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CARBOHYDRATES METABOLISM DISORDERS

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CARBOHYDRATES METABOLISM DISORDERS Diabetic Nephropathy rise in glomerular filtration rate. glomerular lesions increased glomerular permeability. – PowerPoint PPT presentation

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Title: CARBOHYDRATES METABOLISM DISORDERS


1
CARBOHYDRATES METABOLISM DISORDERS
2
GLUCOSE METABOLISM
  • the cornerstone of life
  • neurons are especially dependent on glucose
  • regulatory mechanisms
  • hyperglycemic hormones glycogenolysis,
    gluconeogenesis
  • hypoglycemic hormone insulin

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HYPERGLICEMIA (diabetes mellitus)
  • Diabetes - Greek word to siphon or to pass
    thru.
  • Mellitus - Latin word sweet or honey.
  • group of chronic disorders
  • insulin deficiency ABSOLUTE/RELATIVE
  • !!! also affects protein and fat metabolism

5
CLASSIFICATION
  • type 1 DM - autoimmune pancreatic ß-cell
    destruction absolute insulin deficiency
  • type 2 DM - insulin resistance relative insulin
    deficiency
  • other specific types of DM (associated with
    identifiable clinical conditions or syndromes)
  • gestational DM - appears or is first detected
    during pregnancy.

6
  • !!! pre-diabetes
  • impaired glucose tolerance (IGT)
  • impaired fasting glucose (IFG)

7
ADA diagnosis of DM
  • 1.   classic symptoms of diabetes (polyuria,
    polydipsia, and unexplained weight loss) plus
    random plasma glucose concentration 200 mg/dL
    (11.1 mmol/L)or
  • 2.   fasting (8-hour) plasma glucose
    concentration 126 mg/dL (7.0 mmol/L)or
  • 3.   a 2-hour postload plasma glucose
    concentration 200 mg/dL (11.1 mmol/L) during a
    75-g oral glucose tolerance test.

8
ETIOLOGY
  • Type 1 diabetes
  • Genetic
  • Environmental
  • Autoimmune

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Type 2 diabetes
  • relative insulin deficiency insulin
    resistance / inadequate secretory response
  • complex genetic interactions unrelated to HLA
    genes
  • environmental factors such as body weight
    (obesity) and exercise (lack of physical
    activity).

11
MODY
  • autosomal dominant inheritance
  • onset in at least 1 family member younger than 25
    years
  • absence of autoantibodies
  • correction of fasting hyperglycemia without
    insulin for at least 2 years
  • absence of ketosis.

12
Type 2 DM pathogenic mechanisms
  • progressive loss of insulin secretory capacity.
  • impaired insulin action
  • impaired mitochondrial function and the resulting
    accumulation of free fatty acids in
    insulin-responsive tissues.
  • defects of the insulin receptor.
  • defects in postreceptor pathways
  • Adipocyte-Derived Hormones and Cytokines
  • Leptin
  • Adiponectin
  • other adipocyte-derived factors (resistin,
    angiotensinogen, interleukin-6, transforming
    growth factor-ß, plasminogen activator inhibitor
    1)
  • TNF-a.

13
  • Glucotoxicity.
  • Lipotoxicity.
  • accelerate hepatic gluconeogenesis
  • inhibit muscle glucose metabolism
  • impair pancreatic ß-cell function.

14
  • Type 1 DM produces profound ß-cell failure and
    insulin deficiency with secondary insulin
    resistance,
  • Type 2 DM is associated with less severe insulin
    deficiency but greater insulin resistance.

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diabetes mellitus pathogenesis
17
fasting hyperglycemia
  • mobilization of substrates from muscle and
    adipose tissue
  • accelerated hepatic gluconeogenesis,
    glycogenolysis, ketogenesis
  • impaired removal of endogenous and exogenous
    fuels by insulin-responsive tissues.

18
fasting free fatty acids
  • Insuline deficiency - increase lipolysis
  • Glucagon - accelerating hepatic ketogenesis
  • Catecholamines growth hormone, and cortisol -
    increase lipolysis.
  • type 1 diabetes - converted to ketone bodies
  • type 2 diabetes insulin suppress the conversion
    of free fatty acids to ketones
  • !!! The increase in substrate delivery - hepatic
    steatosis and severe hypertriglyceridemia
    (endogenous).

19
Postprandial Hyperglycemia
  • type 1 diabetes insulin deficiency
  • type 2 diabetes - delayed insulin secretion
    hepatic insulin resistance
  • the liver fails to arrest glucose production
  • fails to appropriately take up glucose for
    storage as glycogen
  • glucose uptake by peripheral tissues is impaired

20
Hyperglycaemia ? renal threshold for glucose
surpassed (gt170mg/dl) ? GLUCOSURIA ? osmotic
diuresis ? POLYURIA ? dehydration ? thirst ?
POLYDIPSIA
21
  • Type 1 diabetic - defects in the disposal of
    ingested proteins and fats as well.
  • Hyperaminoacidemia
  • Hypertriglyceridemia (exogenous)

22
ACUTE METABOLIC COMPLICATIONS
  • diabetic ketoacidosis (DKA)
  • hyperosmolar hyperglycemic syndrome (HHS)
  • hypoglycemia

23
DKA
  • deficient circulating insulin activity
  • excessive secretion of counter-regulatory
    hormones.
  • hyperglycemia, ketosis, acidosis
  • !!! osmotic diuresis - dehydration and
    electrolyte loss.

24
Hyperosmolar Hyperglycemic Syndrome (HHS)
  • patients cannot drink enough liquid to keep pace
    with a vigorous osmotic diuresis.
  • Severe hyperosmolarity (gt320 mOsm/L)
  • Severe hyperglycemia (gt600 mg/dL).
  • severe acidosis and ketosis are generally absent
    in the HHS!!!

25
Hypoglycemia
  • the earliest subjective warning signs autonomic
    symptoms (sweating, tremor, palpitations)
  • Central nervous system symptoms and signs
    neuroglycopenia
  • nonspecific (e.g., fatigue or weakness)
  • more clearly neurologic (e.g., double vision,
    oral paresthesias, slurring of speech, apraxia,
    personality change, or behavioral disturbances).
  • irreversible brain damage.
  • Hypoglycemic unawareness syndrome
  • duration of diabetes
  • autonomic neuropathy
  • switched to intensive insulin regimens.

26
  • Somogyi phenomenon
  • normal or increased blood glucose levels at
    bedtime
  • blood glucose drops in early morning hours (2 to
    3 A.M.) usually because nighttime insulin dose is
    too high.
  • compensate by producing counterregulatory
    hormones resulting in hyperglycemia on awakening.
  • Dawn phenomenon Decrease in the tissue
    sensitivity to insulin between 5 and 8 A.M. -
    prebreakfast hyperglycemia
  • ??? release of nocturnal growth hormone

27
CHRONIC DIABETIC COMPLICATIONSMICROVASCULAR AND
NEUROPATHIC COMPLICATIONS
  • Intracellular glucose
  • advanced glycation end products (AGEs)
  • accelerated polyol pathway
  • reactive oxygen species
  • Others cytokines, angiotensin II, endothelin,
    growth factor stimulation, depletion of basement
    membrane glycosaminoglycans
  • Hemodynamic changes in the microcirculation

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32
Diabetic retinopathy
  • vascular-neuroinflammatory disease.
  • breakdown of the blood-retinal barrier (BRB)
    function and loss of retinal neurons.
  • activated macroglia and neuronal death.
  • activated microglia exacerbate the damage.

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35
Diabetic Nephropathy
  • rise in glomerular filtration rate.
  • glomerular lesions
  • increased glomerular permeability.
  • microalbuminuria (30 to 300 mg/day)
  • diffuse glomerulosclerosis
  • massive proteinuria - nephrotic syndrome
  • Systemic hypertension
  • progression to ESRD.

36
Diabetic Neuropathy
  • metabolic factors
  • vascular
  • Nerve growth factor diminished
  • Autoimmune mechanisms.

37
  • Distal symmetrical (sensorimotor) polyneuropathy
  • Acute sensory neuropathy
  • Focal diabetic neuropathies (mononeuropathies)
    pain
  • Entrapment syndromes
  • Proximal motor neuropathy (diabetic amyotrophy)

38
Autonomic neuropathy
  • Cardiovascular abnormalities
  • preferential dysfunction of parasympathetic
    fibers
  • impaired sympathetic vasoconstrictor response and
    impaired cardiac reflexes.
  • Altered gastrointestinal function
  • hypermotility / hypomotility
  • Gastroparesis

39
  • Genitourinary alterations
  • bladder hypotonia
  • Erectile dysfunction
  • Abnormal sweat production
  • Xerosis.
  • Distal anhidrosis - truncal-facial sweating
  • Generalized anhidrosis

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atherosclerosis
  • lipid abnormalities
  • procoagulant state accentuated platelet
    aggregation and adhesion, endothelial cell
    dysfunction.
  • hyperinsulinemia

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43
  • The diabetic foot
  • chronic sensorimotor neuropathy
  • vascular disease
  • abnormal immune function

44
HYPOGLICEMIA
  • Physiological hypoglycaemia
  • 3-5 hours after ingestion of glucose or during
    prolonged fast
  • Pathological HYPOGLICEMIA
  • Whipples triad
  • LOW BLOOD GLUCOSE below 50 mg/dl
  • symptoms of hypoglycaemia
  • symptoms relieved by glucose

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Classification
  • Fasting hypoglycaemia
  • With hyperinsulinemia
  • Without hyperinsulinemia
  • Non-fasting, postprandial or reactive
    hypoglycaemia

47
Fasting hypoglycemia with hyperinsulinemia
  • diabetes
  • islet cell tumours
  • factitious hypoglycemia
  • autoimmune hypoglycaemia
  • drugs

48
Fasting hypoglycemia without hyperinsulinemia
  • Chronic renal impairment
  • Decreased renal gluconeogenesis
  • impaired hepatic glycogenolysis and
    gluconeogenesis
  • !!!
  • increased insulin half-life due to decreased
    renal degradation
  • exaggerated glucose-induces insulin secretion

49
  • severe liver disease hepatogenous hypoglycaemia
  • deficient caloric intake and exercise-induced
    hypoglycaemia

50
septicaemia
  • early phase - hyperglycemia
  • decrease in insulin-stimulated phosphorylation of
    insulin receptor
  • increased clearance of insulin
  • increased production of corticosteroids.
  • late phase hypoglycemia
  • cytokines from macrophages stimulates insulin
    secretion
  • direct hypoglycemic effect of endotoxins (inhibit
    gluconeogenesis)
  • association of renal failure.

51
  • non-islet cell tumours
  • Increased uptake of glucose to tumors
  • reduced production of glucose
  • reduced gluconeogenesis due to weight loss
  • produce peptides with insulin-like activity
  • cytokines release ? (IGF-2, TNF?)

52
  • drugs
  • Salicylates
  • non-selective beta-blockers
  • endocrine insufficiency
  • hypopituitarism
  • Addisons disease
  • isolate GH or ACTH deficiency

53
Reactive hypoglycaemia
  • Organic causes may lead to rapid emptying of
    gastric contents
  • Type 2 diabetes mellitus
  • Alcohol
  • potentates the hypoglycaemic effect of insulin
  • potentates the insulin-stimulating effect of
    glucose
  • Idiopathic
  • Inborn errors of metabolism
  • Disorders of carbohydrates metabolism
    (galactosemia, hereditary fructose intolerance.)
  • Disorders of amino acid metabolism (maple syrup
    urine disease.)
  • Disorders of fatty acid metabolism (systemic
    carnitine deficiency.)

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