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Biochemical Aspects of Diabetes Mellitus

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Title: Diabetes Mellitus Author: sherif Last modified by: Sherif Saleh Created Date: 1/17/2010 11:18:44 AM Document presentation format: On-screen Show (4:3) – PowerPoint PPT presentation

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Title: Biochemical Aspects of Diabetes Mellitus


1
Biochemical Aspects ofDiabetes Mellitus
ENDO 412
2
Overview
  • DM is a heterogeneous group of syndromes
    characterized by an elevation of fasting blood
    glucose caused by absolute or relative deficiency
    of insulin
  • Two types of DM
  • Type 1 (insulin-dependent DM)
  • Type 2 (noninsulin dependent DM)
  • Prevalence of type 2 is increasing as
  • Aging (increase in rate of life-age of
    population)
  • Increasing prevalence of obesity

3
Comparison between type 1 type 2 DM
4
Type 1 Diabetes Mellitus
5
Type 1 Diabetes Mellitus
  • about 10 of diabetics (in USA)
  • Onset usually during childhood
  • Caused by absolute deficiency of insulin
  • may be caused by autoimmune attack of
    b-cells of the pancreas, viral infection or toxin
  • Destruction is enhanced by environmental
    factors as viral infection a genetic
  • element (that allows b-cells to be
    recognized as nonself)
  • In identical twins if one sibling has type
    1 DM, the other twin has only 30- 50 chance of
    developing DM
  • Rapid symptoms appear when 80-90 of the b-cells
    have been destroyed
  • Commonly complicated by diabetic ketoacidosis
    (DKA)
  • Treated only by insulin

6
Onset of type 1 DM
7
Metabolic changes of type 1 DM
  • 1- Hyperglycemia
  • 2- Diabetic Ketoacidosis (DKA)
  • 3- Hypertriacylglyceridemia hypercholestrolemia

8
Metabolic changes of type 1 DM (cont.)
  • 1- Hyperglycemia increased glucose in blood
  • Due to
  • Decreased glucose uptake by muscles
    adipose tissues (by GLUT-4)
  • Increased hepatic gluconeogenesis (
    glycogenlysis)
  • 2- Diabetic Ketoacidosis (DKA)
  • Increased ketone bodies in blood (ketonemia)
    leads to metabolic acidosis
  • DKA occurs in untreated or uncontrolled cases of
    DM
  • - In 25 40 of newly diagnosed type 1 DM
    (untreated uncontrolled yet)
  • - In stress states demanding more insulin (as
    during infection, illness or during surgery
    Uncontrolled DM)
  • - No comply with therapy (intake of meals with
    no insulin medication i.e. Uncontrolled DM)
  • Biochemical causes of diabetic ketoacidosis
    (DKA)
  • Absence of insulin leads to increased
    mobilization of FFA from adipose tissues
  • in the liver, FFA are oxidized to
    yield excess acetyl CoA that will synthesize
    KETONE BODIES.

9
Metabolic changes of type 1 DM (cont.)Metabolic
Clinical Abnormalities in DKA
Low Insulin
Carbohydrates Metabolism In Sk. Ms. Adipose
In Liver Glucose
Uptake
Glycogenlysis
Gluconeogenesis



Lipids Metabolism
Lipolysis in Adipose
Tissue
Fatty Acids
in liver
ketone Bodies
(KETOGENESIS)
Protein Metabolism
Proteolysis
Uptake of AA by liver
Gluconeogenesis
Hyperglycemia
Plasma Osmolality
Prerenal Uremia
Coma
Glycosuria
Metabolic Acidosis
Low Renal H Excretion
Osmotic diuresis
Ketonemia
With Loss of water Na Hypovolemia
Low Blood Bicarbonate Low pCO2
Acetone Smelt on Breath
Increased Respiration
Nausea Vomiting
Ketonuria
Polyuria, Dehydration
Thirst
Low GFR
10
Metabolic changes of type 1 DM (cont.)Metabolic
Clinical Abnormalities in DKA
  • Diagnosis of DKA
  • 1- History (for a cause of DKA)
  • 2- Clinical Examination
  • 3- Lab Investigations (to confirm the diagnosis
    follow up of treatment)
  • - Urine by dipstick Glucose
    Ketones (RAPID TEST)
  • - Blood Chemistry Analysis
  • Blood Glucose High
  • Blood Urea
    High (due to dehydration)
  • Electrolytes
    Low (or normal) sodium

  • High (or normal) potassium
  • Assessment of
    acid-base status (metabolic acidosis)
  • - Blood
    Bicarbonate Low (usually below 5 mmol/L)
  • - pCO2 Low
    (compensatory)

11
Metabolic changes of type 1 DM (cont.)Metabolic
Clinical Abnormalities in DKA
  • Biochemical Basis of Treatment of DKA
  • AIM (EMERGENCY TREATMENT)
  • 1- Correction of dehydration (Hypovolemia) by IV
    fluids Sodium
  • 2- Correction of acidosis by IV bicarbonate
  • 3- Correction of metabolic abnormality by
    insulin IV infusion
  • 4- Potassium is given with insulin treatment as
    insulin induces K entry into cells
  • 5- IV GLUCOSE SHOULD BE STARTED IN CASE GLUCOSE
    IN BLOOD FALLS BELOW 10 mmol/L (AVOID
    HYPOGLYCEMIA INDUCED BY INSULIN)
  • 6- FOLLOW UP is QUITE IMPORTANT to monitor
  • Blood glucose level
  • Electrolytes (Na K)
  • Acid-base status (blood
    bicarbonate level)

12
Metabolic changes of type 1 DM (cont.)
  • 3- Hypertriacylglyceridemia hypercholestrolemia
  • Released fatty acids from adipose tissues are
    converted to triacylglycerol cholesterol in
    the liver.
  • Triacylglycerol is secreted from the
    liver in VLDL to blood (with liver cholesterol)
  • Chylomicrons (from diet fat) accumulates (due to
    low lipoprotein lipase activity as a result of
    low or absent insulin)
  • Chylomicrons contain Triacyglycerols
    (mainly) Cholesterol
  • Increased VLDL chylomicrons in blood
    results in
  • hypertriacylglyceridemia
    hypercholesterolemia

13
Metabolic changes of type 1 DM
14
Diagnosis of type 1 DM
  • Clinically
  • Age during childhood or puberty (lt 20
    years of age)
  • With Abrupt (Sudden) appearance of
  • Polyuria (frequent urination)
  • Polydepsia (excessive thirst)
  • Polyphagia (excessive hunger)
  • Fatigue
  • Weight loss
  • Complication as ketoacidosis (common,
    may be the cause of diagnosis)
  • Laboratory diagnosis
  • Fasting blood glucose gt or equal 126
    mg/dl

  • 100 125 mg/dl is called impaired fasting blood
    glucose
  • HBA1c High (more than 6 of normal
    hemoglobin)
  • Insulin level in blood low
  • Circulating islet-cell antibodies
    detection

15
Biochemical Aspects for Treatment Control of
Type 1 DM
  • AIM
  • Exogenous insulin by subcutaneous injection is
    given to
  • 1- Control Hyperglycemia (long run complications)
  • 2- Prevent occurrence of Ketoacidosis (emergency
    case!!)
  • Strategies of Treatment
  • 1- Standard Treatment
  • 2- Intensive Treatment (Tight Control)

16
Biochemical Aspects for Treatment Control of
Type 1 DM (cont.)
  • 1- Standard Treatment
  • By one or two injections of insulin/day
  • AIM Mean blood glucose level 225-275 mg/dl
    (normal 110 mg/dl)
  • HbA1c level 8-9 of total Hb
    (normal 6 of total hemoglobin)
  • HbA1c
  • is proportional to average blood
    concentration over the previous several months
  • So, it provides a measure of how proper
    treatment normalized blood glucose in diabetic
    over
  • several months

17
Treatment of type 1 DM (cont.)
  • 2- Intensive Treatment (Tight control)
  • By more frequent monitoring subsequent
    injection of insulin
  • (i.e. 3 or more times / day)
  • It will more closely normalize blood
    glucose to prevent chronic complications of
    existence of hyperglycemia for a long period.
  • AIM Mean blood glucose levels of 150
    mg/dl
  • HbA1c approximately 7 of
    total hemoglobin
  • Advantage Reduction in chances of
    occurrence of chronic complications of DM
  • e.g. retinopathy,
    nephropathy neuropathy by about 60

18
Biochemical Aspects for Treatment Control of
Type 1 DM (cont.)
  • Complications of Treatment by Insulin
  • Hypoglycemia is a common complication of insulin
    treatment
  • (in more than 90 of patients on insulin
    medication)
  • More Common with intensive treatment strategy
  • Causes of hypoglycemia due to insulin treatment
  • Diabetics cannot depend on glucagon or
    epinephrine to avoid hypoglycemia as
  • No glucagon (early in the disease)
  • No epinephrine (with progression of the
    disease diabetic autonomic neuropathy with
    inability to
  • secrete epinephrine in response to
    hypoglycemia)
  • So, patients with long-standing type 1 DM
    are particularly vulnerable to hypoglycemia
  • Hypoglycemia can be caused by strenuous exercise.
  • Exercise promotes glucose uptake into
    muscles decrease the need for exogenous
    insulin.
  • So, blood glucose level should be checked
    before after exercise to avoid hypoglycemia.

19
Biochemical Aspects for Treatment Control of
Type 1 DM (cont.)
  • Contraindications of Intensive Treatment
  • Children risk of episodes of hypoglycemia may
    affect the
  • brain development
  • Elderly people as hypoglycemia can cause strokes
    heart
  • attacks in
    older people

20
Type 2 Diabetes Mellitus
21
Type 2 DM
  • 90 of diabetics (in USA)
  • Develops gradually
  • may be without obvious symptoms
  • may be detected by routine screening tests
  • BUT many type 2 diabetics have symptoms of
    polyuria polydepsia
  • In type 2 DM a combination of insulin resistance
    dysfunctional b-cells
  • Metabolic changes in type 2 are milder than type
    1

  • as insulin secretion, although not
    adequate, restrains ketoacidosis

  • Diagnosis blood glucose concentration equal or
    more than 126 mg/dl
  • Treatment no requirement for insulin to
    sustain life
  • BUT insulin may be
    required to control hyperglycemia in some
    patients

22
Causes of Type 2 DM Insulin Resistance
Dysfunctional b-cell
  • Insulin resistance is the decreased ability of
    target tissues, such as liver, adipose tissue
    muscle to respond properly to normal circulating
    insulin
  • Obesity is the most common cause of insulin
    resistance
  • Obesity causes insulin resistance as
  • - substances produced by fat cells as leptin
    and resistin may contribute to
  • development of insulin resistance
  • - Free fatty acids elevated in obesity is
    involved in insulin resistance

23
Causes of type 2 DM (cont.)Insulin Resistance
Dysfunctional b-cell
  • Obesity, Insulin Resistance DM
  • Obesity is the most common cause for insulin
    resistance.
  • HOWEVER, Most people with obesity insulin
    resistance do not develop DM !!
  • How insulin resistance leads to DM??
  • 1- In the absence of defect in b-cell
    function, nondiabetic, obese individuals can
    compensate for insulin resistance by secreting
    high amounts of insulin from b-cell (i.e.
    Hyperinsulinemia)
  • So, glucose levels in blood remain within
    normal range
  • 2- In late cases, b-cell dysfunction with
    low insulin secretion occurs due to increased
    amounts of free fatty acids other factors
    secreted by fat cells (as leptin resistin) may
    end in development of type 2 DM (hyperglycemia).

24
Causes of type 2 DM (cont.)Insulin resistance
dysfunctional b-cell
  • In Type 2 DM
  • Initially (In early stages with Insulin
    resistance)
  • the pancreas retains b-cell capacity
  • Insulin is secreted (may be higher than
    normal i.e. hyperinsulinemia)
  • Normal blood glucose levels
  • ________________________________________________
  • With time (late stages)
  • b-cells become dysfunctional (low function)
  • (due to harmful effects of FFAs substances
    released by increased fat cells)
  • b-cells fail to secrete enough insulin (low
    insulin)
  • Increased blood glucose levels (hyperglycemia)

25
Progression of Type 2 DM
26
Metabolic changes in Type 2 DM
  • Metabolic abnormalities of type 2 DM are the
    results of insulin resistance (in liver, muscle
    adipose tissue)
  • 1- Hyperglycemia
  • 2- Hypertriacylglyceridemia
  • 3- Nonketotic hyperglycemic coma
  • In cases with severe hyperglycemia
    especially in older age diabetics type 2
  • Hyperglycemia induces osmotic diuresis with
    loss of ECF
  • The osmotic diuresis causes loss of water
    in excess of sodium
  • leading to very high plasma osmolality
    (with hypernatremia)
  • marked dehydration
  • No ketgenesis due to presence of sufficient
    insulin to prevent DKA
  • (or sometimes there is minimal ketogenesis
    with minimal metabolic
  • acidosis i.e. Bicarbonate is not much
    lowered as in DKA)
  • Treatment
  • Fluid replacement Insulin IV infusion follow
    up (Emergency Case!!)

27

Metabolic changes in Type 2 DM
28
Chronic Effects of DM
  • The long-standing hyperglycemia causes the
    chronic complications of DM
  • 1- Atherosclerosis Diabetic Retinopathy

  • Diabetic Nephropathy glomerular proteinuria

  • Diabetic Neuropathy peripheral neuritis

  • Cardiovascular Diseases (as MI) strokes (as
    cereb. hge)
  • 2- Sorbitol accumulation in certain cells
    with its complications
  • 3- Glycated proteins formation with
    microvascular complications
  • For avoiding these complications, long-term
    control of hyperglycemia is recommended for all
    types of DM

29
Chronic Effects of DM (cont.)
  • In cells where entry of glucose is not dependent
    on insulin
  • (eye lens, retina, kidney, neurones)
  • Intracellular Levels of Glucose
  • SORBITOL accumulation in these cells

  • Cataract
  • Diabetic Retinopathy
  • Diabetic Nephropathy
  • Diabetic Neuropathy

30
Treatment of Type 2 DM
  • AIM
  • 1- To maintain blood glucose
    concentrations within normal limits
  • 2- To prevent the development of long-term
    complications occurring due
  • to prolonged hyperglycemia
  • Lines of treatment
  • 1- Weight reduction (to control insulin
    resistance)
  • 2- Exercise
  • 3- Dietary modification
  • 4- Hypoglycemic agents
  • 5- Insulin (required in some cases)

31
Case Study
  • Parents of a 15 years old boy was reported by his
    school that he was found drowsy they have
  • got to take him to hospital according to the
    advice of his school doctor.
  • In the hospital, his mother told the doctor that
    her son seemed unusually thirsty for the last 3
  • months she thought that he had lost weight.
    She admitted also that on the morning
  • before leaving for school, he was complaining
    of abdominal pain discomfort.
  • On examination
  • Semiconscious
  • Deep rapid respiration
  • Pulse rate 120 beats/minute
  • BP 90/50
  • Cold extremities
  • What investigations were recommended for him??
  • What is the diagnosis of this case??
  • What is the treatment ??

32
Case Study cont.
  • Clinical Biochemistry Lab Investigations
  • Blood Chemistry
  • Random Blood Glucose 550 mg/dl
  • Urea 160 mg/dl (N 20 -40)
  • Na 127 mmol/L (N 135 145)
  • K 6.9 mmol/L (N 3.5 4.5)
  • pCO2 2.9 kPa (N 4.4 6.1)
  • HCO3- 7 mmol/L (N 21 27.5)
  • pO2 14 kPa (N 12 17)
  • Urine Analysis
  • Urine Dipstick Test
  • - Glucose
  • - Ketone
  • - Albumin
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