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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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