Physiology Ch 78 939-954
Insulin, Glucagon, and Diabetes Mellitus
-Pancreas secretes insulin and glucagon for regulation of glucose, lipid, and protein metabolism
Physiologic Anatomy of Pancreas – pancreas consists of (1) acini, which secrete digestive juices
into duodenum, and (2) islets of Langerhans, which secrete insulin/glucagon into blood
-islets have 3 major cell types: alpha, beta, and delta
-beta cells are 60% of all islet cells and secrete insulin and amylin
-alpha cells are about 25% of total islet cells and secrete glucagon
-delta cells are about 10% of islets and secrete somatostatin
-PP cell is present in small numbers and secretes pancreatic polypeptide
-insulin inhibits glucagon, amylin inhibits insulin, and somatostatin inhibits both insulin/glucagon
Insulin is a Hormone Associated with Energy Abundance – where there is great abundance of
energy-giving foods in diet, especially excess carbohydrates, insulin secretion increases
-insulin plays a role in storing energy, such as carbohydrates  glycogen in liver/muscle
-those carbs that cannot be stored are converted to fatty acids and stored in adipose
-insulin stimulates amino acid uptake by cells and conversion into protein/inhibits breakdown
Insulin Chemistry and Synthesis – composed of 2 chains linked by disulfide bonds; if split apart,
functional insulin molecule is lost
-synthesized in beta cells by ribosomes attached to rER to form preproinsulin, which is cleaved
in the ER to form proinsulin (3 peptide chains A, B, C)
-further cleaved in golgi to form insulin (composed of A and B chain, connected by the
connecting peptide (C chain))
-proinsulin and C peptide have no insulin activity, but C peptide can bind G protein coupled
receptor to activate it and activates Na/K ATPase and endothelial nitric oxide synthase
-measurement of C peptide can be used to determine how much natural insulin diabetic
patients are receiving
-insulin circulates in unbound form (half-life of 6 minutes), degraded by insulinase in liver
Activation of Target Cell Receptors by Insulin – insulin binds membrane receptor to activate it
-insulin receptor has 4 subunits, 2 alpha subunits (outside of membrane) and 2 beta subunits
that penetrate the membrane into cytoplasm
-insulin binds alpha subunits, and beta subunits become autophosphorylated (enzyme-linked
receptor)
-autophosphorylation activates tyrosine kinase causes phosphorylation of downstream
enzymes called insulin-receptor substrates (IRS)
End effects of insulin stimulation are:
1. 80% of body’s cells increase uptake of glucose (very true in muscle/adipose), NOT true
in brain; glucose is phosphorylated for glycolysis. Increased glucose transport attributed
to translocation of vesicles containing glucose transport proteins
2. membrane becomes permeable to amino acids, K ions and PO4 ions, internalizing them
3. slower effects occur during next 15min to change activity levels of more metabolic
enzymes
4. much slower effects continue to occur for hours resulting from changed rates of mRNA
to ribosomes to form new proteins
Effect of Insulin on Carbohydrate Metabolism – right after high-carb meal, glucose absorbed
into blood causes rapid insulin secretion to cause uptake, storage, and use of glucose
-Insulin Promotes Muscle Glucose Uptake and Metabolism – throughout day, muscle depends
on fatty acids for energy and not glucose, because normal resting muscle membrane is only
slightly permeable to glucose, except when stimulated by insulin
-during exercise, muscles become more permeable to glucose in ABSENCE of insulin
-muscles also use a lot of glucose right after a meal; when blood glucose is high, pancreas
secretes insulin to cause rapid transport of glucose into muscle, where it uses it over fatty acids
-Storage of Glycogen in Muscle – if glucose is transported into muscle at rest, most of the
glucose is stored as glycogen instead of being used, and can later be used for energy – useful for
spurts of anaerobic energy for a few minutes at a time by glycolytic breakdown
-Quantitative Effect of Insulin to Assist Glucose Transport Through Muscle Membrane –
without insulin, glucose concentration in muscle stays at 0 despite extracellular glucose
concentration increases. Intracellular glucose rises dramatically when stimulated by insulin
-Insulin Promotes Liver Uptake, Storage, and Use of Glucose – MOST IMPORTANT effects of
insulin is to cause glucose absorption by liver and storage as glycogen immediately after meal
-when food is not available, insulin secretion decreases rapidly and liver glycogen is split
to glucose, which is released into blood to keep blood glucose from falling too low
Mechanism of glucose uptake in liver due to insulin (net effect is to INCREASE GLYCOGEN):
1. Insulin inactivates liver phosphorylase, the enzyme that breaks down liver glycogen
2. Insulin causes enhanced uptake of glucose from blood by increasing activity of
glucokinase, which is the first initial phosphorylation step of glucose after it diffuses in,
trapping glucose inside the cell
3. Insulin increases activities of enzymes to promote glycogen synthesis (glycogen
synthase) responsible for polymerizing glycogen
4.
-Glucose is released from liver between meals – when blood glucose falls in between meals,
liver releases glucose back through:
1. decreasing blood glucose causes insulin secretion by pancreas to decrease
2. lack of insulin reverses all effects on glycogen storage to stop its synthesis
3. lack of insulin activates phosphorylase  splits glycogen to glucose phosphate
4. glucose phosphatase (first inhibited by insulin) is activated and forms free glucose from
glucose phosphate; thus liver removes glucose from blood when it is in excess, and returns it to
blood when glucose levels in blood fall
-Insulin promotes conversion of excess glucose into fatty acids and inhibits gluconeogenesis in
liver - when quantity of glucose entering liver is more than can be stored as glycogen or used,
insulin promotes conversion of excess glucose  fatty acids, which are packaged into
triglycerides in VLDLs and transported by blood to adipose
-insulin inhibits gluconeogenesis – by decreasing quantities/activities of gluconeogenic enzymes
and decreases availability of precursors such as amino acids from muscle
Lack of effect of Insulin on Glucose Uptake and Usage by the Brain – most of the brain cells are
permeable to glucose and can use it without needing insulin; difficult for brain to use other
forms of energy; low blood glucose can cause hypoglycemic shock characterized by coma,
fainting, seizures, nervous irritability
Effect of Insulin on Carbohydrate Metabolism in Other Cells – insulin increases glucose
transport and usage by most other cells except brain; provides glycerol for fats
Effect of Insulin on Fat Metabolism – insulin lack can cause atherosclerosis  heart attacks
-Insulin promotes fat synthesis and storage – insulin increases utilization of glucose by body’s
tissues and decreases utilization of fat to spare it; but insulin promotes fatty acid synthesis when
there is excessive carbohydrate
-most occurs in liver cells, and transported by lipoproteins to adipose cells
1. Insulin increases transport of glucose into liver cells – once glycogen reaches its max, any
additional glucose becomes available to form fat; it splits to pyruvate  acetyl CoA
2. excess of citrate and isocitrate ions is formed by TCA cycle when excess amounts of glucose
are being used for energy – these ions directly activate acetyl-CoA carboxylase, the enzyme
required to form malonyl-CoA from Acetyl-CoA, the first step in fatty acid synthesis
3. most of fatty acids are synthesized in liver and form triglycerides; released from liver on
lipoproteins
-insulin activates lipoprotein lipase in capillary walls to split triglycerides into fatty acids
for adipose absorption of them
-Role of Insulin in Storage of Fat in Adipose Cells – insulin INHIBITS action of hormone-sensitive
lipase, which normally causes hydrolysis of triglycerides stored in fat cells, therefore release of
fatty acids into blood is inhibited.
-also, insulin promotes glucose transport through cell membrane of fat cells which
forms large quantities of α-glycerol phosphate that supplies glycerol that combines with
fatty acids to form triglycerides in the storage form of fat
Insulin Deficiency Increases Use of Fat for Energy -insulin deficiency causes lipolysis of storage fat and release of free fatty acids
-enzyme hormone-sensitive lipase is no longer inhibited, becomes activated to
hydrolyze triglycerides and release fatty acids + glycerol into blood; fatty acids are then
used by tissues in body for energy except the brain
-immediately after insulin removal, free fatty acid concentration begins to rise more
rapidly than glucose
Insulin Deficiency Increases Plasma Cholesterol and Phospholipid Concentrations – increased
fatty acid concentration in the blood associated with insulin deficiency causes liver conversion of
fatty acids into phospholipids and cholesterol, which are discharged into blood on lipoproteins
Excess usage of fats during insulin lack causes ketosis and acidosis – lack of insulin causes
excessive amounts of acetoacetic acid to be formed in liver due to the following effect
-in absence of insulin but presence of fatty acids, carnitine transport mechanism for
transporting fatty acids into mitochondria becomes increasingly activated, where betaoxidation occurs releasing high amounts of acetyl-CoA
-acetyl-CoA is condensed to form acetoacetic acid, which is released from liver
and can be converted into beta-hydroxybutyric acid and acetone, those three
substances are called ketone bodies, and presence of them in fluids is called
ketosis, which can cause severe acidosis in diabetic patients
Effect of Insulin on Protein Metabolism and on Growth –
-insulin promotes protein synthesis and storage – insulin is required after a meal to store
proteins, carbs, and fats in tissues
1. insulin stimulates transport of many amino acids into cells (V, L, I,Y, and F)
2. insulin increases translation of mRNA to form new proteins
3. insulin increases rate of transcription of selected DNA sequences for protein storage
4. insulin inhibits catabolism of proteins to decrease amino acid release from cells
5. in liver, insulin depresses rate of gluconeogenesis, which conserves AA in protein stores
-insulin deficiency causes protein depletion and increased plasma amino acids – protein
storage stops when insulin is not available; catabolism of proteins increases, synthesis stops and
amino acids are dumped into plasma and excess amino acids are used directly for energy
-degradation of amino acids leads to increased urea excretion, and protein wasting is
most serious consequence of diabetes mellitus
-Insulin and GH interact synergistically to promote growth – insulin required for protein
synthesis and is essential for growth of person similar to growth hormone
-administration of either GH or insulin alone does not increase growth, but together the
hormones cause dramatic growth
Mechanisms of Insulin Secretion – pancreatic beta cells have large numbers of glucose
transporters (GLUT2) that permit rate of glucose influx proportional to blood glucose
1. once inside cell, glucose is phosphorylated to G-6-P by glukokinase (rate limiting step)
2. G6P is oxidized to ATP, which inhibits ATP-sensitive K+ channels, which depolarize
membrane to open voltage-gated Ca channels
3. Influx of Ca causes fusion of docked-insulin containing vesicles to cell membrane
4. Amino acids can also be metabolized by beta cells to increase intracellular ATP and
stimulate insulin secretion
5. Hormones such glucagon, gastric inhibitory peptide, and acetylcholine increase
intracellular calcium and enhance glucose’s effect, but do not work without glucose
a. Epinephrine/norepinephrine INHIBIT insulin exocytosis
6. Sulfonylurea drugs stimulate insulin secretion by binding to ATP-sensitive K channels to
block their activity
Control of Insulin Secretion – factors affecting insulin secretion:
Increase secretion: blood glucose, fatty acids, AA, gastrin, CCK, secretin, gastric inhibitory
peptide, glucagon, GH, cortisol, acetylcholine, B-adrenergic stimulation, obesity, glyburide
Decrease secretion: decreased blood glucose, fasting, somatostatin, alpha-adrenergic, leptin
Increased blood glucose stimulates insulin secretion – at fasting level of 80-90mg/100mL, rate
of insulin is minimal; if glucose is suddenly increased, insulin secretion increases in 2 stages:
1. plasma concentration of insulin increases 10x within 3-5min after acute glucose
elevation due to immediate dumping of insulin from stored vesicles, but then it
decreases again from 5-10 min
2. at about 15min, insulin secretion rises again to reach plateau after 3 hours results from
new synthesis of insulin hormone
Feedback relation between blood glucose concentration and insulin secretion rate – insulin
rises rapidly to increased blood glucose and falls within 3-5 minutes of drop in blood glucose, so
any rise in blood glucose will immediately increase insulin to transport glucose into tissues
Other factors that Stimulate Insulin Secretion –
1. Amino Acids – most potent are arginine and lysine, which can cause mild increase in
insulin secretion on their own, but when administered with glucose, insulin is doubled
compared to glucose alone, thus amino acids strongly potentiate glucose stimulus
a. In effect, insulin helps to transport AA into cells for protein formation
2. GI Hormones – gastrin, secretin, CCK, glucose-dependent insulinotrophic peptide (most
potent) all cause insulin secretion and are released into GI tract after meal
a. Cause anticipatory increase in insulin in preparation for increase in blood
glucose and amino acids, and act same as AA to increase sensitivity of insulin
response to blood glucose
3. Other Hormones – glucagon, GH, cortisol, progesterone and estrogen all either directly
increase insulin secretion or potentiate glucose stimulus for insulin secretion; prolonged
secretion of any of these can lead to exhaustion of beta cells and increase risk for
developing diabetes mellitus
a. Diabetes is common in giants or acromegalic people with GH-tumors
Role of Insulin in Switching Between Carb and Lipid Metabolism – signal that controls switching
between carb and lipid metabolism is blood glucose concentration; when glucose is low, insulin
is suppressed and fat is used exclusively for energy except in brain
-when glucose is high, insulin is stimulated and carb is used instead of fat
-most important function of insulin in body is to control which of these two foods will be used
by cells for energy
-GH, cortisol, epinephrine, and glucagon play a role in switching
-GH and cortisol are secreted during hypoglycemia to inhibit cell utilization of glucose
-epinephrine increases plasma glucose during times of stress, but also increases plasma
fatty acid; reasons for these effects are:
1. epinephrine induces glycogenolysis in the liver released with glucose in blood
2. direct lipolytic effecton adipose cells because it activates hormone-sensitive
lipase to enhance blood fatty acids as well
Glucagon and Its Functions – secreted by alpha cells in islets of Langerhans, and opposes
insulin’s functions to increase blood glucose concentration; called hyperglycemic hormone
Effects on Glucose Metabolism – breakdown of liver glycogen, increased liver gluconeogenesis
Glucagon causes glycogenolysis and increased blood glucose concentration – most dramatic
effect of glucagon, occurs in several steps:
Glucagon activates adenylyl cyclase to form cAMP  activates protein kinase regulator protein
 protein kinase  phosphorylase B kinase, converting phosphorylase B  phosphorylase a
which promotes degradation of glycogen into glucose-1-phosphate  which is
dephosphorylated and glucose is released from liver cells
-all of this happens in an amplifying mechanism, and explains why only a little bit of glucagon
can elicit a huge effect
Glucagon Increases Gluconeogenesis – glucagon increases rate of amino acid uptake by liver
and converts them to glucose by gluconeogenesis, especially by activating enzyme system for
converting pyruvate  phosphoenolpyruvate
Other Effects of Glucagon – in high concentrations, glucagon activates adipose cell lipase,
making fatty acids available to energy systems of body; glucagon inhibits storage of triglycerides
in liver, which prevents liver from removing fatty acids from blood
-in high concentrations, it enhances strength of heart, increases blood flow to tissues, enhances
bile secretion, and inhibits gastric acid secretion
Regulation of Glucagon Secretion
-Increased Blood Glucose Inhibits Glucagon Secretion – most potent factor controlling glucagon
secretion, opposite to effect on insulin; decrease in glucose increases glucagon severalfold, and
opposite is true as well; in hypoglycemia, glucagon is secreted in large amounts to increase
output of glucose from liver
-Increased Blood AA Stimulates Glucagon Secretion – high AA after protein meal
(alanine/arginine), STIMULATE glucagon, the same way that amino acids stimulate insulin, so in
this case, insulin and glucagon responses are not opposites
-glucagon promotes rapid conversion of amino acids to glucose
-Exercise Stimulates Glucagon Secretion – blood concentration of glucagon increases
severalfold during exercise
-Somatostatin Inhibits Glucagon AND Insulin Secretion – DELTA cells of pancreas secretes
somatostatin (3min half life) into blood; all factors related to ingestion of food stimulate
somatostatin secretion: increased blood glucose, increased amino acids, increased fatty acids,
and increased concentrations of GI hormones
-somatostatin acts locally within islets to depress insulin/glucagon
-somatostatin decreases motility of stomach, duodenum, and gallbladder
-somatostatin decreases secretion and absorption from GI tract
-somatostatin extends period of time over which food nutrients are assimilated into blood, and
also prevents rapid exhaustion of food/making it available for a long time by inhibiting
insulin/glucagon
-somatostatin also inhibits growth hormone secretion
Summary of Blood Glucose Regulation – glucose normally kept between 80-90mg/100ml and
increases to 120-140 after a meal
1. liver functions as an important blood glucose buffer – when blood glucose rises, insulin
is secreted and glucose goes to the liver to synthesize glycogen, then when blood
glucose falls, glycogen breaks down to release glucose back into the blood
2. Insulin and glucagon function as important feedback control systems for maintaining a
normal blood glucose concentration – when glucose is too high, insulin secretion causes
concentration to decrease toward normal, converse is true with glucagon; insulin much
more important than glucagon (which is important during starvation)
3. Severe hypoglycemia causes direct effect of low glucose on hypothalamus to stimulate
sympathetics, where epinephrine secreted by adrenal glands increases release of
glucose from liver and protects against severe hypoglycemia
4. Both GH and cortisol are secreted in response to severe hypoglycemia and decrease rate
of glucose utilization by cells converted instead to fat utilization to maintain blood
glucose
Importance of Blood Glucose Regulation – glucose is the only nutrient that normally can be
used by brain, retina, and germinal epithelium of gonads to supply them with sufficient energy
-most of the glucose formed by gluconeogenesis is used by the brain, when pancreas does not
secrete any insulin
-blood glucose shouldn’t rise for 4 reasons:
1. glucose can increase osmotic pressure in extracellular fluid and can cause dehydration
2. high blood glucose causes loss of glucose in urine
3. glucose in urine causes osmotic diuresis which depletes body of fluids/electrolytes
4. long term increases in glucose can damage tissues, especially blood vessels
Diabetes Mellitus – syndrome of impaired carb, fat, protein metabolism caused by lack of
insulin secretion or decreased sensitivity of tissues to insulin. Two types of diabetes mellitus
1. Type I – insulin-dependent diabetes caused by lack of insulin secretion
2. Type II – non-insulin dependent, caused by decreased sensitivity of tissues to insulin
-basic effect of insulin resistance is to prevent efficient uptake and utilization of glucose by most
cells except brain
Type I Diabetes – injury to beta cells or insulin impairment diseases cause type I diabetes, in
addition to viral infections or autoimmune disorders; onset occurs around 14 years old, also
called juvenile onset diabetes mellitus, but can occur at any age; 3 principal issues:
-(1) increased blood glucose, (2) increased utilization of fats for energy, (3) depletion of
body proteins
-blood glucose rises to high levels – lack of insulin decreases peripheral glucose utilization to
raise blood glucose to 300-1200mg/100ml
-increased blood glucose causes loss of glucose in urine – more glucose is filtered into renal
tubules than can be reabsorbed, and so glucose spills over when concentration rises above
180mg/100mL (Threshold for glucose in urine)
-Increased blood glucose can cause dehydration – because glucose does not diffuse easily
through pore of membrane, an increased osmotic pressure in extacellular fluids causes osmotic
transfer of water out of cells
-causes osmotic diuresis where glucose is excreted in urine and excretes water with it to
dehydrate the body
-FIRST CLASSIC SYMPTOM OF DIABETES is intra/extracellular dehydration and thirst
Chronic high glucose concentration causes tissue injury – blood vessels begin to function
abnormally when glucose is poorly controlled, and they undergo structural changes which result
in inadequate blood supply leading to stroke, MI, kidney disease, retinopathy, and gangrene
-high glucose can cause peripheral neuropathy (abnormal function of nerves) and autonomic
nervous system dysfunction
-hypertension, secondary to renal injury and atherosclerosis secondary to impaired renal
metabolism develops in patients
-Diabetes causes increased utilization of Fats and Metabolic Acidosis – shift of carbs to fat
metabolism in diabetes increases release of keto acids (acetoacetic acid and B-hydroxybutyric
acid) more rapidly than can be taken up by tissues, and so patients develop metabolic acidosis
from excess keto acids, leading to diabetic coma
-diabetic acidosis causes rapid/deep breathing, which causes increased expiration of
CO2 and depletes fluid HCO3 stores; kidneys compensate by decreasing HCO3 excretion
and generating new HCO3 added back to fluid
-extreme acidosis occurs only in uncontrolled diabetes, causing acidotic coma and death
-excess fat utilization in liver over long time causes cholesterol in circulating blood and increases
deposition of cholesterol in arterial walls leading to atherosclerosis
Diabetes causes depletion of body’s proteins – failure to use glucose leads to increased
utilization and decreased storage of body’s proteins and fat, so diabetic can suffer rapid weight
loss and asthenia (lack of energy) while eating large amounts of food
Type II Diabetes – Resistance to Metabolic Effects of Insulin – Type II diabetes is more common
than type I, occurs after age 30, called adult-onset diabetes; related to obesity, an important risk
factor for type II diabetes
Obesity, insulin resistance, and metabolic syndrome precede type II diabetes – type II diabetes
is associated with increased plasma insulin (hyperinsulinemia) because of a compensatory
response by pancreatic beta cells for diminished sensitivity of target tissues to metabolic effects
of insulin (insulin resistance), raising blood glucose and stimulates insulin secretion
-insulin resistance is a gradual process beginning with weight gain and obesity; studies suggest
there are a decreased number of insulin receptors in skeletal muscle, liver and adipose in obese
people; most of the insulin resistance occurs from abnormalities of signaling pathways that link
receptor activation
-insulin resistance is part of disorders called metabolic syndrome characterized by:
(1) Obesity, (2) insulin resistance, (3) fasting hyperglycemia, (4) lipid abnormalities such
as increased triglycerides and decreased blood HDLs, (5) hypertension
-major adverse consequence of metabolic syndrome is cardiovascular disease
-Other factors causing insulin resistance and type II diabetes – can occur due to other factors:
Polycystic ovary syndrome – increases in ovarian androgen production and insulin resistance, is
most common endocrine disorder in women, causing hyperinsulinemia and insulin resistance
-Cushing’s Syndrome - through excess glucocorticoid formation or growth hormone, decreases
sensitivity of tissues to metabolic effects of insulin and can lead to diabetes type II
Development of Type II Diabetes During Prolonged Insulin Resistance – in early stages of
disease, hyperglycemia occurs even with increased insulin production, and in late stages, beta
cells are exhausted/damaged and cannot produce enough insulin to prevent hyperglycemia,
especially during protein-rich meal
-can be treated with exercise, caloric restriction, and weight reduction; drugs that increase
sensitivity to insulin are thiazolidinediones, drugs that suppress liver glucose production
(metformin), or drugs that increase insulin production (sulfonylureas)
Physiology of Diagnosis of Diabetes Mellitus – uses various chemical tests
1. urinary glucose – normal person loses undetectable amounts of glucose, person with
diabetes loses glucose proportional to stage of disease
2. fasting blood glucose and insulin levels – fasting blood glucose level above
110mg/100mL often indicates insulin resistance and diabetes
a. type I diabetics show low plasma insulin even after a meal, in type II, insulin may
be increased severalfold
3. Glucose tolerance test – in normal person, ingesting 1g glucose makes blood levels rise
to 120-140mg/100mL and falls in 2 hours. In a diabetic person, fasting levels are always
above 110mg/100mL and glucose tolerance test is always abnormal, causing much
greater rise in glucose and much slower fall, due to abnormal insulin secretion after
glucose ingestion OR there is a decreased sensitivity to glucose
4. Acetone Test – small quantities of acetoacetic acid in blood are converted to acetone
and vaporized into expired air, and can be smelled in the breath
Treatment of Diabetes – type I requires administration of enough insulin so that the patient will
have normal physiology
-several types are available: regular insulin lasts 3-8 hours whereas other forms last 1048 hours because they are absorbed slowly
-in type II diabetes, diet and exercise are recommended to induce weight loss and reverse
insulin resistance
Relation of Treatment to Arteriosclerosis – because of high levels of circulating cholesterol and
lipids, diabetic patients develop arteriosclerosis, atherosclerosis, coronary artery disease, and
multiple microcirculatory lesions more easily than normal people
Insulinoma – Hyperinsulinism – excessive insulin production can occur from an adenoma of
islets of Langerhans; 10-15% are malignant and metastases can occur
-Insulin shock and hypoglycemia – CNS derives its energy from glucose metabolism, and insulin
is not necessary for using this glucose
-if insulin levels rise, the low blood glucose causes CNS depression which can cause
insulin shock; when blood glucose falls to 50-70mg/100mL, CNS is excitable because this
degree of hypoglycemia sensitizes neurons and can cause hallucinations, tremors,
sweating
-at levels of 25-50mg/100mL,, seizures and loss of consciousness occurs, and coma
-treatment is administration of large amounts of glucose, which brings patient out of
shock within a minute, also administration of glucagon