REGULATION OF BLOOD GLUCOSE

Normal Blood glucose levelsFasting levels: 70-110 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.

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, synthesis of glycoproteins.

6. Formation of ribose sugars and nucleic acid synthesis.

Blood glucose levels in Fasting state

Also called as post absorptive state.Aprrox 12-14 hrs after the meal.Only source of glucose – Liver glycogenMuscle glycogen ??

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.

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

Blood glucose regulation

• 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

Glucose Entry in to the Cell

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.

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.

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

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 synthesisSuppression of circulating ketone body concentrations

• Activation of adipose lipoprotein lipase

– 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

Role of Insulin Protein Metabolism and Growth

Summary of feedback mechanism for regulation

↑ blood glucose↓

↑ insulin

↓

↑ transport of glucose into cells,↓ gluconeogenesis, ↓ glycogenolysis

↓

↓ blood glucose↓

↓ insulin

Regulation of Insulin Secretion

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.

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

Role of Glucagon

20

Metabolic Effects of Glucagon

Insulin – Anabolic and Glucagon - Catabolic

Metabolic Action Insulin Glucagon

Glycogen synthesis ↑ ↓

Glycolysis (energy release)

↑ ↓

Lipogenesis ↑ ↓

Protein synthesis ↑ ↓

Glycogenolysis ↓ ↑

Gluconeogenesis ↓ ↑

Lipolysis ↓ ↑

Ketogenesis ↓ ↑

• Early response– Glucagon– Epinephrine

• Delayed response– Cortisol– Growth hormone

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

Counter Regulatory Hormones

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

Glucagon Secretion

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

Role of Glucagon

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.

Role of Epinephrine

• 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.

Role of Cortisol and GH

• 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

Cortisol

• 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.

Growth Hormone (GH)

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%

↑ RaPrimary

Second Defense

↑ Epinephrine 65 - 70 mg%

↑ Ra ↓

Rd

Critical Third Defense

↑ Cortisol, GH 65 - 70 mg%

↑ Ra ↓

Rd

Not Critical

↑ Food ingestion

50 - 55 mg%

↑ Exogenous

Glucose

< 50mg% no cognitive change