Prof. Dr. Mona Sedrak

In the fasting state, blood glucose is

maintained by

Glycogen breakdown in the liver.

Gluconeogenesis (glycerol, lactate,

pyruvate and amino acids)

Hormones mainly are concerned with

regulation of glucose metabolism in the

fed and fasting states:

Insulin, glucagon, somatosation.

Growth hormone, adrenaline, cortisol.

Fasting:

70-110 mg/dl AADM < 126 mg/d.

Postprandial:

< 140 mg/dl, AADM < 200 mg/dl.

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.

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.

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.

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

Blood glucoseOral glucose tolerance testUrine ketonesOther (e.g., insulin, C-peptide, stimulation tests)

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.

Glucose Blood (fasting/random), pp. Urine

Glycated proteins Glycated hemoglobin Frucosamine

Urinary proteinUrinary albumin excretionEvaluation of pancreas (C-peptide, insulin)

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%.

2-2.8 mmol/L.

Reflects the average level of blood

glucose 15-20 days, glucose attached to

albumin (half life 20 days).

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)

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

A. Diabetic ketoacidosis:

DKA (Metabolic acidosis).

pH < 7.3.

Bicarbonate < 15 Eq/L.

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.

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.

3- Serum:3- Serum:

Blood glucose > 250 mg/dl.

Plasma acetone. -hydroxy butyrate + acetoacetate.

3 : 1 mildcases.

5 : 1 sever cases.

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.

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.

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.`

Acute syndrome due to hyperglycemia,

hyperosmolality and combination of

severe dehydration caused by

inadequate fluid intake and insulin

deficiency.

Precipitating factors includePrecipitating factors include

Infections, myocardial infarct complicated

by lactic acidosis, use of corticosteroid

and thiazide diuretics have been

implicated in the etiology.

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.

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.).

B- Fasting: indicating organic dis.:B- Fasting: indicating organic dis.:

Liver: parenchymal disease or enzyme

defect (galactosemia).

Chronic renal insufficiency.

Pancreatic (insulinoma, MEN-1).

Deficiency of hormones that oppose

insulin (function of thyroid, anterior

pituitary, adrenal cortex).

Drugs (including factitious: e.g., insulin,

sulfonylurea, alcohol, salicylates.... etc.).

Deficiency of hormones that oppose

insulin ( function of thyroid, anterior pituitary, adrenal cortex).

Drugs (including factitious: e.g., insulin,

sulfonylurea, alcohol, salicylates.... etc.).

Combined reactive and fasting typesCombined reactive and fasting types

Insulinoma.

Adrenal insuffiency.

Insulin antibodies or insulin receptor

antibodies.

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.

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.

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

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

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%

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.

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

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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