucose absorption from the gastrointestinal

tract, with increased glucose to lactate conversion by enterocytes;

• direct stimulation of glycolysis in tissues, with increased glucose removal from blood; and • reduction of plasma glucagon levels.

Oral Hypoglycemic agents: Biguanides

Adverse effect:

occur in up to 20% of patient including diarrhea, abdominal

discomfort, nausea, flatulence, metallic taste, anorexia,

indigestion. They are dose-related, tend to occur at the onset

of therapy, and are often transient. However, metformin may

have to be discontinued in 3–5% of patients because of

persistent diarrhea. Absorption of vitamin B12 appears to be

reduced during long-term metformin therapy. In the absence

of hypoxia or renal or hepatic insufficiency, lactic acidosis is

less common with metformin therapy than with phenformin

therapy.

Sulfonylurea & Biguanide Combo drugs/ Cocktails

Glucovance® (Glyburide & Metformine HCl)

NH

O

NH

SO

O

O

O

NH

Cl1-[[ p-[ 2-( 5-chloro-o-anisamido) ethyl] phenyl] sulfonyl]-3-cyclohexylurea

N N

N

N

N

H

H

H

H H

+ HCl

&

&

Thiazolidinediones (TZD’s) : make cells more sensitive to insulin (esp. fatty cells)

Pioglitazone- Actos®, Avandia®

- 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

PPAR - γ

- upon activation of this nuclear receptor by a ligand such as a TZD, PPARγ–ligand complex binds to a specific region of DNA and thereby regulates the transcription of many genes involved in glucose and fatty acid metabolism.

SNH

O

O

ON

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

Adverse effect:

CNS: Fatigue, headach

GI: Diarrhea, tooth disorder

Respiratory: Pharyngitis, sinusitis, URTI

Miscellaneous: Anemia,back pain, edema, myalgia

Αlpha – glycosidase inhibitors :Block enzymes that help digest starches slowing the rise in B.G.L.

AGI’s- acarbose,

- miglitol

N

OO

OO

O

H

H H

H H

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

a-glucosidase inhibitors reduce intestinal absorption of starch, dextrin and disaccharides by inhibiting the action a-glucosidase in the intestinal brush border. Acarbose and miglitol are competitive inhibitors of the intestinal a-glucosidases and reduce the postprandial digestion and absorption of starch and disaccharides Prominent adverse effects include flatulence, diarrhea, and abdominal pain and result from the appearance of undigested carbohydrate in the colon that is then fermented into short-chain fatty acids, releasing gas.

Meglitinides : Stimulate more insulin production ; dependant upon level of glucose present

Meglitinides

- repaglinide

- nateglinide

O

OHO

NH

N

O

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

O

OH

NH

O2-[(4-Isopropyl-cyclohexanecarbonyl)-amino]-3-phenyl-propionic acid

Oral Hypoglycemic agents: Meglilitinide

Repaglinide is an insulin secratogogue of meglitinide Class. It stimulate insulin secretion by closing ATP-dependent potassium channels in pancreatic -cells.Adverse reaction:CNS: Headache, paresthesiaGI: Constipation, Diarrhea, Dyspepsia, Nausea, vomitingMusculoskeletal: Arthralgia, Back painResepirotaory: Bronchitis, rhinitiesCVS: chest pain, angina, abnormal EKG, MI, arrhythmia and palpitation

DICYP-450 inhibitors like ketoconazole inhibit metabolismCyp 450 inducer rifampin increase metabolism

Oral Hypoglycemic agents: D-phenylalanine derivatives

Nateglinide is an insulin secratogogue derived from D-phenylalanine. It stimulate insulin secretion by closing ATP-dependent potassium channels in pancreatic -cells. Nateglinide promotes a more rapid but less sustained relese of insulin than other oral agents.

Adverse effectArthropathy, back pain, bronchitis, coughing, diarrhea, dizziness, flu syndrome, Hypoglycemia, URTI

DINateglinde is a inhibitor of CYP2C9 decrease metabolism of tolbutamideMAOI, NSAIDS, beta-blocker potetiate its actionThiazide, corticosteroid, sympathomymetic decrease action

Oral Hypoglycaemic agents: Incretin mimetics

The L cells in the distal intestinal mucosa secrete GLP-1 in response to mixed meals.

β-Cell signalling by glucagon-like peptide-1 (GLP-1), which binds to its receptor on the cell surface and elicits intracellular signaling by activating the coupled G proteins, mainly the Gs type. In turn, Gs activates adenylate cyclase to produce cAMP from ATP. This process results in activation of cAMP-dependent protein kinase A (PKA), which increases calcium uptake. Interacting with calmodulin, PKA stimulates exocytosis on insulin-containing granules.

Exenatide is a GLP-1 receptor agonist (incretin mimetic). Exenatide binds to the GLP-1 receptor, resists DPP-IV degradation, and has produced effects similar to those of endogenous GLP-1. Its plasma half-life is about 2.5 hours, requiring a twice-daily SC dosing schedule. Nausea is one disadvantage of exenatide; this side effect is mild or moderate in 40% of patients, severe in 5%, and causes medication termination in approximately 3%. Nausea tends to subside over time but remains problematic for some patients. Beside dizziness, feeling jittery, headache, diarrhea, dyspepsia may occur

Oral Hypoglycemic agents: Incretin mimetics

Sitagliptin

Sitagliptin is an inhibitor of dipeptidyl peptidase-4 (DPP-4), the

enzyme that degrades incretin and other GLP-1-like molecules.

PramlintidePramlintide suppresses glucagon release via undetermined mechanisms, delays gastric emptying, and has central nervous system-mediated anorectic effects. It is rapidly absorbed after subcutaneous administration; levels peak within 20 minutes, and the duration of action is not more than 150 minutes.

Hypoglycemic agents: amylin analog

Adverse EffectCNS: Dizziness, fatigue, headachGI: abdominal pain, anorexia, nausea, vomitingRespiratory: Coughing, pharyngitisMiscellaneous: Allergic reaction, arthralgia,

Animation showing overview of diabetes: http://www.healthscout.com/animation/1/34/main.html Animation showing mechanism of action of insulin: http://www.vivo.colostate.edu/hbooks/pathphys/endocrine/p

ancreas/insulin_phys.html

References:http://www.webmd.com/content/article/59/66840 http://hms.harvard.edu/public/disease/diabetes/diabetes.html http://focus.hms.harvard.edu/2005/May20_2005/immunology.shtml http://diabetes.niddk.nih.gov/dm/pubs/medicines_ez/index.htm http://www.vivo.colostate.edu/hbooks/pathphys/endocrine/pancreas/insulin_struct.html http://www.vivo.colostate.edu/hbooks/pathphys/endocrine/pancreas/insulin.html http://www.vivo.colostate.edu/hbooks/pathphys/endocrine/moaction/surface.html http://www.cancure.org/insulin_potentiation_therapy.htm http://www.diabetes.org/about-diabetes.jsp http://www.diabetesnet.com/diabetes_treatments/sulfonylureas.php http://www.people.vcu.edu/~urdesai/sulf.htm http://en.wikipedia.org/wiki/Glucohexal http://www.drkoop.com/druglibrary/93/glucovance-warnings_precautions.html 

http://en.wikipedia.org/wiki/Actos http://www.answers.com/topic/peroxisome-proliferator-activated-receptor http://www.mja.com.au/public/issues/176_08_150402/omo10828_fm.html http://www.univgraph.com/bayer/inserts/precose.pdf http://www.drugs.com/pdr/ACARBOSE.html http://www.pfizer.com/pfizer/download/uspi_glyset.pdf http://www.rxlist.com/cgi/generic2/miglitol.htm http://en.wikipedia.org/wiki/Prandin http://redpoll.pharmacy.ualberta.ca/drugbank/cgi-bin/getCard.cgi?CARD=APRD00593.txt