Glucose Metabolism and Diabetes

Glucose Metabolism & Diabetes

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Glucose Metabolism & Diabetes
How does diabetes disrupt the homeostatic levels of glucose in the blood?
THE PANCREAS: Structure
• The pancreas is approximately 20 cm (8 in) and weighs about 80g (3 oz)
• The pancreas has two major types of tissues: the acini (secrete digestive juices
to duodenum) and the islets of Langerhans (secrete insulin and glucagon
directly into blood)
• Human pancreas has 1 – 2 million islets of 0.3 mm in diameter, although the
islets account for only about 1% of the pancreatic cell population

Note :
• Hyperglycemia, or high blood sugar: is a condition in which an excessive amount
of glucose circulates in the blood plasma.
• Hypoglycemia, also known as low blood sugar: is when blood sugar decreases to
below normal levels.
• Glycosuria or glucosuria: is the excretion of glucose into the urine.

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THE PANCREAS: Structure/Function
♦ Alpha cells secrete glucagon
• elevates blood glucose concentrations
♦ Beta cells secrete insulin
• reduces blood glucose concentrations
♦ Delta cells secrete somatostatin
• slows the rate of food absorption and
digestive enzyme secretion
♦ F cells/PP cells secrete pancreatic polypeptide
• Close interrelation among various cell types allow regulation of secretion of some
hormones by other hormones:
• insulin inhibits glucagon secretion, somatostatin inhibits insulin and glucagon
secretion

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THE PANCREAS: Structure

• Islets of Langerhans contain 3 types of hormone-secreting cells
Alpha cells (25%) Beta cells (60%)
Delta cells (10%) F cells (PP cells) (5%)

• The islets are organized around small capillaries into which the cells secrete their
hormones
PART II
HOW DO THE LIVER & PANCREAS ALLOW US TO UTILIZE THE
NUTRIENTS WE CONSUME?
Glucose: the preferred nutrient
• Carbohydrates are the preferred source of energy for the body.
• Final products of carbohydrate digestion in the digestive tract are
monosaccharides (glucose [80%], fructose and galactose)
• Much of fructose and all galactose are converted to glucose in the liver and
released back into the blood.
• Glucose is a large molecule that must be broken down into a form of energy
usable by the cell (ATP).

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Glucose Metabolism
• Intracellular glucose metabolism involves four pathways: Krebs cycle and oxidative
phosphorylation that occur in mitochondria, and pentose phosphate pathway and glycolysis that
take place in cytoplasm

♦ The process of glucose metabolism involves
• 1) Glycolysis.
• 2) The citric acid cycle (Krebs cycle) (Tricarboxylic acid (TCA) cycle).
• 3) Electron transport (Oxidative phosphorylation).
♣ Glycolysis occur in cytoplasm.
♣ Krebs cycle & Electron transport in mitochondria.
♣ Complete reaction:
C6H12O6 + 6O2 6CO2 +
6H2O + 36ATP
• Net gain = 36 ATP

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• Only 40% of the energy released through catabolism of glucose is captured in
ATP.
• The remaining 60% escapes as heat that warms the interior of the cells and the
surrounding tissues.
• If cells have inadequate amounts of glucose to catabolize, the immediately shift
to the catabolism of fats for energy.
♣ In starvation, proteins are used for energy after carbohydrate and fats are depleted.

◘ REGULATION OF NUTRIENTS
• Insulin regulates the uptake of nutrients into the cells, the storage of nutrients not
being used, and the conversion of one nutrient type to another.

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Metabolic Efficiency: Glucose
• Cells rely on insulin for efficient absorption of glucose from the blood (except
brain cells)
• Insulin also enhances ATP production
• Without insulin not enough glucose is supplied to tissues for energy metabolism
♦ Insulin & its chemistry
• Insulin is a small protein (MW of human insulin 5808) composed of two amino
acid chains connected by two disulfide linkages.
• Secreted by beta cells, insulin
circulates in blood in unbound
form.
• It has a plasma half-life of about
6 min and is cleared from
circulation in 10 – 15 min
• Insulin not combined with receptors
• In target cells are degraded by
o insulinase -mostly in liver and
also in kidneys and muscles
• Connecting peptide (white)
o joins the two chains
♦ INSULIN MOLECULE
Protein of 21 amino acid A chain and 30 amino acid B chain, Disulfide linkages

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♦ Mechanism of Action of Insulin:
• The insulin receptor is a combination of 4 subunits held together by disulfide
linkages: two -subunits lying outside the cell membrane and two -subunits
protruding into the cell cytoplasm.
• When insulin binds to the -subunit in target
tissues, the -subunits in turn become activated.
• Activation of the -subunits triggers a series
of reactions that draw the glucose transporter
to the cell membrane.
• Cells (liver, muscle, adipose, but not brain)
are now able to increase their uptake of
glucose (w/in seconds after insulin binds
with its membrane).
• The cell membrane also becomes more
permeable to many amino acids.

Mechanism of Action of Insulin

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Insulin: Glucose Storage
• Only enough ATP for immediate cellular requirements is made at any one time
• Glucose that is NOT needed for ATP is ANABOLIZED into glycogen and
stored for later use in the liver and in muscles.
• GLYCOGENESIS : synthesis of glycogen from glucose molecules
• Insulin:
– stimulates glycogenesis (glycogen anabolism)
– inhibits glycogenolysis (glycogen catabolism)
Why is glucose stored as glycogen?
• Glucose is in liquid form.
• As the number of glucose molecules increases, the pressure inside the cell
increases.
• Converting glucose to glycogen (in solid form) relieves pressure inside the cell.
Glucose Conversion to Fat
• Excess glucose is preferentially stored as glycogen but
• When cells are saturated with glycogen (liver cells store 5 to 8% of their weight
as glycogen, muscle cells 1 to 3%) additional glucose is converted
to fat in the liver and stored as fat in adipose cells.

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Insulin: Glucose>>Fat Storage
• Insulin promotes the conversion of all excess glucose in liver that cannot be
stored as glycogen into fatty acids
• Fatty acids are packaged as triglycerides in low density lipoproteins transported
by blood to adipose tissue
• Insulin activates lipoprotein lipase in the capillary walls of adipose tissue, which
splits triglycerides into fatty acids.
• This enables them to be absorbed into adipose cells where they are converted
again to triglycerides and stored.
Insulin: Protein Metabolism
• Insulin (like growth hormone) stimulates transport of amino acids into cells.
• Insulin increases the translation of messenger RNA, thus forming new proteins.

Insulin: Protein & Fat Metabolism
• Insulin and growth hormone interact synergistically to promote growth
• Insulin stimulates the absorption of fatty acids and glycerol by adipocytes, where
they are stored as triglycerides.

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Summary: Metabolic Effects of Insulin
• Increases rate of glucose transport into
target cell
• Increases rate of glucose utilization and
ATP formation
• Increases conversion of glucose to glycogen
(liver, skeletal muscle)
• Increases amino acid absorption and protein
synthesis
• Increases triglyceride synthesis (adipose
tissue)
*DECREASES HIGH BLOOD GLUCOSE
LEVELS*
(Insulin is anabolic hormone)



THE REGULATION OF BLOOD GLUCOSE

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♣ …and LOW blood glucose…
• After the meal is over and blood glucose level begins to fall to a low level:
– The pancreas decreases insulin secretion
– Glycogen synthesis in liver is stopped
– Glucose uptake by liver from blood is prevented
If blood glucose levels continue to fall,
- GLUCAGON will increase the RELEASE of glucose from the cells.
- GLUCAGON is Catabolic hormone.
♣ …and for MORE glucose…
• GLUCAGON also causes:
– GLYCOGENOLYSIS: Breakdown of glycogen into glucose
– GLUCONEOGENESIS: Increase of synthesis of glucose from amino acids
and the glycerol portion of fat

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♣ FOR ADDITIONAL NUTRIENTS…
• GLUCAGON causes:
– LIPOLYSIS: Activation of adipose cell
lipase making fatty acids available for use
as energy source
• GLUCAGON is a large polypeptide composed of
a chain of 29 amino acids and has a molecular weight of 3485.
• Secreted by alpha cells.

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♦ Somatostatin
• A polypeptide with 14 amino acids with a 3
min half-life in blood.
• Same chemical substance as growth
hormone inhibitory hormone.
• Secreted by delta cells.
• All factors related to ingestion of food stimulate somatostatin secretion
• Somatostatin has many inhibitory effects:
- Depresses secretion of insulin and glucagon
- Decreases motility of stomach, duodenum and gallbladder
- Decreases secretion and absorption in GI tract
• It extends the period of time for assimilation of food
♦ Pancreatic Polypeptide
• Secreted by F cells
• Inhibits gallbladder contractions
• Regulates the production of some pancreatic enzymes
• May help control the rate of nutrient absorption by the digestive tract

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Part III
Diabetes: What’s the problem?
Review: Endocrine Effects of Insulin
Stimulates Inhibits
Liver Glycogenesis
triglyceride synthesis
Glycogenolysis
Ketogenesis
gluconeogenesis
Skeletal Muscle

glucose uptake
protein synthesis
glycogenesis
protein degradation
glycogenolysis
Adipose tissue

glucose uptake
triglyceride storage
lipolysis
Promotes anabolic
processes

Inhibits catabolic
processes

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Importance of Insulin
• Without insulin, glucose transport into the cells will be insufficient.
 Lacking glucose, cells will have to rely on protein and fat catabolism for fuel.
• Also, when there is not enough insulin, excess glucose cannot be stored in the
liver and muscle tissue.
 Instead, glucose accumulates in the blood-- above normal levels.

• The high concentration of glucose in the blood (resulting from the lack of insulin) is
called hyperglycemia, or high blood sugar.
♦ Blood Glucose
• Fasting blood glucose concentration (person who has not eaten in the past 3-4
hours)
– Normal person: 80 - 90 mg / 100 ml
– Diabetic patient: 110 - 140 mg / 100 ml
• After a meal:
– Normal person: 120 - 140 mg / 100 ml
– Diabetic patient: < 200 mg / 100 ml
EXCESS OF BLOOD GLUCOSE…
• Exerts high osmotic pressure in extracellular fluid,
causing cellular dehydration
• Excess of glucose begins to be lost from the body in the
urine: GLYCOSURIA
• Diabetes cause polyuria that lead to dehydration,
Glucose is diuretic.

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GLYCOSURIA
• Excessive glucose in the kidney filtrate
acts as an osmotic diuretic, inhibiting
water reabsorption resulting in
POLYURIA: huge urine output >>>
decreased blood volume and
dehydration.
• Dehydration stimulates hypothalamic
thirst centers, causing POLYDIPSIA:
excessive thirst.
OTHER SIDE EFFECTS of POLYURIA
• The dehydration resulting from polyuria also leads to dry skin.
• During a period of dehydration, blurred vision can be caused by fluctuations in
the amount of glucose and water in the lenses of the eyes.
POLYPHAGIA
• POLYURIA, POLYDYPSIA, & POLYPHAGIA = THE 3 CARDINAL SIGNS
OF DIABETES
• POLYPHAGIA: excessive hunger and food consumption, a sign that the person
is“starving in the land of plenty.”
• That is, although plenty of glucose is available, it cannot be used, and the cells
begin to starve.
• Without fuel, cells cannot produce energy >> fatigue and weight loss.

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Insulin deficiency >> metabolic use of FAT
• A deficiency of insulin will accelerate the breakdown of the body’s fat reserves
for fuel.
• Free fatty acids become the main energy substrate for all tissues except the brain.
• Increased lipolysis results in the production of organic acids called ketones
(KETOGENESIS) in the liver.
KETOGENESIS>>KETOSIS
• The increased ketones in the blood lower the pH
of blood, resulting in a form of acidosis called
KETOSIS, or ketoacidosis.
• Ketones are excreted in the urine: KETONURIA.
Complications of KETOSIS:
• Serious electrolyte losses also occur as the body rids itself of excess ketones.
• Ketones are negatively charged and carry positive ions out with them.
• Sodium and potassium are also lost from the body; because of the electrolyte
imbalance, the person get abdominal pains and may vomit, and the stress
reaction spirals even higher.
• Can result in coma, death

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Effects of insulin deficiency on metabolic use of fat

• Excess fat metabolism
- leads to an increase in plasma cholesterol >>> increased plaque formation on the
walls of blood vessels.
- Leads to atherosclerosis & other cardiovascular
- Problems: cerebrovascular insufficiency, ischemic heart disease, peripheral
vascular disease, and gangrene.
• Degenerative changes in cardiac circulation can lead to early heart attacks.
• Heart attacks are 3-5 times more likely in diabetic individuals than in nondiabetic
individuals.
• The most common cause of death with diabetes mellitus is myocardial infarction.

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♦ Other complications of diabetes:
• A reduction in blood flow to the feet can lead to
tissue death, ulceration, infection, and loss of toes or
a major portion of one or both feet.
• Damage to renal blood vessels can cause severe
kidney problems. (Nephropathy)
• Damage to blood vessels of the retina can also cause blindness. (Retinopathy)
Non-Proliferative Retinopathy

• Blood vessels in the retina leak and hemorrhage.
• Patient may notice a decrease in vision if the swelling and hemorrhage affect the
macula.
• Macula edema is the most common cause of visual loss in diabetic retinopathy.

Proliferative Retinopathy
New blood vessels grow in the eye.
These new blood vessels tend to bleed and leak causing vision loss.
These new blood vessels may also pull on the retina causing retinal detachment.

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Proliferative Diabetic Retinopathy

♦ Side Effects of Excess Sugar
• Loss of vision due to cataracts: Excessive blood sugar chemically attaches to lens
proteins, causing cloudiness.
• Skin infections sometimes occur because excess sugar
in the blood suppresses the natural defense mechanism
like the action of white blood cells.
• And sugar is an excellent food for bacteria for food to
grow in.
Periodontitis
• High blood glucose also helps bacteria in the mouth to grow,
making tooth and gum problems worse.
• Gingivitis: bacteria grow in the shallow pocket where the tooth
and gum meets; gum begins to pull away from the tooth.
Progresses to:
• Periodontitis: infection causes actual bone loss, teeth begin to
pull away from the jaw itself

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Latter Stages of Periodontitis
Damage to the Nerves
• Numbness and tingling in feet and night leg
cramps may result from nerve damage due to
prolonged high glucose levels that cause changes
in the nerves and “neuron starvation” from lack
of cellular glucose.
• Nerve damage can also lead to a loss of the
ability to feel pain in the feet, leading to undue
pressure>>calluses>> ulceration. (Neuropathy)
Diabetic Neuropathy
• Neuropathy can result in two sets of what appear to
be contradictory problems.
• Most patients who have neuropathy have one these problems but some can be
affected by both:
1) symptoms of pain, burning, pins and needles or numbness
which lead to discomfort
2) loss of ability to feel pain and other sensation which leads to
neuropathic ulceration

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• Patients with neuropathy lose their sensation of pain.
• As a result, they exert a lot of pressure at one spot under the
foot when they walk, building up a callus at that site without
causing discomfort.
• The pressure becomes so high that eventually it causes
breakdown of tissues and ulceration.
A TYPICAL NEUROPATHIC ULCER IS… Diabetic Neuropathy
1) PAINLESS
2) SURROUNDED BY CALLUS
3) ASSOCIATED WITH GOOD FOOT PULSES (BECAUSE THE CIRCULATION IS
NORMAL)
4) AT THE BOTTOM OF THE FOOT & TIPS OF TOES

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Glucose and insulin secretion

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GLUCOSE TOLERANCE
• Glucose tolerance is the body’s ability to manage its blood sugar level within
normal range.
• The Cori cycle is a strategy used by the body to accomplish this.
• The blood sugar of normal individuals can sometimes drop to the hypoglycemic
level.
– This can even be caused by ingesting too much sugar, triggering the release
of extra insulin.

TOO MUCH OF A GOOD THING…
• Diabetics use insulin injections to treat high blood glucose levels.
• It is essential that blood glucose levels always be maintained above a critical
level.
• Brain cells use only glucose for energy.
• When blood glucose levels fall too low (20 to 50 mg/ml), symptoms of
hypoglycemic shock develop – nervous irritability leading to
fainting, seizures and coma

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Part Iv
Diabetes:
Type I Vs. Type II
History of Diabetes Mellitus

The disease’s name was derived from two terms:
Diabetes– Greek for siphon or fountain for the characteristic frequent urination
Mellitus– Latin for sweet as honey. In 1679, a physician tasted the urine of a person
with diabetes and described as sweet like honey.

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TYPES OF DIABETES

♦ Classification of Diabetes Mellitus
Type 1 (previously called Type I; Insulin-dependent diabetes mellitus, IDDM,
juvenile diabetes) (Common in Children)
• Pathophysiology
– Immune-mediated destruction of ß cells
– Idiopathic
• Absolute insulin deficiency- insulin therapy required
• Accounts for 5 to 10 percent of cases
• Diabetes Control and Complications Trial (DCCT) showed that control of
glycemia slows the onset and progression of eye, kidney, and nerve
complications

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Pathophysiology of IDDM

Type 2 (Type II; Non-insulin-dependent diabetes mellitus, NIDDM)(common in
Adult)
• Ranges from predominantly insulin resistance with relative insulin deficiency to
a predominantly secretory defect with insulin resistance
• Insulin therapy required in 20-30% patients; oral hypoglycemic drugs used in
most cases; diet and exercise sufficient in mild cases
• Accounts for 90 to 95 percent of the 18 million cases in the United States.
Type I vs. Type II Diabetes

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CAUSES OF DIABETES
• Two factors especially important in the development of diabetes:
1- Heredity: About a 5% risk of developing Type II diabetes if
mother, father, or sibling has diabetes. Higher risk (up to 50%) if
overweight.
2- Obesity: 80% of people with Type II diabetes are overweight
when diagnosed and symptoms disappear in many of the obese
patients when they lose weight.
♣ Other causes/triggers of diabetes:
Age:
• As people age, their bodies may have fewer insulin-producing beta cells.
Viruses:
• Certain viruses may destroy beta cells in susceptible people.
Faulty immune system:
• Scientists now believe that there is not one cause of diabetes, but multiple factors that
may trigger the immune system to destroy beta cells.
Physical trauma:
• An accident or injury may destroy the pancreas, where insulin is normally produced.
Drugs:
• Drugs prescribed for another condition may unmask diabetes.
Stress:
• Hormones released during periods of stress may block the effect of insulin.
Pregnancy:
• Hormones produced during pregnancy may block the effect of insulin.

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Maintaining Control
• Protect heart, nerves, blood vessels, eyes, and kidneys by controlling blood
glucose level.
• Maintain schedule for checking blood glucose level and taking insulin.
• Maintain well-balanced meal plan, exercise program, and healthy weight.
How does exercise help?
• Most of the time muscle tissue depends on fatty acids for energy
• Under two conditions muscles use large amounts of glucose:
– During moderate or heavy exercise (muscle fibers become permeable to
glucose even in the absence of insulin– important in Type I)
– During the few hours after a meal (while pancreas is secreting more
insulin– important in Type II).
– Most of the glucose is stored as muscle glycogen.
The Diabetic Meal Plan
• Under this plan, 60 to 70 percent of your
total daily calories should come from grains,
beans, and starchy vegetables, with the rest
being meat, cheese, fish and other proteins.
• Fats, oils, and sweets should be used
sparingly.
• The Diabetes Food Pyramid suggests the
following daily servings of food for people
with diabetes:
• The Diabetes Food Pyramid differs from
the standard Food Guide Pyramid in the
way that it groups different foods together.

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• Because blood glucose is of primary concern to people with diabetes, the
Diabetes Food Pyramid focuses on the way in which certain foods affect blood
glucose levels.
• For example, in the standard pyramid, beans and legumes are grouped with
meats, due to their protein content.
• In the diabetes pyramid, however, beans are grouped with starches, because they
affect blood glucose in the same way that starchy foods do.
And ONE LASE TIME
• Why are Maintaining a well-balanced meal plan, exercise program, and healthy
weight SO IMPORTANT?
• Why are Maintaining a schedule for checking blood glucose levels taking insulin SO
IMPORTANT?
♦ Heart Disease and Stroke
• Heart disease is the leading cause of diabetes-related deaths.
• Adults with diabetes have heart disease death rates about two to four times
higher than adults without diabetes.
• The risk for stroke is two to four times higher among people with diabetes.
• About 65 percent of deaths among people with diabetes are due to heart disease
and stroke.
♦ Blindness
• Diabetes is the leading cause of new cases of blindness among adults aged 20-74
years.
• Diabetic retinopathy causes 12,000 to 24,000 new
cases of blindness each year.

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♦ Kidney Disease
• Diabetes is the leading cause of end-stage renal disease,
accounting for 44 percent of new cases.
• In 2001, 42813 people with diabetes began treatment for end-
stage renal disease.
• In 2001, a total of 142,963 people with end-stage renal disease
due to diabetes were living on chronic dialysis or with a kidney
transplant.
♦ Nervous System Disease
• About 60 percent to 70 percent of people with diabetes have mild to severe forms
of nervous system damage.
• The results of such damage include impaired sensation or pain in the feet or
hands, slowed digestion of food in the stomach, carpal tunnel syndrome, and
other nerve problems.
• Severe forms of diabetic nerve disease are a major
contributing cause of lower-extremity amputations.
♦ Amputations
• More than 60 percent of non-traumatic lower-limb
amputations occur among
people with diabetes.
• In 2000-2001, about 82,000
non-traumatic lower-limb
amputations were performed
annually among people with
diabetes.

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◘ Maturity onset diabetes of the young (MODY)
• MODY is a rare form of diabetes which is different from both Type 1 and Type 2 diabetes.
• MODY is caused by a mutation (or change) in a single gene.
• If a parent has this gene mutation, any child they have, has a 50 per cent chance of
inheriting it from them.
◘ Gestational diabetes
- only happens during pregnancy.
- It means you have high blood sugar levels, after the born of the baby, gestational
diabetes usually goes away.