Endocrine Physiology (PHS 300)

Physiology Program

College of Health Sciences

Bowen University, Iwo, Nigeria

Dr Michael Olugbenga S

Endocrine Functions

of the Pancreas

Introduction• The pancreas is a unique gland because it has both

exocrine and endocrine glands.

• The acini secretes digestive juice via ducts into the duodenum while the islets of Langerhans secretes hormones into directly into the blood.

• The human pancreas has 1 to 2 million islets of Langerhans.

• The islets are scattered throughout the pancreas, although they are more plentiful in the tail than in the body and head.

Pancreatic Secretions

• Exocrine:

– Secretion of bicarbonate ions

– Digestive enzymes.

• Endocrine:

– islets of Langerhans (2% of pancreas volume)• A cells (25%) secrete Glucagon

• B cells (60%) secrete insulin

• D cells (10%)secrete somatostatin

• F cells secrete the pancreatic polypeptide (PP)

Islets of Langerhans (Pancreatic Islets)

6

Insulin• Insulin was first isolated from the pancreas in 1922 by

Banting and Best.

• It is synthesized in the rough endoplasmic reticulum of the beta cells

• Insulin affects fat and protein metabolism almost as much as it does carbohydrate metabolism.

• Insulin Is a Hormone Associated with Energy Abundance

• The half-life of insulin in the circulation in humans is about 5 min.

Functions of Insulin• It is a hypoglycemic hormone. • The net effect of the hormone is storage of carbohydrate,

protein, and fat. Therefore, insulin is appropriately called the “hormone of abundance.”

• Insulin Promotes Muscle Glucose Uptake and Metabolism• Storage of Glycogen in Muscle• Insulin Promotes Liver Uptake, Storage, and Use of Glucose• Insulin Promotes Conversion of Excess Glucose into Fatty Acids

and Inhibits Gluconeogenesis in the Liver• Insulin Promotes Fat Synthesis and Storage• Insulin Deficiency Increases Use of Fat for Energy• Insulin Deficiency Causes Lipolysis of Storage Fat and Release of

Free Fatty Acids• Insulin Deficiency Increases Plasma Cholesterol and

Phospholipid Concentrations• Excess Usage of Fats During Insulin Lack Causes Ketosis and

Acidosis

Regulation of Insulin

EATING, hyperglycemia (>110mg%)

Beta cells secrete insulin

increased glucose uptake into body cells increase glycogenesis(skeletal muscle, liver) increased lipogenesis

normoglycemia (<110mg%)

(-)

negative feedback

decreased blood glucose

Stimulators of Insulin secretion• Glucose

• Some aminoacids

• Ketone bodies

• GIT hormones mainly GIP

• Parasympathetic stimulation

• Theophylline

• Sulphonylureas

Inhibitors of Insulin secretion• Somatostatin

• Sympathetic stimulation (a receptors)

• Diazoxide

• Hypokalaemia

• Insulin

Metabolic effects of Insulin

• (1) Carbohydrates:

– Enhancing glucose uptake in most cells (muscles, adipose tissues, bone, skin, mammary glands, others)

– Enhancing glucose entry into liver cells

– Increasing glycogen synthesis in the muscles and liver cells

– Decreasing glucose output from the liver

• (2) Fat:

– Insulin stimulates LIPOGENESIS in the liver cells and adipose tissue

– Insulin prevents LIPOLYSIS in adipose tissue

– Insulin decreases KETOGENESIS in the liver cells and increase the uptake of KETONE BODIES by the skeletal muscles

(3) Proteins:Insulin exert an ANABOLIC EFFECT by increasing the protein content in the muscles and liver by:

Increasing the UPTAKE of the amino-acids into the muscle cellsIncreasing PROTEIN SYNTHESIS in the liver

Insulin Actions

LiverSkeletal Muscle

Adipocytes

Intestine & Pancreas

InsulinInsulin

Insulin

Growth effect

• INSULIN + GH are essential for normal growth (ANABOLIC effect). Thus insulin has a growth promoting effect.

Effect of insulin and glucagon on glucose

CONSEQUENCES OF INSULIN DEFICIENCY

• In humans, insulin deficiency is a common pathologic condition.

• In animals, it can be produced by pancreatectomy;

•by administration of alloxan, streptozocin, or other toxins that in appropriate doses cause selective destruction of the B cells of the pancreatic islets;

•by administration of drugs that inhibit insulin secretion;

•and by administration of anti-insulin antibodies.

GLUCOSE TOLERANCE

•In diabetes, glucose piles up in the bloodstream, especially after meals.

•If a glucose load is given to a diabetic, the plasma glucose rises higher and returns to the baseline more slowly than it does in normal individuals.

•The response to a standard oral test dose of glucose, the oral glucose tolerance test, is used in the clinical diagnosis of diabetes.

•Impaired glucose tolerance in diabetes is due in part to reduced entry of glucose into cells (decreased peripheral utilization).

•In the absence of insulin, the entry of glucose into skeletal, cardiac, and smooth muscle and other tissues is decreased.

• Glucose uptake by the liver is also reduced, but the effect is indirect.

Intestinal absorption of glucose is unaff ected, as is its reabsorption from the urine by the cells of the proximal tubules of the kidneys.

Glucose uptake by most of the brain and the red blood cells is also normal.

The second and the major cause of hyperglycemia in diabetes is derangement of the glucostatic function of the liver

Diabetes Mellitus• The constellation of abnormalities caused by insulin deficiency is called diabetes

mellitus

• The cause of clinical diabetes is always a deficiency of the effects of insulin at the tissue level. Type 1 diabetes, or insulin-dependent diabetes mellitus (IDDM), is due to insulin

deficiency caused by autoimmune destruction of the beta-cells in the pancreatic islets, and it accounts for 3–5% of cases and usually presents in children.

• Type 2 diabetes, or non-insulin-dependent diabetes mellitus (NIDDM), is characterized by the dysregulation of insulin release from the beta-cells, along with insulin resistance in peripheral tissues such as skeletal muscle, brain, and liver.

• Diabetes is characterized by:Polyuria (passage of large volumes of urine),Polydipsia (excessive drinking), Weight loss in spite of polyphagia (increased appetite), Hyperglycemia,Glycosuria,ketosis, acidosis, and coma

The fundamental biochemical defects to which most of the abnormalities of diabetes can be traced are :

(1) reduced entry of glucose into various “peripheral” tissues and

(2) increased liberation of glucose into the circulation from the liver.

Therefore, there is an extracellular glucose excess and, in many cells, an intracellular glucose deficiency—a situation that has been called “starvation in the midst of plenty.”

Also, the entry of amino acids into muscle is decreased and lipolysis is increased.

THERAPEUTIC HIGHLIGHTS

In type 1 diabetes, the mainstay of therapy is provision of exogenous insulin, carefully titrated to dietary intake of glucose.

In type 2 diabetes, lifestyle changes such as alterations in the diet or increased exercise can often delay symptoms in early disease, but these are difficult to secure.

Insulin-sensitizing drugs represent second-line agents

Diagnosis of Diabetes1. Fasting blood glucose measurement after 12 hour overnight fast

2. Oral glucose tolerance test;• Adults are given 75 g of glucose in 300 mL of water.

•In normal individuals, the fasting venous plasma glucose is less than 115 mg/dL, the 2-hour value is less than 140 mg/dL, and no value is greater than 200 mg/dL.

•Diabetes mellitus is present if the 2-hour value and one other value are greater than 200mg/dL.

•Impaired glucose tolerance is diagnosed when the values are above the upper limits ofnormal but below the values diagnostic of diabetes.

3. Measurement of glycated hemoglobin (HbA Ic) :When plasma glucose is episodically elevated over time, small amounts ofhemoglobin A are nonenzymatically glycated to form HbA Ic.

Careful control of the diabetes with insulin reduces the amount formed and consequently HbA Ic concentration is measured clinically as an integrated index of diabetic control for the 4- to 6-weeks period before the measurement.

Glucagon and Its Functions

•Glucagon, a hormone secreted by the alpha cells of the islets of Langerhans when the blood glucose concentration falls, has several functions that are diametrically opposed to those of insulin.

• Most important of these functions is to increase the blood glucose concentration, an effect that is exactly the opposite that of insulin.

•Glucagon is also called the hyperglycemic hormone.

Glucagon is glycogenolytic, gluconeogenic, lipolytic, and ketogenic.

Th e calorigenic action of glucagon is not due to the hyperglycemia per se but probably to the increased hepatic deamination of amino acids.

Glucagon also stimulates the secretion of growth hormone, insulin, and pancreatic somatostatin.

Glucagon has a half-life in the circulation of 5–10 min. It is degraded by many tissues but particularly by the liver.

Factors affecting glucagon secretion

Ganong 12th edition

Glucagon in high concentrations also (1) enhances the strength

of the heart; (2) increases blood flow

in some tissues, especially the kidneys; (3) enhances bile

secretion; and (4) inhibits gastric acid secretion.

Glucagon also inhibits the storage of triglycerides in the liver,

which prevents the liver from removing fatty acids from the

blood; this also helps make additional amounts of fatty acids

available for the other tissues of the body.

Macrosomia & GLUT 1 Deficiency

Infants born to diabetic mothers often have high birth weights and large organs termed macrosomia.

This condition is caused by excess circulating insulin in the fetus, which in turnis caused in part by stimulation of the fetal pancreas by high blood glucose and amino acids from the diabetic mother.

Free insulin in maternal blood is destroyed by proteases in the placenta, but antibody-bound insulin is protected, so it reaches the fetus.

Therefore, fetal macrosomia also occurs in women who develop antibodies against various animal insulins and then continue to receive the animal insulin duringpregnancy.

Infants with GLUT 1 deficiency have defective transport of glucose across the blood–brain barrier.

They have low cerebrospinal fluid glucose in the presence of normal plasma glucose, seizures, and developmental delay.

Somatostatin

The delta cells of the islets of Langerhans secrete the hormone somatostatin, a 14

amino acid polypeptide that has an extremely short half-life of only 3 minutes in

the circulating blood.

Almost all factors related to the ingestion of food stimulate somatostatin

secretion. They include (1) increased blood glucose, (2) increased amino acids,

(3) increased fatty acids, and (4) increased concentrations of several of the

gastrointestinal hormones released from the upper gastrointestinal tract in

response to food intake.

Somatostatin has multiple inhibitory effects as follows:

1. Somatostatin acts locally within the islets of Langerhans themselves to depress

the secretion of both insulin and glucagon.

2. Somatostatin decreases the motility of the stomach, duodenum, and gallbladder.

3. Somatostatin decreases both secretion and absorption in the gastrointestinal

tract.

Therefore, the principal role of somatostatin is to extend the

period of time over which the food nutrients are assimilated into

the blood.

At the same time, the effect of somatostatin to depress insulin

and glucagon secretion decreases the utilization of the absorbed

nutrients by the tissues, thus preventing rapid exhaustion of the

food and therefore making it available over a longer period of

time.

It should also be recalled that somatostatin is the same chemical

substance as growth hormone inhibitory hormone, which is

secreted in the hypothalamus and suppresses anterior pituitary

gland growth hormone secretion.

PANCREATIC POLYPEPTIDE

Human pancreatic polypeptide is a linear polypeptide that contains 36 amino acid

residues and is produced by F cells in the islets.

It is closely related to two other 36-amino acid polypeptides, polypeptide YY, a

gastrointestinal peptide, and

neuropeptide Y, which is found in the brain and the autonomic nervous system

Its secretion is increased by a meal containing protein and by fasting,

exercise, and acute hypoglycemia.

Secretion is decreased by somatostatin and intravenous glucose.

Pancreatic polypeptide slows the absorption of food in humans, and it may

smooth out the peaks and valleys of absorption.

However, its exact physiologic function is still uncertain.

ORGANIZATION OF THE PANCREATIC ISLETS

The presence in the pancreatic islets of hormones that affect the secretion of

other islet hormones suggests that the islets function as secretory units in the

regulation of nutrient homeostasis.

Somatostatin inhibits the secretion of insulin, glucagon, and pancreatic

polypeptide; insulin inhibits the secretion of glucagon; and glucagon stimulates

the secretion of insulin and somatostatin.

Effects of islet cell hormones on the secretion of other islet cell hormones. Solid arrows indicate stimulation; dashed arrows indicate inhibition.

Summary of Blood Glucose Regulation

In a normal person, the blood glucose concentration is narrowly controlled, usually

between 80 and 90 mg/100 ml of blood in the fasting person each morning before

breakfast.

This concentration increases to 120 to 140 mg/100 ml during the first hour or so

after a meal, but the feedback systems for control of blood glucose return the

glucose concentration rapidly back to the control level, usually within 2 hours after

the last absorption of carbohydrates.

Conversely, in starvation, the gluconeogenesis function of the liver provides the

glucose that is required to maintain the fasting blood glucose level.

Mechanisms for achieving fine blood glucose control;

1. The liver functions as an important blood glucose buffer system.That is, when the blood glucose rises to a high concentration after a meal and the rate of insulin secretion also increases, as much as two thirds of the glucose absorbed from the gut is almost immediately stored in the liver in the form of glycogen. Then, during the succeeding hours, when both the blood glucose concentration and the rate of insulin secretion fall, the liver releases the glucose back into the blood.

In this way, the liver decreases the fluctuations in blood glucose concentration to about

one third of what they would otherwise be. In fact, in patients with severe liver disease, it

becomes almost impossible to maintain a narrow range of blood glucose concentration.

2. Both insulin and glucagon function as important feedback control systems for

maintaining a normal blood glucose concentration.

When the glucose concentration rises too high, increased insulin secretion causes the blood glucose

concentration to decrease toward normal.

Conversely, a decrease in blood glucose stimulates glucagon secretion; the glucagon then functions in

the opposite direction to increase the glucose toward normal.

Under most normal conditions, the insulin feedback mechanism is much more important than the

glucagon mechanism, but in instances of starvation or excessive utilization of glucose during exercise

and other stressful situations, the glucagon mechanism also becomes valuable.

3. Also, in severe hypoglycemia, a direct effect of low blood glucose on the hypothalamus

stimulates the sympathetic nervous system. The epinephrine secreted by the adrenal

glands further increases release of glucose from the liver. This also helps protect against

severe hypoglycemia.

4. And finally, over a period of hours and days, both growth hormone and cortisol

are secreted in response to prolonged hypoglycemia.

They both decrease the rate of glucose utilization by most cells of the body,

converting instead to greater amounts of fat utilization. This, too, helps return the

blood glucose concentration toward normal.

Glucose is the only nutrient that normally can be used by the brain, retina, and

germinal epithelium of the gonads in sufficient quantities to supply them

optimally with their required energy. Therefore, it is important to maintain the

blood glucose concentration at a sufficiently high level to provide this necessary

nutrition.

It is also important that the blood glucose concentration not rise too high for four

reasons: (1) Glucose can exert a large amount of osmotic pressure in the extracellular fluid, and if the

glucose concentration rises to excessive values, this can cause considerable cellular dehydration.

(2) An excessively high level of blood glucose concentration causes loss of glucose in the urine.

(3) Loss of glucose in the urine also causes osmotic diuresis by the kidneys, which can deplete

the body of its fluids and electrolytes.

(4) Long-term increases in blood glucose may cause damage to many tissues, especially to blood

vessels. Vascular injury associated with uncontrolled diabetes mellitus leads to increased risk for

heart attack, stroke, end-stage renal disease, and blindness.