Download phys chapter 78 [2-9

Phys chap 78
Insulin, Glucagon, and Diabetes Mellitus
 Acini – exocrine pancreas
 Islets of Langerhans organized around small capillaries into which cells secrete their hormones
o Alpha, beta, and delta cells can be distinguished by staining characteristics and morphology
o Majority are beta cells, followed by alpha cells, then delta cells (secrete somatostatin)
o PP cell present in small numbers and secretes pancreatic polypeptide (don’t know what it does)
 Insulin inhibits glucagon secretion
 Amylin inhibits insulin secretion
 Somatostatin inhibits secretion of both insulin and glucagon
Insulin and Its Metabolic Effects
 Abnormalities of fat metabolism (causing acidosis and arteriosclerosis) that are usual causes of death in diabetic
patients, not hypoglycemia itself
 In patients with prolonged diabetes, diminished ability to synthesize proteins leads to wasting of tissues and
cellular functional disorders
 Excess carbs in diet makes insulin secretion increase; insulin causes carbs to be stored as glycogen mainly in liver
and muscles; all excess carbs that can’t be stored as glycogen converted to fats and stored in adipose tissue
(under stimulus of insulin)
 Insulin has direct effect in promoting amino acid uptake by cells and conversion of amino acids into protein;
inhibits breakdown of proteins already in cells
 Insulin composed of 2 amino acid chains connected by disulfide linkages; when amino acid chains split apart,
functional activity of insulin molecule lost
 Synthesized with translation of insulin RNA by ribosomes attached to rER to form preproinsulin; cleaved in rER
to form proinsulin (A, B, and C chains); most of proinsulin cleaved in Golgi apparatus to form insulin (A and B
chains); insulin and C peptide packaged in secretory granules and secreted in equimolar amounts
o 5-10% of secreted product still proinsulin (has virtually no insulin activity)
o C-peptide binds to PM receptor and elicits activation of Na+/K+-ATPase and endothelial NO synthase
o Measurement of C-peptide levels by radioimmunoassay determines how much insulin is patient’s own
 When insulin secreted into blood, it circulates almost entirely in unbound form; plasma half-life averages 6
minutes, so mainly cleared from circulation in 10-15 minutes
o Except for portion that combines with receptors in target cells, remainder degraded by insulinase,
mainly in liver and to lesser extent kidneys and muscles (can happen almost anywhere though)
 Insulin binds to receptor protein on target cell; receptor contains 2 alpha subunits (completely extracellular) and
2 beta subunits (have intracellular domains) linked by disulfide linkages
o Binding of insulin to alpha subunits causes autophosphorylation of beta subunits (enzyme-linked
receptor); autophosphorylation of beta subunits activates local tyrosine kinase, which causes
phosphorylation of insulin-receptor substrates (IRS)
o Different types of IRS expressed in different tissues
 End effects of insulin stimulation are
o Cell PM increases glucose uptake (not most neurons in brain); glucose immediately phosphorylated to
become substrate for carb metabolic functions
 Increased transport from translocation of intracellular vesicles to PM; vesicles carry glucose
transport proteins, which bind with PM and facilitate glucose uptake
 When insulin no longer available, vesicles separate from PM within 3-5 minutes and move back
to cell interior (recycled)
o PM becomes more permeable to amino acids, K+, and HPO42-, causing increased transport into cell
o Changes in activity levels of intracellular metabolic enzymes
o Changed rates of translation of mRNAs at ribosomes to form new proteins; changed rates of
transcription of DNA in cell nucleus
 During much of day, muscle tissue depends on fatty acids for energy; normal resting muscle membrane only
slightly permeable to glucose, except when muscle fiber stimulated by insulin
o
o











Between meals, amount of insulin secreted too small to promote significant amounts of glucose entry
Muscles use large amounts of glucose during moderate to heavy exercise (exercising muscle fibers
become more permeable to glucose even in absence of insulin because of contraction process itself)
o Muscles use large amounts of glucose during few hours after meal; blood glucose concentration high
and pancreas secretes large quantities of insulin, causing rapid transport of glucose into muscle cells
If muscles not exercising after meal, most glucose transported into muscle cells in abundance stored as muscle
glycogen (limited concentration); glycogen later used for energy by muscle (short spurts of anaerobic energy)
Insulin inactivates liver phosphorylase (principal enzyme that causes liver glycogen to split into glucose)
o Causes enhanced uptake of glucose from blood by hepatocytes by increasing activity of glucokinase;
once phosphorylated, glucose temporarily trapped inside hepatocytes because phosphorylated glucose
can’t cross PM
o Increases activities of enzymes that promote glycogen synthesis, including glycogen synthase
(responsible for polymerization of monosaccharide units to form glycogen molecules)
When blood glucose levels begin to fall between meals, decreasing blood glucose causes pancreas to decrease
insulin secretion; lack of insulin stops further synthesis of glycogen in liver and prevents further uptake of
glucose by liver from blood
o Lack of insulin and increase in glucagon activate phosphorylase, which causes splitting of glycogen into
glucose phosphate
o Glucose phosphatase (inhibited by insulin) becomes activated by insulin lack and causes phosphate
radical to split away from glucose, allowing free glucose to diffuse back into blood
When quantity of glucose entering liver cells more than can be stored as glycogen or used for hepatocyte
metabolism, insulin promotes conversion of excess glucose into fatty acids, which are packaged as triglycerides
in VLDL, transported to adipose tissue, and deposited as fat
Insulin inhibits gluconeogenesis mainly by decreasing quantities and activities of enzymes required for it
o Part of effect caused by action of insulin that decreases release of amino acids from muscle and other
extra-hepatic tissues (no precursors for gluconeogenesis)
Most of brain cells permeable to glucose and can use it without intermediation of insulin; normally only use
glucose for energy (very difficult to use fats)
Transport of glucose into adipose cells mainly provides substrate for glycerol portion of fat molecule; hence
insulin promotes deposition of fat in these cells
o Long-term insulin lack causes extreme atherosclerosis
o Insulin increases utilization of glucose by most of body’s tissues, which automatically decreases
utilization of fat, thus functioning as fat sparer
o Insulin promotes fatty acid synthesis, using carbs as substrate; almost all fat synthesis occurs in liver
cells, and fatty acids transported from liver by lipoproteins to adipose cells to be stored
Factors that lead to increased fatty acid synthesis in liver
o Insulin increases transport of glucose into liver cells; after liver glycogen reaches a certain concentration,
it inhibits further glycogen synthesis; all additional glucose entering liver cells becomes available to form
fat; glycolytic pathway makes pyruvate, which is converted to acetyl-CoA for fatty acid synthesis
o Excess of citrate and isocitrate ions formed by TCA cycle when excess amounts of glucose being used for
energy; ions have direct effect in activating acetyl-CoA carboxylase (required for first stage of fatty acid
synthesis)
o Most of fatty acids synthesized in liver and used to form triglycerides; released from hepatocytes to
blood in lipoproteins; insulin activates LPL in capillary walls of adipose tissue, which split triglycerides
into fatty acids for them to be absorbed into adipose cells, where they are converted to triglycerides and
stored
Insulin inhibits action of hormone-sensitive lipase (enzyme that causes hydrolysis of triglycerides already stored
in fat cells; release of fatty acids from adipose tissue into circulating blood inhibited
Insulin promotes glucose transport through PM into fat cells; some glucose used to synthesize minute amounts
of fatty acids, and some forms large quantities of α-glycerol phosphate (supplies glycerol that combines with
fatty acids to form triglycerides that are storage form of fat in adipose)
All aspects of fat breakdown and use for providing energy greatly enhanced in absence of insulin
o








Hormone-sensitive lipase in fat cells becomes strongly activated; causes hydrolysis of stored
triglycerides, releasing large quantities of fatty acids and glycerol into circulating blood
o Free fatty acids become main energy substrate used by essentially all tissues of body
Excess fatty acids in plasma associated with insulin deficiency promote liver conversion of some fatty acids into
phospholipids and cholesterol, which are discharged into blood in lipoproteins (along with excess triglycerides)
o High lipid concentration (especially high cholesterol) promotes development of atherosclerosis
Insulin lack causes excessive amounts of acetoacetic acid to be formed in liver because in absence of insulin and
presence of excess fatty acids in liver, carnitine transport mechanism for transporting fatty acids into
mitochondria becomes increasingly activated
o In mitochondria, beta oxidation of fatty acids proceeds rapidly, releasing excess acetyl-CoA
o Large part of excess acetyl-CoA condensed to form acetoacetic acid, which is released into bloodstream
o Acetoacetic acid converted back to acetyl-CoA by tissues and used for energy in usual manner
o Absence of insulin depresses utilization of acetoacetic acid, so produces metabolic acidosis
o Some of acetoacetic acid converted to ketone bodies
Insulin stimulates transport of many amino acids into cells; increases translation of mRNA to form new proteins;
increases rate of transcription of selected DNA genetic sequences (forming increased quantities of RNA and
protein synthesis), promoting enzymes for storage of carbs, fats, and proteins; inhibits catabolism of proteins,
decreasing rate of amino acid release from cells (results from ability of insulin to diminish normal degradation
of proteins by cellular lysosomes); depresses rate of gluconeogenesis in liver by decreasing activity of enzymes
that promote gluconeogenesis, conserving amino acids in protein stores in body
Virtually all protein storage comes to a halt when insulin not available; catabolism of proteins increases, protein
synthesis stops, and large quantities of amino acids dumped into plasma
o Most excess amino acids used directly for energy or as substrates for gluconeogenesis
o Degradation of amino acids leads to enhanced urea excretion in urine
Insulin required for growth (because of requirement for protein synthesis); functions synergistically with GH
Glucose transport stimulation of insulin secretion from pancreatic beta cells
o Glucokinase is rate-limiting step for glucose metabolism in beta cell;
major mechanism for glucose sensing and adjustment of amount of
secreted insulin to blood glucose levels
o ATP inhibits ATP-sensitive K+ channels of cell; closure of K+ channels
depolarizes PM, opening voltage-gated Ca2+ channels
o Influx of Ca2+ stimulates fusion of docked insulin-containing vesicles
with PM and secretion of insulin via exocytosis
o Other nutrients (certain amino acids) can be metabolized by beta cells
to increase intracellular ATP and stimulate insulin secretion
o Glucagon, GIP, and ACh increase intracellular Ca2+ through other
signaling pathway and enhance effect of glucose (don’t have major
effects on insulin secretion in absence of glucose)
o Somatostatin and norepi (by activating α-adrenergic receptors) inhibit
exocytosis of insulin
o Sulfonylurea drugs stimulate insulin secretion by binding to ATP-sensitive K+ channels and blocking their
activity; depolarizes cell, triggering insulin secretion
Effects of steadily increased glucose level on insulin secretion (plasma glucose held at elevated level)
o First spike results from immediate dumping of preformed insulin
from beta cells; initial high rate of secretion not maintained
o After a while, secretion rises again from additional release of
preformed insulin and from activation of enzyme system that
synthesizes and releases new insulin from cells
Arginine and lysine stimulate insulin secretion; amino acid rise in
absence of rise in blood glucose causes only small increase in insulin
secretion; when administered at same time as blood glucose
concentration elevated, glucose-induced secretion of insulin may be
doubled in presence of excess amino acids (amino acids potentiate glucose stimulus for insulin secretion)
o Important because insulin important for proper utilization of excess amino acids
 Gastrin, secretin, CCK, and GIP cause moderate increase in insulin secretion; cause anticipatory increase in blood
insulin in preparation for glucose and amino acids to be absorbed from meal
o Increase sensitivity of insulin response to increased blood glucose
 Glucagon, GH, cortisol, and to lesser extent progesterone and estrogen all increase insulin secretion
o Prolonged secretion of any one of them in large quantities can lead to exhaustion of beta cells and
increase risk for developing DM
 Under some conditions, stimulation of PNS nerves to pancreas can increase insulin secretion; SNS stimulation
decreases insulin secretion
 GH and cortisol secreted in response to hypoglycemia, and both inhibit cellular utilization of glucose while
promoting fat utilization; effects develop slowly (requiring many hours for max expression)
 Epi increases plasma fatty acid concentration at same time as increasing plasma glucose
o Epi has potent effect of causing glycogenolysis in liver, releasing large quantities of glucose into blood
o Epi has direct lipolytic effect on adipose cells, activating adipose tissue hormone-sensitive lipase, greatly
enhancing blood concentration of fatty acids as well
o Enhancement of fatty acids far greater than enhancement of blood glucose
Glucagon and Its Functions
 Secreted by alpha cells of islets of Langerhans when blood glucose concentration falls; increases blood glucose
concentration
 Major effects of glucagon on glucose metabolism are breakdown of liver glycogen (glycogenolysis) and increased
gluconeogenesis in liver
 Glucagon activates adenylyl cyclase in hepatic PM, which causes formation of cAMP, which activates protein
kinase regulator protein, which activates protein kinase, which activates phosphorylase b kinase, which converts
phosphorylase b into phosphorylase a, which promotes degradation of glycogen into glucose-1-phosphate,
which is dephosphorylated and glucose released from hepatocytes
o Cascade in which each succeeding product produced in greater quantity than preceding product
 Even after all glycogen in liver has been exhausted under influence of glucagon, continued infusion of glucagon
still causes continued hyperglycemia because of increase rate of amino acid uptake by hepatocytes and
conversion to glucose by gluconeogenesis
 Glucagon activates adipose cell lipase, making increased quantities of fatty acids available for energy
 Glucagon inhibits storage of triglycerides in liver, which prevents liver from removing fatty acids from blood and
makes additional amounts of fatty acids available for tissues to use for energy
 Glucagon in high concentrations enhances strength of heart, increases blood flow in some tissues (especially
kidneys), enhances bile secretion, and inhibits gastric acid secretion
 Decrease in blood glucose is most important stimulus for secretion of glucagon
 High concentrations of amino acids (especially alanine and arginine) stimulate secretion of glucagon; glucagon
promotes rapid conversion of amino acids to glucose, making even more glucose available to tissues
 Glucagon level increases in exhaustive exercise, preventing decrease in blood glucose
Somatostatin
 Delta cells secrete somatostatin (1-14); secretion stimulated by increased blood glucose, increased amino acids,
increased fatty acids, and increased concentrations of GI hormones released from upper GI tract in response to
food intake
 Somatostatin depresses secretion of both insulin and glucagon; decreases motility of stomach, duodenum, and
gallbladder; decreases secretion and absorption in GI tract
 Sam chemical substance as growth hormone inhibitory hormone secreted in hypothalamus; suppresses anterior
pituitary secretion of GH
Summary of Blood Glucose Regulation
 Liver functions as important blood glucose buffer system, taking up glucose after meal and storing it as glycogen,
then releasing it later as blood glucose starts to fall; dampens fluctuation in blood glucose
 In severe hypoglycemia, direct effect of low blood glucose on hypothalamus stimulates SNS; epi increases
release of glucose from liver, protecting against severe hypoglycemia
 GH and cortisol decrease rate of glucose utilization by most cells of body, converting to fat utilization

Glucose is only nutrient that normally can be used by brain, retina, and germinal epithelium of gonads in
sufficient quantities to supply them optimally with required energy
o Most of glucose formed by gluconeogenesis during interdigestive period used for metabolism in brain
 Important that blood glucose concentration not rise too high because
o Glucose can exert large amount of osmotic pressure in extracellular fluid, causing cellular dehydration
o Excessively high blood glucose causes loss of glucose in urine
o Loss of glucose in urine causes osmotic diuresis by kidneys, which can deplete body of fluids and
electrolytes
o Long-term increases in blood glucose may cause damage to many tissues, especially blood vessels
(increased risk for MI, stroke, renal disease, and blindness)
Diabetes Mellitus
 DM – syndrome of impaired carb, fat, and protein metabolism caused by either lack of insulin secretion or
decreased sensitivity of tissues to insulin
 Type I diabetes – can be caused by viral infections or autoimmune disorders involved in destruction of beta cells
o Usual onset of type I diabetes around 14 years of age, but can occur at any age
o Onset characterized by increased blood glucose, increased utilization of fats for energy and for
formation of cholesterol by liver, and depletion of body’s proteins
 High blood glucose causes more glucose to filter into renal tubules than can be reabsorbed, and excess glucose
spills into urine
 Very high levels of blood glucose can cause severe cell dehydration throughout body; glucose doesn’t diffuse
easily through pores of PM, and increased osmotic pressure in extracellular fluids causes osmotic transfer of
water out of cells
 Loss of glucose in urine causes osmotic diuresis; osmotic effect of glucose in renal tubules greatly decreases
tubular reabsorption of fluid, so massive loss of fluid in urine, causing dehydration of extracellular fluid, which
causes compensatory dehydration in intracellular fluid
 Peripheral neuropathy and autonomic nervous system dysfunction – frequent complications of chronic,
uncontrolled DM
o Can result in impaired cardiovascular reflexes, impaired bladder control, decreased sensation in
extremities, and other symptoms of peripheral nerve damage
 Hypertension secondary to renal injury and atherosclerosis secondary to abnormal lipid metabolism amplify
tissue damaged caused by elevated glucose
 Shift from carb to fat metabolism increases release of ketoacids more rapidly than they can be taken up and
oxidized by tissue cells, resulting in severe metabolic acidosis from excess ketoacids in association with
dehydration due to excessive urine formation
o Symptoms include deep rapid breathing, which causes increased expiration of CO2 to buffer acidosis, but
also depletes extracellular fluid of bicarb stores, so kidneys compensate by decreasing bicarb excretion
and generating new bicarb, which is added back to extracellular fluid
 Excess fat utilization in liver over long time causes large amounts of cholesterol in circulating blood and
increased deposition of cholesterol in arterial walls, leading to severe arteriosclerosis and other vascular lesions
 Failure to use glucose for energy leads to increased utilization and decreased storage of proteins and fat; patient
suffers rapid weight loss and asthenia despite eating large amounts of food
 Type II diabetes – often occurs between ages 50-60; develops gradually; obesity is most important risk factor
o Associated with hyperinsulinemia as compensatory response for diminished sensitivity of target tissues
to metabolic effects of insulin
o Impairs carb utilization and storage, raising blood glucose and stimulating compensatory increase in
insulin secretion
o Most of insulin resistance caused by abnormalities of signaling pathways that link receptor activation
with multiple cellular effects; impaired insulin signaling related to toxic effects of lipid accumulation in
tissues such as skeletal muscle and liver secondary to excess weight gain
o Can also occur as result of acquired or genetic conditions that impair insulin signaling
 Metabolic syndrome – obesity (especially abdominal fat), insulin resistance, fasting hyperglycemia, lipid
abnormalities (increased blood triglycerides and decreased blood HDL), and hypertension; closely related to
accumulation of excess adipose tissue in abdominal cavity around visceral organs
o Major adverse effect is cardiovascular disease (atherosclerosis)
o Increased risk for insulin resistance, which predisposes to development of type II DM
 Polycystic ovary syndrome (PCOS) associated with marked increases in ovarian androgen production and insulin
resistance; insulin-resistance and hyperinsulinemia found in 80% of patients
 Excess formation of glucocorticoids (Cushing’s syndrome) or GH (acromegaly) decreases sensitivity of various
tissues to metabolic effects of insulin and can lead to development of DM
 With prolonged and severe insulin resistance, even increased levels of insulin not sufficient, and moderate
hyperglycemia occurs after ingestion of carbs in early stages of disease
o In later stages of type II DM, pancreatic beta cells become exhausted or damaged and are unable to
produce enough insulin to prevent more severe hyperglycemia, especially after carb-rich meal
o Genetic factors play role in whether type II diabetes ever turns to low insulin secretion
o Effectively treated in early stages with exercise, caloric restriction, and weight reduction
o Drugs that increase insulin sensitivity (TZDs), drugs that suppress liver glucose production (metformin),
or drugs that cause additional release of insulin by pancreas (sulfonylureas) may be used
o In later stages of type II DM, insulin administration usually required to control plasma glucose
 Can frequently make diagnosis of type I DM by smelling acetone on breath of patient; ketoacids can be detected
by chemical means in urine
o In early stages of type II DM, ketoacids not produced in excess amounts; when insulin resistance
becomes severe and there is greatly increased utilization of fats for energy, ketoacids can be formed
 Patients given long-lasting insulin as once-daily to maintain basal level and additional quantities of regular
insulin during mealtimes
o Human insulin produced by recombinant DNA widely used because some patients develop immunity
and sensitization against animal insulin, limiting its effectiveness
 Diabetics, mainly because of high levels of circulating cholesterol and other lipids, develop atherosclerosis,
arteriosclerosis, severe coronary heart disease, and multiple microcirculatory lesions far more easily than
normal people
o Limiting carbs in diet keeps blood glucose from increasing too high and attenuates loss of glucose in
urine, but doesn’t prevent abnormalities of fat metabolism
o Modern day treatment has patient eat normal diet and just use insulin to compensate for what they eat
o Because complications of diabetes (atherosclerosis, susceptibility to infection, diabetic retinopathy,
cataracts, hypertension, and chronic renal disease) closely associated with levels of blood lipids and
blood glucose, most physicians use lipid-lowering drugs to help prevent disturbances
Insulinoma – Hyperinsulinism
 Excessive insulin production from adenoma of islet of Langerhans; 10-15% malignant and metastases spread
throughout body, causing tremendous production of insulin by primary and metastatic cancers
 CNS normally derives essentially all energy from glucose metabolism, and insulin not necessary for CNS
 When blood glucose levels fall around 50-70 mg/dL, CNS usually becomes excitable because degree of
hypoglycemia sensitizes neuronal activity
o Sometimes hallucinations, but more often patient experiences nervousness, trembling, sweating
o As blood glucose falls to 20-50 mg/dL, clonic seizures and loss of consciousness likely
o As blood glucose levels fall farther still, seizures cease and only state of coma remains
 IV administration of large quantities of glucose usually brings patient out of shock in minutes
 Administration of glucagon (less effectively, epi) causes glycogenolysis in liver and increase blood glucose level
 If treatment not administered immediately, permanent damage to neuronal cells of CNS often occurs