1. REGULATION OF BLOOD GLUCOSE

2. Normal Blood glucose levels
Fasting levels: 70-110 mg/dL
Postprandial : up to 140 mg/dL
Maintained with in physiological limits by
1. Rate of Glucose entrance into blood
circulation
2. Rate of its removal from the blood stream.

3. Rate of glucose entrance in to the blood by:
1. Absorption from intestine
2. Hepatic glycogenolysis
3. Gluconeogenesis
4. Glucose obtained from other
carbohydrates, eg: fructose, galactose etc

4. Rate of Removal of Glucose from blood depends on:
1.
2.
3.
4.
5.
Oxidation of glucose by tissue to supply energy
Hepatic glycogenesis
Glycogen formation in muscles
Conversion of glucose to fats in adipose tissues
Synthesis/formation of fructose in seminal fluid,
lactose in mammary gland, synthesis of
glycoproteins.
6. Formation of ribose sugars and nucleic acid
synthesis.

5. Blood glucose levels in Fasting state
Also called as post absorptive state.
Aprrox 12-14 hrs after the meal.
Only source of glucose – Liver glycogen
Muscle glycogen ??

6. Blood glucose levels in postprandial state
Condition following ingestion of food.
Absorbed monosaccharides are utilised for
oxidation to provide energy.
Remaining in excess is stored as glycogen in the
Liver and Muscle.
40% of the glucose absorbed is used for
lipogenesis and remaining is used for synthesis
of glycoproteins and glycolipids.

7. Response to low Blood Glucose
In the fasting state there will be decreased blood
glucose levels.
This stimulates the secretion of Glucagon from
pancreas.
The Glucagon released into the blood will stimulate
hepatic glycogenolysis and
gluconeogenesis, there by increasing the blood
glucose levels.
Once the blood glucose levels raises to the normal
levels, the stimulus for the release of Glucagon
will diminish.

8. Response to Elevated Blood Glucose
In the post prandial state (after a meal)

Remember there are two separate signaling events

First signal is from the ↑ Blood Glucose to pancreas

To stimulates insulin secretion in to the blood
stream

The second signal from insulin to the target cells

Insulin signals to the muscle, adipose tissue and
liver to permit to glucose in and to utilize glucose

This effectively lowers Blood Glucose

9. Blood glucose regulation

10. Glucose Entry in to the Cell
• Insulin/GLUT4 is not the only pathway
• Insulin-dependent, GLUT 4 - mediated
– Cellular uptake of glucose into muscle and
adipose tissue (40%)

InInsulin-independent glucose disposal (60%)
- GLUT 1 – 3 in the Brain, Placenta, Kidney
– SGLT 1 and 2 (sodium glucose symporter)
– Intestinal epithelium, Kidney

11. Hormonal Regulation of Blood glucose
There are two categories of endocrine
influences.
a) Hormone which will decrease the blood
glucose levels : Insulin
b) Hormones which will increase the blood
glucose levels:
Glucagon, Epinephrine, Cortisol, Thyroid
hormones.

12. Action of Insulin on Carbohydrate
metabolism
Diminishes the supply of glucose to the blood by
• Facilitates the conversion of glucose to glycogen
for storage in the liver and muscle by Activation of
glycogen synthase.
• Decreases the breakdown and release of glucose
from glycogen by the liver by Inhibition of glycogen
phospharylase activity.
• Diminishes gluconeogenesis by Inhibiting
–
–
–
–
pyruvate carboxylases activity
PEP carboxykinases.
Fructose 1,6 bisphosphatase.
glucose 6 phosphatase.

13. Increases the rate of utilization of glucose by
tissues by
Facilitates the transport of glucose into
muscle and adipose cells(GLUT 4).
Activating the Oxidation of glucose for energy
production
Increased glycogenesis – activating glycogen
synthase

14. Action of Insulin on Lipid metabolism
• Increased lipogenesis (by activation of acetyl CoA
carboxylase)
• Inhibition of FFA mobilization from adipose
tissue via suppression of lipolysis by
inhibiting activity of hormone sensitive lipase
• Inhibition of plasma FFA uptake and oxidation
via suppression of lipolysis
• Inhibition of hepatic VLDL synthesis
Suppression of circulating ketone body
concentrations
• Activation of adipose lipoprotein lipase

16. Role of Insulin Protein Metabolism and Growth
– Increases transport of amino acids
– increases mRNA translation and new Proteins,
– A direct effect on ribosomes
– Increases transcription of selected genes,
– Especially enzymes for nutrient storage
– Inhibits protein catabolism
– Acts synergistically with growth hormone

17. Regulation of Insulin Secretion
Summary of feedback mechanism for regulation
↑ blood glucose
↓
↑ insulin
↓
↑ transport of glucose into cells,
↓ gluconeogenesis, ↓ glycogenolysis
↓
↓ blood glucose
↓
↓ insulin

18. Lack of insulin
– Occurs between meals, and in diabetes.
– Transport of glucose and amino acids into the
cells decreases, leading to hyperglycemia.
– Hormone sensitive lipase is activated,
– Causing TG hydrolysis and FFA release.
– ↑ FFA conversion in liver →
– Phospholipids and cholesterol →
– Lipoproteinemia,
– FFA breakdown leads to ketosis and acidosis.

19. Role of Glucagon
• Metabolic Effects of Glucagon
–
–
–
–
Increases hepatic glycogenolysis
Increases gluconeogenesis
Increases amino acid transport
Increases fatty acid metabolism (ketogenesis)

20. Metabolic Effects of Glucagon
20

21. Insulin – Anabolic and Glucagon - Catabolic
Metabolic Action
Insulin
Glucagon
Glycogen synthesis
↑
↓
Glycolysis (energy release)
↑
↓
Lipogenesis
↑
↓
Protein synthesis
↑
↓
Glycogenolysis
↓
↑
Gluconeogenesis
↓
↑
Lipolysis
↓
↑
Ketogenesis
↓
↑

22. Counter Regulatory Hormones
• Early response
– Glucagon
– Epinephrine
• Delayed response
– Cortisol
– Growth hormone

23. Counter Regulatory Hormones
• Glucagon
– Acts to increase blood glucose
– Secreted by alpha cells of the pancreas
– Chemical structure 29 amino acids
– Derived from 160 aminoacid proglucagon
precursor

24. Glucagon Secretion
Stimulation of Glucagon secretion
– Blood glucose < 70 mg/dL
– High levels of circulating amino acids
– Especially arginine and alanine
– Sympathetic and parasympathetic stimulation
– Catecholamines
– Cholecystokinin, Gastrin and GIP
– Glucocorticoids

25. Role of Glucagon
• Metabolic Effects of Glucagon
–
–
–
–
Increases hepatic glycogenolysis
Increases gluconeogenesis
Increases amino acid transport
Increases fatty acid metabolism (ketogenesis)

26. Role of Epinephrine
Epinephrine
– The second early response hyperglycemic hormone.
– This effect is mediated through the hypothalamus in
response to low blood glucose
– Stimulation of sympathetic neurons causes release
of epinephrine from adrenal medulla .
– Epinephrine causes glycogen
breakdown, gluconeogenesis, and glucose release
from the liver.
– It also stimulates glycolysis in muscle
– Lipolysis in adipose tissue,
– Decreases insulin secretion and
– Increases glucagon secretion.

27. Role of Cortisol and GH
• These are long term hyperglycemic
hormones
• Activation takes hours to days.
– Cortisol and GH act to decrease glucose
utilization in most cells of the body
– Effects of these hormones are mediated
through the CNS.

28. Cortisol
• Cortisol is a steroid hormone
– It is synthesized in the adrenal cortex.
– Synthesis is regulated via the hypothalamus
(CRF) and anterior pituitary (ACTH).
• Clinical correlation: Cushing’s Disease

29. Growth Hormone (GH)
• GH is a single chain polypeptide hormone.
• Source is the anterior pituitary
somatotrophs.
• It is regulated by the hypothalamus.
• GHRH has a stimulatory effect.
• Somatostatin (GHIF) has an inhibitory
effect.
• Clinical correlation: Gigantism and
Acromegaly cause insulin resistance.

30. Responses to decreasing Glucose levels
Response
Glycemic
theshhold
Physiological
effects
Role in counter
regulation
↓ Insulin
80 - 85 mg%
↑ Ra (↓ Rd)
Primary
First Defense
↑ Glucagon
65 - 70 mg%
↑ Ra
↑ Epinephrine
65 - 70 mg%
↑ Ra ↓ Rd
Critical
Third Defense
↑ Cortisol, GH
65 - 70 mg%
↑ R a ↓ Rd
Not Critical
↑ Food ingestion 50 - 55 mg%
Primary
Second Defense
↑ Exogenous
< 50mg% no
Glucose
cognitive change