Endocrine

Pancreas:

After studying these lectures, you should be able to . . .
Kew the endocrine function of pancreas.
Understand the physiological effects of insulin on different body parts.
Knew the physiological cause of the signs and symptoms of diabetes mellitus.

An endocrine and an exocrine gland:

The endocrine portion of the pancreas consists of scattered clusters of cells called the pancreatic islets or islets of Langerhans. These endocrine structures are most common in the body and tail of the pancreas Pancreatic Islets (Islets of Langerhans). On a microscopic level, the most conspicuous cells in the islets are the alpha and beta cells.



Alpha cells secrete glucagon in response to a fall in blood glucose concentrations. Glucagon stimulates the liver to hydrolyze glycogen to glucose (glycogenolysis), which causes the blood glucose level to rise. This effect represents the completion of a negative feedback loop. Glucagon also stimulates the hydrolysis of stored fat (lipolysis) and the consequent release of free fatty acids into the blood. This effect helps to provide energy substrates for the body during fasting. Glucagon also Increases Gluconeogenesis: Even after all the glycogen in the liver has been exhausted under the influence of glucagon, continued infusion of this hormone still causes continued hyperglycemia. This results from the effect of glucagon to increase the rate of amino acid uptake by the liver cells and then the conversion of many of the amino acids to glucose by gluconeogenesis.

Beta cells secrete insulin in response to a rise in blood glucose concentrations. One of the most important of all the effects of insulin is to cause most of the glucose absorbed after a meal to be stored almost immediately in the liver in the form of glycogen. Then, between meals, when food is not available and the blood glucose concentration begins to fall, insulin secretion decreases rapidly and the liver glycogen is split back into glucose, which is released back into the blood to keep the glucose concentration from falling too low.
When the quantity of glucose entering the liver cells is more than can be stored as glycogen or can be used for local hepatocyte metabolism, insulin promotes the conversion of all this excess glucose into fatty acids. These fatty acids are subsequently packaged as triglycerides in very-low-density lipoproteins and transported in this form by way of the blood to the adipose tissue and deposited as fat.
Insulin increases glucose transport into and glucose usage by most other cells of the body (with the exception of the brain cells). The brain is quite different from most other tissues of the body in that insulin has little effect on uptake or use of glucose. Instead, the brain cells are permeable to glucose and can use glucose without the intermediation of insulin.
The brain cells are also quite different from most other cells of the body in that they normally use only glucose for energy. Therefore, it is essential that the blood glucose level always be maintained above a critical level, which is one of the most important functions of the blood glucose control system. When the blood glucose falls too low, into the range of 20 to 50 mg/100 ml, symptoms of hypoglycemic shock develop, characterized by progressive nervous irritability that leads to fainting, seizures, and even coma.
Insulin deficiency causes lipolysis of storage fat and release of free fatty acids. The absence of insulin causes hydrolysis of the stored triglycerides, releasing large quantities of fatty acids and glycerol into the circulating blood. Consequently, the plasma concentration of free fatty acids begins to rise within minutes. This free fatty acid then becomes the main energy substrate used by essentially all tissues of the body.
the excess fatty acids in the liver cells causes excessive amounts of acetoacetic acid to be formed so in the mitochondria, oxidation of the fatty acids then proceeds very rapidly, releasing extreme amounts of acetyl-CoA. A large part of this excess acetyl-CoA is then condensed to form acetoacetic acid, which in turn is released into the circulating blood. The absence of insulin also depresses the utilization of acetoacetic acid in the peripheral tissues. Thus, so much acetoacetic acid is released from the liver that it cannot all be metabolized by the tissues.
Some of the acetoacetic acid is also converted into b-hydroxybutyric acid and acetone. These two substances, along with the acetoacetic acid, are called ketone bodies, and their presence in large quantities in the body fluids is called ketosis.


Insulin Promotes Protein Synthesis and Storage. During the few hours after a meal when excess quantities of nutrients are available in the circulating blood, not only carbohydrates and fats but proteins as well are stored in the tissues; insulin is required for this to occur though:
Insulin stimulates transport of many of the amino acids into the cells.
Insulin inhibits the catabolism of proteins, thus decreasing the rate of amino acid release from the cells, especially from the muscle cells.
In the liver, insulin depresses the rate of gluconeogenesis.

Insulin Lack Causes Protein Depletion and Increased Plasma Amino Acids: Virtually all protein storage comes to a halt when insulin is not available. The catabolism of proteins increases, protein synthesis stops, and large quantities of amino acids are dumped into the plasma.
The plasma amino acid concentration rises considerably, and most of the excess amino acids are used either directly for energy or as substrates for gluconeogenesis.
This degradation of the amino acids also leads to enhanced urea excretion in the urine. The resulting protein wasting is one of the most serious of all the effects of severe diabetes mellitus. It can lead to extreme weakness as well as many deranged functions of the organs.

Insulin and Growth Hormone Interact Synergistically to Promote Growth: Because insulin is required for the synthesis of proteins, it is as essential for growth of an animal as growth hormone is. It appears that the two hormones function synergistically to promote growth, each performing a specific function that is separate from that of the other.

Diabetes Mellitus:

Diabetes mellitus is a syndrome of impaired carbohydrate, fat, and protein metabolism. There are two general types of diabetes mellitus:
1. Type I diabetes, also called insulin-dependent diabetes mellitus (IDDM), is caused by lack of insulin secretion.
2. Type II diabetes, also called noninsulin-dependent diabetes mellitus (NIDDM), is caused by decreased sensitivity of target tissues to the metabolic effect of insulin. This reduced sensitivity to insulin is often called insulin resistance.
In both types of diabetes mellitus, metabolism of all the main foodstuffs is altered. The basic effect of insulin lack or insulin resistance on glucose metabolism is to prevent the efficient uptake and utilization of glucose by most cells of the body, except those of the brain. As a result, blood glucose concentration increases, cell utilization of glucose falls increasingly lower, and utilization of fats and proteins increases.

Type I DiabetesLack of Insulin Production by Beta Cells of the Pancreas

Injury to the beta cells of the pancreas or diseases that impair insulin production can lead to type I diabetes. Viral infections or autoimmune disorders may be involved in the destruction of beta cells in many patients with type I diabetes. In some instances, there may be a hereditary tendency for beta cell degeneration even without viral infections or autoimmune disorders.
The usual onset of type I diabetes occurs at about 14 years of age, and for this reason it is often called juvenile diabetes mellitus. Type I diabetes may develop very abruptly, over a period of a few days or weeks, with three principal sequelae: (1) increased blood glucose, (2) increased utilization of fats for energy and for formation of cholesterol by the liver, and (3) depletion of the bodys proteins.
Blood Glucose Concentration Rises to Very High Levels in Diabetes Mellitus. The lack of insulin decreases the efficiency of peripheral glucose utilization and augments glucose production, raising plasma glucose to 300 to 1200 mg/100 ml. The increased plasma glucose then has multiple effects throughout the body.
Increased Blood Glucose Causes Loss of Glucose in the Urine: The high blood glucose causes more glucose to filter into the renal tubules than can be reabsorbed, and the excess glucose spills into the urine. This normally occurs when the blood glucose concentration rises above 180 mg/100 ml, a level that is called the blood threshold for the appearance of glucose in the urine.
Increased Blood Glucose Causes Dehydration The very high levels of blood glucose (sometimes as high as 8 to 10 times normal in severe untreated diabetes) can cause severe cell dehydration throughout the body. This occurs partly because glucose does not diffuse easily through the pores of the cell membrane without insulin, and the increased osmotic pressure in the extracellular fluids causes osmotic transfer of water out of the cells. In addition to the direct cellular dehydrating effect of excessive glucose, the loss of glucose in the urine causes osmotic diuresis. causing massive loss of fluid in the urine, causing dehydration of the extracellular fluid, which in turn causes compensatory dehydration of the intracellular fluid. Thus, polyuria (excessive urine excretion), intracellular and extracellular dehydration, and increased thirst are classic symptoms of diabetes.
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. For example, peripheral neuropathy, which is abnormal function of peripheral nerves, and autonomic nervous system dysfunction are frequent complications of chronic, uncontrolled diabetes mellitus. These abnormalities can result in impaired cardiovascular reflexes, impaired bladder control, decreased sensation in the extremities, and other symptoms of peripheral nerve damage.
Diabetes Mellitus Causes Increased Utilization of Fats and Metabolic Acidosis: The shift from carbohydrate to fat metabolism in diabetes increases the release of keto acids, such as acetoacetic acid and b-hydroxybutyric acid, into the plasma more rapidly than they can be taken up and oxidized by the tissue cells. As a result, the patient develops severe metabolic acidosis from the excess keto acids, which, in association with dehydration due to the excessive urine formation, can cause severe acidosis. This leads rapidly to diabetic coma and death unless the condition is treated immediately with large amounts of insulin and fluids.
All the usual physiologic compensations that occur in metabolic acidosis take place in diabetic acidosis. They include rapid and deep breathing, which causes increased expiration of carbon dioxide; this buffers the acidosis. The kidneys compensate by decreasing bicarbonate excretion and generating new bicarbonate that is added back to the extracellular fluid.
Diabetes Causes Depletion of the Bodys Proteins: Failure to use glucose for energy leads to increased utilization and decreased storage of proteins as well as fat. Therefore, a person with severe untreated diabetes mellitus suffers rapid weight loss and asthenia (lack of energy) despite eating large amounts of food (polyphagia).


Type II DiabetesResistance to the Metabolic Effects of Insulin:
Type II diabetes is far more common than type I, accounting for about 90% of all cases of diabetes mellitus. In most cases, the onset of type II diabetes occurs after age 30, often between the ages of 50 and 60 years, and the disease develops gradually. Therefore, this syndrome is often referred to as adult-onset diabetes. In recent years, however, there has been a steady increase in the number of younger individuals, some less than 20 years old, with type II diabetes. This trend appears to be related mainly to the increasing prevalence of obesity, the most important risk factor for type II diabetes in children as well as in adults.
Insulin resistance is part of a cascade of disorders that is often called the metabolic syndrome. Some of the features of the metabolic syndrome include: (1) obesity, especially accumulation of abdominal fat; (2) insulin resistance; (3) fasting hyperglycemia; (4) lipid abnormalities such as increased blood triglycerides and decreased blood high-density lipoprotein-cholesterol; and (5) hypertension. All of the features of the metabolic syndrome are closely related to excess weight gain, especially when it is associated with accumulation of adipose tissue in the abdominal cavity around the visceral organs.
In the type II diabetes, the pancreatic beta cells become exhausted and are unable to produce enough insulin to prevent more severe hyperglycemia, especially after the person ingests a carbohydrate-rich meal.
In many instances, type II diabetes can be effectively treated, at least in the early stages, with exercise, caloric restriction, and weight reduction, and no exogenous insulin administration is required. Drugs that increase insulin sensitivity or drugs that cause additional release of insulin by the pancreas may also be used. However, in the later stages of type II diabetes, insulin administration is usually required to control plasma glucose.

Physiology of Diagnosis of Diabetes Mellitus

Urinary Glucose: Simple tests used to determine the quantity of glucose lost in the urine. In general, a normal person loses undetectable amounts of glucose, whereas a person with diabetes loses glucose in small to large amounts, in proportion to the severity of disease and the intake of carbohydrates.
Fasting Blood Glucose: The fasting blood glucose level in the early morning is normally 80 to 90 mg/100 ml, and 110 mg/100 ml is considered to be the upper limit of normal. A fasting blood glucose level above this value often indicates diabetes mellitus or at least marked insulin resistance.
Glucose Tolerance Test: when a normal, fasting person ingests 1 gram of glucose per kilogram of body weight, the blood glucose level rises from about 90 mg/100 ml to 120 to 140 mg/100 ml and falls back to below normal in about 2 hours.
In a person with diabetes, the fasting blood glucose concentration is almost always above 110 mg/100 ml and often above 140 mg/100 ml. Also, the glucose tolerance test is almost always abnormal above 200 mg/100 ml.








Dr. Ghassan Endocrine Physiology Lec. 2

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