Blood Glucose Homeostasis

4. Blood Glucose Homeostasis ,
Biochemistry of Starvation and
Diabetes mellitus

5. Contents
• 1. Introduction
• Homeostasis: Maintenance of normal levels
• Fed-Fast Cycle: Absorptive and post-
absorptive states
• Metabolic Fuel Molecules: Glucose, fatty
acids, amino acids, ketone bodies
• Integration of Metabolism: Carbohydrate, lipid
and protein

6. • 2. Mechanism of Blood Glucose Homeostasis or
• Regulation of Blood Glucose
• Normal blood glucose values: Fasting,
postprandial
• Biomedical importance: Hypoglycemia,
hyperglycemia
• Regulating factors: Neuronal, Hormones
(hypoglycemic & hyperglycemic)
• Role of Insulin: Metabolic effects
• Role of Glucagon: Metabolic effects

7. • 3. Biochemistry of Starvation
• Definition
• Metabolic changes
• Complications: Ketoacidosis, Fatty liver,
Muscle-wasting

8. • 4. Diabetes mellitus
• Definition
• Types: Type 1, Type 2, others
• Metabolic changes
• Biochemical basis of clinical manifestations:
Polyuria, polyphagia, polydypsia, glucosuria,
weight loss, muscle weakness
• Biochemical basis of acute complications:
Diabetic ketoacidosis, Hyperosmolal non-
ketotic coma

9. • Biochemical basis of chronic complications:
Cataract, polyneuropathy, retinopathy,
nephropathy, myocardial infarction, stroke,
gangrene, fatty liver
• Diagnosis: Plasma glucose estimation, glycosuria
(glucosuria), oral Glucose Tolerance Test (GTT)
• Monitoring: Plasma glucose estimation, Glycated
Hb (HbA1c)
• Treatment

10. Introduction
• Homeostasis is an adaptive mechanism in a
living organism that regulates its internal
environment and tends to maintain a stable,
constant condition under wide environmental
variations.
• It allows an organism to function effectively in
a broad range of environmental conditions
(both internal and external)1.

11. Fed-Fast Cycle (or Feed-Fast Cycle)
• Human beings usually take their food
intermittently, 2 to 4 times a day as large
meals.
• Therefore, they go through two alternating
physiological nutritional states –
• Fed or Absorptive State
• Fasting or Post-absorptive State,
• Constituting a fed-fast cycle.

12. Metabolic Fuel Molecules
• They are sources of energy (produce ATP) for the
cells.
• Glucose and fatty acids, present in blood, are the
major or principal metabolic fuel molecules.
• Other fuel molecules are amino acids (produced
from proteins) and ketone bodies (produced
from fatty acids).

13. • However, ketone bodies are more important
during prolonged fasting and starvation than
during normal physiological nutritional states.
• Dietary glucose in excess is stored as glycogen
and fatty acids as TAG. The energy/calories of
excess glucose and amino acids are stored as
TAG in adipose tissues.

14. Integration of metabolism
• Carbohydrates, lipids and proteins are the
principal foods providing essential fuel to the
body.
• Their metabolisms are interrelated, coordinated
or integrated to ensure provision of fuels to
various tissues and have an impact on health and
disease.
• Metabolic changes or adaptations occur during
blood glucose homeostasis, starvation and in
diabetes mellitus.

15. • The blood glucose level is normally
maintained within fairly narrow range.
• In a healthy individual, the normal fasting
blood glucose level is 70-110 mg /dl
(Normoglycemia).
• After ingestion of a meal (post prandial) blood
glucose level may normally rise to
120-140 mg /dl.
Mechanism of Blood Glucose Homeostasis or
Regulation of Blood Glucose Concentration

16. Fasting (8-10 hours after meal)
70-110 mg /dl
Normal blood glucose values
Postprandial (2 hours after meal)
< 140 mg /dl
Random (irrespective of meal times)
70-140 mg /dl

17. Maintenance of normal blood glucose level is
important because-
Brain, RBC and renal medulla have an obligatory
requirement for glucose as energy source.
Increased blood glucose level (Hyperglycemia) can cause
complications of Diabetes mellitus.
Decreased blood glucose level (Hypoglycemia) can cause
coma and even death mainly due to deprivation of glucose
to brain.

18. • Homeostasis mechanisms are brought into
play following a meal when the blood glucose
level rises and again during fasting, when the
level falls.
• Plasma glucose concentration is dependent
on the quantity of glucose that enters
circulation from various sources and the
amount that is utilized by tissues, as shown in
the figure below.

19. • Sources of blood glucose Utilization of blood glucose
• Dietary intake, Glycolysis & TCA cycle
• intestinal absorption
• Glycogenesis (Liver)
• Glycogenolysis (liver)
• Gluconeogenesis Fatty acid synthesis
•
TAG synthesis
Capillary
Blood
Glucose
c
c

20. • Factors regulating blood glucose level are as
follows.
– Neuronal Activity
– Hormones
• Neuronal Activity
• Eating behavior which influences the glucose
levels is controlled by hypothalamus (satiety
centre and feeding centre) in response to
falling and raising blood glucose levels.

21. • Normal blood glucose is a result of balance between
2 sets of hormones.
• 1.hyperglycemic hormones- 6 hormones which
increase bl.glucose- they are, Glucagon, ACTH,
steroid hormones, thyroid hormone, adrenal
hormones, growth hormone.
• 2. hypoglycemic hormones- hormones which
decrease blood glucose.
• Insulin is the only hypoglycemic hormone.
Hormones

23. Hormones
• Insulin and Glucagon are the principal
hormones for controlling plasma glucose
levels.
• Insulin decreases the blood glucose level and
is called hypoglycemic hormone.
• Glucagon raises the blood glucose level and is
called hyperglycemic hormone.
• Insulin antagonists

24. • Hormones are the principal mediators of
metabolic changes required for glucose
homeostasis.
• They regulate activities of-
• 1) key enzymes of metabolic pathways
• (By induction/repression,
phosphorylation/dephosphorylation etc)
• 2) membrane transporters
• Important tissues involved and targeted by
hormones in the maintenance of blood glucose
level are liver, adipose tissue and skeletal
muscles.

25. Glucose-sparing effect
• Alternative fuel molecules – free fatty acids,
aminoacids and ketone bodies have
• glucose-sparing effect
• because they are utilized by cells for energy in
preference to glucose.

26. Role of Insulin in Glucose
Homeostasis
• Insulin is secreted by -cells of pancreas in
response to raising blood glucose level during
fed state.
• Insulin brings down blood glucose level
(hypoglycemic in action) by increasing
utilization of glucose by cells as shown below.
• Another action of insulin is that it inhibits the
secretion of glucagon, which is an insulin
antagonist.

28. Actions of Insulin (Metabolic effects)
Extrahepatic cells Liver Capillaries Adipose Tissue
↑Glucokinase → ↑ Glucose uptake
↑ Glycogenesis
 Glycogenolysis
 Gluconeogenesis
↑ Glycolysis →↑ Acetyl CoA

↑ Fatty acid synthesis
↑TAG synthesis→ ↑VLDL export
↑Lipoprotein Lipase

↑ Mobilization of fatty acids
from VLDL and chylomicrons
and entry to Adipose tissue
↑ Glucose transporter
(GLUT-4)

↑ Glucose uptake into cells
 Hormone-Sensitive Lipase

↑TAG synthesis
 Free Fatty acid
release into blood
 Blood glucose
concentration

29. Role of Glucagon in Glucose
Homeostasis
• Glucagon is secreted by -cells of the pancreas in
response to falling blood glucose level.
• Glucagon raises blood glucose level by
mechanisms shown below.
• Glucagon also mobilizes fatty acids and glycerol
from adipose tissue.
• Fatty acids are the most important alternative
fuel molecules and glycerol serves as substrate
for gluconeogenesis.

30. • Actions of glucagon(Metabolic effects)
Liver
↑Glycogenolysis
Glycogenesis
↑ Gluconeogenesis
Glycolysis →  Acetyl CoA

Fatty acid synthesis

TAG synthesis
↑ Blood
Glucose
concentration
Adipose Tissue
↑Hormone Sensitive Lipase
TAG synthesis
↑ Free Fatty acid release into blood
↑Glucose- sparing action

31. During the fed state
• blood glucose level tends to rise due to
intestinal absorption of glucose.,which
stimulates insulin release.
• glucose is converted to storage compounds –
glycogen in liver and triacylglycerol in adipose
tissue
• This prevents the rise of blood glucose level.

33. During the fasting state
• blood glucose level tends to decrease due to
utilization of glucose by cells for energy.,which
stimulates Glucagon release.
• This causes mobilization of glucose from
glycogen, synthesis of glucose (both in liver) and
• mobilization of alternative fuel molecules – free
fatty acids (from adipose tissue) and ketone
bodies (from liver).
• Amino acids (from tissue proteins – mainly
skeletal muscles) and glycerol (from adipose
tissue) are utilized in the liver to synthesize
glucose.

35. Biochemistry of Starvation
• Starvation is a state caused due to acute
deprivation of food for more than 18 hours.
• It may result from:
– An inability to obtain food Eg: famine, natural
calamities, war.
• From the desire to lose weight rapidly

36. Metabolic changes in Starvation
• are adaptations of the body to lack of fuel
supply and are an exaggeration of the normal
response of the body to fasting.
• The metabolic changes are required to:
• provide energy to brain
• provide alternative fuel molecules
• principally involve degradation of stored forms
of metabolic fuel- glycogen, TAG and proteins

37. The cause and effect chain of
metabolic changes in starvation
• Starvation (absence of food) →  Basal Metabolic Rate
•
•
Falling blood glucose level
•
• Decrease in insulin secretion and an increase in glucagon
release
• ( Insulin/glucagon ratio).
•
• Changes in the metabolisms of carbohydrate, fat and proteins
• (mainly in liver, adipose tissue and skeletal muscles,
respectively)

38. Complications of Starvation
• Major complications of starvation are-
• Ketoacidosis
• Fatty liver
• Muscle-wasting

39. Biochemical basis (mechanism)
Falling blood glucose level
 Insulin/glucagon ratio
↑ Lipolysis (in adipose tissue)

↑ Plasma free fatty acids

↑ Hepatic uptake of free fatty acids

↑Triacylglycerol synthesis in liver

Fatty liver
↑ Gluconeogenesis (in liver)
Oxaloacetate (in liver)
↑ Acetyl CoA (in liver)
↑ Ketogenesis (in liver)
Ketosis - Ketoacidosis
Coma → Death

40. • Biochemical basis (mechanism) cont’d
Falling blood glucose level
 Insulin/glucagon ratio
↑ catabolism of skeletal muscle protein
Muscle wasting

41. Diabetes Mellitus
• Introduction:
• Diabetes mellitus is a major public health
problem affecting about 3% of global population.
• Diabetes mellitus is the 3rd leading cause of death
in many developed countries (after heart disease
and cancer).
• India is the ‘Diabetes Capital’ of the world. The
prevalence of diabetes mellitus in urban India is
12.1% (2001-National Survey), is rising, and is
higher in South India than in the North.

42. • Definition:
• Diabetes mellitus is a metabolic disorder
characterized by hyperglycemia.
• Types:
• Type 1 diabetes mellitus
• [Formerly Insulin-Dependant Diabetes Mellitus or
IDDM, Juvenile-onset]
• destruction of insulin producing -cells leading to
absolute insulin deficiency may be caused due to
viral infection and autoimmune attack

43. • blood level of insulin is always very low
• comprises about 10 % of diabetic cases
• patients < 35 years age
• Type 2 diabetes mellitus
• [Formerly Non Insulin-Dependant Diabetes
Mellitus or NIDDM, Adult-onset]
• relative insulin deficiency with insulin resistance
due to down-regulation
• (decrease in number) of insulin receptors on cells
• blood level of insulin is either normal or high
• comprises about 90% of diabetic cases
• patients aged > 40 years and usually obese

44. • Other rarer causes of Diabetes Mellitus are:
• Hormonal – Acromegaly (↑growth hormone),
Cushing’s syndrome (↑corticosteroid),
glucagonoma, pheochromocytoma ( adrenalin),
hyperthyroidism, etc.
• Diseases of pancreas – e.g., chronic pancreatitis
• Gestational diabetes mellitus (seen during later
months of pregnancy)

45. Metabolic Changes in Diabetes
Mellitus
• The metabolic changes that occur in diabetes
mellitus are due to decrease of insulin or
rather, decrease in insulin/glucagon ratio.
• The body cells are starved of energy despite
high glucose concentration around them
(starvation in the midst of plenty).

46. Metabolic Changes in Diabetes Mellitus (cont.)
Diabetes Mellitus
Insulin/glucagon ratio
Glucose uptake Glycogenolysis Gluconeogenesis Lipolysis
(extrahepatic tissues) (liver) (liver) (adipose tissue)
Plasma FFA’s
Glucose sparing effect
 Hepatic uptake of FA’s
Hyperglycemia
 Ketogenesis
Glucose sparing effect
Ketonemia

47. Biochemical Basis for Clinical
Manifestations in Diabetes Mellitus
• Major symptoms of diabetes mellitus are-
• polyuria (increased urine output)
• polydypsia (increased thirst)
• polyphagia (increased hunger)
• weakness and weight loss in spite of
adequate calorie intake
• Other cardinal manifestation of diabetes mellitus is
glycosuria (glucosuria).

48. ↑Lipolysis
Insulin/glucagon ratio
Blood glucose level
> 180mg/dl ( Renal threshold ) ↑Loss of
Glucosuria Hyperglycemia adipose
tissue
↑ conc of glucose ↑ Gluconeogenesis
in renal tubular fluid
↑ Protein metabolism
↑ Muscle wasting
Osmotic diuresis  Glu uptake feeding centre
in muscles chronically active
in brain
Polyuria Weakness Hunger(polyphagia) Weight loss

49. Polyuria
↑ Osmotic pressure in extra cellular fluid
Tissue dehydration (in brain)
+
Thirst centre
↑ Thirst (polydypsia)

50. Biochemical basis of Glucosuria in
Diabetes mellitus
• Normally, when blood glucose levels are within
normal limits, all the glucose that is filtered by
the glomerulus is completely reabsorbed by the
renal tubules. So, glucose is not excreted in urine.
• In diabetes mellitus, glucosuria i.e. excretion of
glucose in urine, occurs because of an abnormal
increase of blood glucose level (hyperglycemia)
above the renal threshold of 160 to 180 mg/dL.

51. Biochemical Basis for Complications
of Diabetes Mellitus
• Diabetes mellitus has both acute (short term) and
chronic (long term) complications
• Acute Complications:
• Diabetic ketoacidosis (seen commonly in Type 1
diabetes mellitus)
• Hyperosmolal non-ketotic coma (seen commonly
in Type 2 diabetes mellitus) are the acute
complications of untreated diabetes mellitus.
• The mechanisms of these complications are as
follows.

52. 1) Mechanism of Ketoacidosis in Type 1 Diabetes
Mellitus
 Insulin/glucagon ratio
↑ Lipolysis (in adipose tissue) ↑ Gluconeogenesis (in liver)
↑ Plasma free fatty acids  Oxaloacetate (in liver)
↑ Hepatic uptake of free fatty acids ↑ Acetyl CoA (in liver)
↑ Ketogenesis (in liver)
Ketoacidosis (in type 1 diabetes mellitus), Hyperkalemia
Coma → Death

53. 2) Mechanism of Hyperosmolal Non-ketotic
Coma in Type 2 Diabetes Mellitus
Insulin/glucagon ratio
Hyperglycemia
 Osmotic pressure in extra cellular fluid
Dehydration of brain tissue
Hyperosmolal coma → Death

54. Chronic (long term) Complications of
Diabetes Mellitus and their Biochemical Basis
• The long-term complications of diabetes mellitus
include cataract, polyneuropathy, retinopathy,
nephropathy, myocardial infarction, stroke,
gangrene, fatty liver, etc.
• These complications are thought to be due to the
direct consequences of either-
• 1) high blood glucose levels (hyperglycemia) or
• 2) decreased insulin/glucagon ratio.

55. 1) Hyperglycemia
Non-enzymatic glycosylation (glycation) of proteins
Atherosclerosis (in arteries) – Angiopathy
Macrovascular disease Microvascular disease
(Due to damage to arteries) (Due to damage to the arterioles)
Myocardial infarction Retinopathy and
Nephropathy
Stroke
Gangrene

56. 1) Hyperglycemia(cont’d)
 Substrate flux
Activation of the polyol pathway
Glucose
Sorbitol production
Osmotic effect due to accumulation of sorbitol
Cataract (in lens)
Polyneuropathy ((In Schwann cells)

57. 2)  Insulin/Glucagon ratio
↑ Lipolysis (in adipose tissue)
↑Plasma free fatty acids in blood
↑ Hepatic uptake of free fatty acids
↑ Hepatic triacylglycerol synthesis
Fatty Liver

58. Diagnosis of Diabetes Mellitus
• In addition to clinical symptoms, tests useful in
the diagnosis are-
• Estimation of plasma glucose: Blood samples are
drawn under fasting, postprandial or random
conditions.
• Normal values:
• Fasting (8-10 hours after meal) 70-110 mg /dl
• Postprandial (2 hours after meal)< 140 mg /dl
• Random (irrespective of meal times) 70-140
mg /dl

59. WHO Criteria for Diagnosis of
Diabetes Mellitus
• Fasting plasma glucose –– > 125 mg/dL
• Or
• 2 hour plasma glucose –– > 200 mg/dL
• Or both
•
• Glycosuria is seen usually in at least one urine
sample.
• Higher values indicate more severe diabetes
mellitus

60. Glycosuria
• Glycosuria refers to excretion of (any) sugar in
urine.
• Glucosuria (excretion of glucose in urine) is
the most common form of glycosuria.
• Urine tests for Glycosuria or Glucosuria are
used most often to screen for, confirm a
diagnosis of or monitor the control of
diabetes mellitus.

61. Types of Glycosuria Causes
Glucosuria Diabetes mellitus, Renal glycosuria,
Alimentary glycosuria (after
ingestion of excess carbohydrates)
Lactosuria Pregnancy and Lactation, Lactase
Deficiency
Galactosuria Galactosemia
Fructosuria Essential Fructosuria, Hereditary
fructose intolerance
Pentosuria Essential Pentosuria

62. Renal glycosuria
• In this condition, glucosuria (excretion of
glucose in urine) occurs even when blood
glucose levels are normal.
• Biochemical basis of Renal Glucosuria
• normal renal threshold for glucose is 160 to 180
mg/dL.
• But, due to defect in renal tubules in Renal
glycosuria ,The capacity of renal tubules to
reabsorb glucose is decreased– lowering the
renal threshold for glucose.
• Hence glucose is excreted in urine
,even though blood glucose levels are
normal.
It is normoglycemic glucosuria.

63. Renal glycosuria..contd..
• Blood glucose estimation can differentiate
diabetes mellitus from renal glycosuria. Blood
glucose level will be higher than normal in
diabetes mellitus and normal in renal
glycosuria.
• Harmless condition, doesn’t require any
treatment.

64. Glycated hemoglobin- HbA1C
• Non enzymatic addition of glucose to Hb
is called glycosylation of Hb.,and such Hb
is called glycated Hb.
• Extent of Hb glycation is directly
proportional to blood glucose levels and
it is irreversible.
• Glycated Hb remains in circulation for the
entire life span of RBC(120 days)
• Normal value is <5.5% (4-5.5%)

66. diabetes

67. Significance of HbA1C
-HbA 1C level increases in diabetes.
HbA 1C levels reflect average blood glucose conc.
Or glycemic control of previous 8-10 weeks.
-Since extent of Hb glycation is directly
proportional to blood glucose levels, levels
indicate severity of diabetes, hence used for
monitoring the response to treatment.
-Hence it has a prognostic significance.

68. • Interpretation of HbA1C Values
• <5.5% - non diabetic or very good control of
diabetes.
• 5.5 – 7% - adequate control
• > 7% - poor control