DIABETES, INSULİN VE ORAL ANTIDIABETICS

(1)

EBRU ARIOĞLU İNAN, PhD

(2)

Aims:

Having knowledge about;

• Pancreatic hormones and their roles

• Diabetes

• Types of diabetes

• Antidiabetic drugs

• Insulin types

• Complications and adverse effects of insulin

• Features, action of mechanism and adverse effects of all antidiabetic drugs

• New drugs for diabetes

(3)

Content

• Pancreatic hormones

• Glucose metabolism

• Diabetes

• Types of diabetes

• Antidiabetic drugs

• Insulin

• New drugs

(4)

Pancreas, Islet of Langerhans

• Alpha cells; glucagon, proglucagon

• Beta cells; insulin, C peptid, proinsulin, amylin

• Delta cells; somatostatine

• Epsilon cells; ghreline

(5)

Type 1 Diabetes

• Selective beta cell damage

• Partial/complete insulin secretion deficiency

• İmmun based or idiopathic

• Usually before age of 30

• Weak genetic predisposition

• Insulin replacement

(6)

Type 2 diabetes

• Relative insulin deficiency and insulin resistance

• Insulin secretion is not effective because of insulin resistance on target tissues

• Usually after age of 30

• Oral antidiabetics (insulin if needed)

• Ketoasidosis is not seen but may occur due to infections, some drugs (glucocorticoids…), stress

• Fatal nonketotic hyperosmolar coma due to dehydratation

(7)

Gestational diabetes

• Seen in pregnancy (prevalance %7)

• OGTT between weeks of 24-28

• Usually not seen after term

• Type 2 diabetes risk in the future

(8)

Gestational Diabetes

• Fasting BG> 95 mg/dl

• 1.hour BG>180mg/dl

•100g glucose loading

•No diet or excercise for at least 3 days

•After 14-hour fasting

•2 values out of the range is enough for diagnosis

(9)

Diabetes insipidus

• 1.neurogenic: due to antidiuretci hormon (ADH) deficiency

• 2.nephrogenic:due to abolished sensitivity of the kidneys to ADH effect

• 3.gestagenic: due to ADH deficiency in pregnancy

• 4.dipsogenic: due to excessive thirst and fluid intake

(10)

Prediabetes

• Fasting blood glucose:100-125mg/dl

• 75g OGTT, 2-hour BG 140-199mg/dl

• HbA1C %5.7-6.5

(11)

Diabetes

• Fasting blood glucose 126mg/dl or higher

• 75g OGTT, 2-hour BG higher than 200mg/dl’den fazladır

• HbA1C %6.5 or higher

• Random BG 200mg/dl or higher

(12)

Diabetic complications

• Peripheral neuropathy

• Stroke

• Myocardical infarction

• Periphearl artery disease

• Diabetic retinopathy

• Cataract

• Glaucoma

• Diabetic foot

• Diabetic nephropathy

(13)

• Type 1 diabetes is treated with insulin

• It is discovered by Banthing and Best

(14)

Insulin secretion

Glucose is taken into beta cell by GLUT2, it is converted to

glucose-6-phosphate by glucokinase, ATP sensitive K+ channels are closed due to increased ATP levels, depolarization occurs, Ca++ chanells are opened, Ca++ enters into the cell, insulin is secreted

(15)

Insulin in the circulation

• 5-15 μU7ml (30-90pmol/L), in healthy person

• Increased to 60-90μU/ml’ye (360-540pmol/L) after a meal

(16)

Metabolism of insulin

• Metabolized in liver and kidney

• Liver clears %60 of it

• Kidney clears %35-40 of it

(17)

Insulin receptor

• Insulin receptor is abundant in the membranes of most of the tissues

• Insulin is bound to receptor in picomolar levels with high affinity

• Receptor has 2 heterodimers bound covalently, each heterodimer has one extracellular alpha unit and beta unit embedded to the membrane

• Beta unit has tyrosinekinase activity

• Receptor is activated when insulin is bound to alpha unit which causes a conformational change, beta units are getting closer, tyrosine part in the beta unit is phosphorylated, thyrosine kinases are directed to

cytoplasmic proteins

(18)

IRS (insulin receptor substrate)

• IRS, one of the cytoplasmic proteins which is phosphorylated by thyrosine kinases

• After phosphorylation, IRS activates other kinases in the energy metabolism

• It also stimulates mitogenic pathyways (Ras, MAPK system…)

(19)

Target tissues of insulin

• Liver

• Skeletal muscle

• Adipose tissue

(20)

• After insulin is bound to its receptor, GLUTs (glucose

transporters) is translocated to the membrane, act as a gate and bind glucose and takes into the cell

• GLUT1 (all tissues), GLUT2 (pancreas beta cells, liver, kidney, gut), GLUT3 (brain, placenta), GLUT4 (muscle, adipose tissue), GLUT5 (gut, kidney)

(21)

Effects of insulin

In the liver:

• Inhibition of glycogenolysis

• Inhibition of convertion of fatty acides and aminoacides to keta acides

• Inhibition of convertion of aminoacides to glucose

• Storage of glucose as glycogen

• Increased formation of VLDL and triglycerides

(22)

Effects of insulin

In the skeletal muscle:

• Increased protein synthesis

• Increased aminoacide transport

• Increased ribosomal protein synthesis

• Increased glycogen synthesis

• Increased glucose transport

(23)

Effects of insulin

In the adipose tissue:

Increased storage of triglyceride

(24)

Stimulatory factors of insulin secretion

• Humoral: glucose, mannose, arginine, fatty acides, aminoacides

• Neural: beta adrenergic stimulation, vagal stimulation

• Drugs: sulphonylureas, meglitinides, isoprenaline, acetylcholine

(25)

Discovery of Insulin

• Frederick Banting and Charles have discovered insulin in 1921

• First human trial on Leonard Thompson, 1922, it was succesfull

• Nobel price in 1923 to the discovery of insulin

(26)

Diabetic ketoacidosis

• May be fatal

• Mostly seen in type 1 diabetes

• Rarely in type 2 diabetes (due to sepsis, pancreatitis, high dose steroids)

• The formation of ketoacids from fatty acids is increased, acidosis is observed

• Symptoms; nausea, vomiting, abdominal pain, deep breath (Kussmaul), altered mental status, increased keton and glucose in blood and urine

• Blood pH, 7.3 or lower

• Low bicarbonate levels

• Treatment; agresive intravenous hydratation, insulin (reguler, iv), potasium and regulating the electrolyte balance

(27)

Hiperosmolar hyperglycemic coma

• Mostly seen in T2DM

• Characterized with hyperglycemia and dehydratation

• Caused by inadequate fluid intake (geriatric patients)

• Phenytoin, steroids, diuretics, beta blockers, peritoneal dialysis, hemodialysis may result in this coma

• Symptoms; impaired mental status, seizures, blood glucose is 600mg/dl or higher, serum osmalility is higher than 320 mmol/l

• No acidosis

• Treatment; agresive rehydratation, reestablishing glucose and alectrolyte balance, low dose insulin treatment is possible.

(28)

Rapid Acting Insulin

Insulin lispro

Insulin aspart

Insulin glulisine

Short Acting Insulin

Regula insulin r

Intermediate and long

acting insulins

Intermediate and long

acting insulins

insulin NPH (I)

Insulin glargine

(L)

Insulin detemir

(L)

Mixtures of insulins

70 NPH Regular30

75/25 NPL, Lispro

70/30 NPA, Aspart

Characteristic of Available Insulin Preparations

(29)

Complication of Insulin Therapy

Hypoglycemia Hypoglycemia

Insulin allergy Insulin allergy Immune insulin

resistance

Immune insulin resistance

Lipodystrophy Lipodystrophy Increased

cancer risk Increased cancer risk

(30)

Inhaled Insulin

The only inhaled insulin on the market is Afrezza. It's fast acting, so you take it only at mealtimes. It comes in 4-unit and 8-unit cartridges that you pop into a small gadget, like the ones people with asthma use. Those with asthma, COPD or who smoke should not use this medication.

Long Acting Insulin

Insulin degludec (Tresiba) is an injectable form of insulin that lasts up to 42 hours. It is used once daily for type 1 or

type 2 diabetes. It also comes premixed with insulin aspart (Ryzodeg 70/30).

(31)

Subclass, Drug Mechanism of action Effects Clinical application Pharmacokinetics, Toxicities, Interactions INSULINS

• Rapid acting:

Lispro, aspart, glulisine, inhaled regular

• Short acting:

Regular

• Intermediate acting: NPH

• Long acting:

Detemir, glargine

Activate insulin

receptor Reduce circulating

glucose Type 1 and Type 2

Diabetes Parenteral (sc or iv) Toxicity:

hypoglycemia, weight gain,

lipodistrophy (rare)