PHYSIOLOGY OF PANCREAS

S. Sh. Sadr MD

Professor of Tehran University

Department of Physiology

General Informations

W : 50 – 75 gr Langerhans Islet : 0.5 – 1.5 million Histology :

α : 20 – 30 % ; Glucagon (around of islet) β : 60 – 80 % ; Insulin (center of islet) δ : 8 % ; Sumatostatin & Gastrin (between α, β) PP or F : variable ; pancreatic polypeptide)

Insulin

W : 6000 d 51 aa (A chain = 21, B chain = 30) Pro-insulin : 9000 d, 84 aa (= 51+33)

C-peptide : 33 aa Store : 4 u/kg (in adult = 200 u) Gene on short arm of Chr. 11

Secretion of Insulin

1- Basal secretion : Continuous, 1 u/h

2- Stimulated secretion : IV Glu. : peak : after 3 – 5 min = 8 – 10 x BS Oral Glu. : peak : after 0.5 – 1 h = 6 – 8 x BS Insulin response to Glu. Infusion shows a rapid

first phase of release followed by a fall and a later slower second phase

Metabolism of Insulin

Half life : 6 min

When insulin is secreted into the blood, it circulates almost entirely in an unbound form

Each hepatic passage : 40 – 50 % inactivation

Mechanism of Action

Receptor : W = 300,000 d 2α (extracellular) + 2β(intracellular) Insulin + α subunit → autophosphorilation of β

subunit → tyrosine kinase activity ↓ cAMP ↑ Glycogenesis, lipogenesis and Pr. Synthesis ↓ Glycogelolysis, lipolysis, proteolysis,

gluconeogenesis and ketogenesis

Effects of Insulin

Metabolism of Carbohydrates : ↑ Glu. Uptake from plasma Facilitates Glu. entrance into cells ↓ rate of release of Glu. From liver by :

By Inhibiting glycogenolysis By Stimulating glycogen synthesis By Stimulating Glu. Uptake By Stimulating glycolysis By indirectly inhibiting glycogenesis via inhibition of fatty acid

mobilization from adipose tissue Insulin is necessary for entrance of Glu. Into the most of cells

(Except of CNS, intestine epithelium, pancreas cells and renal tubul epithelium)

Effects of Insulin

Metabolism of Carbohydrates : Effect on Liver:

Glu. Uptake from plasma ↑ glycogenesis ↓ glycogenolysis ↓ glyconeogenesis Glu. Converting to fatty acids

Effect on Muscles: Most of day time: fatty acid At rest: glu. resistant during sport: needs glu. for providing energy After meal: rapid glu. Transport into muscle cells

Effects of Insulin

Metabolism of Proteins: ↑ transport of aa into hepatic and muscle cells (unrelated to glu.

transport but may be related to Na/K pump activity)

Val Leu Ile Tyr Phe

↑ synthesis of protein ↓ proteolysis

Insulin Promotes Protein Synthesis and Storage.

1 . Insulin stimulates transport of many of the amino acids into the cells

2. Insulin increases the translation of messenger RNA

3. Insulin also increases the rate of

transcription of selected DNA genetic sequences in the cell nuclei

Effect of Insulin on Protein Metabolism and on Growth

4. Insulin inhibits the catabolism of proteins

5. In the liver, insulin depresses the rate of gluconeogenesis

Insulin Deficiency Causes Protein Depletion and Increased Plasma Amino Acid

Insulin and Growth Hormone Interact Synergistically to Promote Growth

Effects of Insulin

Metabolism of Lipids: ↓ lipolysis ↑ synthesis of fatty acids in liver

As a result: Insulin is an Anabolic Hormone Effect on growth:

In embryonic life, Insulin is the most important hormone for embryonic growth.

Effect on Glucagon: Insulin refuses glucagon secretion

The end effects of Insulin

1. Within seconds after insulin binds with its membrane

receptors, the membranes of about 80 percent of the body’s cells

markedly increase their uptake of glucose.

2. The cell membrane becomes more permeable to many of

the amino acids, potassium ions, and phosphate ions,causing

increased transport of these substances into the cell

3. Slower effects occur during the next 10 to 15 minutes to change the activity levels of many more intracellular metabolic

enzymes.

• 3. Slower effects occur during the next 10 to 15 minutes to change the activity levels of many more intracellular metabolic enzymes

4. Much slower effects continue to occur for hours and even several days. They result from changed rates

of translation of messenger RNAs at the ribosomes to

form new proteins and still slower effects from changed

rates of transcription of DNA in the cell nucleus

Insulin Secretion

Increased by Decreased byD-glucoseGalactoseMannoseGlyceraldehydeProtein: Arg, Lys, Leu, AlaKetoacidsFree fatty acidsPotassiumCalciumGlucagon

Glucagon-like peptide IGasteric inhibitory polypeptideSecretinCholecystokininVagal activityAcetylcholineβ-adrenergic activitySulfounylurea drugs

FastingExerciseEndurance trainingSomatostatinGalaninPancreastatinInterleukine Iα2-adrenergic activityProstaglandin E2Diazoxide

Glucagon

Single chain polypeptide 29 aa 3485 d α cells Entro-glucagon:

Larger molecule Half life = 6 min Hepatic and renal metabolizing Glomerule infiltration

Effects of Glucagon

(Completely against Insulin effects) Metabolism of Carbohydrates :

↑ glycogenolysis in liver ↑ glyconeogenesis (slow process) Inhibition of glycogen synthesis in liver

Metabolism of Lipids : ↑ lipolysis

Other effects: β cell stimulation Catecholamine secretion stimulation ↑ heart muscle contractility ↑ bile and calcitonin secreton

Glucagon Causes Glycogenolysis and Increased Blood Glucose

Factors Influencing Glucagon Release

Stimulation Inhibition

Amino acidsGastrointestinal polypeptide hormonesCatecholamine (exercise)Growth HormoneGlucocorticoid

GlucoseInsulinFree fatty acids

Pancreas Islets Control

Effective agents:

Metabolites

Hormones

Neural factors

Pancreas Islets Control

Metabolites: Glucose: ↑ insulin, ↓ glucagon and

hypothalamic effects Amino acids: Arg, lys and Leu

aa. amplifies glu. effect on insulin secretion Lipids:

Fatty acids and Ketons: inhibitory effects on α cells and stimulatory effect on β cells.

Pancreas Islets Control

Hormones: GI hormones:

oral glu. increases insulin more than IV glu. Gastrin Secretin CCK GIP Entroglucagon

Gastrin, CCK and GIP, ↑ glucagon secretion. glucagon Other hormones: GH, Thyroxin, Glucocorticoids, SS

Pancreas Islets Control

Neural factors:

α2 adrenergic: ↓ insulin

β adrenergic: ↑ insulin

Parasympathetic, dopamine, serotonin and PG : ?

Somatostatin

δ cells Polypeptide with 14 aa Half life = 2 min All of the factors related to digestion and

absorption stimulates SS. secretion: ↑ glu. ↑ aa ↑ fatty acids ↑ GI hormones

Effects of Somatostatin

Insulin and glucagon secretion inhibition (local effect)

↓ gastric, duodenal and biliary bladder motility

↓ GI secretions and absorption

GH inhibitor

Blood Sugar Control

Normal FBS = 70 – 100 mgr/100cc 1 hour after eating = 120 – 140 mgr/100cc Control Mechanism:

Liver Insulin and glucagon Hypoglycemia

Early Late

Blood Sugar Control

↑ BS:

↑ extracellular osmotic pressure → cellular dehydration

Excretion in urine → osmotic dieresis → polydipsia and polyuria signs → dehydration

↓ BS: Cerebral cells, retina and testicular epithelium

Diabetes Mellitus (pathophysiology)

↓ insulin : ↓ metabolism of gu. in cells ↑ fatty acids from lipid storages Protein emptying in tissues

Abnormalities: Glu. excretion in urine: > 180 mgr/100cc

Intra and extra cellular dehydration: shock Acidosis and Coma: metabolism changing from

carbohydrate to lipid

Chronic High Glucose Concentration Causes Tissue Injury

When blood glucose is poorly controlled over long periods in

diabetes mellitus, blood vessels in multiple tissues throughout

the body begin to function abnormally and undergo structural

changes that result in inadequate blood supply to the tissues.

This in turn leads to increased risk for heart attack, stroke,

end-stage kidney disease, retinopathy and blindness, and

ischemia and gangrene of the limbs.

Chronic high glucose concentration also causes damage

to many other tissues.

Peripheral neuropathy,

( which is abnormal function of peripheral nerves)

Autonomic nervous system dysfunction

These abnormalities can result in impaired cardiovascular reflexes

Impaired bladder control

Decreased sensation in the extremities

Other symptoms of peripheral nerve damage.

Hypertension

(secondary to renal injury)

Atherosclerosis

( secondary to abnormal lipid metabolism)

Diabetes Mellitus Causes Increased Utilization of Fats and

Metabolic Acidosis.

Rapid and deep breathing

Clinical Characteristics of DM type I and type II

Type I Type II

Age at Beginning Usually under 20 Usually above 40

Body Mass ↓ (Thin) abnormal Obese

Plasma Insulin ↓ or empty Normal to ↑ at beginning

Plasma Glucagon ↑ it can be suppressed ↑, resistant to suppression

Plasma Glucose ↑ ↑

Insulin Susceptibility Normal ↓

Treatment Insulin ↓ Weight, Insulin, Drugs*

Insulin Resistance: Causes

1) Obesity and Overweight

2) Glucocorticoid excess (Cushing syndrome)

3) ↑ GH

4) Pregnancy and GDM

5) PCO

6) Lipodystrophy

7) Insulin Receptor Ab

8) Insulin Receptor Mutation

9) Hemochromatosis

Metabolic Syndrome

Obesity

Insulin Resistance

Fasting Hyperglycemia

Lipid Disorders (↑ TG and ↓ HDL)

Hypertension

Obesity, insulin resistance and metabolic syndrome are usually

present before DM II