Physiology:

Carbohydrate Metabolism

• The pancreas the gland responsible.

• Insulin production and secretion.

• Insulin receptors.

• Glucose transporters.

• Insulin action.

• Abnormal carbohydrate metabolism.

Pancreas:• Only 2% of the pancreas weight is beta cell.

• Those cell produce insulin in the rate of one unit per each kilogram of body weight.

• Over 80% of beta cells should be lost before diabetes develops.

GLUCAGON

INSULIN

Proinsulin

Centr-omereCATCALPTH

c-Ha-ras

INS IGF-2 -globin

Short arm of chromosome 11

C peptide

Insulin A chain

Insulin B chain

Proinsulin

Insulin A chain

Insulin B chain

C peptide

Insulin Production

Glu

ThrLys

ThrTyr Phe Phe Gly Ar

g Glu Gly

Cys

ValLe

TyrLeuAla

Val

Leu

HisSer

GlyCysLeuHisGlnAsnValPhe

Asn CysTyr

Asn

Glu

Leu

Gln

TyrLeu

SerCysIleSerThrCysCys

Gln

Glu

Val

Ile

Gly

Pro

Insulin Structure

Alpha chain

Beta chain

Disulfide bridges

• The hormone is protein with high molecular weight. • Unstable if taken orally.• Metabolized by the kidney.

• Glucokinase ( GK ) is the rate limiting step for glucose metabolism by the islets.

• Generation of ATP from the electron transport chain closes an ATP-dependent potassium channel.

• Opens a voltage-dependent calcium channel.

• Increase intracellular calcium leads to the stimulation of insulin secretion.

Diabetes 1996; 45: 223-241

x

Insulin Secretion

Insulin Secretion

Free Fatty Acids:• Fatty acid acyl-CoA can augment insulin secretion.• Increase intracellular calcium stimulate exocytosis.• Protein kinase C ( PKC ) enhance exocytosis.

K+

Sulphonylureas

Dépolarisation

KATP Channel closex

Ca 2+

Ca 2+

Ca2+

Influ

x

Ashcroft, Gribble, Diabetologia (1999) 42: 903-919

SulphonylureasPancreatic mode of action

Insuline secretion through exocytosis

Insulin

0

20

40

60

80

100

120

Loss of the first phase in insulin secretion is the initial biological abnormality type 2 patient will manifest. This will result in an elevation of the postprandial glucose.

In type 2 diabetes the second phase will be more and longer which can result in post-meal hypoglycemia.

Insulin Secretion

0

5

10

15

20

25

30

60 140 220 300

Fast

ing

Plas

ma

Insu

lin (

U/m

l )

Fasting Plasma Glucose ( mg/dl )

Glucose toxicity

• Increase of fasting blood glucose, fasting plasma insulin will increase.

• At the level of 140 mg/dl there will be a decline in fasting insulin level.

• Glucose concentration more than 200 mg/dl will paralize the pancrease.

Metabolism 1989; 38:387-395

1 2 3

The insulin receptor gene:

• 1370 amino acids.

• Two parts alpha and beta subunits.

• Three mutation have been described.

• Clinical presentation: 1- Sever insulin resistance. 2- Acanthosis nigrican. 3- Hirsutism and virilization. 4- Mental retardation. 5- Mental retardation. 6- Dental dysplasia.

Chromosome 19

Alpha-subunit Alpha-subunit

COOH COOH

COOHCOOH

NH2 NH2

Cell membrane

Rabson-Mendenhallsyndrome

The Insulin Receptor

Insulin receptor• The first step in insulin action is the activation of tyrosine kinase of the sub-unit.

• Initiate a series of events involving a cascade of phosphorylation-dephosphorylation.

• Stimulation of intracellular glucose metabolism.

• Initial step is the activation of the glucose transport system.

Glucose uptakeGLUT-4 transporteron cell membraneInsulin

insulin-stimulated translocation of glucose

transporters

Organ Glucose transporter HK coupler Classification

Brain GLUT1 HK-I Glucose dependentErythrocyte GLUT1 HK-I Glucose dependentAdipocyte GLUT4 HK-II Insulin dependentMuscle GLUT4 HK-II Insulin dependentLiver GLUT2 HK-IVL Glucose sensorGK - cell GLUT2 HK-IVB ( glucokinase ) Glucose sensorGut GLUT3-symporter ---- Sodium dependentKidney GLUT3-symporter ---- Sodium dependent

Glucose transporters

B cell

High blood glucose

Insulin

Impaired insulin releaseGlucoseGlucoseuptakeuptake

Excessive

glucose output Impairedglucose transport

FFAFFA

FFAFFA

Glucose Metabolism

Skeletalmuscle

Brain

Splanchnic bedAdipose tissue

Control NIDDM

Glucose uptake ( m

g/kg/min )

Insulin resistance is the major contributor for the pathogenesis of type 2 diabetes.

Resistance could be at the level of insulin receptors or post receptor defect.

Skeletal muscle is the major contributor to insulin resistance in patients with type 2 diabetes.

Hepatic glucose production

Indogenous glucose production should balance with total body glucose uptake.

Major production come from glycogenolysis.

Major uptake is through glucose oxidation.

0

0.5

1

1.5

2

2.5

Endogenous Glucose production Total Body Glucose Uptake

Glycogenolysis

Glycerol (2%)Pyruvate (1%)

Lactate (16%)

Amino Acids (6%)

Other

Glycolysis

GlucoseOxidation

SplanchnicGlucoseUptake

Hepatic glucose production

Glucose

Fatty acid

Citrate

Acetyl CoA

Fatty acid

Glucose

Glucose 6-Phosphate

Phospho-

fructokinase

Frucose 6-

Phosphate

Frucose 1,6-bisphosphat

e

Pyruvate

Acetyl CoA

Randle cycle

Glucose metabolism during fast state

Non-diabetic subject:

• During an over night fast liver will supply energy from glycogen store.

• Muscle will utilize energy from free fatty acids (FFA) by Randle cycle.

• This will decrease glucose transport through cellular membrane.

Fasted state

Fructose 6-Phosphate

Fructose 2,6-

bisphosphate

Fructose 1,6-bishosphate

Phosphoenolpyruvate

Oxaloacetate

pyruvate

Fed state

Fructose 6-Phosphate

Fructose 2,6-

bisphosphate

Fructose 1,6-bishosphate

Phosphoenolpyruvate

Oxaloacetate

pyruvate

Glucose metabolism during fast and fed state

Insulin deficiency

Blood glucose

Insulin resistance

• Diabetes Mellitus is a group of metabolic disease characterized by hyperglycemia resulting from defects in insulin secretion, insulin action, or both.

• The chronic hyperglycemia of diabetes is associated with log-term damage, dysfunction, and failure of various organs, especially the eyes, Kidneys, nerves, heart, and blood vessels.

Pathogenesis of type 2 Diabetes Mellitus

Natural History of Type 2 Diabetes Mellitus

Age 0-5+ 15-40+ 15-60+ 25-70+

Microvascular Complication

IGT Postprandial Fasting Hyperglycemia Hyperglycemia

Macrovascular Complication

Disability

Insulin resistanceHyperinsulinemia HDL cholesterolTriglycerideHypertensionAtherosclerosis

Normo-insulinemiaRetinopathyNephropathyNeuropathy

HypoinsulinemiaBlindnessRenal FailureAmputationIHDStroke

Genetic background for:Insulin secretionInsulin sensitivitycomplicationsEnvironmental factors:NutritionObesityPhysical inactivity

Disability

Deat

h

Natural History of Type 2 Diabetes Mellitus

Decrease Glucose-induced insulin secretion

Insulin deficiency

Insulin resistance

Decrease Tissue response to insulin

GeneticAcquiredGlucotoxicityLipotoxicity

GeneticAcquiredObesityVo2maxAgeSmoking

Increase Hepatic glucose

production

Increase Cellular glucose

uptake

Hyperglycemia

Impaired beta

cell function

Post- receptordefect

Decrease Glucose transport

Decrease Insulin binding

Basal Hyperinsulinemi

a

Hyperglycem

ia

Hypoinsulinem

ia

-12 -6-10 0- 2 2 6 10 14

Beta

Cel

l fun

ctio

n (%

)

IGT PPHyperT2

Phase IT2

Phase II

1

2

3

Phase III

Years from diagnosis

100

75

50

25

0

UKPDS data

05

101520253035404550

15-20 21-30 31-40 41-50 51-60 >61

Male (Urban)Male (Rural)Female (Urban)Female (Rural)

0

5

10

15

20

20-44 45-54 55-64 65-74

Male Female

Prev

ale n

ce

Age groups

Age :• Prevalence of type 2 diabetes increase with age.

• Females are significantly higher than males.

•The prevalence is almost double after the age of 55 years.