Disorder of Carbohydrate

Metabolism

Chapter 11 P. 205 Glucose is a major energy substrate

Sources
- diet
Dr. Khalid Al-Ani - endogenous
Department of Clinical Pharmacy
Faculty of Pharmacy liver glycogen
Jordan University of Science & Technology gluconeogenesis

Blood glucose maintained under control

- fasting state ( 70-110 mg/dl)
(3.9-6.1mmol/l) How the body maintained a narrow limit of
- postprandial state ( state after food blood glucose level in both states?
ingestion <120mg/dl (6.6mmol/l)

For SI unit divided by 18

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 Postprandial state Fasting state
1.Glycogen in the
live sufficient up
Liver removes 70% of glc load brain Liver brain
to 24hr
Glycogen Glycogen
E+ Fat 100gm
glc Blood glc glc Blood glc

TG TG

Adipose Adipose
E+ Tissue E+ Tissue
reabsorbed reabsorbed
glycogen Glycogen
400gm
BS>180 BS>180
Muscle Muscle

Urine Urine

Fasting state-cont

2. Gluconeogenesis Glucose homeostasis

(90%in the live), the Liver
brain
principle source of Achieved through the action of five hormones
glc during fasting Glycogen
100gm Insulin
glc Blood glc
glucagon
TG epinephrine
Cortisol
Adipose
Growth hormone
E+ Tissue
reabsorbed
Glycogen
400gm
BS>180
Muscle

Urine

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 Insulin

The active form is 51

The only hypoglycemic hormone AA of two chains,
Insulin is a peptide hormone synthesized as
proinsulin of 86 AA ( granules in the Golgi app) Chain A- 21 AA and
secreted from - cell of the pancreas in chain B-chain 30 AA
response to hyperglycemia linked together by S-S
glucagon, glucose dependent insulinotrophic bond
peptide and (GIP) also stimulates insulin secretion

Insulin-conti Insulin Receptor (IR)

IR is a member of the
Works through receptor found on class II of tyrosine
the cell surface of some cells such receptor kinase
as adipose tissue and muscles and Has two types of
internalized after insulin binding subunit & .
is 735 AA each
Brain, RBCS, retina, intestine and linked to ( 620AA) by
kidney are non-insulin target S-S bonds.
tissues

3
 IRS which act as a second messenger to
Insulin Receptor (IR)
produce a wide variety of cellular effects such as
increase the transport of glucose into cells
throw movement glucose transporter protein
(GLUT-4) from the intracellular vesicles to the
When insulin binds to cell membrane
-subunit the - subunit GLUT-4 found in adipose tissue and muscles
autophosphorylated
which intern GLUT-4

phosphorylate proteins
called insulin receptor
substrate (IRS)

Glucagon Epinephrine

a 29 AA polypeptide Secreted by adrenal medulla

secreted from -cell of the pancreas
secreted in response to low blood glucose
glucagon action opposes insulin
stimulates glycogenolysis
stimulates glucagon secretion
inhibits insulin secretion
stimulated by stress

Growth hormone
Secreted by anterior pituitary
antagonizes glucose uptake by cells

4
 Measurement of glucose concentration
4

FastingBS approx 10-15% lower than

plasma (due to lower water content)

is of less significant for normal BS

Arterial
> capillary > venous
Due to peripheral clearance

Measurement of glucose concentration-cont.

Diabetes mellitus
DM is a metabolic disorder
characterized by chronic hyperglycemia
with disturbances of CHO, protein and
fasting plasma glucose = 70- 110mg/dl fat metabolism

2hr PG= < 120mg/dl( 7.7mmol/l) Inadequate insulin secretion and/ or

abnormal insulin action

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 Prevalence of Types 1 & 2 Classification
1-2% 0f western world
Primary DM
Type 1
In 2002, the U.S was 6.3% (18.2 million people Type 2 Type 1 <10%
Third leading cause of death-- United States
Alarming incidence of type 2 DM Secondary DM
18 yr old and younger type 2 DM sky rocking Gestational diabetes
200 million world wide by the year of 2010 Chronic pancretitis
Cushing syndrome
Acromegaly Type 2 >90%
in Jordan? Drugs- thiazides in high dose, other

Types of Diabetes mellitus

Type 1-Insulin dependent DM (IDDM)-conti
Type 1-Insulin dependent DM (IDDM)
l occurs in non- obese children & young adult
l Acute onset (days or few weeks)
l but could occur at any age
l weight loss usual
l little or no insulin l family history of DM is less common
l destruction of pancreatic cells
l insulin required for treatment
l Autoimmune condition-islet cell antibodies
that react with B-cell of the pancreases have
been demonstrated in the serum of >90%
l viral infection
l Protein in cow milk has been implicated

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 Type 1-Insulin dependent DM (IDDM)-conti
Types of Diabetes mellitus

Type 2-non insulin DM (NIDDM)

Signs/symptoms inadequate insulin secretion to prevent
Polydipsia hyperglycemia
l 80% have insulin resistance
Polyphagia
l >40 y ,gradual onset
Polyuria, glycosuria
l 80% of patients are obese;
Weight loss
l Weight gain is usual
ketoacidosis l usually nonketotic

Hyperventilation l most the patient can be treated by

abdominal pain and vomiting diet ,W/o OHG
l Insulin may required to correct BS

Major characteristic of type 1 and 2

Causes of type 2 DM DM Fig 11.5 P 210
Obesity
80% of Type 2 DM are overweight
o family history of DM
o Sedentary lifestyle
o lack of physical activity

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 What is Insulin Resistance (IR)-conti

What is Insulin Resistance (IR)

IR is a state in which a given concentration of insulin Insulin resistance can be identified by
produces a less-than-expected biological effect.
these markers:
l 1) Hyperglycemia
IR the body RESISTS taking sugar into the cells
l 2) Dyslipidemia- high triglyceride, low HDL
l 3) Central obesity
IR has also been arbitrarily defined as the
l 4) Hypertension- greater than 130/80
requirement of 200 or more units of insulin per day to
attain glycemic control and to prevent ketosis

Complications of DM Acute Complications

1. Hyperglycemia as a result of increased
Acute complication- complication related production and reduce uptake by cells
directly to metabolic disturbances

Long term (Chronic) complication BS >180mg/dl - polyuria and polydipsia

(symptom)

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 2. Diabetic Ketoacidosis (DKA)
Definition
Hyperglycemia causes osmotic diuresis A complex disordered metabolic state
decrease plasma volume characterized by hyperglycemia, acidosis,
ketonemia
increases plasma osmolality which stimulates
A medical emergency requiring intensive therapy
thirst center.
Osmotic diuresis and thirst causes the It may be be precipitated by omitting insulin dose
classical symptom of polyuria and or insulin become an adequate due increase H
polydipsia with opposing action
decrease plasma volume - pre-renal uremia infection, trauma or psychological stress.

Pathophysiology of KA
Lack of insulin
KB are substances related to
Increase of glycogenolysis, gluconeogenesis, and
lipolysis acetone ( 3 compounds)
Produced in the liver when
Increase of glucagon, cortisol, growth hormone, large amount of Acetyl-CoA
epinephrine
glucagon / insulin ratio are produced by beta
oxidation
Increase mobilization of fat from adipose tissue
to liver ( H S Lipase)
1.Diabetes mellitus
NOTE Insulin and glucose inhibit the mobilization of fat 2.Starvation
3.High fat low carbohydrate diet

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 Pathophysiology of KA-cont.

KB increases nausea, vomiting and

Therapy general aspects
abdominal pain
Regular Insulin - IV infusion (low dose 0.1/kg/hr : *BG <180, lower to
.05U/kg/hr to prevent hypoglycemic counterhormone effect.)

Vomiting increases dehyration and the Fluids

acidosis, and enhances lost of Na+, K+, Monitor electrolytes replace potassium as the
serum potassium responds to the insulin and
shifts into the cell, replace magnesium and
Acidosis causes K+ to shift into cells other electrolytes as needed
(hyperkalemia even when total K + is
relatively decreased) Multivitamins especially thiamine
*BG = blood glucose mg/dl

hyperventilation- Kussmaul breathing

Non- ketotic hyperglycemia Diabetic long-term complications

Occur in type-2 DM Occurs in both types

Microvascular

Can develop when BS>50mmol/L(

900mg/dl) with Macrovascular
Serum osmolality =/> 320mOsm/kg
no ketosis or little ketosis
WHY??

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 Microvascular complications:
Microvascular Complications
(Proposed mechanisms)
The risk of the complications increases with It appears to be directly related to Hyperglycemias
poor glycemic control
Narrowing of the lumen of small vessels which
directly related to prolong exposure to high BS
Nephropathy

Neuropathy

Retinopathy

Microvascular complications (Proposed mechanisms)-conti Why the damage by sorbitol occur in retina, kidney
and nerve cells and not in other cells?

1.Non-enzymatic glycation of proteins

(Advanced Glycation End products (AGE)
which can cause inflammation and structural
damage

2.Hyperglycaemia- stimulates aldol

reductase enzymes metabolise glucose to
sorbitol (polyol sugar) - tissue accumulation-
causes osmotic damage

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 Retinopathy:
Diabetic retinopathy (damage to the
retina) is caused by complications of
diabetes mellitus,
which could eventually lead to
blindness.
affects up to 80% of all diabetics
who have had diabetes for 15 years
or more
Diabetic Nephropathy
the kidney loses its ability to function
properly.
The condition is characterized by high
protein levels in the urine
Diabetic nephropathy is the most common
cause of chronic kidney failure
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Neuropathy Diabetic
Diabetic neuropathy is a peripheral nerve
disorder caused by diabetes.
neuropathy are often slight at first.
Numbness, pain, or tingling in the feet, or
legs may, after several years, lead to
weakness in the muscles of the feet.
May affect specific nerves
Diabetic Nephropathy
The earliest detectable abnormality is
microalbuminuria
 Diabetic long-term complications Diabetic Macrovascular Disease
Pathophysiology
Macrovascular
Due to multiple metabolic changes
Related to atherosclerosis Lipid changes in DM
Clinical
Manifestations: Coronary Artery
Disease (Angina, MI) and Peripheral
Vascular Disease

Lipoprotein metabolism in DM
p.223
Exercise

Weight reduction
can reduce insulin
resistance, and
reduce the need
for medication.
Eat less!

Drugs

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 DIAGNOSIS Criteria for DIAGNOSIS of
Criteria for the DIAGNOSIS OF D M-
DM
WHO-1997
P.212 fig. 11.7
symptoms symptoms

polyuria, polydipsia, polyphagia and weight polyuria, polydipsia, polyphagia and weight
loss & loss &
random venous plasma glucose level >200
random venous plasma glucose level >200
mg/dl(11.1mmol/l)
mg/dl(11.1mmol/l)
or
or
fasting venous plasma glucose >126 mg/dL
fasting venous plasma glucose >126 (>7.0mmol/L N <6.1)
mg/dL;(>7.0mmol/L N <6.1) ((Venous or capillary blood glc>or=110mg/dl
or 6.1mmol/L (N 5.6) ))

DIAGNOSIS OF DIABETES MELLITUS

other finding

Impaired Fasting Glucose (IFG): fasting venous in the absence of symptoms venous
plasma glucose between 110 and 125 mg/dL plasma glucose in the diabetic range
(>6.1-<7.0) and 2-hour post glc load glucose < should be detected on at least two
140 (<7.8)
separate occasions
Impaired Glucose Tolerance:
fasting venous plasma glucose <126 mg/dL;
and
2-hour post glc load glucose between 140 and
199 mg/dL (>7.8-<11.1)

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 Oral Glucose Tolerance Test
perform OGTT after at least 3 days of
(OGTT) unrestricted diet (> 250gm CHO daily)
Indication fast patient overnight (10-16 hours)
vague Fast/Random BS rest during the test.
Unexplained glycosuria take fating blood sample
Clinical feature of DM with normal BS give 75 gm glc in water orally
take blood at 1 hr & 2 hr
Some lab consider blood sample other
than 0 and 2 hours are not necessary for
diagnosis

Management of DM
Education of patients

Regular follow- up
- blood sugar
- urine sugar
- HbA1c
Normal fasting plasma sugar < 6.1mmol/l Diet, physical activity
IFG - <6.8 mmol/l
IGT 2h post glucose load >=7.8<=11.1
Drugs
DM fasting >=7.0 or 2h post glucose load>=11.1

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 Glycated Hb (HbA1c)
HbA1c is a test that measures the amount of
glycosylated hemoglobin in your blood. Plasma Fructoseamine
-measure glycated plasma albumin
Glucose binds slowly spontaneously to hemoglobin
-index of glycemic control for 10-15 days
A, forming the HbA1c subtype.

The test gives a good estimate of how well diabetes

is being managed over time of
1-2 months
Normal value <6gm/dl in uncontrolled DM

Hypoglycemia Clinical feature

Definition tiredness palpitation
Glucose less than 45mg/dl Confusion sweating
Most common acute complication in Dm Ataxia tremor
Two types Dizziness anxiety
- Fasting hypoglycemia Convulsion blurred vision
- Reactive( postprandial) hypoglycemia coma

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 Causes of hypoglycemia
Reactive hypoglycemia
Fasting hypoglycemia
Drug induced
Insulin induced:
Insulinoma,
-dietary noncompliance,
Hyperthyroidism, Adrenal insufficiency
- increased exercise, pituitary failure
- excessive insulin Drugs ethanol
Sulphonyluria glycogen storage diseases
inherited metabolic carbohydrate disorders
galactosemia

Therapy Hypoglycemia in children

Glucose Tabs Neonatal hypoglycemia
Sugar <25 mg/L
If patient has coma, IV glucose Infant
of diabetic mother
prematurity

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