Chapter 22

The Pancreas and Diabetes Mellitus

Learning Objectives

• Describe pathogenesis and treatment of acute and chronic pancreatitis

• Describe pathogenesis, manifestations, complications, prognosis of cystic fibrosis

• Differentiate type 1 and type 2 diabetes mellitus– Pathogenesis– Incidence– Manifestations– Complications– Treatment

Pancreas (1 of 2)

• Two glands in one– Digestive gland– Endocrine gland

• Exocrine function: exocrine tissue of the pancreas– Concerned solely with digestion– Secretes alkaline pancreatic juice rich in digestive

enzymes into the duodenum through the pancreatic duct to aid digestion

Duct System of pancreas.

Pancreatic Islets

• Pancreatic tissue that functions as an endocrine gland

• Produce hormones– Beta cells: insulin production– Alpha cells: glucagon– Delta cells: somatostatin

Pancreas (2 of 2)• Endocrine function: endocrine tissue of the

pancreas• Consists of multiple small clusters of cells

scattered throughout the gland as pancreatic islets or Islets of Langerhans– Discharge secretions directly into the bloodstream– Each islet is composed of different types of cells

• Alpha cells: secrete glucagon; raise blood glucose• Beta cells: secrete insulin; lower blood glucose• Delta cells: secrete somatostatin; inhibit secretion of

glucagon and insulin

Photomicrograph of pancreatic islet surrounded by exocrine pancreatic tissue.

Acute Pancreatitis (1 of 3)

• Pathogenesis– Escape of pancreatic juice from the ducts into the

pancreatic tissue– Pancreatic digestive enzymes cause destruction

and severe hemorrhage– Involves active secretion of pancreatic juice

despite an obstructed pancreatic duct at its entrance into the duodenum

– Resulting build-up of pancreatic juice increases pressure within the duct system, causing ducts to rupture

Acute Pancreatitis (2 of 3)• Predisposing factors

– Gallbladder disease/gallbladder stones• Common bile duct and common pancreatic duct enter

the duodenum via the ampulla of Vater• Impacted stone in ampulla obstructs pancreatic duct

– Excessive alcohol consumption• Potent stimulus for pancreatic secretions• Induces edema, spasm of pancreatic sphincter, in

ampulla of Vater• Result in high intraductal pressure, duct necrosis, and

escape of pancreatic juice

Acute Pancreatitis (3 of 3)

• Clinical manifestations– Severe abdominal pain– Seriously ill– High mortality rate

Chronic Pancreatitis• Repeated episodes of mild inflammation of pancreas• Each bout destroys some pancreatic tissue• Inflammation subsides and damaged pancreatic

tissue is replaced by scar tissue, leading to progressive destruction of pancreatic tissue

• Manifestations– Difficulty digesting and absorbing nutrients– Not enough surviving pancreatic tissue to produce

adequate enzymes– Destruction of pancreatic islets may lead to diabetes

Cystic Fibrosis• Autosomal Recessive Disorder• Problem with the gene that codes for a protein

known as the Cystic Fibrosis Transmembrane Conductance Regulator

• Gene Found on Chromosome 7 at the p31.2 locus

• Gene is 230,00 base pairs creating a protein 1,480 AA long

• Most common problem is a deletion of three nucleotides – thus causing phenylalanine to not be placed at the 508th position

• The protein created by this gene is anchored to the outer membrane of cells in the sweat glands, lungs, pancreas, and other affected organs. The protein spans this membrane and acts as a channel connecting the inner part of the cell (cytoplasm) to the surrounding fluid.

• This channel is primarily responsible for controlling the movement of halogens from inside to outside of the cell; however, in the sweat ducts it facilitates the movement of chloride from the sweat into the cytoplasm.

• When the CFTR protein does not work, chloride and thiocyanate ([SCN]−). are trapped inside the cells in the airway and outside in the skin. Then hypothiocyanite, OSCN, cannot be produced by immune defense system.

• Normally, as primary sweat moves along the duct most of the NaCl is reabsorbed.  Reabsorption is driven by a large inward gradient for Na+, which flows into the cell through epithelial Na+ channels (ENaC) in the apical membrane.  The basolateral sodium pump then transports Na+ out of the cell and into the blood. Cl- is electrically attracted to Na+ and  follows it by flowing through CFTR Cl- channels in the apical membranes of the duct cells; the exit pathway may also be  via CFTR.

• The duct epithelium has an unusually high conductance for ions and is thought to have a low permeability to  water, allowing reabsorption of salt in excess of water. This results in the production of dilute sweat, so that we can be  cooled by evaporation without losing an undue amount of salt.

• In CF sweat ducts, the Cl- conductance is virtually abolished because CFTR is the only apical pathway for chloride: no other anion channels appear to be in the duct.  The sodium conductance also seems to be low, leading to the hypothesis that CFTR activates ENaC in the sweat duct.   When Na+ attempts to flow out of a CF duct through remaining sodium-selective pathways, it is unaccompanied by Cl- and so it creates an excess of negative charge in the duct that attracts Na+ and prevents its further absorption.

• The net result is that very little  NaCl is reabsorbed, resulting in a high salt content in CF sweat.  The salt is so high (>100 mM vs. typical values of 20 or 30 mM in healthy individuals,  that the sweat chloride concentration is the most reliable single physiological marker of CF.

Figure 5.5b

(b) Photomicrograph of a sectioned eccrine gland (220x)

Secretory cells

Dermal connectivetissue

DuctSebaceousgland

Sweat pore

Eccrinegland

Cystic Fibrosis (1 of 3)• Serious hereditary disease, autosomal recessive

trait• Mutation of a normal gene, CF gene, on long arm

of chromosome 7• Manifests in infancy and childhood• Incidence in whites: 1 in 3,000• Incidence in blacks and other races: rare• Mortality, more than 50% die before age 32• Pathogenesis

– Defective transport of chloride, sodium, and H2O across cell membrane

– Deficient electrolyte and H2O in the mucus secreted by the pancreas, bile ducts, respiratory tract, and other secretory cells

Cystic Fibrosis (2 of 3)• Pathogenesis

– Mucus becomes abnormally thick, precipitates, and forms dense plugs that obstruct the pancreatic ducts, bronchi, bronchioles, and bile ducts

– Obstruction of pancreatic ducts: causes atrophy and fibrosis

– Obstruction of bronchi: causes lung injury– Obstruction of biliary ducts: causes liver scarring– Abnormal function of sweat glands: unable to

conserve sodium and chloride with excessively high salt concentration in sweat; basis of diagnostic test

Cystic Fibrosis (3 of 3)• Treatment

– Oral capsules containing pancreatic enzymes to compensate for lack of pancreatic digestive enzymes

– Various treatments to preserve as much pulmonary function as possible

– Vigorous treatment of pulmonary bacterial infections

– Lung transplant may eventually be required if lungs are severely damaged

Low magnification photomicrograph with pancreas of patient with cystic fibrosis.

Diabetes

• Inability to regulate blood glucose levels• Type 1 diabetes• Type 2 diabetes• Gestational diabetes• Uncontrolled diabetes can cause nerve

damage, kidney damage, blindness, and can be fatal

Diabetes Mellitus• Very common and important metabolic disease• Two major groups depending on cause

– Type 1 diabetes• Insulin deficiency• Occurs primarily in children and young adults

– Type 2 diabetes• Inadequate response to insulin• Typically an adult-onset diabetes• More common than Type 1• Becoming more common in children

• Manifestation: Increased glucose levels in blood or hyperglycemia

Some Skin Problems Linked to Diabetes

• Scleroderma diabeticorum: While rare, this skin problem affects people with type 2 diabetes, causing a thickening of the skin on the back of the neck and upper back. The treatment is to bring your blood sugar level under control. Lotions and moisturizers may help soften skin.

• Vitiligo: Vitiligo, a skin problem more commonly associated with type 1 diabetes than type 2 diabetes, affects skin coloration. With vitiligo, the special cells that make pigment (the substance that controls skin color) are destroyed, resulting in patches of discolored skin. Vitiligo often affects the chest and abdomen, but may be found on the face around the mouth, nostrils, and eyes.

• Acanthosis nigricans. This is a skin problem that results in the darkening and thickening of certain areas of the skin especially in the skin folds. The skin becomes tan or brown and is sometimes slightly raised and described as velvety. Most often the condition, which typically looks like a small wart, appears on the sides or back of the neck, the armpits, under the breast, and groin. Occasionally the top of the knuckles will have a particularly unusual appearance. Acanthosis nigricans usually strikes people who are very overweight. While there is no cure for acanthosis nigricans, losing weight may improve the skin condition. Acanthosis nigricans usually precedes diabetes and is considered to be a marker for the disease.

• Diabetic neuropathies are neuropathic disorders that are associated with diabetes mellitus. These conditions are thought to result from diabetic microvascular injury involving small blood vessels that supply nerves (vasa nervorum) in addition to macrovascular conditions that can culminate in diabetic neuropathy. Relatively common conditions which may be associated with diabetic neuropathy include third nerve palsy; mononeuropathy; mononeuropathy multiplex; diabetic amyotrophy; a painful polyneuropathy; autonomic neuropathy; and thoracoabdominal neuropathy.

Insulin

Insulin• Influences carbohydrate, protein, and fat

metabolism on liver cells, muscle, and adipose tissues

• Main stimulus for release: high glucose in blood• Promotes

– Entry of glucose into cells– Utilization of glucose as source of energy– Storage of glucose as glycogen– Conversion of glucose into triglycerides– Storage of newly formed triglyceride in fat cells– Entry of amino acids into cells and stimulates protein

synthesis

Insulin Actions• Increased glycogen synthesis – insulin

forces storage of glucose in liver (and muscle) cells in the form of glycogen; lowered levels of insulin cause liver cells to convert glycogen to glucose and excrete it into the blood. This is the clinical action of insulin, which is directly useful in reducing high blood glucose levels as in diabetes.

• Increased fatty acid synthesis – insulin forces fat cells to take in blood lipids, which are converted to triglycerides; lack of insulin causes the reverse.

• Increased esterification of fatty acids – forces adipose tissue to make fats (i.e., triglycerides) from fatty acid esters; lack of insulin causes the reverse.

• Decreased proteolysis – decreasing the breakdown of protein

• Decreased lipolysis – forces reduction in conversion of fat cell lipid stores into blood fatty acids; lack of insulin causes the reverse.

• Decreased gluconeogenesis – decreases production of glucose from nonsugar substrates, primarily in the liver (the vast majority of endogenous insulin arriving at the liver never leaves the liver); lack of insulin causes glucose production from assorted substrates in the liver and elsewhere.

• Increased amino acid uptake – forces cells to absorb circulating amino acids; lack of insulin inhibits absorption.

• Increased potassium uptake – forces cells to absorb serum potassium; lack of insulin inhibits absorption. Insulin's increase in cellular potassium uptake lowers potassium levels in blood.

• GLUT1 Is widely distributed in fetal tissues. In the adult, it is expressed at highest levels in erythrocytes and also in the endothelial cells of barrier tissues such as the blood-brain barrier.

• GLUT2 Is expressed by renal tubular cells and small intestinal epithelial cells that transport glucose, liver cells and pancreatic β cells. All three monosaccharides are transported from the intestinal mucosal cell into the portal circulation by GLUT2 Is a high-capacity and low-affinity isoform

• GLUT3 Expressed mostly in neurons (where it is believed to be the main glucose transporter isoform), and in the placenta. Is a high-affinity isoform

• GLUT4 Found in adipose tissues and striated muscle (skeletal muscle and cardiac muscle).

Diabetes—Type 1• Accounts for 10% of all cases• Body does not produce enough insulin• Causes hyperglycemia (high blood glucose)• Requires insulin injections• May be an autoimmune disease

Type 1 Diabetes Mellitus• Results from damage to pancreatic islets

leading to reduction or absence of insulin secretion

• Often follows a viral infection that destroys the pancreatic islets

• Abnormal immune response may play part: production of autoantibodies directed against islet cells

• With a hereditary predisposition• Complication

– Diabetic ketosis

• Maturity onset diabetes of the young (MODY) refers to any of several hereditary forms of diabetes caused by mutations in an autosomal dominant gene (sex independent, i.e. inherited from any of the parents) disrupting insulin production. MODY is often referred to as "monogenic diabetes" to distinguish it from the more common types of diabetes (especially type 1 and type 2), which involve more complex combinations of causes involving multiple genes (i.e., "polygenic") and environmental factors.

Diabetes—Type 2• Insulin insensitivity (insulin resistance):

cells become less responsive to insulin• Metabolic syndrome: a cluster of risk

factors that increase the risk for type 2 diabetes

• Once known as adult-onset diabetes• Increasing in children and adolescents

Metabolic SyndromeInternational Diabetes Federation

• Central obesity (defined as waist circumference# with ethnicity specific values)

• AND any two of the following:• Raised triglycerides: > 150 mg/dL (1.7 mmol/L), or

specific treatment for this lipid abnormality. • Reduced HDL cholesterol: < 40 mg/dL• Raised blood pressure: systolic BP > 130 or diastolic

BP >85 mm Hg, or treatment of previously diagnosed hypertension.

• Raised fasting plasma glucose :(FPG)>100 mg/dL

Type 2 Diabetes Mellitus (1 of 2)• Complex metabolic disease• Occurs in older, overweight, or obese adults• Increasingly seen among younger people who

are overweight or obese• Insulin secretion is normal or increased• Reduced response of tissues to insulin• Cause is not completely understood but weight

reduction restores insulin responsiveness• Islet function is not completely normal as

pancreas is not able to increase insulin output to compensate for the insulin resistance

Type 2 Diabetes Mellitus (2 of 2)

• Hereditary disease• Children of parents with diabetes are at a

significant risk• Incidence in some populations as high as 40%

(Pima Indians of Arizona)• Complication• Hyperosmolar nonketotic coma due to marked

hyperglycemia

Insulin Resistance and Type 2 Diabetes

• 40% of older people are insulin resistant mostly secondary to obesity and inactivity (important in prevention and treatment)

• 20% of the elderly have type 2 diabetes• 8.5% of all adults have type 2 diabetes• 90% of diabetics are managed in

primary care

Major metabolic derangements in type 1 diabetes mellitus.

Complications of Diabetes

• Increased susceptibility to infection• Diabetic coma• Ketoacidosis• Hyperosmolar coma• Arteriosclerosis• Blindness• Renal failure• Peripheral neuritis

• Diabetic nephropathy (nephropatia diabetica), also known as Kimmelstiel-Wilson syndrome, or nodular diabetic glomerulosclerosis and intercapillary glomerulonephritis, is a progressive kidney disease caused by angiopathy of capillaries in the kidney glomeruli. It is characterized by nephrotic syndrome and diffuse glomerulosclerosis. It is due to longstanding diabetes mellitus, and is a prime indication for dialysis in many Western countries.

Diabetic Nephropathy

• Diabetic retinopathy is caused by damage to blood vessels of the retina.

• There are two types, or stages of retinopathy: Nonproliferative or proliferative

• Nonproliferative diabetic retinopathy develops first. Blood vessels in the eye become larger in certain spots (called microaneurysms). Blood vessels may also become blocked. There may be small amounts of bleeding (retinal hemorrhages), and fluid may leak into the retina. This can lead to noticeable problems with your eyesight.

• Proliferative retinopathy is the more advanced and severe form of the disease. New blood vessels start to grow in the eye. These new vessels are fragile and can bleed (hemorrhage). Small scars develop, both on the retina and in other parts of the eye (the vitreous). The end result is vision loss, as well as other problems.

Ketone Bodies (1 of 2)• Glucose is absorbed normally but is not used properly

for energy due to insulin deficiency or insensitivity• Body turns to fat as a source of energy• Fat is broken down into a fatty acid and glycerol• Fatty acid broken down further into 2 carbon

fragments combined with carrier molecule, acetyl coenzyme A

• Some acetyl-CoA are converted by the liver into ketone bodies

• More acetyl-CoA molecules are produced than can be oxidized as a source of energy

• Ketosis: accumulation of ketone bodies in blood and excreted in the urine together with H2O and electrolytes

Ketone Bodies (2 of 2)• Acetoacetic acid: from condensation of 2

acteyl-CoA molecules• Beta-hydroxybutyric acid: from addition of a

hydrogen atom to an oxygen atom and converted into a –OH group

• Acetone: from removal of a carboxyl group of acetoacetic

• Type 1 diabetes complication• Ketoacidosis: overproduction of ketone bodies

– Buffer systems cannot maintain normal pH– May lead to coma

Structure of ketone bodies.

Hyperosmolar Hyperglycemic Nonketotic Coma

• Type 2 diabetes complication• Severe hyperglycemia

– Blood glucose increases 10 to 20 x normal value• Absence of ketosis

– Less insulin is required to inhibit fat mobilization than is needed to promote entry of glucose into cells

– Patients have enough insulin to prevent ketosis, not enough to prevent hyperglycemia

• Results in coma due to extreme hyperosmolarity of blood– H2O moves out of the cells into the extracellular fluid– Cells become dehydrated disturbing functions of neurons

leading to coma

Hyperglycemia

• Elevated blood glucose levels• Also from other conditions that impair glucose

utilization but are less common than diabetes– Chronic pancreatic disease: damage or

destruction of pancreatic islets– Endocrine diseases: overproduction of pituitary or

adrenal hormones that raise blood glucose– Drugs that impair glucose utilization as a side

effect– Hereditary diseases characterized by disturbed

carbohydrate metabolism

Hypoglycemia in Diabetes (1 of 2)• Pancreas regulates the glucose in blood by

adjusting its output of insulin– Hypoglycemia: low blood sugar– Adrenal medulla: responds by discharging

epinephrine that raises blood glucose• Neurologic manifestations appear if blood

glucose continues to fall• Other causes of hypoglycemia

– Oral hypoglycemic drugs in type 2 diabetics– Self-administration of oral hypoglycemic drugs

or insulin by emotionally disturbed person– Islet cell tumor

Hypoglycemia in Diabetes (2 of 2)• Must adjust dose of insulin to match the amount of

ingested carbohydrate– Insufficient insulin, glucose levels increase– Too much insulin, glucose levels decrease

• Conditions predisposing to hypoglycemia in a diabetic patient taking insulin– Skipping a meal: carbohydrate intake is insufficient in

relation to amount insulin and blood glucose falls– Vigorous exercise: with high physical activity there is high

glucose utilization; excess insulin

• Too much insulin causes a precipitous drop in glucose leading to insulin reaction or insulin shock

• A fasting plasma glucose (FPG) test measures blood glucose in a person who has not eaten anything for at least 8 hours. This test is used to detect diabetes and pre-diabetes.

• An oral glucose tolerance test (OGTT) measures blood glucose after a person fasts at least 8 hours and 2 hours after the person drinks a glucose-containing beverage. This test can be used to diagnose diabetes and pre-diabetes.

• The FPG test is the preferred test for diagnosing diabetes because of its convenience and low cost. However, it will miss some diabetes or pre-diabetes that can be found with the OGTT. The FPG test is most reliable when done in the morning. Results and their meaning are shown in Table 1. People with a fasting glucose level of 100 to 125 milligrams per deciliter (mg/dL) have a form of pre-diabetes called impaired fasting glucose (IFG). Having IFG means a person has an increased risk of developing type 2 diabetes but does not have it yet. A level of 126 mg/dL or above, confirmed by repeating the test on another day, means a person has diabetes.

• Research has shown that the OGTT is more sensitive than the FPG test for diagnosing pre-diabetes, but it is less convenient to administer. The OGTT requires fasting for at least 8 hours before the test. The plasma glucose level is measured immediately before and 2 hours after a person drinks a liquid containing 75 grams of glucose dissolved in water. If the blood glucose level is between 140 and 199 mg/dL 2 hours after drinking the liquid, the person has a form of pre-diabetes called impaired glucose tolerance (IGT). Having IGT, like having IFG, means a person has an increased risk of developing type 2 diabetes but does not have it yet. A 2-hour glucose level of 200 mg/dL or above, confirmed by repeating the test on another day, means a person has diabetes.

• Gestational diabetes is also diagnosed based on plasma glucose values measured during the OGTT, preferably by using 100 grams of glucose in liquid for the test. Blood glucose levels are checked four times during the test. If blood glucose levels are above normal at least twice during the test, the woman has gestational diabetes.

• . Gestational diabetes: Above-normal results for the OGTT* When Plasma Glucose Result (mg/dL) Fasting 95 or higher At 1 hour 180 or higher At 2 hours 155 or higher At 3 hours 140 or higher

Treatment of Diabetes

• Diet• Type 1 diabetes: requires insulin; dosage

adjusted to control level of blood glucose• Type 2 diabetes

– Management: weight reduction and diet– Oral hypoglycemic drugs if patient does not

respond adequately to diet and exercise regimen

Types of Insulin• There are four basis types of insulin based

primarily on the time of onset of action and the duration of action

• Rapid Acting – onset generally in 10 – 30 minutes – duration 30 – 90 minutes

• Short Acting - onset generally in 30 minutes to 1 hour – duration 2 – 5 hours

• Intermediate Acting - onset generally in 1 – 2 ½ hours – duration 3 – 12 hours

• Long Acting - onset generally in 1 – 3 hours – duration 6 – 20 hours

Types of Oral Hypoglycemics (1)• Oral hypoglycemic drugs are used only in

the treatment of type 2 diabetes which is a disorder involving resistance to secreted insulin.

• There are now four classes of hypoglycemic drugs:

• Sulfonylureas • Metformin • Thiazolidinediones • Alpha-glucosidase inhibitors.

Classes of Oral Medicationsfor Type 2 Diabetes

• Drugs that help the body use insulin (sensitizers)

• Drugs that stimulate the pancreas to release more insulin (secretagogues)

• Drugs that block the breakdown of starches and sugars (a-glucosidase inhibitors)

Types of Oral Hypoglycemics (2)• SULFONYLUREAS – Sulfonylureas are the most

widely used drugs for the treatment of type 2 diabetes and appear to function by stimulating insulin secretion.

• METFORMIN –It is effective only in the presence of insulin but, in contrast to sulfonylureas, it does not directly stimulate insulin secretion. Its major effect is to increase insulin action. How metformin increases insulin action is not known but it is known to affect many tissues. One important effect appears to be suppression of glucose output from the liver.

Metformin (Glucophage and Glucophage XR)• Decreases hepatic glucose output• Increases insulin sensitivity• Decreases LDL and triglycerides• Decreases C-reactive protein• Causes weight loss or stabilization• No risk of hypoglycemia• Causes nausea, cramps and diarrhea• Lactic acidosis rare (contraindications –

CHF, renal impairment, age greater than 80)

Types of Oral Hypoglycemics (3)

• THIAZOLIDINEDIONES – The thiazolidinediones such as Avandia (Rosiglitazone) reverse insulin resistance by acting on muscle, fat and to a lesser extent liver to increase glucose utilization and diminish glucose production. The mechanism by which the thiazolidinediones increase insulin action is not well understood but they may be acting by redistributing fat from the visceral compartment to the subcutaneous compartment. We know that visceral fat is associated with insulin resistance.

Types of Oral Hypoglycemics (4)

• ALPHA-GLUCOSIDASE INHIBITORS –They inhibit the upper gastrointestinal enzymes that converts dietary starch and other complex carbohydrates into simple sugars which can be absorbed. The result is to slow the absorption of glucose after meals.

Monitoring Control of Diabetes

• Goal: achieve control of blood glucose as close as possible to normal– 1. Frequent periodic measurements of blood

glucose– 2. Urine test: detects glucose spilling into the

urine when blood glucose is too high– 3. Measurement of glycosylated hemoglobin:

serves as an index of long-term control of hyperglycemia

Glycosylated Hemoglobin, HgA1c• Glycosylated hemoglobin monitors how well blood

glucose is being controlled by treatment– Excess glucose molecules attach permanently to red

blood cells that circulate in body for about 3 months before they die

– Concentration of glycosylated hemoglobin is directly proportional to average blood glucose for the preceding 6-12 weeks

• Normal persons: 6% of hemoglobin is glycosylated• Well-controlled diabetes: 7% or less• Poorly controlled diabetes: 8% and above

Tumors of the Pancreas• Carcinoma of the pancreas

– Usually develops in the head of the pancreas• Blocks common bile duct• Causes obstructive jaundice

– Tumors elsewhere in pancreas: no specific symptoms, usually far advanced when first detected

• Islet cell tumors– Benign– Beta cell tumors produce hyperinsulinism and

hypoglycemia

Discussion• Insulin performs all of the following functions

EXCEPT– A. It promotes entry of amino acids into the cells– B. It promotes storage of glucose in muscle and

liver cells– C. It promotes entry and absorption of glucose

into cells for use as energy– D. It promotes the breakdown of fat– E. It lowers blood glucose