Carbohydrates provide the largest source of calories and include starch, lactose, and sucrose. The small intestine breaks down carbohydrates into monosaccharides like glucose through digestion by enzymes attached to the intestinal wall. These monosaccharides are then absorbed into the bloodstream and transported to tissues like muscle and liver to be used for energy or stored as glycogen for later use.

2.  Carbohydrates are the largest source of dietary
calories.
 The major carbohydrates are starch, lactose and
sucrose
 The main carbohydrates in body metabolism is
glucose
 transported to muscle (and other tissues) via blood
 stored in liver and muscle as glycogen
 ATP produced more quickly from CHO than from fats
or proteins
 CHO stores can be depleted
Carbohydrates (Fuels)

3. Digestion
 Starch digestion begins in mouth by the
salivary α-amylase which converts starch to
smaller polysaccharides called α-dextrins
 Pancreatic α-amylase continue the digestion of
α-dextrins into maltose, maltotriose &
oligosaccharides called limited dextrins
 Digestion of maltose, maltotriose, sucrose &
lactose continues by disaccharidases attached
to the membrane of surface of the brush
border (microvilli)of intestinal epithelial cells
 The monosaccharides produced are
transported into the intestinal cells

4. Sucrase-isomaltase complex
 Similar to glucosamylase attached to membrane
with two polypeptides. Protrudes into the
intestinal lumen, an intestinal protease clips in
into two separate subunits that remain
attached to each other. Each subunit site has a
catalytic site that differs in substrate specificity.
The sucrase-maltase site accounts for 100% of
intestinal ability to hydrolyze sucrose in addition
to maltase activity. The isomaltase-maltase site
accounts for almost all activity to hydrolyze α 1-
6 bonds in addition to maltase activity.

5. Trehalase & Lactase
 Trehalase: One catalytic site & hydrolyzes
the glycosidic bond in trehalose
(disaccharide of two glucosyl units
attached by their anomeric carbons.
 Lactase - Glucosyl cermidase Complex:
Glycoprotein found in the brush border
that has two caralytic sites extending in
the intestinal lumin. It hydrolyzes lactose
and the B-bonds between glucose or
galactose and ceramide in glycolipids.

6. Dietary Fiber
 Composed principally of polysaccharides which
can not be digested by human enzymes of
intestinal tract
 Derivatives of lignan ( cellulose, hemicellulose,
lignin, pectin s, mucilages & gums)
 Bacterial flora of the colon metabolize the
fibers to gases(H2,CO2,CH4) & short chain fatty
acids
 Fatty acids are absorbed by colonic cells
 Fibers is seen to soften the stool, thereby
reducing pressure on colonic wall & enhancing
expulsion of feces

7. Glucose Absorption
 Two types of glucose transport
proteins are present in the intestinal
cells
– Na+ dependent: an active transport which
depends on cotransport of sodium and
glucose
– Facilitated : passive transport known as
Glut 1 -4

8.  Cell membranes are not inherently permeable to
glucose. There are many glucose transporters.
 GLUT- 1 enables basal non- insulin stimulated
glucose uptake (erythrocytes)
 GLUT- 2 transport glucose into beta cells, a pre-
requisite for glucose sensing.
 GLUT- 3 enables non- insulin mediated glucose
uptake into brain.
 GLUT- 4 enables much of the peripheral action of
insulin (muscles, adipose)
Glucose transporters

9. Absorption of carbohydrates
 Sugars are transported
across the intestinal
epithelial cells into the
blood
 Not all complex sugars
are digested in the
same rate within the
intestine
 Glycemic index of the
food is an indication of
how rapidly blood
glucose level rises after
consumption
Whole weat 100
pasta 67
cornflakes 121
potatoes 120
Ice cream 69
fruits 52

10. The waiting room
 Deria Voider is a 20 year old exchange student
from Nigeria who has noted gastrointestinal
bloating, abdominal cramps, and intermittent
diarrhea ever since arriving in the united states
6 months earlier. A careful history shows that
these symptoms occur most commonly about
45 minutes to 1 hour after eating breakfast but
may occur after other meals as well. Dairy
products, not a part of Deria’s diet in Nigeria,
were identified as the probable offending agent
because her gastrointestinal symptoms
disappeared when milk & milk products were
eliminated from here diet.

11. The waiting room
 Lactose intolerance can either be the result
of a primary deficiency of lactase production
in the small bowel or it can be secondary to
an injury to the intestinal mucosa, where
lactase is normally produced.
 The lactose that is not absorbed is
converted by colonic bacteria to lactic acid .
Methane gas and H2 gas
 The osmotic effect of lactose & lactic acid in
the bowel lumen is responsible for the
diarrhea seen often

12.  A 15 year old complained of abdominal discomfort, a
feeling of bloated, increase passage of urine, more
recently, the development of diarrhea. His only change
in diet noted at the time was the introduction of yogurt
into his diet. He was consuming 1-2 large cartons per
day. A lactose test was performed, whereby the young
man was given 50 g lactose in an aqueous vehicle to
drink. Plasma glucose levels did not rise by more than
1 mmol/ l ( 18g /dl) over the next 2 hour, with
sampling at 30 minutes interval. A diagnosis of lactose
intolerance was made.
 Comment: This is due to deficiency of lactase. Lactase
activity decreases with age in children but this decline
is genetically predetermined. A diagnosis is made by
challenging the small bowel with lactose and
monitoring the rise in plasma glucose. An increase of
more than 1.7 mmol/l (30 g/dl) is considered normal.
Lactose intolerance

13. Glycogen Metabolism

15. Glycogenolysis
 Occurs mainly in liver & muscles
 Both pathways in the liver & muscle
are the same
 End product in liver is glucose, while in
muscle is glucose 6 phosphate

20. Regulation of Glycogen Metabolism in Liver
 When blood glucose level increases immediately after
a meal, insulin level increases, whole glycogen level
decreases.
 Increase in insulin/glycogen ration inhibits
glycogenolysis & stimulates glycogenesis.
 The immediate removal of blood glucose helps bring
circulating blood glucose levels back to normal 80-100
mg/dl range.
 Postprandilly, insulin levels decrease & glucagon levels
increase.
 The fall of the insulin/glycogen ratios results in
inhibition of glycogenesis and increased
glycogenolysis.
 Substantial proportion of liver glycogen is degraded
within the few first hours after eating.

22. Regulation of Glycogenolysis &
Glycogenesis in Skeletal Muscle
 Skeletal muscle glycogen is degraded only when
the demand for ATP generation is high.
 Regulation of glycogen metabolism differs from
that in liver.
1. Glucagon has no effect (muscle glycogen do not
vary with fasting/feeding state)
2. AMP is an alosteric activator of muscle glycogen
phosphorylase but not liver isozyme.
3. Glucose is not a physiological inhibitor of
glycogen phosphorylase.
4. Epinephrine effects are similar to that in liver.

23. Epinephrine & Ca2+ in the Regulation of Liver
Glycogen
 Epinephrine released from adrenal medulla in
response to neural signals reflecting an increased
demand for glucose.
 Epinephrine stimulated glycogenolysis in liver
through two different receptors.
– B-Receptors: transmit a signal through G-
protein to adenylate cyclase, which increases
cAMP.
– Α-Receptors: increases CA2+ levels in the liver,
which is mediated by the phosphatidylinositol
bisphosphate - CA2+ signal transduction
system.

24. Function of glycogen in Skeletal Muscle & Liver
 It functions as a reservoir of glucosyl units for ATP
generation.
 Glycogen is usually degraded to glucose-1-
phosphate which is converted into glucose-6-
phosphate.
 In skeletal muscles and other cell types, glucose-6-
phosphate is used by the cell to produce ATP
(Absence of glucose-6-phosphatase).
 In liver, glycogen serves a very different purpose.
Liver glycogen is the first and immediate source of
glucose for the maintenance of blood glucose
level. In liver, glucose-6-phosphate is converted to
free glucose by G-6-phosphatase, present only
liver and kidneys.

25. Futile Cycles
 Regulation of glycogen synthesis serves to
prevent futile cycling and waste of ATP.
 Futile cycle refers to a situation in which a
substrate is converted to a product through one
pathway & the product converted back to the
substrate through another pathway.
 Because biosynthesis pathway is energy
requiring, futile cycling results in a waste of high
energy phosphate bonds.
 Therefore, glycogenesis is activated when
glycogenolysis is inhibited and vice versa.

26. The Waiting Room (1)
A newborn baby girl, Getta Garbo, was born
after a 38-week gestation. Her mother, a 36-
year-old woman, had moderate hypertension
during the last trimester of pregnancy related
to a recurrent urinary tract infection that
resulted in a severe loss of appetite and
recurrent vomiting in the month preceding
delivery. Fetal bradycardia (slower than normal
feta heart rate) was detected with each uterine
contraction of labor, a sign of possible fetal
distress. At birth Getta was cyanotic (a bluish
discoloration caused by lack of adequate
oxygenation of tissues) and limp. She
responded to several minutes of assisted
ventilation.

27. The Waiting Room (2)
Physical examination in the nursery at 10 minutes,
showed a thin, malnourished female newborn. Her
body temperature was slightly low, her heart rate
was rapid and her respiratory rate of 35
breaths/minute was elevated. Getta’s birth weight
was only 2,100g (normal 3,300 g). Her length was
47 cm, and her head circumference was 33cm (low
normal). Getta’s serum glucose when she was
unresponsive was 14 mg/dL. (glucose below 40
mg/dL (2.5 mM) is abnormal in newborn). At 5
hours of age, she was apneic (not breathing) and
unresponsive. Ventilatory resuscitation was initiated
and a cannula placed in the umbilical vein. Blood
for a glucose level was drawn through this cannula,
and 5mL of a 20% glucose solution was injected.
Getta slowly responded to this therapy.

28. The Waiting Room (3)
Maternal blood glucose readily crosses the placenta to enter the
fetal circulation. During the last 9 or 10 weeks of gestation,
glycogen formed from maternal glucose is deposited in the fetal
liver under the influence of the insulin-dominated hormonal
milieu of that period. At birth, maternal glucose supplies cease,
causing a temporary physiologic drop in glucose levels in the
newborn’s blood even in normal healthy infants. This drop
serves as one of the signals for glucagon release from the
newborn’s pancreas, which, in turn stimulates glycogenolysis.
As a result, the glucose levels in the newborn return to normal.
Healthy full-term babies have adequate stores of liver glycogen
to survive short (12 hours) periods of caloric deprivation
provided other aspects of fuel metabolism are normal. Because
Getta Garbo’s mother was markedly anorexic during the critical
period when the fetal liver is normally synthesizing glycogen
from glucose supplied in the maternal blood, Getta’s liver
glycogen is the major source of fuel for the newborn in the
early hours of life, Getta became profoundly hypoglycemic
within 5 hours of birth because of her low levels of stored
carbohydrates.

29. electron
transport
chain
Aerobic Metabolism
Oxidation Phosphorylation
Kreb’s
cycle
Glycolysis
(carbohydrates)
(proteins)
Beta Oxidation
(fats)
NADH
FADH2
O2 H2O
ADP + Pi ATP
acetyl
CoA
mitochondria
oxidation
phosphorylation

30. Glycolysis

31.  uses only CHO
 occurs in sarcoplasm
 first step is glucose transport into tissues
 after entry, 2 ATP are used (with glucose)
 glucose (C6) is split into two C3 molecules
 final product is pyruvate
 4 ATP are synthesized
 pyruvate forms either lactate or enters
mitochondria
Glycolysis

32. Functions of Glycolysis
 ATP Production
 Synthesis of UDP-glucose, sialic
acid & mannosa
 Synthesis of serine & alanine
 Synthesis of TG from DHAP & fatty
acids
 In RBC, synthesis 2,3 DPG

33. glucose
ATP
ATP
PFK
4 ATP
pyruvate
lactate acetyl CoA
mitochondria
glycogenolysis
sarcolemma
blood
glycolysis
Overview of Glycolysis

34. Glycolysis

38. Lactate Production
 Major tissue sites of lactate production in a
resting man (g/day)
RBC 29
Skin 20
Brain 17
Skeletal muscles 16
Renal medulla 15
Intestinal mucosa 8
Other tissues 10
Total Production 115

39. Electron Transport Chain (ETC)
Oxidative Phosphorylation
Oxidation
 NADH and FADH2 transfer electrons to ETC
 final acceptor of electrons is O2
Phosphorylation
 energy generated by oxidation used to
resynthesize ATP
– 3 ATP from each NADH
– 2 ATP from each FADH2

40. 1,3 DPG
2,3 DPG mutase
2,3 DPG
2,3 DPG phosphatase
2-PG
2,3 DPG synthesis & degradation
ADP
ATP

42. Regulation of Glycolysis
 Hexokinase inhibited by G-6-P with low km for
glucose
 PFk-1 is the rate limiting enzyme activated by
AMP and Fructose-2-6 bisphosphate (alosteric)
 PFK-1 inhibited by ATP & citrate.
 Pyruvate kinase present in brain and skeletal
muscles has no alosteric site & hence does not
contribute toward regulation of glycolysis in
these tissues.
 Liver pyruvate kinase is inhibited by
phosphorylation (CAMP) & alosterically inhibited
by ATP.

46. Dental Caries
 Ivan Applebod is a 56-year-old morbidly
obese accountant. He decided to see his
dentist because he felt excruciating pain in
his teeth when he ate ice-cream. He really
likes sweets and keeps hard candy in his
pocket. The dentist noted from Mr.
Applebod’s history that he had numerous
cavities as a child in his baby teeth. At this
visit, the dentist found cavities in two of
Mr. Applebod’s teeth.

47. Comment
 The dental caries in Ivan Applebod’s mouth were
case principally by the low ph generated from lactic
acid production by oral bacteria. Below a ph of 5.5
decalcification of tooth enamel & dentine occurs.
Lactobacilli and s. mutants are major contributors
to this process because almost all of their energy is
derived from the conversion of glucose or fructose
to lactic acid, and they are able to form well at low
ph generated by this process. The dentist explained
that bacteria in his dental plaque could convert all
the sugar in his candy into acid in less than 20
minutes. The acid is buffered by bicarbonate &
other buffers in saliva, by saliva production
decreases in the evening. Thus, the acid could
dissolve the hyroxyapptite in his tooth enamel
during the night.

48.  lactate formation
 enters mitochondria (i.e. Kreb’s cycle)
 formation of Kreb’s cycle intermediates
Pyruvate goes in one of three directions
Metabolic Fate of Pyruvate

51. TCA Cycle

52.  primary function is to reduce NAD+ and FAD
 acetyl CoA (C2) combines with a C4
molecule forming a C6 molecule
 C6 molecule is partially degraded back to a
C4 molecule
 each loss of C gives off a CO2
Kreb’s Cycle
(Citric Acid Cycle)

56. electron
transport
chain
Overview of Aerobic
Metabolism
Kreb’s
cycle
(proteins)
NADH
FADH2
O2 H2O
ADP + Pi ATP
acetyl
CoA
1. Preparation
for entry into
Kreb’s cycle
2. Removal of
“energized”
electrons
3. 1º ATP synthesis;
Oxidation-
phosphorylation
mitochondria
Beta Oxidation
(fats)
Glycolysis
(carbohydrates)

57. Gluconeogenesis

58.  Sites include liver & kidney while
substrates include, amino acids,
lactate, pyruvate, glycerol.
 Cori & alanine cycles for transport of
intermediates between site of
production of these metabolites and
site of synthesis.
 Many enzymes of glycolysis are
common to gluconeogenesis.
Gluconeogenesis(1)

60.  Irrversible enzymes of glycolysis are
replaced by gluconeogenesis
enzymes.
1. Pyruvate kinase – pyruvate
carboxylase & PEPCK
2. PFK ---- F 2,6 diphosphatase
3. Glucokinase --- Glu 6 phosphatase
Gluconeogenesis(2)

61. Gluconeogenesis - Bypass Enzymes
Glucose
oxaloacetate
Glucose-6-Phosphate
Fructose-6-Phosphate
Fructose 1,6 Bisphosphate
DHAP + Glyceraldehyde-3-P
Glyceraldehyde-3-P
Pyruvate
PEP
2-Phosphoglycerate
3-Phosphoglycerate
1,3-BPG

62. Gluconeogenesis - Bypass Enzymes
pyruvate + CO2 + ATP + H2O  oxaloacetate + ADP,Pi + 2H+
oxaloacetate + GTP  PEP + GDP + CO2
10. Pyruvate carboxylase & PEP carboxykinase
(+) acetylCoA & (-) ADP
3.Fructose 1,6-bisphosphatase
(-) fructose 2,6-bisphosphate (low fasting – high Fed)
(-) AMP
fructose 1,6 bisphosphate + H2O  fructose 6-phosphate + Pi
1. Glucose 6-phosphatase
glucose 6-phosphate + H2O  glucose + Pi

63. GLUCONEOGENESIS
Liver
2Pyruvate + 4ATP + 2NADH
2GTP
Glucose + 4ADP + 2NAD+
2GDP
to blood

64.  Galactose metabolism occurs in liver.
 Galactose UDP-galactose
GK
Uridyl transferase
UDP- glucose
Galactose metabolism

65.  Occurs in liver & adipose tissue
 Fructose Fructose 6 phos
fructokinase
Glucose 6 phos
Fructose metabolism

66.  The plasma glucose concentration reflects the
balance between intake, tissue utilization &
endogeneous production .
 Insulin promotes up take of glucose thus decreasing
plasma glucose while glucagon stimulates both the
release of glucose from glycogen stores & its denovo
synthesis, thus causing an increase in plasma
glucose.
 Glucose stimulates the secretion of insulin &
suppresses the secretion of glucagon.
Glucose Homeostasis

67.  Insulin acts on three main targets, liver, adipose &
muscles.
 In liver insulin stimulates, glycolysis, glycogenesis &
lipogenesis & suppresses lipolysis.
 In peripheral tissues, insulin induces lipoprotein
lipase activity & thus stimulates triglyceride synthesis.
 In muscles, insulin increases glucose & amino acid
transport & glycogen synthesis.
Metabolic effects of insulin

68.  Glucagon main effect is the mobilization of the fuel
reserves for the maintenance of the blood glucose
level between meals.
 Glucagon inhibits glucose- utilizing pathways and the
storage of metabolic fuels.
 It acts on liver, to stimulate glycogenolysis and inhibit
glycogenesis, glycolysis and lipogenesis.
 Gluconeogenesis and ketogenesis are then activated
 Epinephrine has effects similar to glucagon in the
liver but works through a different receptor. It
promotes an increase in blood glucose in response to
stress
Metabolic effects of Glucagon

69.  The glucose level in the vicinity of the B- cell is
sensed by the transporter GLUT- 2. Glucose is carried
into the cell, where it is phophorylated into G-6- P by
glucokinase which also is a part of the glucose
sensing mechanism. Increased G-6- P increases
glucose utilization and ATP production in the B- cell.
This changes the flux of ions across the cell
membrane, depolarizes the cell and increases the
concentration of Ca2+. Hence insulin is exocytosed.
 Insulin secretion is biphasic. The first phase occurs
over 10- 15 minutes of stimulation which release the
preformed insulin. The second phase, which lasts up
to 2 hours, is the release of newly synthesized
insulin.
Stimulation of insulin secretion by glucose

70.  Insulin secretion is also stimulated by gastrointestinal
hormones (insulinotropic peptide, cholecystokinin)
and amino acids, such as leucine, arginine, and
lysine. Thus, the insulin response to orally
administered glucose is greater than to an
intravenous infusion.
Stimulation of insulin secretion by glucose

71.  Hypoglycemia is defined as a blood glucose
concentration below 2.5 mmol/ L ( 45 mg/dl).
 Epinephrine and glucagon are released, resulting in a
stress response, the manifestation of which may
include sweating, trembling, increased heart rate and
feeling of hunger. If blood glucose continues to fall,
brain function is compromised (neuroglycopenia).
 Hypoglycemia in healthy individuals is usually mild
and may occur during exercise, after a period of
fasting or due to alcohol ingestion.
 Hypoglycemia may be caused by a rare insulin
secreting tumor of the beta- cells ( insulinoma) or
overdose of exogenous insulin.
Hypoglycemia

72.  A 12 year old diabetic boy was playing with his
friends. He received his normal insulin injection in the
morning but continued playing through the lunch
time without a meal. He became confused and
fainted. He was instantly given an injection of
glucagon from the emergency kit his father carried,
and recovered within minutes.
 Comment : An immediate improvement after
glucagon injection confirms this boy’s symptoms
were caused by hypoglycemia ,caused by the
exogenous insulin and insufficient food intake.
Spectacular recovery from hypoglycemia was due to
the action of glucagon. In hospital, hypoglycemic
patients who can not eat or drink are treated with an
intravenous infusion of glucose. An intramuscular
glucagon injection is an emergency measure that can
be applied at home.
Severe hypoglycemia is a medical emergency

73.  A middle aged man, emaciated, chronic alcoholic
collapsed and was transported to ER. Physical
examination revealed a somewhat clammy skin, unusual
for winter morning, rapid breathing and a rapid heart
rate. Laboratory tests indicate a blood sugar of 2.5
mmol/l ( 50g/dl), and a blood alcohol level of 0.2 %.
Subsequent tests indicated a normal level of CPK, high
serum level of AST, a slight acidic pH (7.29), low pCO2
and high blood lactate. The man responded to infusion of
a glucose solution & regained consciousness.
 Comment: This patient probably had not eaten breakfast
before starting his morning drinking. His glycogen stores
were negligible, so he was dependent on
gluconeogenesis for maintenance of blood glucose
concentration, but gluconeogenesis may be compromised
both by liver damage and by limited muscle mass
Alcohol Excess and Hypoglycemia-1

74.  Alcohol is metabolized primarily in the liver. Two steps
metabolism of alcohol is relatively unregulated, leading
to a rapid increase in hepatic NADH. This shifts the
equilibrium of LDH catalyzed reaction towards lactate
formation ( lacticacidemia). Also shifts cytosolic
oxaloacetate towards malate formation, reducing
gluconeogenesis from TCA. In addition DHAP is shifted
toward glycerol- 3- phosphate formation and thus
reducing gluconeogenesis from glycerol.
 The low blood glucose leads to a stress response 9
rapid heart beat, clammy skin), an effort to enhance
stimulation of gluconeogenesis combined action of
glucagon and epinephrine. Rapid breathing is
physiological response to metabolic acidosis.
Alcohol Excess and Hypoglycemia 2

75.  Premature babies are more susceptible to
hypoglycemia than normal babies because:
They have larger brain to body ratio.
 Small stores of glycogen.
 Limited capacity of live gluconeogenesis
because of immaturity of the liver cells
and the immaturity of PEPCK.
 Limited capacity for ketogenesis.
Sudden Infant Death Syndrome (SIDS)

76.  DM is a group of metabolic diseases characterized by
hyperglycemia leading to long term complication.
 It is common, which affects 1-2 % of populations.
 There are two main forms diabetes, 10 % have type
I and 90% have type 2.
 Type 1 patients are unable to produce insulin and
must receive exogenous insulin to survive.
 Type 2 patients have at least partially preserved
insulin secretion, but often insulin resistant.
 Some patients may have no clinical symptoms at all,
with diagnosis made exclusively on the basis of
laboratory results.
Diabetes Mellitus ( DM)

78.  Type one
 It is not genetically predetermined.
 Increase susceptibility to the diseases is inherited.
 Sibling has a 10 % chance of developing diabetes
by the age of 40.
 Susceptibility is associated with HLA genes ( HLA
DR3 and or DR4, DQ W)
Genetics of Diabetes

79.  Type two
 It is polygenic disorder ( no evidence of immune
involvement)
 Sibling have 50 % increased risk of developing
diabetes.
 Genes for majority of cases have yet to be
identified.
 Many genetic causes which include:
Mutations of insulin receptors
Deletion of mitochondrial DNA
Mutations effect the structure of insulin
Genetics of Diabetes

80.  In absence of insulin
 Hepatic glucose production accelerate
 Peripheral glucose uptake is reduced
 Hyperglycemia leads to
 Osmotic diuresis
 Loss of fluid and electrolytes
 Dehydration
 Plasma osmolality rises and renal perfusion falls
Metabolism in uncontrolled diabetes

81.  In parallel:
 Rapid lipolysis occurs
 Elevated circulatory FFA
 Rising ketogenesis
 Rising plasma ketone bodies which produce
metabolic acidosis
 Vomiting leads to further loss of fluid and
electrolytes
 Progressive dehydration impairs renal excretion of
hydrogen ions and ketones
Metabolism in uncontrolled diabetes

82.  Type I diabetes develop in young people, with the
peak incidence at approximately 12 years of age.
 It is caused by autoimmune destruction of pancreatic
B- cells. The precipitating cause is still unclear ( viral
infection initiate the chain of autoimmune reaction,
alternatively, cytokine response to viral infection, or
another insult, could attract monocytes and
macrophages that infiltrate and destroy the pancreatic
islets).
 A proportion of patients have antibodies against B- cell
proteins.
 Auto- antibodies to insulin are also seen in some
individuals.
Type I Diabetes

83.  Type 2 diabetes usually develop in patients who are
over 40 years old and are typically obese.
 The pathogenesis in type 2 diabetes involve the
impairment of insulin secretion and insulin resistance.
 The response of the diabetic B- cell to the glucose
stimulus is suboptimal and there is no first phase of
insulin secretion.
Type 2 Diabetes

84.  Diabeteic ketoacidosis, a sudden (acute ) metabolic
disturbance, is only one part of the diabetic syndrome.
 The other is the slow development of changes in small
(microangiopathy) and large (macroangiopathy)
arteries.
 Diabetic complications lead to diabetic kidney failure (
nephropathy), blindness ( retinopathy) and to the
impairment of nerve function ( neuropathy).
 Peripheral vascular disease is a major cause of foot
ulcers and lower limb amputations.
Long term complications of Diabetes

85.  Type 1: Daily subcutaneous insulin injections
throughout life. Patients in whom blood glucose is
difficult to control are treated with several injections
per day, or sometimes, with a constant insulin
infusion, delivered by a programmable, portable
pump. Diet and exercise are also important in the
management of diabetes.
 Type 2 : Diabetic patients do not usually require
insulin treatment because insulin synthesis is at least
partly preserved. Instead, the treatment relies on diet
and oral hypoglycemic agents. Drugs such as
sulfonylurea derivatives stimulate insulin secretion.
Another class of compounds ( metformin) reduce
hyperglycemia by increasing peripheral glucose
uptake.
Treatment of Diabetes:

86.  A 15 year old girl is admitted to the Accident and
Emergency department. She is confused and her breath
smells of acetone. She has dry skin and tongue, which
are signs of dehydration. She also takes quick, deep
breaths ( hyperventilation). Here RBG is 18.0 mmol/l (
324 mg/dl) and ketones are present in the urine. Her
serum potassium concentration is 3.5 mmol/l ( normal
3.5- 5.0 mmol/l) and her arterial blood pH is 7.2
( normal 7.37 – 7.44).
 Comment: this is a typical presentation of diabetic
ketoacidosis. Hyperventilation is a compensatory
response to acidosis. This patient needs to be treated as
a medical emergency. She will receive an intravenous
infusion containing physiologic saline with potassium
supplement to replace lost fluid, and an insulin infusion.
Typical presentation of diabetic ketoacidosis

87. Address four issues:
 Insulin infusion to reverse the metabolic effects of
the excess of anti- insulin hormones.
 Infusion of fluids to treat dehydration.
 Intravenous fluids normally contain potassium
supplements to prevent a decrease in plasma
potassium ( hypokalemia).
 When acidosis is severe, infusion of an alkaline
solution ( sodium bicarbonate) may be required.
Emergency treatment of diabetic ketoacidosis

88.  Insulin increases potassium uptake by cells. Lack of
insulin leads to release of potassium, particularly
from skeletal muscle. Since uncontrolled diabetes is
accompanied by an osmotic diuresis, the released
potassium is excreted through the kidney. Most
diabetic patients admitted to hospital with
ketoacidosis are potassium depleted. Exogenous
insulin given to such patients stimulates the entry of
potassium into cells. This further depletes the plasma
potassium pool and can lead to very low plasma
potassium level ( hypolkalemia). Hypokalemia is
dangerous, owing to its effects on cardiac muscle.
Thus, except for patients with very high potassium
level, potassium supplementation needs to be
considered in treatment of diabetic ketoacidosis.
Diabetic ketoacidosis and potassium

89.  Maintaining near normal blood glucose levels
prevents the development of late complications of
diabetes. A recently completed landmark clinical
study, the Diabetes Control Complications trial , has
shown that the development of late complications of
diabetes in type I diabetes is related to long term
glycemia. This study has also shown that in patients
who have complications, good control of glycemic
delays further development of retinopathy,
nephropathy and neuropathy. Similar results were
obtained for type 2 diabetic patients during the UK
Prospective Diabetes Study completed in 1998. Thus
the aim of treatment of diabetes should be the
achievement of blood levels as close to normal as
possible, without precipitating hypoglycemia.
The importance of good glycemic control

90.  The entry of glucose into brain, peripheral nerve
tissue, kidney, intestine, lens and RBC does not
depend on insulin action.
 During hyperglycemia, the intracellular level of
glucose in these cells is high, which promotes the
non- enzymatic attachment of glucose to protein
molecules.
 Glycation involves glucose and alpha- amino terminal
amino acid and ε- amino groups of lysine residues.
 Hemoglobin, albumin and collagen become glycated
which effects their function.
 For instance, glycation of apolipoprotein B slows
down the rate of receptor dependent metabolism of
LDL.
Protein modification by glucose

91.  The measurement of blood glucose remains the most
important laboratory test in diabetes.
 As erythrocytes age, there is gradual conversion of a
fraction of native hemoglobin ( HbA) to its glycated
form, HbA1C, so that an older red cell, a greater
fraction of HbA exist as HbA1C.
 HbA1C concentration in blood reflects the time –
averaged level of glycemia over the 3-6 weeks
preceding the measurement.
 The normal concentration of HbA1C is 4-6% of HbA.
Levels below 7% indicate acceptable control of
diabetes. Higher levels suggest poor control.
Glycated Hemoglobin (HbA1C)

92.  A 15 year old insulin dependent boy visited a Diabetic
Clinic for a check up. He tells the doctor that he
complies with all the dietary advice and never misses
insulin. Indeed, his random blood glucose is 6 mmol/l
( 108 mg/dl), but his HbA1C concentration is 11 % (
normal 4- 6 %). He has no glucosuria or ketones in
his urine.
 Comment: blood and urine glucose results indicate
good control of this boy’s diabetes at the time of
measurements, whereas the HbA1C level suggests
poor control over the last 3-6 weeks. The probability
is that he only complies with treatment days before
he was due to come to the clinic. This is not
uncommon in adolescent, who find it hard to accept
the necessity to adjust to their lifestyle to the
requirement of diabetes
HbA1C identifies patients who do not
comply with treatment

93.  Insulin consists of two chains linked by two
disulphide bonds. During insulin synthesis a signal
sequence is cleaved from pre proinsulin by a
peptidase, yielding proinsulin.
 Proinsulin consists of the insulin sequence
interspersed by a connecting peptide ( C – peptide).
At the final stage of insulin synthesis, proinsulin is
split into insulin and C- peptide released.
 C- peptide is released in an amount equimolar to
insulin. This is used to asses beta cell function in
patients treated with exogenous insulin.
 In these patients, endogenous insulin cannot be
measured directly, because the exogenous insulin
would interfere in the assay. In such circumstances,
C- peptide measurement provides an assessment of
beta cell function.
Insulin and C- peptide

94.  Glucose can be reduced to sorbitol by the action of aldose
reductase. Sorbitol is further oxidized by sorbitol
dehydrogenase to fructose. Since aldose reductase has a
high Km for glucose, the pathway is not very active at
normal glucose level.
 In hyperglycemia, however, glucose levels in insulin
independent tissues, such as the RBC, nerve and lens,
increase and consequently there is an increase in the activity
of the polyol pathway with depletion of NADPH.
 Like glucose, sorbitol exerts an osmotic effect. This is
thought to play a role in the development of diabetic
cataracts.
 In addition, the high level of sorbitol decreases cellular
uptake of another alcohol, myoinositol, which in turn causes
a decrease in the activity of membrane Na+/ K+ ATPase. This
in turn effects nerve function and, along with hypoxia and
reduced nerve blood, contributes to the development of
diabetic neuropathy. Drugs inhibiting aldose reductase
improve nerve function in diabetes.
The Polyol Pathway

95.  An apparently normal baby began to vomit and develop
diarrhea after breast feeding. These problems, together
with dehydration continued for several days, when the
baby began to refuse food and developed jaundice,
indicative of liver damage, followed by hepatomegaly and
then lens opacification ( cataracts). Measurements of
glucose in the blood and urine by specific enzymatic
technique indicated that levels of glucose were low,
consistent with the failure to absorb foods. However
glucose measured by a test that determined total
reducing sugar was eventually identified as galactose,
indicating an abnormality in galactose mechanism known
as galactosemia. This finding was consistent with the
observation that, when milk was removed from the diet
and replaced with an infant formula containing sucrose
rather than lactose, the vomiting and diarrhea stopped,
and hepatic function was gradually restored.
Galactosemia

96.  Comment: the accumulation of galactose in the blood is
most often a result of deficiency of Gal-1- P uridyl
transferase in liver tissues. Accumulation of the latter
interferes with phosphate and glucose metabolism,
leading to widespread tissue damage, organ failure, and
mental retardation. In addition, accumulation of
galactose in tissues results in galactose conversion via
polyol pathway to galactitol, and the accumulation of
galactitol in the lens results in osmotic stress and
formation of cataracts. A milder form of galctosemia is
caused by galactokinase deficiency.
Galactosemia

97.  A baby, born of poorly controlled, chronically hyperglycemic,
diabetic mother was large and chubby at birth ( 5kg.), but
appeared otherwise normal. He declined rapidly, however
and, within 1 hour showed all of the symptoms of
hypoglycemia, similar to the previously described case of baby
girl born of a malnourished mother. The difference, in this
case, was that the boy was thin, rather than heavy.
 Comment: This child has experienced a chronically
hyperglycemic environment during uterine development. He
adapted by increasing insulin, which has a GH like activity,
resulting in macrosomia. At birth, when placental delivery of
glucose ceases, he has a normal blood glucose level. However
his high blood insulin promotes glucose uptake into muscles
and adipose tissue. The resultant insulin induced
hypoglycemia leads to stress response, which was corrected
by glucose infusion. His ample body mass will provide good
blood supply from muscle proteins when gluconeogenesis is
activated at 1-2 days post partum.
Large child born of a diabetic mother

98.  An autosomal recessive condition, due to deficiency
of fructose – 1- phosphate aldolase. The defect
causes:
 Intracellular accumulation of fructose -1-
phosphate.
 Inhibition of fructokinase.
 Increased blood level of fructose.
 Inhibition of glycogen phosphorylase due to
depletion of Pi.
 Profound hypoglycemia.
Fructose intolerance

99.  A baby girl is irritable, sweaty and lethargic and
demands food frequently. Physical examination
indicates an extended abdomen, resulting from
enlarged liver. Blood glucose, after a meal, was 3.5
mmol/l (70 mg/ dl). After 4 h, the child was exhibiting
irritability and sweating, her heart rate was increased
and blood glucose had declined to 2 mmol/l ( 40
mg/dl). These symptoms were corrected by feeding. A
liver biopsy showed massive deposition of glycogen in
the liver cytosol.
 Comments: She has deficiency in glycogen
mobilization. Because of the severity of hypglycemia,
the most likely mutation is in hepatic glucose- 6-
phosphatase, which is required for glucose production
by both gluconeogenesis and glycogenolysis.
Von Gierk’s Disease

100.  A genetic recessive disorder, due to absence of
lysosomal glucosidase which results in
 Generalized (liver, heart and muscle)
 Excessive glycogen concentrations found in
abnormal vacuoles in the cytosol.
 Normal blood sugar
 Severe cardiomegaly
 Early death usually occurs
 Normal glycogen structure
Pompe’s disease

101.  A 30 year old man complains of chronic arm and leg
muscle pain and cramps during exercise. The pain
generally disappeared after about 15- 30 minutes, then
he could continue his exercise without discomfort. This
blood glucose level was normal during exercise, but his
serum creatine kinase (MM) was elevated. Blood glucose
declined slightly during exercise, but unexpectedly blood
lactate also declined, rather than increased, even when
he was experiencing muscle cramp. A biopsy indicated
an unusually high level of glycogen in muscle.
 Comment: this patient suffers from rare deficiency of
muscle phosphorylase activity. Since the patient did not
excrete lactate into the blood after intense exercise,
suggests a failure to mobilize muscle glycogen. His
recovery after half an hour results from epinephrine
mediated response that provides both glucose and fatty
acids from blood overcoming deficiency in muscle
glycogenolysis.
McArdle’s disease

104.  Just prior to planned departure to the tropics, a
patient visits his physician, complaining of weakness
and noting that his urine had recently become
unexplainably dark. Physical examination revealed
slightly jaundiced ( yellow, icteric ) sclera. Laboratory
tests indicated a low hematocrit, a high reticulocyte
count, and significantly increased blood level of
bilirubin. The patient has been quite healthy during a
previous visit a month ago when he received
immunizations and prescriptions for drugs related to
his travel plan
Glucose 6 phosphate dehydrogenase deficiency 1

105.  Comments: A number of drugs, particularly primaquine
and related antimalarials, undergo reactions in the cell,
producing large quantities of superoxide and H2O2.
Superoxide dismutase converts superoxide into H2O2,
which is inactivated by glutathione peroxidase using
NADPH. Some persons have genetic defect in G6PD,
typically yielding an unstable enzyme that has a
shorter life in the RBC. Therefore insufficient
production of NADPH under stress, the cell ability to
recycle GSSG to GSH is impaired and drug induced
oxidative stress leads to lysis of RBC’s and hemolytic
anemia. If the hemolysis is severe enough Hb spills
over into the urine, resulting in hematuria and dark
colored urine. Older cells, which can’t synthesize and
replace their enzyme are therefore particularly
affected. Genetically the deficiency is X- linked. Favism
is associated with G6PD deficiency.
Glucose 6 phosphate dehydrogenase deficiency 2