REGULATION OF BLOOD GLUCOSE

Normal Blood glucose levelsFasting levels: 70-100 mg/dLPostprandial : up to 140 mg/dL

Maintained with in physiological limits by 1. Rate of Glucose entrance into blood

circulation2. Rate of its removal from the blood stream.

Plasma glucose level Glucose Concentration ( mg/dl ) 200 post prandial level Diagnostic for Diabetics 180 ( Renal thereshold ) Hyperglycemia 140 PP Normal 126 Fasting level Diagnostic for Diabetics 100Normal (F) 70Hypoglycemia 40 Hypoglycemic Coma

What goes wrong when the concentration decreases?

HypoglycaemiaThe symptoms associated

with low blood sugar are: tiredness, confusion,

dizziness, headaches, mood swings, muscle weakness, tremors, cold sweating , irreversible CNS damage, coma, death

What goes wrong when the concentration increases too far?

HyperglycaemiaThe symptoms include: Excessive thirst; frequent urination; fatigue; weight loss; vision problems, such

as blurring; increased susceptibility to infections, Dibetes mellitus

Rate of glucose entrance in to the blood by:1. Absorption from intestine2. Hepatic glycogenolysis3. Gluconeogenesis4. Glucose obtained from other carbohydrates,

eg: fructose, galactose etc

Rate of Removal of Glucose from blood depends on:

1. Oxidation of glucose by tissue to supply energy2. Hepatic glycogenesis3. Glycogen formation in muscles4. Conversion of glucose to fats in adipose tissues5. Synthesis/formation of fructose in seminal fluid,

lactose in mammary gland.6. Formation of ribose sugars and nucleic acid

synthesis.

Stages of maintenance of blood glucose level

Absorptive stage

• Absorptive stage starts from feeding and lasts upto 3-4 hours after meal. During this phase following activities takes place with regards to glucose.

• Dietary glucose to liver and then to most tissue.• Glucose is used as a fuel by most tissues.• Excess of glucose is stored as glycogen in liver

and muscles.

Post absorptive phase

The post absorptive phase lasts for about 16-18 hours after the absorption(3-4hours after meal) is completed. The main activities necessary with regards to glucose are as follows:

• Lever glycogenolysis become the major source of blood sugar.

• Muscle use its glycogen stores for energy.• Gluconeogenesis starts gradually and peaks about 24 hours

after the last meal.• Glycogenolysis starts declining after 16-18 hours and by

about 24-30 hours is negligible.

Starvation

• After about 1-11/2 day of the starvation, gluconeogenesis is the main source of glucose.

• Fatty acids mobilized from adipose tissue become an alternate fuel for energy for most tissue.

• Lactate and glycerol are reutilized for gluconeogenesis .ATP produced in fatty acid oxidation is used in liver for gluconeogenesis and other body functions.

• High rate of hepatic gluconeogenesis continues for few days in early starvation.

Prolonged starvation• If starvation continues further beyond 2-3 days and

extend into weeks, hepatic gluconeogenesis decrease and gluconeogenesis in kidney becomes more significant.

• Protiens in muscle are broken down to provide gluconeogenic amino acids. Fats are the energy source of most tissue.

• If starvation continue beyond without any feeding, lipid stores are also depleted and several associated complication, like ketoacidosis, dehydration, etc., occur ultiemately death follows.

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.

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

Response to Elevated Blood Glucose

Role of Liver and Extrahepatic Tissues• GLUT-2 is freely permeable to glucose and is the

main hepatic glucose transporter ( None insulin dependent).

• GLUT-4 is main glucose transporter of extrahepatic tissues i.e muscle, adipose tissues, etc. ( insulin dependent).

• Hence,the glucose uptake from blood by extrahepetic tissues is regulated by insulin. This is become rate limiting step in glucose utilization in the absence of insulin.

• But the glucose uptake by liver is independent of insulin.

Role of Hexokinase and Glucokinase• Liver has glucokinase and hexokinase while most extrahepetic

tissue have only hexokinase.• Hexokinase is saturable, has low Km for glucose and is

product feed back inhibited.• Glucokinase is non-saturable , has high Km for glucose and not

product feed back inhibited.• Liver continues to have high glucose uptake during

hyperglycaemia.• Extrahepatic tissue is product feed back inhibited due to

accumulation of glucose-6-phosphate even though insulin is present.

• So at high blood glucose concentration, liver has a net uptake of glucose. But it is net producer of glucose at low or normal blood glucose concentration.

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 and Glucocorticoids .

Summary of feedback mechanism for regulation↑ blood glucose

↓↑ insulin

↓↑ transport of glucose into cells,

↓ gluconeogenesis, ↓ glycogenolysis↓

↓ blood glucose↓

↓ insulin

Regulation of Insulin Secretion

Insulin Control

Muscle Glucose uptake Glycogen synthesis

Liver Glucose uptake Glycogen synthesis Fatty acid synthesis¯ Glucose synthesis

BrainNo effect

PancreasBeta cells

Gastrointestinalhormones

Feedback

¯ amino acids

¯ glucose

¯ triglyceridesAdipose Glucose uptake Glycerol production¯ Triglyceride breakdown Triglyceride synthesis Insulin

Most Cells Protein synthesis

Amino acids

Bloodglucose

GLUCOGON• Overall effects of glucogon are hyperglycemic.• It is produced by α-cells of islet cells of pancreas in response

to hypoglycemia.• Its action are mostly opposite to those of insulin and most

actions are on liver.• It promotes glucose sparing by inhibiting glucose utilizing

pathways, i.e.– ↓ glycolysis through PFK-1 by decreasing fructose-1, 6-bisphosphate.– ↓ Citric acid cycle due to reduced PDH activity due to low insulin levels.– ↓ Glycogenesis by inhibiting glycogen synthase through phosphorylation

• It promotes glucose production by the following:– ↑Glycogenolysis by stimulating phosphorylase through phosphorylation.– ↑ Gluconeogenesis by inducing pyruvate carboxylase, pyruvate carboxykinase

and glucose 6-phosphatase.

Glucagon Control

Liver Glycogen breakdown Glucose synthesis Glucose release

BrainNo effect

PancreasAlpha cells

Exercise

Feedback

Adipose Triglyceride breakdown¯ Triglyceride storage

Blood glucose

Fatty acids

Epinephrine(stress)

Amino acids

Insulin – Anabolic and Glucagon - Catabolic

Metabolic Action Insulin GlucagonGlycogen synthesis ↑ ↓Glycolysis (energy release)

↑ ↓

Lipogenesis ↑ ↓Protein synthesis ↑ ↓Glycogenolysis ↓ ↑Gluconeogenesis ↓ ↑Lipolysis ↓ ↑Ketogenesis ↓ ↑

Epinephrine

– The second early response hyperglycemic hormone.

– 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.

Role of Epinephrine

Glucocorticoids Hormones

• Glucocorticoid hormones are mainly secreated from adrenal cortex and some amount is also synthesized in adipose tissue.

• They induce aminotransferase enzyme synthesis leading to enhanced amino-acids catabolism.

• They also cause the induction of key enzymes of gluconeogenesis (Fructose-1,6-biphosphatase, pyruvate carboxylase ).

• Overall they increase the glucose level. ().

• These are long term hyperglycemic hormones. Activation takes hours to days.

• Cortisol is a steroid hormone – Cortisol act to decrease glucose

utilization in most cells of the body– Effects of these hormones are mediated

through the CNS. -- It is synthesized in the adrenal cortex.

Cortisol

Growth hormone: i)Decreases glucose uptake in tissues

ii)Increase liver gluconeogenesis

iii)It promotes fatty acids mobilization from adipose tissues leading to incressed fatty acid oxidation and ATP production

. iv)Increased ATP and NADH inhibit glucose

utilization by cell in glycolysis .