Diabetes mellitus Biochemistry By Dr. Ashok KUmar Jeppu

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  • DIABETES MELLITUS

    Dr. Ashok Kumar J

    Department of Biochemistry

    Management and Science University

    Malaysia

  • Islet cell structure

    cell : glucagon cell : insulincell : somatostatin

    cell

    cell

    cell

  • Type 1 Type 2

    Heterogeneous group of syndromes characterized

    by an elevated plasma glucose caused by

    relative or absolute deficiency of INSULIN

    Diabetes Mellitus

  • Classification of Diabetes Mellitus

    by Etiology

    Type 1 -cell destructioncomplete lack of insulin

    Type 2 -cell dysfunction and insulin resistance

    Gestational -cell dysfunction and insulin resistance during pregnancy

    Other specific types Genetic defects of -cell function Exocrine pancreatic diseases Endocrinopathies Drug- or chemical-induced Other rare forms

    11

  • Diabetes Mellitus

    Polyuria

    (frequent urination)

    Polydipsia (Excessive

    thirst)

    Polyphagia (Excessive

    hunger)

  • Polyuria

    Uptake of glucose by the extra-hepatic

    tissues is decreased

    Hyperglycemia

    Glucose is osmotically active

    Urine volume is increased

    Polyuria

  • PolydipsiaExcess loss of water

    Osmolality of blood

    increases

    Stimulates thirst center in

    hypothalamusOther Symptoms:Polyphagia

    recurrent infection

  • Diabetes Mellitus

    Type 1 Type 2

    Age of onset Usually during

    childhood or puberty

    Symptoms develop

    rapidly

    Frequently after

    the age of 35

    Symptoms

    develop

    gradually

    Nutritional

    status at the

    time of disease

    onset

    Frequently

    undernourished

    Obesity usually

    present

  • Type 1 Type 2

    Prevalence 10% of the

    diagnosed

    cases

    90% of the

    diagnoses cases

    Genetic

    predisposition

    Moderate Very strong

    Defect or

    deficiency

    cells are destroyed

    Insulin resistance

    combined with

    inability of cells to produce appropriate

    quantities of insulin

  • Type 1 Type 2

    Frequency of

    Ketosis

    Common Rare

    Plasma insulin Low to absent High early in

    disease; low in

    disease of long

    duration

    Acute

    complications

    Ketoacidosis Hyperosmolar

    state

  • Type 1 Type 2

    Treatment

    with oral

    hypoglycemic

    drugs

    Unresponsive Responsive

    Treatment Insulin is

    always

    necessary

    Diet, exercise, oral

    hypoglycemic

    drugs; insulin may

    or may not be

    necessary

  • Type 1

    Absolute deficiency of insulin

    Autoimmune attack on the cells of pancreas

    cell destruction requires both a stimulus from the environment (such as viral infection)

  • Type 2 Diabetes mellitus

    Most common form of the disease

    Often detected by routine screening tests

    Symptoms of polyuria and polydipsia of several weeks duration

    Polyphagia may be present but less common

  • Symptoms appear abruptly when 80 to 90%

    of the cells are destroyed

    Among the monozygotic twins

    if one sibling develops type 1 diabetes mellitus

    chance of the other twin developing diabetes mellitus

    is only 30 to 50%

    but

    incase of type 2 diabetes mellitus both individuals

    develop disease

  • Insulin resistance

    Decrease ability of the target tissue to

    respond properly to normal circulating

    concentration of insulin

    Insulin resistance and obesity:

    Most common cause

  • In the absence of defect in the cells function, nondiabetic obese individuals compensate for

    insulin resistance with elevated levels of insulin

    Most of the individuals with obesity and insulin resistance

    do not become diabetic

    Insulin secretion is higher in obese subjects than it is

    in lean individuals

  • Insulin resistance

    Hyperinsulinemia

    Impaired glucose tolerance

    Decline of beta cell function

    Type 2 diabetes

    Genetics,

    Obesity,

    Sedentary lifestyle

    Aging

    +

    Genetis

    Glucose toxiity

    Free fatty acids

    +

  • Metabolic changes Due to deficiency of insulin

    Profoundly affect three tissues

    Liver

    Muscle

    Adipose tissue

    Hyperglycemia and ketoacidosis

    Elevated levels of blood glucose and ketones are hallmarks of untreated diabetes mellitus

  • Hyperglycemia and ketoacidosis

    Increased hepatic production and diminished

    peripheral utilization of glucose hyperglycemia

    Increased mobilization of fatty acids ketone body production and ketosis

    Diabetic ketoacidosis occurs in

    25 to 40% of those newly

    diagnosed type I cases

  • Triglyceride

    Fatty Acids

    Glycerol

    Albumin

    adipose

    tissue

    Fatty

    Acids

    liver

    Fatty Acids

    Fatty

    Acids

    albumin

    Acetyl Co A

    -oxidation

    Energy for the Brain and

    Extrahepatic tissues

    TCA

    Cycle

    Hormone

    Sensitive

    Lipase

    Glucagon

    Epinephrine

    Glucocortic-

    oids

    +

    1

    3

    2

    Fatty Acids

    mitochondria

    Dr. Ashok Kumar;Professor;

    Department of Biochemistry

    Ketone

    Bodies

    21

  • American Diabetes Association

    Criteria for diabetic ketoacidosis

    GLUCOSE > 250 mg/dl

    ANION GAP > 10 mEq/L

    BICARBONATE < 18 mEq/ L

    pH < 7.3

    Urine ketone bodies +ve

  • Hyperglycemia

    Neuropathy

    Peripheral Autonomic

    Biology of

    Microvascular Complications

    Retinopathy

    Cataract

    Glaucoma

    Nephropathy

    Microalbuminuria Gross albuminuria

    Blindness Kidney failure Amputation

    Death and/or disability

  • Retinopathy

    RETINA

    NORMAL DIABETES

  • Cataract

    Glucose

    Sorbitol

    Osmotic damage of the tissue

    Opacity of the lens of the eye

    (CATARAT)

  • Diabetic Foot

  • Hypertriglyceridemia

    Hypercholesterolemiaemia

  • Laboratory investigation

    Blood Glucose level

    Complete lipid profile

    Blood urea and creatinine

    Microalbuminuria

    Glycated hemoglobin (HbA1c)

  • Diagnosis

    Oral glucose tolerance test

    Test done to assess the ability of

    an individual to handle excess

    amount of glucose

  • Preparation of the patient

    Performed at least 3 days of unrestricted diet (>150gm carbohydrate/day) and usual

    physical activity.

    Reasonable carbohydrate containing meal (30 to 40 grams) to be consumed on the

    evening before the test

    Overnight fasting (8 to 12 hours)

    Smoking is not permitted during the test

  • Test procedure

    Collect the fasting blood and Urine sample

    Weigh 75 g of anhydrous glucose or 82.5 gms of glucose monohydrate

    For children 1.75gms of glucose per kg body weight

    Dissolve glucose in about 200 ml of water

    Ask the patient to drink this glucose solution

  • After giving the glucose load collect blood and urine sample every half an hour for

    about 2 Hour

    Estimate the glucose present in the blood sample and analyze the urine sample to

    detect the presence of glucose

  • Interpretation

  • Diagnostic Criteria for Diabetes Mellitus

    1. If the fasting plasma glucose is more than

    126 mg/dl, on more than one occasion.

    2. Or, if 2 hr post-glucose load value of OGTT is

    more than 200 mg/dl (even at one occasion).

    3. Or, if both fasting and 2 hr values are above

    these levels, on the same occasion.

    4. If the random plasma glucose level is more than

    200 mg/dl, on more than one occasion.

    Diagnosis should not be based on a single

    random test alone; it should be repeated.

  • OGTT Graph

  • Glycated Hemoglobin

    When there is hyperglycemia, proteins in the bodymay undergo glycation

    When glucose is attached to hemoglobin,glucose is not removed from hemoglobin.

    [ remains inside the erythrocyte, throughout the

    life span of RBCs (120 days)]

    HbA1c - where glucose is attached to the N-terminal valine of beta chain of hemoglobin

  • Hb A1c level

    reveals the mean glucose level over the

    previous 10-12 weeks

    Used for monitoring the response to treatment

    1.Normal Level of is 5.5% ( very good control)

    2.Adequate control 7%

    3.Inadequate control 8%

    4.Very poor control 9%

    The estimation should be done at least every 3

    months in all diabetic patients

  • Used for Diagnosis of diabetes mellitus

    HbA1c level more than 6.5% at any occasion

    person can be considered diabetic

    (Recommendations of Associaation of clinical

    chemistry and American Diabetes Association)

  • Fructoseamine

    Glycated albumin

    Half life of albumin is 20 days

    It reflects the glycemic control over the past 2 to 3 weeks

  • Microalbumin(Presence of albumin in the urine 30 to 300mg/dl)

    Kimmelsteil Wilson syndrome

    Complication of diabetes resulting from nephrosclerosis

    Characterized by proteinuria and renal failure

    Glycation of basement membrane protein may be the cause for nephropathy

  • CASE 1

    Hyperglycemia: Type I Diabetes Mellitus

    David Mandel was diagnosed with type I (insulin-dependent)