Pancreatic Hormones &

Antidiabetic Drugs

By

M.H.Farjoo M.D. , Ph.D.Shahid Beheshti University of Medical Science

Pancreatic Hormones & Antidiabetic Drugs Introduction Classification of Diabetes Insulin Insulin receptor Types of Insulin Preparations Insulin therapy basics Insulin Delivery Systems Glycemic Control in Diabetes Hypoglycemia Treatment of Hypoglycemia Oral Antidiabetic Agents Combination Therapy of Diabetes Glucagon Drug Pictures

Introduction

The pancreatic hormones: Insulin: the anabolic hormone of the body Glucagon: hyperglycemic factor Somatostatin: universal inhibitor of secretory cells Islet amyloid polypeptide (IAPP, or amylin) Pancreatic peptide: facilitates digestive processes

Diabetes: inadequate insulin secretion, with or without concurrent impairment of insulin action

Classification of Diabetes

The disease is classified into four categories: Type 1: insulin-dependent diabetes Type 2: noninsulin-dependent diabetes Type 3: specific causes Type 4: gestational diabetes mellitus

Type 1 Diabetes Mellitus

There is selective B cell destruction and severe insulin deficiency

Administration of insulin is essential It is further subdivided into immune and idiopathic

causes The immune form is the most common form of type 1

diabetes Most patients are younger than 30 years of age at the

time of diagnosis

Type 2 Diabetes Mellitus

Characterized by tissue resistance to the action of insulin combined with a relative deficiency in insulin secretion

A given individual may have more resistance or more B cell deficiency

Patients may not require insulin to survive, but 30% will benefit from insulin therapy

15% of patients have both type 1 & type 2, or a slowly progressing type 1, and ultimately require full insulin replacement

Type 2 Diabetes Mellitus Cont,d

Patients will not develop ketosis Ketoacidosis occurs in stress (infection) or use of drugs

that enhances resistance, (corticosteroids) Dehydration in poorly controlled patients leads to a

lethal condition: "non-ketotic hyperosmolar coma“ Blood glucose may rise to 6–20 times the normal range

and the person may lose consciousness

Other types of diabetes

Type 3 diabetes mellitus Other causes of elevated blood glucose: nonpancreatic

diseases, drug therapy, etc Gestational diabetes (GDM)

Any abnormality in glucose levels for the first time during pregnancy

Diagnosed in 4% of pregnancies Placental hormones create insulin resistance

especially in the last trimester

Insulin

Present insulin standards contain 28 units per milligram

Beef insulin differs by three amino acids from human insulin

Only a single amino acid distinguishes pork and human insulins

Insulin receptor

The network of phosphorylations within the cell is insulin's second message

Insulin increases: Glucose uptake Glycogen formation Protein synthesis Lipogenesis DNA synthesis, cell growth and division

Various hormonal agents (glucocorticoids) lower the affinity of insulin receptors for insulin

Transporter Tissues Function

GLUT 1 All tissues, especially red cells, brain

Basal uptake of glucose; transport across the blood-brain barrier

GLUT 2 Beta cells of pancreas; liver, kidney; gut

Regulation of insulin release, other aspects of glucose homeostasis

GLUT 3 Brain, kidney, placenta, other tissues

Uptake into neurons, other tissues

GLUT 4 Muscle, adipose Insulin-mediated uptake of glucose

GLUT 5 Gut, kidney Absorption of fructose

Different types of GLUT

Types of Insulin Preparations

Four types of insulins are available:

Rapid-acting : very fast onset and short duration Short-acting : rapid onset of action Intermediate-acting Long-acting : slow onset of action

Rapid & short acting insulins are clear solutions.

Other types of insulin are turbid.

Regular

Aspart recombinant in 3 ml prefilled pen

Biphasic Isophane Isophane Insulin 70% + Insulin Reg 30% in Cartridge for PEN

Biphasic IsophaneIsophane Insulin 75% + Insulin Regular 25% in Cartridge for PEN

Glargine Recombinant

Isophane NPH

Insulin Zinc

Types of insulin preparations in Iran

Rapid-Acting Insulin

Three rapid-acting insulins: Aspart Lispro (Not yet in Iran) Glulisine (Not yet in Iran)

Mimic endogenous prandial insulin secretion Allow insulin to be taken immediately before the

meal without sacrificing glucose control Have the lowest variability of absorption of all

available insulin formulations (5% vs. Up to 50%)

Rapid-Acting Insulin Cont,d

Onset of action is in 5–15 min. Reach peak activity in 1 hr. Duration of action is 3–5 hr. Which decreases

the risk of late postmeal hypoglycemia The time of insulin Lispro for peak action is

constant, regardless of the dose

Short-Acting Insulin (regular insulin)

Its effect appears in 30 minutes, peaks 2-3 hr. And lasts 5–8 hr.

Creates insulin hexamers which causes a delayed onset and prolongs the time to peak action

Is the only type that should be administered intravenously for dilutional breaking of hexamers

It is particularly useful for: Intravenous therapy in ketoacidosis Insulin requirement is changing rapidly (after surgery or

during acute infections)

Intermediate Acting Insulin

NPH (Neutral Protamine Hagedorn, or isophane) Combination of insulin and protamine in an isophane

form Has an onset of 2–5 hrs and duration of 4–12 hrs it is usually mixed with regular, lispro, aspart, or

glulisine insulin The action of NPH is highly unpredictable, and its

variability of absorption is over 50%. So its clinical use is waning

Long-Acting Insulin

Two types of long-acting insulins: Glargine Detemir (Not yet in Iran)

Glargine is a "peakless“, ultralong-acting insulin

Onset of action is in 1 hr. and peak effect is in 4–5 hours. Duration of action is ≥24 hr.

Since its formulation is acidic (ph 4.0) so: Glargine should not be mixed with another insulin Separate syringes must be used

Insulin Therapy Basics Rapid-acting or short-acting insulin is used for

mealtime Intermediate or long acting insulin is used for basal

coverage Split-dose injections of mixtures of rapid or short-

acting and intermediate-acting insulins are used For mixing an intermediate-acting insulin with regular

insulin, NPH is usually used.

Insulin Therapy Basics Cont,d

Insulin Lispro & Aspart can be mixed just before injection with NPH, lente, or ultralente insulin but premixed preparations are unstable

The time of onset, peak and duration of action of regular, NPH, lente, and ultralente insulins are dose-dependent

Clinical profile of small doses of these insulins vary greatly with large doses

Healthy

Diabetic

Insulin Delivery Systems

Continuous subcutaneous insulin infusion devices (CSII, insulin pumps) Programmable pump that delivers basal & bolus

insulin based on blood glucose self-monitoring results The pump contains an insulin reservoir, the program

chip, the keypad, and the display screen is the size of a pager

The abdomen is the favored site for subcutaneously inserted infusion set

CSII delivery is regarded as the most physiologic method of insulin replacement

Insulin Delivery Systems Cont,d

Portable pen injectors Contain cartridges of insulin and replaceable

needles

Inhaled insulin Not yet applicable

Insulin Aspart Pen

Insulin Aspart Protamin Pen

Insulin Glargine Pen

Glycemic Control in Diabetes

Intensive insulin therapy is the standard therapy in type 1 patients after puberty

Exceptions include: Advanced renal disease (hypoglycemia) The elderly (hypoglycemia) Children under the age of 7 years (brain damage)

Hypoglycemia Is the most common complication of insulin therapy Rapid development of hypoglycemia causes

Sympathetic activity: tachycardia, palpitations, sweating, tremulousness

Parasympathetic activity: nausea, hunger Convulsions and coma

If frequent hypoglycemia occur, autonomic warning signals may be absent (hypoglycemic unawareness)

These patients show only: weakness, bizarre behavior, coma and seizure

Treatment of Hypoglycemia

Any sugar-containing beverage or food may be given Liquid form is preferable In an unconscious patient:

Intravenous infusion of 20–50 ml of 50% glucose solution in 2–3 minutes

If intravenous therapy is not available: 1 mg of glucagon injected either SC or IM is usually effective in 15 minutes

If glucagon is not available: small amounts of honey or syrup can be inserted into the buccal pouch

Oral feeding is contraindicated in unconscious patients

Oral Antidiabetic Agents

Insulin secretagogues Sulfonylureas Meglitinides D-phenylalanine derivatives

Biguanides: Metformin Thiazolidinediones Alpha glucosidase inhibitors Bile Acid Sequestrants Amylin Analog Incretin-based Therapies SGLT2 Inhibitors

Hypoglycemia, is a side effect common to almost ALL these drugs

Almost ALL of them are contraindicated in severe liver, renal and cardiac disease and should be used with extreme caution in elderly

Sulfonylureas

Mechanism of action Increases insulin release from the pancreas Inhibits the efflux of potassium ions through the

channel and results in depolarization Depolarization, opens a voltage-gated calcium

channel, calcium influx and the release of insulin Chronic administration of sulfonylureas also

reduces serum glucagon levels Divided into first and second generations

First-Generation Sulfonylureas

Tolbutamide (Not yet in Iran) Its half-life is relatively short (5 hr.) Is the safest sulfonylurea for use in elderly

Chlorpropamide Has a long half-life (32 hr.) Contraindicated in elderly patients

Tolazamide (Not yet in Iran) Comparable to chlorpropamide in potency but

shorter acting (half life 7 hr.)

Second-Generation Sulfonylureas Glyburide (Glibenclamide in Iran)

Has few adverse effects other than hypoglycemia. Contraindicated in the presence of hepatic and

renal insufficiency. Glipizide (Not yet in Iran)

Has the shortest half-life (3 hr.) Is much less likely to produce serious

hypoglycemia. Glimepiride (Not yet in Iran)

Has the lowest dose of any sulfonylurea (a single daily dose of 1 mg)

Meglitinides

Repaglinide Modulates insulin release by regulating potassium

efflux through the potassium channels Has a very fast onset of action, with a peak effect

within 1 hour, the duration of action is 5–8 hr. Is indicated for use in controlling postprandial

glucose excursions

D-phenylalanine derivatives

Nateglinide (Not yet in Iran) Stimulates release of insulin through closure of the ATP

sensitive K+ channel May have a special role in the treatment of isolated

postprandial hyperglycemia Dose titration is NOT required Is ingested just prior to meals, absorbed within 20 min.

And peak concentration of <1 hour Incidence of hypoglycemia may be the lowest of all the

secretagogues It is safe in individuals with very reduced renal function

Biguanides: Metformin They decrease hepatic glucose production. They are "euglycemic" since hypoglycemia actually

does not occur Biguanides are for patients with ineffective insulin

action (insulin resistance syndrome) Side effects of metformin (Glucophage) are: anorexia,

nausea, vomiting, abdominal discomfort, diarrhea (in 20% of patients)

Contraindicated in alcoholism and anoxic states (cardiopulmonary dysfunction) because of an increased risk of lactic acidosis

Thiazolidinediones (Tzds) Tzds are ligands of peroxisome proliferator-activated

receptor gamma (PPAR-γ)

PPAR is part of the steroid and thyroid superfamily of nuclear receptors.

Tzds decrease insulin resistance and are "euglycemics“.

PPAR-γ receptors modulate the expression of the genes involved in lipid and glucose metabolism, and insulin signal transduction.

Two Tzds are: Rosiglitazone (Not yet in Iran) & Pioglitazone.

Thiazolidinediones (Tzds) Cont’d

Contraindicated during pregnancy. The metabolism of estrogen containing OCPs may be

affected by pioglitazone (unwanted pregnancy).

Pioglitazone may increase the risk of bladder cancer with high doses.

Tzds have a slow onset and offset of activity over weeks or even months.

Alpha Glucosidase Inhibitors Consist of : Acarbose & Miglitol (the latter not in

Iran). Reduce digestion and absorption of starch and

disaccharides. Adverse effects: flatulence, diarrhea, and abdominal

pain (undigested carbohydrate is fermented in colon and releases gas).

Hypoglycemia should be treated with glucose (dextrose) and NOT sucrose.

Contraindicated in inflammatory bowel disease or any intestinal condition that could be worsened by gas & distention.

Bile Acid Sequestrants

Colesevelam (Not in Iran) is used for type 2.

The mechanism of action involves: An interruption of the enterohepatic circulation

(decrease in hepatic glucose output) A decrease in farnesoid X receptor (FXR) activation.

FXR is a nuclear receptor with multiple effects on cholesterol, glucose, and bile acid metabolism.

Bile acids are natural ligands of the FXR.

The drug may also impair glucose absorption.

Amylin Analog

They decreases post-meal glucose levels and reduces appetite.

Pramlintide (Not in Iran), is an injectable agent.

It is administered in addition to insulin in those who do not achieve their target postprandial sugar levels.

Pramlintide also suppresses glucagon release, and has CNS mediated anorectic effects.

Amylin Analog (Cont’d)

It peaks within 20 minutes, and the duration of action is not more than 150 minutes.

Pramlintide should be injected immediately before eating.

concurrent rapid- or short-acting mealtime insulin doses should be decreased by 50% or more.

Concurrent insulin secretagogue doses also may need to be decreased in type 2 diabetes.

Incretin-based Therapies

In type 2 diabetes, the release of glucagon-like polypeptide (GLP-1) is diminished after food intake.

This leads to inadequate glucagon suppression and excessive hepatic glucose output.

The incretin-based drugs are: Agonists of GLP-1 receptor

Inhibitors of Dipeptidyl peptidase-4 (DPP-4)

Agonists of GLP-1 receptor

Two analogs of GLP-1are Exenatide (Not in Iran) and Liraglutide.

Exenatide , is obtained from Gila monster venom.

It has a reduced degradation susceptibility by DPP-4.

Exenatide is approved as an injectable, adjunctive therapy.

Liraglutide is a long-acting synthetic GLP-1 analog with 97% homology to native GLP-1.

Its prolonged half-life permits once-daily dosing.

Liraglutide caused thyroid C-cell tumors in rodents, and is contraindicated in individuals with a personal or family history of medullary cancer or multiple endocrine neoplasia type 2.

Inhibitors of DPP-4

Sitagliptin, Saxagliptin, and Linagliptin (None of them in Iran) are inhibitors of DPP-4

They increase GLP-1 and glucose-dependent insulinotropic polypeptide (GIP), which increases insulin and decreases glucagon levels.

They are adjunctive therapy in type 2 diabetics who have failed to achieve glycemic goals.

SGLT-2 Inhibitors

Sodium-glucose Cotransporter 2 (SGLT2) is responsible for most renal glucose reabsorption in the kidney.

SGLT2 Inhibitors reduce the absorption of glucose in the kidney, so reduce the blood sugar.

Canagliflozin and Dapagliflozin (None in Iran) are in this group.

The urine will test positive for glucose while on this medication.

Effectiveness depends on your kidney function.

There is a risk of genital infections and urinary tract infections.

Combination Therapy of Diabetes

Type 1 diabetes: There is no indication for combining insulin with

oral antidiabetic agents

Type 2 diabetes: Patients who have not responded to maximal oral

therapy, are candidates for bedtime insulin

If this combination fails, full insulin replacement and multiple daily injections of insulin is indicated

Glucagon Glucagon increases cAMP. Raises blood glucose at the expense of hepatic glycogen. Has a potent inotropic & chronotropic effect (by the

cAMP) Its effect is similar to β agonists without requiring

functioning β receptors Clinical uses:

Emergency treatment of hypoglycemia

β blocker poisoning

HDD

1 ton

5 MGB

1956

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