BLOOD GLUCOSE REGULATION

OUTLINE • Why to know?• Different Terms used.. • Normal levels.. • What should we study in BGR?• Factors regulating…• Glucose regulation in special situations…

BASIC PRINCIPLES• Humans have a constant requirement for energy but

eat only intermittently.• Ingestion of food in excess of the immediate caloric

needs of our vital organs. • Store the extra calories

• Hepatic and muscle: glycogen, • Adipose tissue: triglyceride,• Tissue :protein.

• Fuel reservoirs used when needed.

• The two principal circulating fuels, • Glucose (glycogen)• Free fatty acids (triglycerides)

• The largest reservoir of glycogen• Liver (10 gm/100 gm)• Skeletal muscle (1-2 gm/100 gm)

• But liver glycogen provides free glucose during fasting.• Provides glucose for about 16 hrs-18 hrs of fasting.• After that fatty acid oxidation meets energy

requirement.

WHY TO KNOW BGR…..• The brain has a continuous need for fuel but stores

almost no energy as glycogen or fat.• Instead, it uses glucose derived from the liver either

directly from glycogen or indirectly from other fuel reservoirs through gluconeogenesis.

• The brain does not use FFAs directly.• Not capable of gluconeogenesis.

TERMS USED IN BLOOD GLUCOSE MONITORING…

• FASTING BLOOD GLUCOSE• When measured after 12 hours over night fast

• POST-PRANDIAL• Measured 2 hours after meal• Prandium in Latin means meal or repast

• RANDOM BLOOD GLUCOSE• Measured without any prior preperations

NORMAL VALUES*

• FASTING GLUCOSE < 100 mg/dL < 6.1 mmol/L

• POST PRANDIAL (2 HRS AFTER EATING ) < 140 mg/dL < 7.8 mmol/L

• RANDOM 70 - 140 mg/dL

* AMERICAN DIABETIC ASSOCIATION

WHAT TO KNOW…

• Five phases of glucose homeostasis• Glucose homeostasis• Hormonal • Non-hormonal

• Details of hormonal regulation

FIVE PHASES OF GLUCOSE HOMEOSTASIS

• Based on the source and quantity of glucose entering the circulation.

I • well fed state (< 4 hrs)

II • hepatic glycogenolysis(16 hrs)

III• hepatic gluconeogenesis (<40

hrs)IV

• gluconeogenesis & ketogenesis (24 days)

V •ketogenesis mainly (40 days)

PHASE I• First few hours after a carbohydrate meal, glucose

meets metabolic needs of the brain and other organs. • Excess of these is used to rebuild fuel reservoirs. • Plasma insulin levels are high, plasma glucagon levels

are low, • Glycogen synthesis is stimulated in liver and muscle.

PHASE II(EARLY STARVATION)

• With plasma insulin decrease and increase in plasma glucagon that accompany an overnight fast, fuel homeostasis shifts from energy storage to energy production

• At this stage, glucose is derived principally from the breakdown of liver glycogen and,

• Gluconeogenesis from lactate, amino acids, and glycerol in the liver, kidneys and intestines

PHASE III(PROLONGED STARVATION)

• Limits the need for gluconeogenesis and thereby conserve body protein .

• Increase utilization of lipid-derived fuels• The second is a change in the fuels used by the brain.

• During early starvation, the CNS continues to use glucose as its exclusive fuel.

• as starvation is prolonged it uses ketone bodies• Decrease in plasma leptin, which by diminishing

sympathetic nervous system activity, would diminish the basal metabolic rate.

PHASE IV• Gluconeogenesis still decreases and more ketone

body formed.• Brain starts using both glucose and more of

ketone body.• RBCs, renal medulla still utilize glucose.

PHASE V (VERY PROLONGED

STARVATION )• Occurs in very prolonged starvation and extreme

obese individuals.• Very less glucose utilized • Almost all tissues use ketone bodies or fatty

acids.

FACTORS REGULATING•Hormonal factors • Insulin • Glucagon • Cortisol • Epinephrine • Growth hormone• Thyroid hormone • Somatostatin • Pancreatic polypeptide.

NON-HORMONAL REGULATION

• Changes in the concentrations of the fuels themselves may also play a direct role.

• Increase in circulating glucose levels• Diminish hepatic gluconeogenesis & glycogenolysis• Enhance glycogen synthesis

• FFAs stimulate hepatic gluconeogenesis;

• Recent studies suggest• anti-gluconeogenic action of insulin may be secondary to

its antilipolytic action on the fat cell

HORMONES • Insulin • Hypoglycemic hormone• Favors glycogenesis• Promotes glycolysis • Inhibits gluconeogenesis• Anabolic hormone • Helps in storage of glycogen, lipids & protein

ACTIONS OF INSULIN• Rapid (seconds)    

• Increased transport of glucose, amino acids• K+ into insulin-sensitive cells

• Intermediate (minutes)    • Stimulation of protein synthesis  • Inhibition of protein degradation  • Activation of glycolytic enzymes and glycogen synthase  • Inhibition of phosphorylase and gluconeogenic enzymes

• Delayed (hours)    • Increase in mRNAs for lipogenic and other enzymes

ADIPOSE TISSUE   • Increased glucose entry   • Increased fatty acid

synthesis  • Increased glycerol

phosphate synthesis  • Increased triglyceride

deposition  • Activation of lipoprotein

lipase  • Inhibition of hormone-

sensitive lipase  • Increased K+ uptake

MUSCLE • Increased glucose entry   • Increased glycogen

synthesis  • Increased amino acid

uptake   • Increased protein

synthesis by ribosomes   • Decreased protein

catabolism   • Decreased release of

gluconeogenic amino acids   

• Increased ketone uptake   

• Increased K+ uptake

• Liver    • Decreased ketogenesis   • Increased protein synthesis   • Increased lipid synthesis   • Decreased glucose output due to decreased

gluconeogenesis, • Increased glycogen synthesis, and • Increased glycolysis

• General    • Increased cell growth

GLUCAGON • Hyperglycemic hormone• Promotes glycogenolysis• Enhances gluconeogenesis• Depresses glycogen synthesis • Inhibits glycolysis • It acts via Gs to activate adenylyl cyclase and increase

intracellular cAMP. • This leads via protein kinase A to activation of

phosphorylase and therefore to increased breakdown of glycogen and an increase in plasma glucose

EFFECTS OF GLUCAGON ON ENZYMES • Phosphoenolpyruvate carboxykinase, which

facilitates the conversion of oxaloacetate to phosphoenolpyruvate.

• Fructose 1,6-diphosphatase, which catalyzes the conversion of fructose diphosphate to fructose 6-phosphate.

• Glucose 6-phosphatase, which controls the entry of glucose into the circulation from the liver.

INSULIN:GLUCAGON MOLAR RATIO

• Insulin –glucagon molar ratio on a balanced diet is approximately 2.3

• When energy is needed during starvation, the insulin–glucagon molar ratio is low, favouring glycogen breakdown and gluconeogenesis.

• When the need for energy mobilization is low, the ratio is high, favouring the deposition of glycogen, protein, and fat.

CORTISOL • The glucocorticoids are necessary for glucagon to

exert its gluconeogenic action during fasting. • They are gluconeogenic themselvesCarbohydrate/lipid metabolism:• Hepatic glycogen deposition• Peripheral insulin resistance• Gluconeogenesis• Free fatty acid production• Overall diabetogenic effect

CORTISOL EFFECTS…• Metabolic PPAR-γ• Tryptophan hydroxylase• Tyrosine

aminotransferase• Metalloprotease• Glutamine synthase

• Glycogen synthase• Glucose-6-phosphatase• PEPCK• γ-Fibrinogen• Cholesterol 7α-

hydroxylase

CATECHOLAMINES • Catecholamines have a dual effect on insulin

secretion;• They inhibit insulin secretion via α2-adrenergic

receptors and • Stimulate insulin secretion via β2-adrenergic

receptors. • The net effect of epinephrine and norepinephrine is

usually inhibition.• Major role in muscle glycogenolysis by increasing

cAMP levels.

GROWTH HORMONE• The effects of growth hormone are partly direct and

partly mediated via IGF-I.• Growth hormone mobilizes FFA from adipose tissue,

thus favoring ketogenesis.• It decreases glucose uptake into some tissues ("anti-

insulin action"), increases hepatic glucose output & decrease tissue binding of insulin

SOMATOSTATIN• Somatostatin 14 (SS 14) and its amino terminal-

extended form somatostatin 28 (SS 28) are found in the D cells of pancreatic islets.

• Both forms inhibit the secretion of insulin, glucagon, and pancreatic polypeptide and act locally within the pancreatic islets in a paracrine fashion.

• SS 28 is more active than SS 14 in inhibiting insulin secretion, and it apparently acts via the SSTR5 receptor

PANCREATIC POLYPEPTIDE

• Its secretion is increased by a meal containing protein and by fasting, exercise, and acute hypoglycemia

THYROID HORMONES• Thyroid hormones make experimental diabetes

worse.• The principal diabetogenic effect of thyroid hormones

is to increase absorption of glucose from the intestine,

• But the hormones also cause (probably by potentiating the effects of catecholamines) some degree of hepatic glycogen depletion.

BGR IN SPECIAL SITUATIONS…• Stress and injury

• Pregnancy & lactation • Exercise • Obesity • Cancer • Liver and renal disorder

STRESS AND INJURYDefinition • Any injury• Surgery • Renal failure • Burns • Infection

• Increase need of glucose for increased demand.• Increase in hyperglycemic hormones.

• Blood cortisol• Glucagon• Catecholamines• Growth hormone.

• Resistance to insulin• Catabolic and less anabolic• BMR, blood glucose and FFA increased.• For unknown reasons ketogenesis in not increased

Mechanism • Cytokines released in response to injury and infection.• IL-1 – activates proteolysis• IL-6- responsible for fever• TNF α • Suppress adipocyte TAG synthesis• Inhibits lipoprotein lipase• Stimulates lipolysis• Inhibits insulin release and promotes insulin resistance.

PREGNANCY • Fetus needs energy• Mainly uses glucose, FFA, lactate & KB.• Placental lactogen (PL) , estrogen and progestrone

important hormones.• PL- lipolysis• Steroid hormones- insulin resistance• Post prandial duration reduced in mother.• In fed state- glucose, insulin are increased.

• Maternal hypoglycemia can be reached too early as fetus needs for its growth.• Frequent small meals advised

• If other factors present like obesity then maternal hyperglycemia will lead to GDM.• Due to Insulin resistance.

• Swings in hormones & fuels are exaggerated in pregnancy.

• Lactation• Breast use glucose for milk production• Hormonal effect

EXERCISE • Aerobic and anaerobic exercise• Insulin mediated glucose absorption by GLUT 4

mechanism• Vessels constricted due to muscle contraction

• Depend on glycogen INSTANT ENERGY• Phosphocreatine

• FFA used in aerobic exercise…

LIVER DISEASES• Mainly affects AA.• Fails to produce glucose• Affects production of IGFs• Hypoglycemia can cause

death.• Wasting seen due to

impaired action of IGF and GH

RENAL DISEASES• Mainly affects protein

and AA.• Loss of carnitine

especially in dialysis• Affects fatty acid

metabolism which in turn affect blood glucose levels.

OBESITY • Important cause of insulin resistance

• Reduces receptor number.• Decreases affinity• Affects GLUT transport towards cell membrane.

• Severity of obesity to insulin resistance.• Mechanism

• Adipokines and adiponectin reduced• Resistin, TNF increased

CANCER • Cells function independently of starve feed cycle.• Use more glucose and Aas• Warburg hypothesis

• Cancer cachexia• Hypoxia-inducible factors (HIFs) responsible.

• Anaerobic state.• Activate GLUT transporter.• Activate glycolysis enzymes especially PDH

SUMMARY…• Glucose essential for vital organs…• Brain needs constant supply of energy..• Tightly regulated for its constant supply..