Basic Concepts in Metabolismand

Regulation of Blood sugar levels

Dr.S.Chakravarty, MBBS,MD

The metabolic States

• FASTING STATE OR POST ABSORPTIVE STATE :- 12 to 14 hrs after a meal

• 70- 110 mg/dl (5 to 7.2 mmol/L)

• POST PRANDIAL STATE :- AFTER A MEAL • generally upto 140mg/dl (<10mmol/L)due to prompt

secretion of Insulin

Two basal requirements during starvation

1.Glucose (must for some tissues like Brain and RBCs)

2. ATP

PROXIMATE PRINCIPLES

• CARBOHYDRATE

• LIPIDS

• PROTEINS

Regulation of Blood Sugar Level

Dr.S.Chakravarty M.D.

Specific learning objectives

• At the end of this lecture you should be able to describe– How blood sugar level is maintained during the

absorptive and post absorptive states.– The secretion, functions and role of insulin in

metabolism.– The role of hyperglycemic hormones like glucagon,

epinephrine and cortisol in metabolism.

BIOMEDICAL IMPORTANCE• BASAL REQUIREMENT FOR GLUCOSE :-There is always a basal requirement for

Glucose, even when fat is supplying most of the caloric requirements.– GLUCOSE IS IMPORTANT FOR MAINTAINING THE INTERMEDIATES OF THE CITRIC ACID

CYCLE EVEN WHEN FATTY ACIDS ARE THE MAIN SOURCE OF ENERGY.

• OBLIGATORY REQUIREMENT FOR GLUCOSE :-There is an obligatory requirement of glucose for the brain and RBCs.(although the brain can utilize ketone bodies)

• ONLY FUEL FOR SKELETAL MUSCLE IN ANAEROBIC CONDITIONS:- Glucose is the only fuel that will supply energy to skeletal muscle under anaerobic conditions.

• PROFOUND CONSEQUENCES IN ACUTE GLUCOSE DEPLETION :-A sudden decrease in blood glucose will cause convulsions, as in insulin overdose. – However, lower concentrations can be tolerated if there has been

progressive adaptation.

The metabolic States

• FASTING STATE OR POST ABSORPTIVE STATE :- 12 to 14 hrs after a meal

• 70- 110 mg/dl (5 to 7.2 mmol/L)

• POST PRANDIAL STATE :- AFTER A MEAL • generally upto 140mg/dl (<10mmol/L)due to prompt

secretion of Insulin

NORMAL RANGE

Glucose uptake by cells:Major Glucose transporters (GLUT):Receptor Tissues Km Function

Facilitative bidirectional transporters

GLUT – 1 Most tissues (Brain, RBCs, Colon ,Placenta)

1 mMLOW Km-High affinity Basal uptake

GLUT – 2 LiverPancreas Small intestineKidney

15 mMHIGH Km(Low affinity transporter)

• Uptake and release of glucose by liver( AFTER A MEAL )

• Glucose sensor

GLUT-3 Brain KidneyPlacenta

1 mMLow Km-High AFFINITY Basal uptake

GLUT – 4 Skeletal muscle

Adipose tissue Heart

5 mM • Insulin stimulated glucose uptake

GLUT -5 Small Intestine •Absorption

Sodium dependent unidirectional transporter

SGLT1 Small Intestine and Kidney •Active uptake of glucose against a concentration gradient

NORMAL BLOOD GLUCOSE CONCENTRATION 4-6 mM (70-110 mg/dl)Glut 1 and Glut 3 are at Vmax at Normal glucose concentration

• Km is inversely proportional to affinity:

OVERVIEW OF BLOOD SUGAR REGULATION

• Absorption from GI TRACT

• Glycogenolysis• Gluconeogenesis_________________

Hyperglycemic hormones – Glucagon– Adrenalin– Corticosteroids– Growth Hormones

• Glycolysis• Glycogen Synthesis• Lipogenesis

______________

Hypoglycemic Hormone

INSULIN

Plasma glucose

70-110mg/dl

HYPERGLYCEMIC FACTORS

HYPOGLYCEMIC FACTORS

USMLE CONCEPT !!

Metabolic and Hormonal Mechanisms regulate the concentrations of Blood Glucose

Blood Glucose is derived from the following :-

• DIET• GLYCOGENOLYSIS• GLUCONEOGENESIS

Diet• THE DIETARY CARBOHYDRATES that are

actively digested contain glucose , galactose and fructose residues that are released in the intestine.

• They are transported to the Liver via the portal vein .

• Galactose and Fructose are converted to glucose in the Liver.

ROLE OF GLUCOKINASE

• Glucokinase is important in regulating Blood Glucose after a meal.

Difference between Glucokinase and Hexokinase

HEXOKINASE GLUCOKINASE

Occurrence In all tissues Only in Liver

Km 10-2 mmol/L(Low) 20 mmol/L ( high)

Affinity to substrate HIGH AFFINITY LOW AFFINITY

Specificity ACTS ON GLUCOSE ,FRUCTOSE AND MANNOSE

INDUCED BY INSULIN AND GLUCOSE

Induction NOT INDUCED INDUCED BY INSULIN AND GLUCOSE

Feedback inhibition Inhibited by glucose 6 phosphate

Not affected by Glucose 6 Phosphate conc.

Function Even when blood sugar is less , glucose is utilized by body cells

When plasma glucose level is > 100mg/dl then Glucose is taken up by Liver for Glycogen synthesis

USMLE CONCEPT !!

Glucokinase(Km=10mmol/L)

Hexokinase(Km= 0.05mol/L)

5

100

50

Vmax

Blood Glucose mmol/L

0 15 20 2510

ROLE OF HORMONES

HYPERGLYCEMIC HORMONES

BASIC CONCEPT IN REGULATION

• HYPERGLYCEMIC HORMONES (GLUCAGON , EPINEPHRINE etc) PHOSPHORYLATE KEY ENZYMES IN REGULATION Stimulates a protein kinase

• INSULIN ALWAYS DEPHOSPHORYLATESi.e it stimulates a protein phosphatase

USMLE concept !!

Example :- Covalent modification of Pyruvate kinase :

Pyruvate Kinase Pyruvate Kinase

PO4ATP ADP

Protein kinase A

Glucagon cAMP

(+)

(+)

Inactive Active

(+)

Protein phosphataseInsulin

(+)

Inhibition of Glycolysis in liver and increase blood glucose

USMLE concept !!

Glucagon

• Polypeptide with 29 amino acids• It is secreted by the alpha cells of the pancreas • Synthesized as a precursor –PROGLUCAGON• PLASMA t ½ is 5 mins• INACTIVATED IN LIVER – PHYSIOLOGICAL ACTIONS:-

• Most POTENT HYPERGLYCEMIC hormone :- ANTI – INSULIN in nature

• CAUSES GLYCOGENOLYSIS • Stimulates GLUCONEOGENSIS• CAUSES LIPOLYSIS

MECHANISM OF ACTION • Liver is the primary target of glucagon action.

• Glucagon Binds To Specific Receptors In Hepatic Cell Plasma Membrane , And This

Activates Adenylyl Cyclase Through a G –Protein Linked Mechanism.

• The c-AMP generated activates PHOSPHORYLASE and enhances rate of glycogen degradation while inhibiting glycogen synthase .

• Glucagon has no effect on glycogenolysis in muscle.

• It’s a potent lipolytic agent also. It increases adipose tissue c-AMP levels and this

activates the hormone sensitive lipase which breaks down TAG to FA +Glycerol.

• It also enhances gluconeogenesis – ( ACTIVATOR OF PEPCK AND FRUCTOSE 1,6 BPASE ).

CLINICAL USE OF GLUCAGON• An injectable form of glucagon, manufactured

by Eli Lilly and Company, is vital first aid in cases of severe hypoglycemia when the victim is unconscious or for other reasons cannot take glucose orally.

• Epinephrine • RELEASED FROM ADRENAL MEDULLA AS A RESULT OF

STRESSFUL STIMULI ( fear , excitement, hemorrhage , hypoxia , hypoglycemia etc)

• Promotes gycogenolysis in BOTH liver and muscle ( stimulates PHOSPHORYLASE )- MAIN IMMEDIATE ACTION

• Increases gluconeogenesis • Enhances lipolysis

• Glucocorticoids :-• They are secreted by adrenal cortex.

• Increases Gluconeogenesis mainly.• Increased protein catabolism release of amino acids by the muscles

increased hepatic uptake of a.a .• Induces the enzymes PEPCK, fructose 1,6 Bisphosphatase , glucose 6-

phosphatase and amino transferases.– Long term use of corticosteroids increases plasma glucose levels!!

GROWTH HORMONE • GH secretion is stimulated by hypoglycemia.• It decreases glucose uptake by muscle cells.• It mobilizes FFA from adipose tissue which themselves inhibit glucose utilization.

(decreases glycolysis ).• Chronic administration leads to diabetes.

THYROID HORMONES :-

• EXPERIMENTAL EVIDENCE THAT THYROIDECTOMY INHIBITS THE DEVELOPMENT OF DIABETES.

• THYROTOXIC PATIENTS :- GLYCOGEN IS ABSENT IN LIVER.

• FBS IS ELEVATED IN HYPERTHYROID PATIENTS AND DECREASED IN HYPOTHYROID PATIENTS.

• HYPERTHYROID PATIENTS UTILIZE GLUCOSE AT AN INCREASED RATE AND HYPOTHYROID PATIENTS HAVE DECREASED ABILITY.

• HYPOTHYROID PATIENTS ARE LESS SENSITIVE TO INSULIN THAN NORMAL OR HYPERTHYROID INDIVIDUALS.

Structure of Insulin

• Protein hormone with 2 polypeptide chains• A chain --> 21 a.a• B chain --> 30 a.a– Two chains are joined by interchain disulphide

bonds, b/w A7 to B7 and A20 to B19.– Intrachain disulphide link in A chain b/w 6th and

11th A.A– SPECIES VARIATION 8,9,10 of A chain and C

terminal of B chain

• 30th AMINO ACID – Thr (Human)– Ala (Bovine)– Ala (Pig)

• 8th ,9th and 10th AMINO ACID • ALA –SER VAL (BOVINE)• THR-SER-ILE (HUMAN)• THR-SER-ILE (PIG)

A7 to B7 A20 to B19

A6 to A11

PRO INSULIN

Insulin is a hexamer with 2 Zn ions and 1 Ca+2 ions

BIOSYNTHESIS OF INSULIN• SYNTHESIZED AS A LARGER PRECURSOR POLYPEPTIDE

CHAIN – > PRE-PRO-INSULIN WITH 109 AA

PRO INSULIN ( 86 AA )

INSULIN(53 AA)

INSULIN (51 AA)

-23 AA IN E.R

-C PEPTIDE (33 AA) BY

PROHORMONE CONVERTASE 1 AND 2(GOLGI APPARATUS )

-2 AA BY CARBOXYPEPTIDASE H

FACTORS INCREASING INSULIN SECRETION

• GLUCOSE

• GI HORMONES :- Secretin, Pancreozymin , Gastrin

• PROTEINS AND AA :- Leucine , Arginine

• Parasympathetic and beta –adrenergic stimulation

• Glucagon and growth hormone

• INCRETIN HORMONES :- – GIP (Glucose dependent

insulinotropic polypeptide )

– Glucagon like peptide 1 ( GLP-1 ,31 AA)

• Drugs – Sulfonylureas(eg.Tolbutamide)

BETA CELL

GLU

GLU

GLU

GLU

ATP

Ca +2

Glycolysis TCA

ATP GATED K+ CHANNELS CLOSE AND MEMBRANE DEPOLARIZES

INSULIN RELEASE

Voltage gated calcium channel opens

Sulfonylurea group of oral hypoglycemic drugs bind to these K+ channels !!!

FACTORS DECREASING INSULIN SECRETION

• Epinephrine • Alpha adrenergic stimulation

INSULIN DEGRADATION• Plasma t ½ of INSULIN is 5 mins• It is degraded by an insulin specific protease (INSULINASE) and a

hepatic –glutathione –insulin –transhydrogenase.

Normal Insulin level :- 2-25 µIU/ml ( 12-150 pmol/L)• Proinsulin contributes 5-10% of total insulin activity(1/3 biological

activity as that of insulin)• In case of antibodies to insulin , measurement of C-peptide may be

useful :-– t ½ 35 mins and Fasting range is: 0.78 - 1.89 ng/ml

0.26 - 0.62 nmol/L SI unit

– Range one hour after a glucose load is: 5.00 -12.00 ng/ml” (During a glucose tolerance test)

MECHANISM OF ACTION OF INSULIN

• INSULIN RECEPTOR– Insulin acts by binding to a plasma membrane receptor

on the target cells.– INSULIN RECEPTOR is a glycoprotein with 2 α and 2β

subunits.– β- subunit has TYROSINE KINASE activity.

I

Cell membrane

Beta subunit

Alpha subunit

GLUT-4

G

GG

GI

Insulin Response substrates

GLUT-4

G

G

G

PHOSPHORYLATION OF TYROSINE RESIDUES

Actions of Insulin on Carbohydrate metabolism

Key enzyme Action of Insulin Direct effect Overall effect

TRANSLOCASE

STIMULATIONGLYCOLYSIS FAVOURED H

YPOGLYCEMIA

GLUCOKINASE

PFK

PYRUVATE KINASE

PYRUVATE CARBOXYLASE

INHIBITION GLUCONEOGENESIS DEPRESSED

PEPCK

FRUCTOSE 1,6 BPASE

GLUCOSE 6 PHOSPHATASE

GLYCOGEN SYNTHASE ACTIVATION GLYCOGEN DEPOSITION

GLYCOGEN PHOSPHORYLASE

INACTIVATION

GPD STIMULATION NADPH GENERATION

Metabolism Key Enzyme Action of insulin Direct effect Overall effect

LIPID Acetyl CoA carboxylase

STIMULATION LIPOGENESIS FAVOURED

GLUCOSE USED FOR LIPOGENESIS:- PLASMA GLUCOSE LOWERED

Glycerol Kinase

Hormone sensitive Lipase

INHIBITION LIPOLYSIS INHIBITED

DECREASED KETOGENESIS

HMG CoA reductase STIMULATION CHOLESTEROL SYHTHESIS

PROTEIN TRANSAMINASES INHIBITION CATABOLISM INHIBITED

ORNITHINE TRANSCARBAMOYLASE

INHIBITIONPROTEIN SYNTHESIS FAVOURED

ANABOLISMRNA POLYMERASE AND RIBOSOME ASSEMBLY

FAVOURED

EFFECT OF INSULIN ON LIPID AND PROTEIN METABOLISM

METABOLIC EFFECTS OF INSULIN(summary)• 1)UPTAKE OF GLUCOSE BY TISSUES( GLUT 4)

• 2)UTILIZATION OF GLUCOSE • STIMULATION OF GLYSOLYSIS• INHIBITION OF GLUCONEOGENSIS• INHIBITION OF GLYCOGENOLYSIS

• 3)LIPOGENESIS• MORE Acetyl CoA from Glycolysis• INCREASED FA SYNTHESIS AND ESTERIFICATION AS TAG• PROVIDES NADHP FOR REDUCTIVE BIOSYNTHESIS

• 4)ANTI –LIPOLYTIC EFFECT • INHIBITION OF LIPOLYSIS BY INHIBITION OF HSL

• 5) ANTI KETOGENIC • DEPRESSES HMG CoA SYNTHASE• EFFECTIVE & COMPLETE UTILIZATION OF acetylCoA as OAA is abundant

• 6)ANABOLISM • INCREASED PROTEIN SYNTHESIS, DECREASED BREAKDOWN• INCREASED CELL GROWTH AND REPLICATION

INGESTED GLUCOSEOr CARBS( 100 % )

GLYCOLYSIS ( ~ 50 %)

CONVERTED TO FATS

(30-40%)

GLYCOGEN(10%)

So , Obesity results even if you eat only excess CARBs and to reduce body weight both CARBS AND FATS MUST BE REDUCED(i.e TOTAL CALORIES SHOULD BE LESS)

HYPOGLYCEMIA • CAUSES :-

–1. PHYSIOLOGICAL –DURING STARVATION–AFTER SEVERE EXERCISE–NEONATES ( esp .PREMATURE INFANTS AS

THERE IS LESS ADIPOSE TISSUE + NON-FUNCTIONAL ENZYMES OF GLUCONEOGENESIS)–PREGNANCY (INCREASED DEMAND )

–2.PATHOLOGICAL–1. DUE TO EXCESS OF INSULIN »EXCESSIVE DOSAGE»NO FOOD INTAKE AFTER INSULIN

ADMINISTRATION»TUMORS OF PANCREAS (insulinoma)

–2. ORAL HYPOGLYCEMIC DRUGS –3.GLYCOGEN STORAGE DISORDERS–4.IMPAIRMENT OF FATTY ACID OXIDATION–5.HYPOACTIVITY OF THYROID, ADRENALS AND

PITUITARY GLANDS

SymptomsSymptoms you may have when your blood sugar gets too low include:-

• Double vision or blurry vision• Fast or pounding heartbeat• Feeling cranky or acting

aggressive• Feeling nervous• Headache• Hunger• Shaking or trembling• Sleeping trouble• Sweating• Tingling or numbness of the skin• Tiredness or weakness

• Unclear thinking

Sometimes your blood sugar may be too low, even if you do not have symptoms. If your blood sugar gets too low, you may:-

• Faint• Have a seizure• Go into a coma

MCQ 1

• Which of the following substances will BE elevated in a starving cell?

• A. 5’AMP• B. c-AMP• C. ATP• D. GTP• E. glucose

MCQ2 • Which of the following statements correctly describe human glucose

metabolism?

A. Liver is impermeable to glucose in the absence of insulin

B. Pancreatic β-cells, liver and brain are freely permeable to glucose due to specific glucose transporters

C. Liver glucokinase phosphorylates glucose at high rates under all conditions

D. Extrahepatic tissues are permeable to glucose when glucagon is present

E. Liver takes up glucose when serum glucose is normal but releases it when serum glucose is high

Thank you