carbohydrare metabolism+1
DESCRIPTION
biochemistryTRANSCRIPT
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Prof. Dr. Mona Sedrak
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In the fasting state, blood glucose is
maintained by
Glycogen breakdown in the liver.
Gluconeogenesis (glycerol, lactate,
pyruvate and amino acids)
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Hormones mainly are concerned with
regulation of glucose metabolism in the
fed and fasting states:
Insulin, glucagon, somatosation.
Growth hormone, adrenaline, cortisol.
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Fasting:
70-110 mg/dl AADM < 126 mg/d.
Postprandial:
< 140 mg/dl, AADM < 200 mg/dl.
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After overnight fast:Fasting blood sample is taken.
Then the patient is given a standard dose of: 75g glucose (adult). 1.75 g/kg body weight (children).
Blood samples are taken every half an hour for two hours.
Urine samples are collected with the fasting and other post glucose samples.
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Diabetes mellitus
Any one of the following is diagnostic:
Classic symptoms of diabetes and random plasma glucose concentration 200 mg/dl.
Fasting palsma glucose 126 mg/dl.
2-h postload plasma glucose concentration 200 mg/dl during the OGTT.
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Impaired fasting glucose
Fasting plasma glucose between 100 and 125 mg/dl
Impaired glucose tolerance
Two criteria must be met:
Fasting palsma glucose < 126 mg/dl (100-125 mg/dl).
2-h OGT plasma glucose concentration is between 140 and 199 mg/dl.
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Immunologic markers Islet cell antibodies (ICA) Insulin autoantibodies (IAA) Glutamic acid decarboxylase antibodies
(GAD) Protein tyrosine phosphatase antibodies
(IA-2)Genetcic markers (e.g., HLA)Insulin secretionFastingPulsesIn response to glucose challenge
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Blood glucoseOral glucose tolerance testUrine ketonesOther (e.g., insulin, C-peptide, stimulation tests)
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Glucose Blood Urine
Ketones Blood Urine
Acid-base status (pH, bicarbonate)LactateOther abnormalities related to cellular dehydration or therapy (e.g. potassium, sodium, phosphate, osmolality)N. Osmolality: 282-295mmol/l.
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Glucose Blood (fasting/random), pp. Urine
Glycated proteins Glycated hemoglobin Frucosamine
Urinary proteinUrinary albumin excretionEvaluation of pancreas (C-peptide, insulin)
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Once formed, the glycated Hb stays
within the red cells for life time, half life
60-120 days, therefore glycated Hb value
reflects the average level of blood
glucose for the last 2-3 months.
Good control 4-6%.
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2-2.8 mmol/L.
Reflects the average level of blood
glucose 15-20 days, glucose attached to
albumin (half life 20 days).
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Fasting 2-25 lU/ml
Postprandial 20-60 IU/ml.
Serum C-peptide:0.8-2 ng/ml.
30-300 mg/24 Hs. 30 mg/24 Hs.
20 mg/L (Random, morning sample)
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Feature Type 1 DM Type 2 DM
Typical age of onset Children, young adults
Middle-aged, elderly
Onset Acute Gradual
Habitus Lean Often obese
Weight loss Usual Uncommon
Ketosis-prone Usually Usually not
Plasma insulin concentration
Lower or absent Often normal; may be
Family history of diabetes
Less common Common
HLA association DR3, DR4 None
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A. Diabetic ketoacidosis:
DKA (Metabolic acidosis).
pH < 7.3.
Bicarbonate < 15 Eq/L.
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Insulin deficiency combined with Increased
glucagons secretion Increased glucagons:
insulin ratio in:
1-1- The portal blood :The portal blood :
Inhibition of glycolysis.
Stimulate gluconeogenesis.
qlycogen synthesis.
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2- Adipose T:2- Adipose T:
Increased lipolysis FFA release from adipose tissue liver, where they are
converted to acetoacetic acid, - Hydroxy
butyric acid (ketogenesis) Acetoacetic
acid Acetone.
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3- Serum:3- Serum:
Blood glucose > 250 mg/dl.
Plasma acetone. -hydroxy butyrate + acetoacetate.
3 : 1 mildcases.
5 : 1 sever cases.
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Some lactic acidosis may exist esp. If shock,
sepsis or mecrosis is present, suspect this if
it does not respond to insulin therapy.
Volume and electrolyte depletion due to
glucose induced diuresis.
Very low sodium due to hypertriglyc. In 67 %
of cases.
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Serum potassium:
N 43 %, 39 %, 18 % (depletion). Serum phosphate:
Phosphate 71%, 10% with onset of therapy due to osmotic diuresis.
BUN, serum creatinine. Osmolailty but < 340 m 0 sm/L.
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4- Glycosuria causes osmotic diuresis and 4- Glycosuria causes osmotic diuresis and
fluid depletion, which is exacerbated by fluid depletion, which is exacerbated by
hyperventilation and vomiting :hyperventilation and vomiting :
Decreased plasma volume.
Renal hypoperfusion, prerenal uremia.
glomerular filtration rate oliguria.`
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Acute syndrome due to hyperglycemia,
hyperosmolality and combination of
severe dehydration caused by
inadequate fluid intake and insulin
deficiency.
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Precipitating factors includePrecipitating factors include
Infections, myocardial infarct complicated
by lactic acidosis, use of corticosteroid
and thiazide diuretics have been
implicated in the etiology.
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HypoglycemiaHypoglycemia
Blood glucose (< 60 Mg/dl) 40mg/dl (2.2
mmol/L) deagnosis requires triad of
1. Low blood glucose at the time.
2. Spontaneous hypoglucemic symptoms.
3. Alleviation by administration of glucose
that corrects hypoglycemia.
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A- Reactive (after eating):A- Reactive (after eating): Alimentary (rapid gastric emptying) e.g.,
subtotal gastrectomy.
Impaired glucose tolerance (mild maturity
onset DM).
Idiopathic.
Rare conditions (galactosemia, familial
fructose and galactose Intol.).
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B- Fasting: indicating organic dis.:B- Fasting: indicating organic dis.:
Liver: parenchymal disease or enzyme
defect (galactosemia).
Chronic renal insufficiency.
Pancreatic (insulinoma, MEN-1).
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Deficiency of hormones that oppose
insulin (function of thyroid, anterior
pituitary, adrenal cortex).
Drugs (including factitious: e.g., insulin,
sulfonylurea, alcohol, salicylates.... etc.).
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Deficiency of hormones that oppose
insulin ( function of thyroid, anterior pituitary, adrenal cortex).
Drugs (including factitious: e.g., insulin,
sulfonylurea, alcohol, salicylates.... etc.).
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Combined reactive and fasting typesCombined reactive and fasting types
Insulinoma.
Adrenal insuffiency.
Insulin antibodies or insulin receptor
antibodies.
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N. Insulin: glucose ratio < 0.3, Insulinoma,
theratio > 0.3. Insulin level > 1000 pU/ml
factitious hypoglycemia due to exogenous
insulin.
Patients with insulinoma, insulin rarely
exceeds > 200 pUImI.
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Insulin antibodies appear in 90% of pts
injected with beef or pork insulin and
50% of those injected with human
insulin for more than few weeks. But
are never present in pts, not taking
insulin.
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Classification of Diabetes Mellitus (DM) and other hyperglycemic disorders
Type 2 DM Type 1 DMFormerly called insulin-dependent (IDDM), juvenile-onset, or brittle UM Represents 5%-10l0 of diabetic patients Autoimmune disease in which pancreatic beta islet a-e11 are targets of destruction
Formerly called non-insulin-dependent [NIDDMI or adult-onset DM Represents 90%-95% of diabetic patientsvaries from predominantly insulin resistance in muscle and fat with relative deficiency to predominantly insulin secretory defect with insulin resistance.Relative rather than absolute insulin deficiency.
Autoantibodies are present in We-90% of casesOther autoimmune disorders may be present (e.g., Graves disease, Hashimoto thyroiditis, Addison disease, pernicious anemia).
Associated with dyslipidemia, obesity (in 80%-90% of cases), increasing age, hypertension, family history
Other autoimmune disorders may be present (e.g., Graves disease, Hashimoto thyroiditis, Addison disease, pernicious anemia).
Plasma insulin may be normal or increased but is expected to be higher relative to blood glucose concentration
Ketosis prone Ketosis occurs with stress (e.g., infection), but seldom spontaneously
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Comparison of Diabetic ketoacidosis and hyperosmolar hyperglycemic Nonketotic Coma.
Diabetic Ketoacidosis (DKA)
Hyperosmolar Hyperglycemic Nonketotic
Coma (HHS)
Laboratory findings:Plasma glucose (mg/dL) 250-600 >600; often > 1,00Plasma acetone + in diluted plasma Less + in diluted plasmaSerum sodium (mEq/L) Usually low N , I , or lowSerum potassium (mEq/L) N , I , or low N or ISerum phosphorus (mEq/L) N or I N or ISerum magnesium N or I N or ISerum bicarbonate (mEq/L) Usually < 15 Usually > 20Blood pH >7.30
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Comparison of Diabetic ketoacidosis and hyperosmolar hyperglycemic Nonketotic Coma. (Cont.)
Diabetic Ketoacidosis (DKA) Hyperosmolar Hyperglycemic Nonketotic Coma (HHS)Clinical findingsAge Younger Usually elderly or middle aged Type of diabetes Usually Type 1 Usually Type 2Previous history of diabetes Usually 50% of cases Onset Acute / subacute Insidious Precipitating factors Infection (30%)
non compliance (20%), new diagnosis (25%), new diagnosis (25%), unknown (25%)
Most common: infection MI, CVA; new onset (35%). drugs (e.g., doiretocs, glucocorticoids)
Prodrome < 1 day Several days Dehydration Less More Acetone breath Yes No Kussmaul respiration Yes NoAbdominal pain Yes No Temperature N or low N or IChange in mental status Moderate Severe (coma, sizures)Neurologic findings Rare Very Common Cardiovascular or renal disease 15% 85% Thrombosis Rare Frequent Mortality < 10% 20%-20%
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Differential Diagnosis of Diabetic Coma
Condition Serum
glucose (mg/dL)
Serum Ketones
(undiluted)Blood pH
Serum Osmolality (mOsm/kg)
Serum Lactate
(mmol/L)Plasma insulin
Diabetic ketoacidosis 300-1,000 ++++ D 300-350 2-3 0-L
Lactic acidosis 100-200 0 D N-300 7 L
Alcoholic Ketoacidosis 40-200 ++++ D 290-310 2-6 L
Hyperosomolar coma 500-2,000 0/+ N 320-400 1-2 Some
Hypoglycemia 10-40 0 N 2856 Low I
0 = none; + = small amount; up to ++++ = large amount; D = decreased; I = increased; L = low; N = normal.Normal serum lactate = 0.6 1.1 mmol/L.Lactic acidosis occurs in one-third of patients with diabetic ketoacidosis. Hypersomlar coma and alcoholic ketoacisosis may occur in diabetic ketoacidosis.
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Comparison of Laboratory findings in Causes of Hypoglycemia
Facitious
Insulinoma Exogenous insulin Sulfonylurea Insulin
Autoimme Syndrome
Serum insulin High; usually < 200 U/mlOccasionally very low because serum has a very high proinsulin level that interferes with the insulin assay
Very high; often 2,000 U/ml
High High
Serum C-peptide Increased endogenous insulin secretion is always associated with increased C-peptide .
During hypoglycemic episode, high insulin and low C-peptide levels in serum confirm diagnosis of exogenous insulin administration.
N or L
Serum Insulin/C-peptide ratio
Absent Very high levels, fall rapidly
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Comparison of Laboratory findings in Causes of Hypoglycemia (Cont.)
Facitious
Insulinoma Exogenous insulin Sulfonylurea Insulin Autoimme Syndrome
Insulin antibodies
Absent In 90% of persons injected with beef or pork insulin and 50% of those injected with human insulin for more than a few weeks but are almost never present in persons not taking insulin (rarely occurs on an autoimmune basis), although this may be less useful with the future use of more purified and human insulin
Serum proinsulin
I in ~95% of cases N or L I
Insulin-glucose ratio
> 0.3 in serum (normal is < 0.3) increased ratio is also seen in autonomous production due to insulinoma
Other Fasting provokes hypoglycemia infusion of fish insulin (not measured by assay for human insulin) does not suppress serum insulin in patients with insulinoma but does in normal persons
Demonstration of sulfonylurea or tolbutamide
in urine
Other autoimme syndromes may
be preset may be receiving drugs
containing sulfhydral groups
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