Diabetes Mellitus and Insuline analogs

1605 Abubakkar Raheel

1553 Nazia Hassan1652 Abrar Afridi

1638 Kehkashan AlamDiabetes Mellitus4th Clinico-Pharmacological ConferenceFrontier Medical College 3rd year MBBS

4th Clinico-Pharmacological ConferenceFrontier Medical College

Learning Objectives

Diabetes Mellitus

Define the term Diabetes mellitus. Discuss brief History of Diabetes Identify the incidence and prevalence of diabetes mellitus. Discuss the Etiology of diabetes Discuss the Biostatical analysis of Diabetes Differentiate between Type 1 Diabetes and Type 2 Diabetes Know the drugs used for its treatment


Discuss the mechanism of action of Proto-Type Drugs Understand the Adverse Affects of mentioned Drugs Learn the Treatment and Management of Diabetes Discuss a Clinical Scenario Brief Question/Answer Session

Diabetes Mellitus

Learning Objectives


• In Simple terms, Diabetes Mellitus is a disease marked by high levels of sugar in the blood. Mellitus is Latin for “sweet as honey”.

• According to our Textbook Lippincott’s Pharmacology, “Diabetes is not a single disease rather it is a heterogeneous group of Syndromes characterized by elevation of blood glucose caused by a relative or absolute deficiency of Insulin.”

Diabetes Mellitus

Definition


Diabetes Mellitus

History


Diabetes Mellitus


Diabetes Mellitus


• There are currently over 2 million people diagnosed with diabetes in the UK and there are up to another 1 million people with diabetes who have the condition and don’t know it!

• The global incidence of diabetes is rising and the number of people affected is projected to exceed 300 million by the year 2025.

(www.diabetes.org.uk)

Diabetes Mellitus

Incidence of Diabetes


• Estimated 245 million people globally• 20% of adult population• 5% of all deaths each year• 80% of people with diabetes live in low and middle income

countries

Diabetes Mellitus

Incidence of Diabetes


Diabetes Mellitus

Biostatical Analysis


Diabetes Mellitus


Diabetes Mellitus


• A parent, brother, or sister with diabetes • Obesity • Age greater than 45 years • Some ethnic groups• Gestational diabetes or delivering a baby weighing more

than 9 pounds • High blood pressure • High blood cholesterol level • Not getting enough exercise

Diabetes Mellitus

Risk Factor which predispose to Diabetes


Diabetes Mellitus

Normal Metabolism of Glucose


Diabetes Mellitus

Type 1 Diabetes

Type 1 Diabetes

• Insulin not produced due to non fuctional beta-cell Hence no maintainance of basal secretion level of Insuline and no response to variations in circulating fuels.

• No insulin to ‘unlock’ the receptors • Glucose cannot enter the cell • Glucose re-enters the blood stream • Extent of glycemic control related to

metabolic complications


Diabetes Mellitus


Diabetes Mellitus

Type 1 Diabetes


Diabetes Mellitus

Blood Sugar &Spine connection• Journal of Vertebral

Subluxation research

• Vagus, T-8, T-9• Disturbed Nerve

supply• Loss of pancreatic

function & insuline production


Diabetes Mellitus

Symptoms of type 1 Diabetes

• Polyuria • Polydipsia • Weight loss in spite of polyphagia• Fatigue • Nausea • Vomiting • Coma• Patients with type 1 diabetes usually develop symptoms

over a short period of time, and the condition is often diagnosed in an emergency setting.


Diabetes Mellitus

Morbidity/Complications

Complications of diabetes can be divided into three categories•Metabolic complications of low blood glucose levels (hypoglycaemia) and of high blood glucose levels (hyperglycaemia) e.g. Diabetic coma.•Damage to small blood vessels (microvascular) leading in turn to damage of:

retina (retinopathy)kidney (nephropathy)nerves (neuropathy)


Diabetes Mellitus

Morbidity/Complications

• Damage to the larger arteries (macrovascular) leading to damage of:brain (leading to stroke)heart (leading to coronary heart disease) legs and feet (leading to peripheral vascular disease)


Diabetes Mellitus

• Associated with aging, obesity, Peripheral Insuline resistance rather than by auto-immune processes or viruses.

• Metabolic alterations are less (Non-ketotic)• Occurs mostly in people over 40• Type 2 diabetes is the most common of the two main

types and accounts for between 85 - 95% of all people with diabetes.


Diabetes Mellitus

Pancreas retain some beta-cell function but variable insuline production is insufficient and there is a decrease in the number of receptors (insulin resistance)

Lack of sensitivity of target organs to either endogenous or exogenous insuline

Glucose does not enter the cell effectively Glucose re-enters the blood stream Blood glucose levels rise.


Diabetes Mellitus

• Slower onset• Polydipsia • Polyuria • Polyphagia • Fatigue • Blurred vision • Slow-healing infections • Impotence in men

Symptoms of Type 2 Diabetes


Diabetes Mellitus

• Hyperglycemia• Diabetic Ketoacidosis / DKA • Microvascular complications• Macrovascular complications

Complications of Diabetes


Diabetes Mellitus

• Polyuria • Polydipsia • Fatigue • Nausea and vomiting • Muscular stiffness or aching • Mental stupor/ decreased consciousness may progress to

coma • Rapid breathing • Fruity breath (pear drops / nail varnish smell) • Headache • Low blood pressure • Decreased appetite • Abdominal pain

Symptoms of DKA


Diabetes Mellitus

Microvascular Complications


Diabetes Mellitus



Diabetes Mellitus



Diabetes Mellitus



Diabetes Mellitus

Macrovascular Complications


Diabetes Mellitus



Diabetes Mellitus



Diabetes Mellitus



Diabetes Mellitus

Treatment: Dugs Classification


Diabetes Mellitus

Insuline and its Preparations

ByNazia Hassan


Insuline is a polypeptide hormone, consisting of two peptide chains that are connected by disulphide bonds. It is synthesized as a precursor insuline (pro-insuline) that undergoes proteolytic cleavages to form insuline and C-peptide, both of which are secreted by the Beta-Cells of the pancreas.

Diabetes Mellitus

Insuline


Diabetes Mellitus

Insuline is secreted from pancreatic B-Cell at a low basal rate and at a much higher stimulated rate in response to a variety of stimuli, especially glucose. Other stimulants include•Sugars (Mannose)•Certain Amino acids (Leucine, Arganine)•Hormones (Glucagon like polypeptide)•Glucose dependent insulinotropic polypeptide•Glucagon•Cholecystokinin•Vagal activity

Secretion


Diabetes Mellitus

Insuline and Glucagon


• Insulin is stored in beta cells of pancreas in the form of granules as crystals.

• Each crystal consist of 6 molecules of insulin binding with 2 atoms of Zn.

• Human pancreas can store 8gm of inuslin.

Diabetes Mellitus

Storage


Diabetes Mellitus

Because insuline is a polypeptide, it is degraded in the gastrointestinal tract if taken orally. Therefore it is generally administered by subcutaneous injection. During Hyperglycemic emergency, it is injected Intravenously.

Administration


Diabetes Mellitus

• Liver and kidney remove insulin from circulation• Liver clears 60% while kidney removes about 40% of the

insulin• This ratio is inverted for exogenous subcutaneous insulin• Half life of insulin is 3-5min in the blood

Degradation


Diabetes Mellitus

• Insulin is measured in units u/ml • 1mg is equal to 28u• Basal insulin value is 5-15microU/ml• Peak concentration can rise to 60-90microU/ml during

meals

Circulating insuline


Diabetes Mellitus

The symptoms of hypoglycemia are the most serious and common adverse reactions to an excessive dose of Insuline.Other adverse affects include •Weight gain•Lipodystrophy•Allergic reactions •local Injection site reactions

Adverse reactions to Insuline


Diabetes Mellitus

• S.t therapy involves twice injections daily• Int.t therapy involves three or more times injection daily• Frequency of hypogylcemic episodes, coma and seizures

are higher in Int.t than st.t therapy due to insulin excessiveness

• Patient with Int.t therapy has significant reduction in nephropathy, neuropathy and retinopathy

Standard and Intensive Therapy


Diabetes Mellitus

Insuline Preparations


Diabetes Mellitus

Treatment: Drugs ClassificationInsuline Preparations (Combinations)


Diabetes Mellitus

Treatment: Drugs ClassificationInsuline Preparations (Combinations)


Diabetes Mellitus

• This group includes lispro, aspart and glulisine • They have rapid onset of action and short acting duration

• Peak levels can be seen within 30-90min after injection • Short acting insulin includes regular insulin

Rapid acting Insuline


Diabetes Mellitus

• It includes Neutral protamine hagedron or Isophane

• They act intermediately because of delayed absorption due to formation of less soluble complexes

• Can be used in all type of diabetes except ketoacidoses and emergency diabetes

Intermediate acting Insuline


Diabetes Mellitus

• This group include glargine and detemir

• Its has slower onset of action and no peak level

• These can be used in combination with rapid acting insulins

Long acting Insuline


Diabetes Mellitus

Plasma Insuline Levels/Hours


Diabetes Mellitus

Synthetic Amylin Analogs &Insulin Secretagogues

ByKehkashan ALam


Diabetes Mellitus

• Pramlintide is indicated as an adjunct to mealtime insulin therapy in patients with Type 1 & Type 2 Diabetes by acting as amylinomimetic.

• Pramlintide delays gastric emtying & delays postprandial Glucagon secretion.

Synthetic Amylin Analogs: Pramlintides


Diabetes Mellitus

Pharmacokinetics


Diabetes Mellitus

• Inhibits Glucagon release from pancrease

• Delays Gastric Emptying

• Also causes Anorexia by acting on CNS

Mechanism of action


Diabetes Mellitus

• Along with insulin in Type 1 & Type 2 Diabetes Mellitus to control Blood Glucose level after meal

• May help in weight loss

Clinical Uses


Diabetes Mellitus

• Hypoglycemia• Nausea• Vomiting• Anorexia

Adverse Effects


Diabetes Mellitus

• Gastroparesis( delayed stomach emtying)• Cresol Hypersensitivity • History of Hypoglycemic unawareness

Contraindications


Diabetes Mellitus

1) Sulfonylureas 2) Glinides1st Generation Repaglinide

• Tolbutamide Nateglinide• Tolazamide• Acetohexamide• Chlorpropamide

2nd Generation• Glibenclamide• Glyburide• Glipizide• Glimepiride

Insulin Secretagogues


Diabetes Mellitus

• Given Orally before meals• Bind to serum proteins• Metabolized by liver• Excreted by liver or kidney• Duration of Action ranges from 12-24 hours

Sulfonylureas: Pharmacokinetics


Diabetes Mellitus

Tolbutamide 4-5 hoursChlorpropamide 32 hoursTolzamide 7 hoursGlipizide 2-4 hoursGlimepiride 5 hours

Note: Chlorpropamide in contraindicated in elder patients because it may prolong Hypoglycemia.

Half Life


Diabetes Mellitus

Mechanism of action

• Blockage of ATP sensitive Potassium channels

• Depolarization

• Calcium ion Influx

• Stimulation of Insulin Release from Beta cells of Pancreas

• Resulting in decrease Glucose level in body


Diabetes Mellitus

•Hyperinsulinemia•Prolonged Hypoglycemia•Increase in Body Weight•Nausea, Vomiting, Diarrhea•Allergic Reactions like Skin Rashes•Rarely Bone Marrow depression can occur

Adverse affects


• Severe Hepatic & Renal Failure • Pregnancy• Lactation• Porphyria• Ketoacidosis

Diabetes Mellitus

Contraindications


• Orally administered

• Well absorbed after being taken 1-30 minutes before meal

• Metabolized to inactive products by cytochrome p450 3A4 in the liver

• Excreted through bile

• Repaglinide should be used courtiously in individuals with renal and

hepatic impairment

Diabetes Mellitus

Glinides: Pharmacokinetics


• Bind to sulphonylurea receptor of ATP sensitive potassium

channels

• Initiate the release of insulin

• Lowers the blood glucose level

Diabetes Mellitus

Mechanism of action


• Hypoglycemia in patients who are also taking lipid lowering

drugs like Gemfibrozil

• Weight gain

Diabetes Mellitus

Adverse affects


Diabetes Mellitus


Diabetes Mellitus

Insulin Sensitizers: Oral AgentsInsulin Sensitizers: Oral Agents


Diabetes Mellitus

Biguanides


Diabetes Mellitus

Mechanism of action


Diabetes Mellitus

Pharmacokinetics


Diabetes Mellitus

• Used in insulin resistant patient. i-e, insulin resistance syndrome• It does not increase weight, useful in obese diabetic

patient.• Can be given as monotherapy OR with combination

of insulin secretogogues drugs.

Clinical Uses


Diabetes Mellitus

Adverse affects

• Lactic acidosis• Reduce B12 absorption• GIT disturbance • anoxia• nausia• vomitting• Diarrhea


Diabetes Mellitus

Contraindications

• Renal disease• Alcohalism• Hepatic disease• Acute M.I


Diabetes Mellitus

• These are also insulin sensitizers.• Also known as glitazones.• Rosiglitazone & pioglitazone are currently available

agents.• Does not promote insulin release from pancrease.

Thiazolidinediones


Diabetes Mellitus

• Tissues to be targeted are adipocytes, liver & skeletal muscles.

• It binds with peroxisome proliferator activated receptor gamma, a nuclear hormone receptor.

• These receptors regulate metabolism of glucose, production of free fatty acids.

• Ultimately increasing sensitivity of insulin.

M.O.A


Diabetes Mellitus

• Both pioglitazone and rosiglitazone are well absorbed orally.• Bound extensively to plasma protein.• Metabolized by cytochrome p450 enzymes in liver.• Excreted through urine.

Pharmacokinetics


Diabetes Mellitus

• Hepatotoxicity• Weight gain• Osteopenia• M.I• Anemia• Headache

Adverse Effects


Diabetes Mellitus

• This group includes acarbose and Miglitol• They don’t have any effect on insulin production

Alpha glucosidase inhibitors


Diabetes Mellitus

• Inhibits glucosidases located on the intestinal brush boarder

• So oligosaccharrides cant be converted to glucose• In addition these also inhibit pancreatic amylase• Postprandial hyperglycemia does not occure

M.O.A


Diabetes Mellitus

• These agents are intermediatly absorbed• They don’t have any systemic affects• Excrected by kidneys in unchanged form

Pharmacokinetics


Diabetes Mellitus

• Diarrhea• Abdominal cramp• Inflammatory bowl syndrome• Colonic ulceration

Adverse affects


What is an Incretin affect?

Oral glucose results in a higher secretion of insulin than occurs when equal load of glucose is given IV. This effect is referred to as Incretin effect. And is markedly reduced in diabetes type 2.

Diabetes Mellitus

Incretin Mimetics


Diabetes Mellitus

Incretin hormone


Diabetes Mellitus

Classification


LIRAGLUTIDE EXENATIDE

ADMINISTRATION S/C S/C

HALF LIFE LONG SHORT

INJECTION ONCE DAILY TWICE DAILY

EXCRETION - RENAL

AVOIDANCE - RENAL IMPAIRED

ADVERSE AFFECTS N.V.D.C, PANCREATITIS, ABD PAIN

N.V.D.C, PANCREATITIS, ABD PAIN

Diabetes Mellitus

Liraglutide vs Exenatide


• Act as GLP-1 Receptor Agonists• Improve Glucose Dependent Insuline Secretion• Slow gastric Emptying time• Decrease Food Intake• Decrease post-prandial Glucagon secretion• Promote Beta-Cell proliferation

Diabetes Mellitus

Mechanism of action


Diabetes Mellitus

Oral Agents: DPP-IV Inhibitors


Diabetes Mellitus

GLP-1Dipeptidyl

Peptidase- IV Inhibitors

inactivates

inhibit

enzyme

Glucagon like peptide-1

Mechanism of ActionOral Agents: DPP-IV Inhibitors


Diabetes Mellitus

A 54-year-old woman is diagnosed with type 2 diabetes mellitus after a routine follow-up for impaired fasting glucose showed that her hemoglobin A1C is now 7.6%. She has attempted to lose weight and to exercise with no improvement in her hemoglobin A1C, and drug therapy is now recommended. She has mild systemic hypertension that is well controlled and no other medical conditions.

Which of the following is the most appropriate first-line therapy?

A. AcarboseB. ExenatideC. GlyburideD. MetforminE. Sitagliptin

Short Clinical Scenario


Diabetes Mellitus


Diabetes Mellitus

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Health & Medicine

Diabetes Mellitus and Insuline analogs