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Pancreas Digestive functions Secretes two important hormonesInsulinGlucagonSecretes other hormones, such as amylin,somatostatin, and pancreatic polypeptide
Physiologic Anatomy of the Pancreas Two major types of tissues1) The acini,which secrete digestive juices into duodenum2) The islets of Langerhans, which secrete insulin andglucagon into blood. 1 to 2 million islets of Langerhans, organized around smallcapillaries into which its cells secrete their hormones. The islets contain three major types of cells alpha, beta, deltacell The beta cells 60 % of all the cells of the islets, lie mainly inthe middle of each islet and secrete insulin and amylin, The alpha cells, 25 % of the total, secrete glucagon The delta cells, about 10 %, secrete somatostatin. One other type of cell, the PP cell, is present in small numbersin the islets and secretes pancreatic polypeptide.
Hormones Both insulin and glucagon are synthesized as large preprohormones. In Endoplasmic reticulum, the prohormones are formed. Most of this is further cleaved in the Golgi apparatus to formhormone and peptide fragments before being packaged in thesecretory granules. In the case of the beta cells, insulin and connecting (C) peptide arereleased into the circulating blood in equimolar amounts. Insulin is a polypeptide containing two amino acid chains (21 and 30amino acids, respectively) connected by disulfide bridges. Glucagon is a straight-chain polypeptide of 29 amino acid residues. Both insulin and glucagon circulate unbound to carrier proteins andhave short half-lives of 6 minutes. Approximately 50% of the insulin and glucagon in blood ismetabolized in the liver; most of the remaining hormone ismetabolized by the kidneys.
Insulin and Its Metabolic Effects Insulin was ﬁrst isolated from the pancreas in 1922 byBanting and Best Associated with ―blood sugar,‖ Insulin has effects on carbohydrate metabolism. Insulin affects fat and protein metabolism
Insulin Is a Hormone Associated withEnergy Abundance When there is great abundance of energy-giving foods inthe diet, especially excess amounts of carbohydrates,insulin is secreted in great quantity. Insulin plays an important role in storing the excess energy. In the case of excess carbohydrates, it causes them to bestored as glycogen mainly in the liver and muscles. Excess carbohydrates is also converted under the stimulusof insulin into fats and stored in the adipose tissue. Insulin has a direct effect in promoting amino acid uptakeby cells and conversion of these amino acids into protein. In addition, it inhibits the breakdown of the proteins that arealready in the cells.
Actions of Insulin To initiate its effects on target cells, insulin first binds with andactivates a membrane receptor protein The insulin receptor is a tetramer made up of two α-subunits thatlie outside the cell membrane and two β-subunits that penetratethe cell membrane and protrude into the cytoplasm When insulin binds with the alpha subunits on the outside of thecell, portions of the beta subunits protruding into the cell becomeautophosphorylated. Thus, the insulin receptor is an example of an enzyme-linkedreceptor Autophosphorylation of the beta subunits of the receptor activatesa local tyrosine kinase, which in turn causes phosphorylation ofmultiple other intracellular enzymes including a group calledinsulin-receptor substrates (IRS). The net effect is to activate some of these enzymes whileinactivating others. In this way, insulin directs the intracellular metabolic machinery toproduce the desired effects on carbohydrate, fat, and proteinmetabolism.
Effect on Carbohydrate Metabolism Immediately after a high-carbohydrate meal, glucosethat is absorbed into the blood causes rapid secretion ofinsulin Insulin causes rapid uptake, storage, and use ofglucose by almost all tissues of the body, but especiallyby the muscles, adipose tissue, and liver.
In Muscle, Insulin Promotes the Uptakeand Metabolism of Glucose Mostly muscle tissue depends not on glucose for its energybut on fatty acids, because normal resting muscle membraneis only slightly permeable to glucose, except when the musclefiber is stimulated by insulin. Under two conditions the muscles do use large amounts ofglucose.1. During moderate or heavy exercise. because exercisingmuscle fibers become more permeable to glucose even inthe absence of insulin because2. During few hours after a meal: At this time the blood glucoseconcentration is high and the pancreas is secreting largequantities of insulin. The extra insulin causes rapid transportof glucose into the muscle cells. Abundant glucose transported into the muscle cells is storedin the form of muscle glycogen
In the Liver, Insulin Promotes Glucose Uptakeand Storage, and Use Insulin causes most of the glucose absorbed after ameal to be stored almost immediately in the liver in theform of glycogen. The mechanism of glucose uptake and storage in theliver :1. Insulin inactivates liver phosphorylase, which normallycauses liver glycogen to split into glucose.2. Insulin causes enhanced uptake of glucose from bloodby liver by increasing the activity of the enzymeglucokinase, causes the initial phosphorylation ofglucose after it diffuses into liver3. Insulin also increases the activities of the enzymes thatpromote glycogen synthesis, glycogen synthase
Glucose Is Released from the Liver Between Meals When the blood glucose level begins to fall to a low levelbetween meals, several events cause the liver to releaseglucose back into the circulating blood:1. The decreasing blood glucose causes the pancreas todecrease its insulin secretion.2. The lack of insulin then reverses all the effects for glycogenstorage3. The lack of insulin activates the enzyme phosphorylase,causes the splitting of glycogen into glucose phosphate.4. The enzyme glucose phosphatase, now becomes activatedby the insulin lack and causes the phosphate radical to splitaway from the glucose Thus, the liver removes glucose from the blood when it ispresent in excess after a meal and returns it to the blood whenthe blood glucose concentration falls between meals
Insulin Promotes Conversion of Excess Glucose intoFatty Acids and Inhibits Gluconeogenesis in Liver. When the quantity of glucose entering the liver cells ismore, insulin promotes the conversion of all this excessglucose into fatty acids. These packaged as triglycerides in VLDL and transportedby blood to the adipose tissue and deposited as fat. Insulin also inhibits gluconeogenesis.
Lack of Effect of Insulin on Glucose Uptakeand Usage by the Brain Insulin has little effect on uptake or use of glucose inbrain Instead, the brain cells are permeable to glucose The brain cells are also quite different from most othercells of the body in that they normally use only glucosefor energy and can use other energy substrates, such asfats, only with difficulty. It is essential that the blood glucose level always bemaintained above a critical level When the blood glucose falls too low, symptoms ofhypoglycemic shock develop, characterized byprogressive nervous irritability that leads to fainting,
Effect of Insulin on CarbohydrateMetabolism in Other Cells Insulin increases glucose transport into and glucoseusage by most other cells of the body The transport of glucose into adipose cells mainlyprovides substrate for the glycerol portion of the fatmolecule. Therefore, in this indirect way, insulin promotesdeposition of fat in these cells.
Effect of Insulin on Fat Metabolism Insulin Promotes Fat Synthesis and Storage Insulin has several effects that lead to fat storage inadipose tissue. Insulin increases the utilization of glucose by body Insulin promotes fatty acid synthesis, in liver cells Fatty acids are then transported from the liver by way ofthe blood lipoproteins to the adipose cells to be stored
Role of Insulin in Storage of Fat in theAdipose Cells Insulin has two other essential effects that are requiredfor fat storage in adipose cells:1. Insulin inhibits the action of hormone-sensitive lipase.This is the enzyme that causes hydrolysis of thetriglycerides already stored in the fat cells.2. Insulin promotes glucose transport through the cellmembrane into the fat cells. Some of this glucose isthen used to synthesize minute amounts of fatty acids,but forms large quantities of a-glycerol phosphate. Thissubstance supplies the glycerol that combines withfatty acids to form the triglycerides that are the storageform of fat
Insulin Deficiency Increases Use of Fat forEnergy All aspects of fat breakdown and use for providingenergy are greatly enhanced in the absence of insulin. This occurs even normally between meals whensecretion of insulin is minimal, but it becomes extremein diabetes mellitus . Insulin Deficiency Causes Lipolysis of Storage Fatand Release of Free Fatty Acids. Consequently, the plasma concentration of free fattyacids begins to rise within minutes. This free fatty acid then becomes the main energysubstrate used by essentially all tissues of the bodybesides the brain.
Insulin Deficiency Increases PlasmaCholesterol and PhospholipidConcentrations The excess of fatty acids in the plasma associated withinsulin deficiency also promotes liver conversion ofsome of the fatty acids into phospholipids andcholesterol, two of the major products of fat metabolism. These two substances, along with excess triglyceridesformed at the same time in the liver, are then dischargedinto the blood in the lipoproteins, so the plasmalipoproteins increase This high lipid concentration—especially the highconcentration of cholesterol—promotes the developmentof atherosclerosis in people with serious diabetes.
Excess Usage of Fats During Insulin LackCauses Ketosis and Acidosis Insulin lack also causes excessive amounts ofacetoacetic acid to be formed in the liver cells. At the same time, the absence of insulin also depressesthe utilization of acetoacetic acid in the peripheraltissues. Thus, so much acetoacetic acid is released from the liver 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 largequantities in the body fluids is called ketosis. In severe diabetes the acetoacetic acid and the b-
Effect of Insulin on Protein Metabolism andon Growth Insulin Promotes Protein Synthesis and Storage During the few hours after a meal proteins are alsostored in the tissues by insulin1. Insulin stimulates transport of many of amino acids intothe cells, eg valine, leucine, isoleucine, tyrosine, andphenylalanine.2. Insulin increases the translation of mRNA, thus formingnew proteins3. Over a longer period of time, insulin also increases therate of transcription of selected DNA, forming increasedquantities of RNA and still more protein synthesis
4. Insulin inhibits the catabolism of proteins5. In the liver, insulin depresses the rate ofgluconeogenesis, this suppression ofgluconeogenesis conserves the amino acids in theprotein stores of the body. In summary, insulin promotes protein formation andprevents the degradation of proteins Insulin Lack Causes Protein Depletion and IncreasedPlasma Amino Acids The resulting protein wasting is one of the most seriousof all the effects of severe diabetes mellitus. It can lead to extreme weakness as well as many
Insulin and Growth Hormone InteractSynergistically to Promote Growth Because insulin is required for the synthesis ofproteins, it is as essential for growth of an animal asgrowth hormone is. A combination of these hormones causes dramaticgrowth. Thus, it appears that the two hormones functionsynergistically to promote growtheach performing aspecific function that is separate from that of the other.
Glucagon Glucagon is also called the hyperglycemic hormone Most of the Actions of Glucagon Are Achieved byActivation of Adenylyl Cyclase in hepatic cellmembrane The binding of glucagon to hepatic receptors resultsin activation of adenylyl cyclase and generation of thesecond messenger cyclic AMP, which in turn activatesprotein kinase, leading to phosphorylation that resultsin the activation or deactivation of a number ofenzymes.
Effects on Glucose Metabolism Glucagon Promotes Hyperglycemia Greatly enhance the availability of glucose to theorgans of the body Glucagon stimulates glycogenolysis: Glucagon has immediate and pronounced effects on theliver to increase glycogenolysis and the release ofglucose into the blood. This effect is achieved through activation of liverphosphorylase and simultaneous inhibition of glycogensynthase.
Glucagon stimulates gluconeogenesis: Glucagon increases the hepatic extraction of aminoacids from the plasma and increases the activities ofkey gluconeogenic enzymes. Consequently, glucagon has delayed actions to promoteglucose output by the liver.
Other Effects of Glucagon Occurs only when its concentration rises well abovethe maximum normally found in the blood. Activates adipose cell lipase, making increasedquantities of fatty acids available to the energysystems of the body. Glucagon also inhibits the storage of triglycerides inthe liver, which prevents the liver from removing fattyacids from the blood. Enhances the strength of the heart Increases blood ﬂow in some tissues, especially thekidneys Enhances bile secretion Inhibits gastric acid secretion.
Diabetes Mellitus Diabetes mellitus is a syndrome of impairedcarbohydrate, fat, and protein metabolism caused byeither lack of insulin secretion or decreased sensitivityof the tissues to insulin Two forms of diabetes mellitus Type I diabetes mellitus, also called insulin-dependentdiabetes mellitus (IDDM), is caused by impairedsecretion of insulin. Type II diabetes mellitus, also called non–insulin-dependent diabetes mellitus (NIDDM), is caused byresistance to the metabolic effects of insulin in targettissues.
Type I Diabetes Caused by Impaired Secretion of Insulin by the BetaCells of the Pancreas Often, type I diabetes is a result of autoimmunedestruction of beta cells, but it can also arise from theloss of beta cells resulting from viral infections. Because the usual onset of type I diabetes occursduring childhood, it is referred to as juvenile diabetes. Pathophysiological features: Hyperglycemia as a result of impaired glucose uptakeinto tissues and increased glucose production by theliver (increased gluconeogenesis)
Depletion of proteins resulting from decreased synthesisand increased catabolism Depletion of fat stores and increased ketosis As a result of these fundamental derangements:• Glucosuria, osmotic diuresis, hypovolemia• Hyperosmolality of the blood, dehydration, polydipsia• Hyperphagia but weight loss; lack of energy• Acidosis progressing to diabetic coma; rapid and deepbreathing• Hypercholesterolemia and atherosclerotic vasculardisease
Chronic High Glucose Concentration CausesTissue Injury When blood glucose is poorly controlled over longperiods, blood vessels in multiple tissues throughoutthe body begin to function abnormally and undergostructural changes that result in inadequate bloodsupply to the tissues. This in turn leads to increased risk for heart attack,stroke, end-stage kidney disease, retinopathy andblindness, and ischemia and gangrene of the limbs. Chronic high glucose concentration also causesdamage to many other tissues. For example,peripheral neuropathy and autonomic nervous systemdysfunction
Type II Diabetes Mellitus Insulin Resistance Is the Hallmark of Type II DiabetesMellitus Type II diabetes is far more common than type I diabetes(accounting for approximately 90% of all cases ofdiabetes) Usually associated with obesity. This form of diabetes is characterized by impaired abilityof target tissues to respond to the metabolic effects ofinsulin, which is referred to as insulin resistance. In contrast to type I diabetes, pancreatic beta cellmorphology is normal throughout much of the disease,and there is an elevated rate of insulin secretion.
Metabolic syndrome Metabolic syndrome include:(1) obesity, especially accumulation of abdominalfat;(2) Insulin resistance(3) fasting hyperglycemia(4) lipid abnormalities such as increased bloodtriglycerides(5) hypertension.
Type II diabetes usually develops in adults andtherefore is also called adult-onset diabetes. Caloric restriction and weight reduction usuallyimprove insulin resistance in target tissues Drugs that increase insulin sensitivity, such asthiazolidinediones and metformin, or drugs that causeadditional release of insulin by the pancreas, such assulfonylureas, may also be used. In the late stages of the disease when insulinsecretion is impaired, insulin administration isrequired.
Physiology of Diagnosis of Diabetes Mellitus Urinary Glucose Fasting Blood Glucose and Insulin Levels. FBG levels in the early morning is normally 80-90 mg/100ml. FBG above 110 mg/100 ml often indicates diabetes In type I diabetes, plasma insulin levels are very low orundetectable during fasting and even after a meal. Acetone Breath Increased Acetoacetic acid in the blood is converted toacetone. This is volatile and vaporized into the expired air. Consequently, one can frequently make a diagnosis of type Idiabetes mellitus simply by smelling acetone on the breath ofa patient.
Glucose Tolerance Test•when a normal, fastingperson ingests 1 gramof glucose per kg of bodyweight, the bloodglucose level rises fromabout 90 mg/100 ml to 120 to140 mg/100 ml and falls backto below normal inabout 2 hours.•In a person with diabetes,this test is always abnormal