Endocrine PhysiologyEndocrine Physiology

CaseCase

o 50 year old maleo 122 mg/dL plasma glucoseo Family history:

o Two siblings with Type II Diabetes Mellitus

o Sedentary lifestyle

Experiment No. 30Experiment No. 30

Oral Glucose Tolerance Test

ObjectiveObjective

To determine changes in blood glucose level after a carbohydrate load using the Oral Glucose Tolerance Test (OGTT)

MethodologyMethodology

high carb diet of >= 300 gm per day for 3 days

On the day of the experiment: NPO for 8 hours

FBS (glucometer)

75 gm glucose

Blood sugar taken (60 min, 90min and 120 min)

All results were recorded

MethodologyMethodology

Results and DiscussionResults and Discussion

ResultsResults

Subjects

Blood Glucose level (mg/dL)

F.B.S.O.G.T.T. at 60 min.

O.G.T.T. at 90 min.

O.G.T.T. at 120 min.

Male 59 101 68 122

Female 95 143 73 159

0

50

100

150

200

MaleFemale

Male 59 101 68 122

Female 95 143 73 159

FBS 60mins 90mins120min

s

ResultsResults

Graphical Representation

ResultsResults

SubjectBlood Glucose levels (mg/dL)

Fasting After 120 minutes

Male 59 122

Female 95 159

Normal <110 <140

Impaired Fasting Glycemia

>110 & <126 <140

Impaired Glucose Tolerance

<126 >140

Diabetes Mellitus >126 >200

ResultsResults

Subject Fasting Blood Glucose level

(mg/dL)

After 120 minutes

After 150 minutes

Female 95 159 89

Impaired Glucose

Tolerance

<126 >140 -

DiscussionDiscussion

Error in usage of glucometer – Prolonged exposure of strips

Failure to comply with high carbohydrate diet– Causes misdiagnosis of impaired glucose tolerance

due to decreased insulin secretion and activation of glucose-fatty acid cycle

Insulin resistance– Prediabetic Metabolic syndrome

DiscussionDiscussion

Our bodies desire blood glucose to be maintained between 70 mg/dl and 110 mg/dl.

Below 70 is termed "hypoglycemia". Above 180 is termed "hyperglycemia" If you have two blood sugar measurements above

200 after drinking a sugar-water drink (glucose tolerance test), then you are diagnosed with diabetes. 

CarbohydratesCarbohydrates

Carbohydrates are widely distributed in plants and animals

They fulfill both structural and metabolic roles In plants, glucose is synthesized from carbon

dioxide and water by photosynthesis and stored as starch or is converted to cellulose of plant framework

Animals can synthesize some carbohydrate from fat or protein, but the bulk of animal carbohydrate is derived ultimately from plants

GlucoseGlucose

The sugar glucose is the most important carbohydrate

It is as glucose that the bulk of dietary carbohydrate is absorbed into the bloodstream or into which it is converted to the liver

it is from glucose that all the other carbohydrates in the body can be formed.

The maintenance of stable glucose levels in the blood is one of the most finely regulated of all homeostatic mechanisms and one in which the liver, the extrahepatic tissues, and several hormones play a part.

GlucoseGlucose

Normal regulation of blood glucoseNormal regulation of blood glucose

Insulin and glucagon are two important hormones which regulate the blood glucose (blood sugar) of the body.

They are both secreted by the pancreas in response to blood sugar levels , but in opposite fashion.

Insulin and glucagon secretionInsulin and glucagon secretion

When blood glucose levels  increase over about 5 mmol/L the beta-cells increase their output of insulin and C-peptide.  The glucagon-producing alpha-cells remain quiet, and hold on to their hormone.

Insulin and glucagon secretionInsulin and glucagon secretion

A fall in blood glucose under about 4 mmol/L leads to a pronounced decrease in insulin secretion.  The alpha-cells become active and deliver glucagon to the blood. 

Glucokinase is important in regulating blood glucose after a meal

Insulin plays a central role in regulating blood glucose.

Glucagon opposes the action of insulin

Increased glycogen synthesis Increased fatty acid synthesis Increased esterification of fatty acids Decreased proteolysis Decreased lipolysis Decreased gluconeogenesis Increased amino acid uptake Increased potassium uptake Effects on arterial muscle tone

Actions of InsulinActions of Insulin

Actions of insulin on a cellular levelActions of insulin on a cellular level

Insulin binds to its receptor (1) which in turn starts many protein activation cascades (2). These include: translocation of Glut-4 transporter to the plasma membrane and influx of glucose (3), glycogen synthesis (4), glycolysis (5) and fatty acid synthesis (6).

Regulatory action on blood glucoseRegulatory action on blood glucose

Mechanism of glucose dependent insulin release

Regulation of insulin secretionRegulation of insulin secretion

Stimulates insulin release– Acetylcholine (PNS)– Cholecystokinin– Gastrointestinal Inhibitory Peptide

Inhibits insulin release– α2-adrenergic agonists, like norepinephrine (SNS)

Actions of GlucagonActions of Glucagon

Increased glycogenolysisIncreased gluconeogenesisIncreased lipolysisIncreased ketogenesisDecreased glycolysisDecreased cholesterol synthesis

Regulation of glucagon secretionRegulation of glucagon secretion

Stimulates glucagon release– –

Inhibits glucagon release– glucose– fatty acids– GLP-1 and secretin– somatostatin

The change in the insulin/glucagon ratio seen in fasting and between meals activates adipocyte lipolysis. 

Adipose tissue supplies fatty acids to drive aerobic metabolism in muscle, liver and other tissues.

Energy metabolism during fastingEnergy metabolism during fasting

Excess fat can be converted to ketone bodies in the liver.

Glycerol arising from lipolysis cannot be reused in fat cells but is circulated to the liver where it enters gluconeogenesis. 

After a meal, insulin secretion is activated, glucagon secretion is minimized.

Liver takes up glucose which is then stored as glycogen to be used to buffer blood glucose at a later time. 

Insulin also stimulates glucose uptake and glycogen synthesis in muscles.

Energy metabolism during fastingEnergy metabolism during fasting

Glucose ToleranceGlucose Tolerance

Glucose tolerance is indicated by the nature of the blood glucose curve following the administration of the test amount. Diabetes mellitus (type I, insulin-dependent diabetes mellitus, IDDM) is characterized by decrease glucose tolerance due to decreased secretion of insulin in response to the glucose challenge

Glucose Tolerance test Curve

0

2

4

6

8

10

12

14

FBS 30mins 1 hour 1.5 hours 2 hours

Time

Blo

od

Glu

co

se

(m

mo

l/L)

diabetic

normal

Glucose ToleranceGlucose Tolerance

Categories of glucose toleranceCategories of glucose tolerance

Normal Glucose ToleranceNormal Glucose Tolerance Plasma glucose levels below 140 mg/100cc both fasting and 2 hr after

glucose load

Impaired Glucose TransportImpaired Glucose Transport Requires a two hour plasma glucose level equal to or greater than 140

mg/100 cc but below 200 mg/100 cc and at least one value between 0 time and 2hr equal to or greater than 200 mg/100cc

Definite DiabetesDefinite Diabetes > Require either two fasting plasma glucose values 140 mg/100cc or

more; or a 2 hr plasma glucose level equal to or above 200 mg/100 cc, and at least one value between zero time and 2 hr equal to or greater than 200 mg/100 cc

ConclusionConclusion

The fasting blood sugar value of subject A (Male) is 59 mg/dl, it is slightly below the normal range, and for subject B (Female) it is 95 mg/dl which is within the normal range, (60-100 mg/dl for whole

blood).

After the administration of 75 g glucose, both subjects showed a rapid rise in blood glucose, 101

mg/dl and 143 mg/dl for subjects A and B respectively.

ConclusionConclusion

The 2nd hour values are within the normal range. 122mg/dl for subject A and 159 mg/dl for subject B. The values did not exceed 200 mg/dl and no other

value in the test exceeded 200 mg/dl.

Both the subjects are NOT suggestive of diabetes or of impaired glucose tolerance.

Questions and Answers:Questions and Answers:

1. What are the normal values of blood sugar for this test?

1999 WHO Diabetes criteria - Interpretation of Oral Glucose Tolerance Test

Glucose levels

NORMAL Impaired Fasting Glycaemia

Impaired Glucose Tolerance

Diabetes Mellitus

(I.F.G.) (I.G.T.) (D.M.)

Venous Plasma

Fasting

2hrs Fasting 2hrs Fasting 2hrs Fasting 2hrs

(mmol/l) <6.1 <7.8 > 6.1 & <7.0

<7.8 <7.0 >7.8 >7.0 >11.1

(mg/dl) <110 <140 >110 & <126

<140 <126 >140 >126 >20

Questions and Answers:Questions and Answers:

2. What is the significance of this test?

To measure how well the body can use or metabolize glucose in response to a high glucose intake

Used for detection of both hyperglycemia and hypoglycemia and to help diagnose diabetes.

Most commonly done to check for gestational diabetes

Questions and Answers:Questions and Answers:

3. What diseases can cause abnormal glucose tolerance test results?

High Values• Gestational diabetes.

• Polycystic ovary syndrome (PCOS).

• Medications, (corticosteroids, niacin, phenytoin, some diuretics, and some medications used to treat high BP)

• Severe stress.

• Cushing's syndrome.

• Inherited diseases, such as cystic fibrosis, pheochromocytoma, or hemochromatosis.

• Acromegaly

Questions and Answers:Questions and Answers:

3. What diseases can cause abnormal glucose tolerance test results?

Low Values• Medications, such as medications for diabetes, BP medications

(propranolol), and some medications for depression (isocarboxazid).

• Celiac disease.

• Decreased production of the hormones cortisol and aldosterone (Addison's disease)

• Hypothyroidism

• Pancreatic tumor (insulinoma)

• Liver cirrhosis

Questions and Answers:Questions and Answers:

3. What diseases can cause abnormal glucose tolerance test results?

Other factors• Alcohol

• Recent surgery, heart attack, or childbirth

• Low-carbohydrate diet

• Vomiting during the test

• Emotional stress

• Fever and infection

Clinical CorrelationClinical Correlation

Diabetes Mellitus

Diabetes MellitusDiabetes Mellitus

Diabetes mellitus is a group of metabolic diseases characterized by high blood sugar (glucose) levels, which result from defects in insulin secretion, or action, or both.

Insufficient production of insulin (either absolutely or relative to the body's needs), production of defective insulin (which is uncommon), or the inability of cells to use insulin properly and efficiently leads to diabetes.

Types:

► Type I DM – insulin dependent

► Type II DM – non-insulin dependent

Diabetes MellitusDiabetes Mellitus

TYPE I DM

- Type IA DM results from beta cell destruction that usually leads to insulin deficiency, while for the Type IB DM lack immunologic markers.- major susceptibility gene for type IA is located in chromosome 6, HLA region.- classically occurs in juvenile but can occur at any age

Diabetes MellitusDiabetes Mellitus

Diabetes MellitusDiabetes Mellitus

TYPE II DM

- Defect in insulin receptors in insulin targets cells

- Patients are usually obese/overweight

- Stronger genetic basis

- Non-ketosis prone

- Usually occurs at age 40 or over

Diabetes MellitusDiabetes Mellitus

TYPE II DM 3 pathophysiologic abnormalities: Insulin resistance – decreased ability of insulin to act

effectively on peripheral target tissues. Impaired insulin secretion – endogenous production

continues, but the amount secreted is less than the normal at same plasma glucose concentration.

Increased hepatic glucose production – failure of hyperinsulinemia to suppress gluconeogenesis

Diabetes MellitusDiabetes Mellitus

Risk Factors for Type II DMRisk Factors for Type II DM

Family history of diabetes (parent or sibling) Obesity (≥ 20% of desired body weight or BMI ≥ 27

kg/m2) Age ≥ 45 years Race/ethnicity (African American, Hispanic American,

Native American, Asian American, Pacific Islander) History of GDM or delivery of baby over 9 lbs Hypertension Low HDL cholesterol (≤0.90 mmol/L) levels and/or

high triglyceride levels (≥ 2.82 mmol/L) Polycystic ovary syndrome

Diabetic SymptomsDiabetic Symptoms

Glucosuria Dehydration Acidosis Polyuria Polydipsia Polyphagia Weight loss Asthenia

Criteria for diagnosisCriteria for diagnosis

Symptoms of diabetes plus random/casual blood glucose concentration greater than or equal to 11.1 mmol/L or 200mg/dL.

Fasting plasma glucose greater than or equal to 7 mmol/L or 126mg/dL.

Two-hour plasma glucose greater than or equal to 11.1 mmol/L or 200 mg/dL during an OGTT.

DiagnosisDiagnosis

Urinalysis– not a reliable diagnostic tool but may be used in

conjunction with blood glucose estimation– persons with no sugar in their urine, but very

high blood sugar levels– less than 0.1% of glucose normally filtered by

the glomerulus appears in urine (< 130 mg/24 hr)– Detects glycosuria or glucosuria

DiagnosisDiagnosis

Fasting Plasma Glucose– usually preferred: easy to perform, faster, and more

convenient for the patient– under-diagnoses the problem: normal FPG, but will

have an elevated 2-hour PG – first abnormality that occurs is the rise in post-prandial

blood glucose– fasting levels rise to abnormal values much later– on the basis of FPG alone, complications due to tissue

damage might already be present before diagnosis

DiagnosisDiagnosis

Oral Glucose Tolerance Test– Sensitive– Lack specificity– Defines diabetes chemically– Abnormal in many diseases– Influenced by diet and other variables

Case correlationCase correlation