Diabetes Mellitus

Diabetes Mellitus A Silent Killer

Points to Consider What is Diabetes? Types of Diabetes Epidemiology Complications of Diabetes Diagnostics in Diabetes

How Does Glucose Enter Cells?

What is diabetes? Diabetes mellitus (DM) is a chronic, potentially debilitating and often fatal disease, characterized by hyperglycemia (increased blood glucose levels). It occurs as a result of problems with the production and supply of insulin in the body. Thus, there is reduced breakdown of glucose resulting in raised blood sugar levels that have a detrimental effect on the body. Diabetes mellitus is called ‘the silent killer’, because it causes serious complications without symptoms, and can affect many of the major organs in the body by the time it is diagnosed.

Insulin A hormone made by the beta-cells of pancreas Helps the body to utilize glucose for bodily functions

Types of Diabetes Diabetes is a disease in which; -

Either the body produces no or insufficient insulin (Type 1 diabetes) or

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The body cannot use the insulin it produces effectively (Type 2 diabetes).

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Gestational diabetes

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Other types o

Maturity-Onset Diabetes of Youth (MODY)

Type 1 Diabetes Type 1 diabetes was previously called insulin-dependent diabetes mellitus (IDDM) or juvenileonset diabetes. Body's immune system destroys pancreatic beta cells leading to a total halt in insulin production This form of diabetes usually strikes children and young adults Type 1 diabetes accounts for about 5% all diagnosed cases of diabetes Risk factors for type 1 diabetes may be autoimmune, genetic, or environmental.

Type 2 Diabetes Type 2 diabetes was previously called non-insulin-dependent diabetes mellitus (NIDDM) or adult-onset diabetes. Type 2 diabetes accounts for about 94-95% of all diagnosed cases of diabetes in India. It usually begins as insulin resistance. The body does not respond well to the insulin made by the pancreatic beta cells. As the need for insulin rises, the pancreas gradually loses its ability to produce it Type 2 diabetes is associated with older age, obesity, family history of diabetes, history of gestational diabetes, impaired glucose metabolism, physical inactivity, and race/ethnicity.

Gestational Diabetes Gestational diabetes is a form of glucose intolerance diagnosed in some women during pregnancy. It is also more common among obese women and women with a family history of diabetes. Gestational diabetes requires treatment to normalize maternal blood glucose levels to avoid complications in the infant. Women who have had gestational diabetes have a 40% to 60% chance of developing diabetes in the next 5–10 years.

Other Types Other types of diabetes result from specific genetic conditions (such as maturity-onset diabetes of youth), surgery, drugs, malnutrition, infections, and other illnesses. Such types of diabetes account for 1% to 5% of all diagnosed cases.

Pre-Diabetes Pre-diabetes is a condition that raises the risk of developing type 2 diabetes, n heart disease, and stroke. tha

e r o but m People with pre-diabetes have blood glucose levels higher than normal e b not high enough to be classified as diabetes. o t d e t People with pre-diabetes have impaired fasting glucose (IFG) or impaired a l glucose tolerance (IGT). tu s o p re a ts n e i t a p s e t e b ia D er P a di n I In

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Impaired Glucose Tolerance (IGT) IFG is a condition in which the fasting blood sugar level is between 100 and 125 milligrams per deciliter (mg/dL) after an overnight fast. IGT is a condition in which the blood sugar level is 140 to 199 mg/dL after a 2-hour oral glucose tolerance test. Studies have shown that people with pre-diabetes who lose weight and increase their physical activity can prevent or delay diabetes and even return their blood glucose levels to normal.

Epidemiology Diabetes currently affects 246 million people worldwide and is expected to affect 380 million by 2025. Diabetes is the fourth leading cause of global death by disease. Each year 3.8 million worldwide deaths are attributable to diabetes, about 6% of total global mortality.  80% of diabetes deaths are now occurring in low- and middle-income countries. At least 50% of all people with diabetes are unaware of their condition. The number of people with diabetes in India: 40.9 million (2007) [IDF] Every 10 seconds a person dies from diabetes-related causes. Cardiovascular disease is the major cause of death in diabetes, accounting for >50% of all diabetes fatalities, and much disability. On average, people with type 2 diabetes will die 5-10 years before people without diabetes, mostly due to cardiovascular disease. 10% to 20% of people with diabetes die of renal failure.

Ref.: Diabetes Atlas, third edition, International Diabetes Federation, 2007.

India “Diabetes Capital of the World” Diabetics: 4 crores (2007) Expenses: International Dollar 210 billion in India in 2005 for diabetes, heart disease and stroke together 5.75 crores diabetic people by the year 2025. Projected Expenses: $333.6 billion in India Compared to north India, the incidence was more in the south, particularly in cities like Chennai and Hyderabad with about 16 per cent people becoming diabetic. Indians tend to suffer from it 10 years earlier than people in developed countries

A Constellation of Complications Diabetes accounts for an extraordinary amount of human suffering as it is a major cause of blindness, kidney failure, amputations, and cardiovascular disease, (responsible for 50-80% of deaths in diabetic patients).

Sexual Dysfunction

Renal Disease

Peripheral Neuropathy

Peripheral Vascular Disease

Gastropathy

Complications of Diabetes

Retinopathy/ Macular Edema Autonomic Neuropathy

Dyslipidemia Cardiovascular Disease

Hypertension

A Constellation of Complications: Diagnosis Diabetes accounts for an extraordinary amount of human suffering as it is a major cause of blindness, kidney failure, amputations, and cardiovascular disease, (responsible for 50-80% of deaths in diabetic patients). Clinical

Microalbuminuri a/Urea/Creatinin e/Cystatin C

Clinical/Nerve studies

Clinical/Imaging Studies

Gastropathy

Ophthalmological Tests

Complications Hb A1c of Diabetes

Clinical/Nerve Studies Lipid Prfiles Clinical Haptoglobin Genotyping/Lipid Profiles/CRP

Diagnostic Tests in Diabetes

The Role of Diagnostic testing: A primary preventive measure Blood and urine tests help to show if a diabetes treatment is working and can alert the doctor to early signs of diabetes complications. Usually, a diabetes diagnostic test follows eight hours of fasting, as with a fasting plasma glucose (FPG) test or an oral glucose tolerance test (OGTT). Not only diagnosis but, monitoring of glycemic status is also considered a cornerstone of diabetes care.

Diabetes Mellitus Diagnostic Criteria: ADA 2007 Symptoms of diabetes plus casual plasma glucose concentration ≥200 mg/dl. Casual is defined as any time of day without regard to time since last meal. The classic symptoms of diabetes include polyuria, polydipsia, and unexplained weight loss.

OR FPG ≥126 mg/dl. Fasting is defined as no caloric intake for at least 8 h.

OR 2-h postload glucose ≥200 mg/dl during an OGTT. The test should be performed as described by WHO, using a glucose load containing the equivalent of 75 g anhydrous glucose dissolved in water.

Fasting Plasma Glucose (FPG) The fasting plasma glucose (FPG) test, also known as the fasting blood sugar test, measures blood sugar levels and is used to diagnose diabetes. Relatively simple and inexpensive, the test exposes problems with insulin functioning. The test consists of a noninvasive blood test. Prior to being tested, a person must not to eat for 12 to 14 hours.

Understanding the Results Doctors interpret test results by looking at glucose levels in the blood. Diagnosis categories include the following, measured in milligrams per deciliter (mg/dL): In the fasting plasma glucose test, 70 mg/dL to 99 mg/dL is considered within the normal range. A reading of 100 mg/dL to 126 mg/dL suggests prediabetes. A reading above 126 mg/dL is the threshold at which diabetes is diagnosed. Blood glucose levels lower than 70 mg/dL imply an episode of hypoglycemia.

If the results are borderline, other tests might be done, including the oral glucose tolerance test or the postprandial plasma glucose test.

Oral Glucose Tolerance Test (OGTT) A glucose tolerance test in medical practice is the administration of glucose to determine how quickly it is cleared from the blood. The glucose is most often given orally so the common test is technically an oral glucose tolerance test (OGTT). The OGTT is a more sensitive test and therefore often considered a better diabetes diagnostic test to identify the existence of a pre-diabetes condition. An OGTT is also used as a specific diabetes diagnostic test to help identify gestational diabetes

Procedure for OGTT The patient should have been fasting for the previous 8-14 hours (water is allowed). The patient is then given a glucose solution to drink. The standard dose since the late 1970s has been 1.75 grams of glucose per kilogram of body weight, to a maximum dose of 75 g. Blood sample is then drawn at timed intervals (after 2 hours) for the measurement of glucose (blood sugar).

Interpretation of OGTT results Two-hour plasma glucose ≥ 200 mg/dL confirms diabetes.

Tests Offered Test Name

Sample

Test Code

Diabetes Screen

EDTA WB, Fasting Plasma FL, Fasting Urine, PP Plasma FL, PP Urine

3180DS

Diabetes Mellitus Panel II

EDTA WB, Serum, Fasting Plasma FL, Fasting Urine, PP Plasma FL, PP Urine, Urine 24hr or 12hr OR Random

DT9201

Diabetes Monitor

EDTA WB, Serum, Fasting Plasma FL, Fasting Urine, PP Plasma FL, PP Urine, Urine 24hr OR Random

1579

Diabetes Monitoring Panel

14hr Fasting Serum, EDTA WB, Fasting Plasma FL, Fasting Urine, PP Plasma FL, PP Urine, Urine 24hr or 12hr OR Random

DT9200

Markers for Classification of Diabetes Once diagnosed, the classification of diabetes as Type 1 or Type 2 is highly important. Markers C-peptide Autoantibodies to islet cells (ICA) Antibodies to insulin (IAA) Glutamic acid decarboxylase autoantibodies (GAD Ab)

C-Peptide C-peptide test measures the level of this peptide in the blood. C-peptide is generally found in amounts equal to insulin. The level of C-peptide in the blood can show how much insulin is being made by the pancreas. A person with type 1 diabetes has a low level of insulin and C-peptide. A person with type 2 diabetes has a normal or high level of C-peptide. Prior to being tested, a person must not to eat for 8 to 10 hours.

Test Name C-peptide

Sample

Test Code

Serum (Freeze, immediately after separation)

3140

Understanding the Results Normal Values The level of C-peptide in the blood must be read with the results of a blood glucose test. Both these tests will be done at the same time. Fasting: 1.89 (ng/mL) or 0.62 (nmol/L) High values High levels of both C-peptide and blood glucose are found in people with type 2 diabetes. A high level of C-peptide with a low blood glucose level may mean an insulin-producing tumor of the pancreas (insulinoma) is present Low values Low levels of both C-peptide and blood glucose are found in liver disease, a severe infection. A low level of C-peptide with a high blood glucose level is found in people with type 1 diabetes.

Antibodies in Type I Diabetes Type I diabetes or insulin-dependent diabetes mellitus (IDDM) is also known as an organ-specific autoimmune disease because it develops as a results of pancreatic islet cell destruction.

Antibodies Markers Evidence of cellular destruction includes autoantibodies to islet cells (ICA), antibodies to insulin (IAA) and glutamic acid decarboxylase autoantibodies (GAD Ab). ICA are present in 80% of newly diagnosed IDDM patients. ICA, GAD Ab and IAA are all helpful in screening first-degree relatives of patients with IDDM. ICA, GAD Ab and IAA do not appear all at once, but at random, varying rates depending on the patient. These antibodies also occur before the onset of IDDM, increasing their potential for early disease detection. Specifically, IAA is among the first to appear during the asymptomatic period which characterizes IDDM (lasting anywhere from years to decades).

Clinical Utility Autoantibody detection is useful to screen for those relatives of IDDM patients who may be at risk of developing Type I diabetes. 60-80% of first-degree relatives with both ICA and IAA will develop IDDM within 10 years. Measurement of GAD Ab is a useful adjunct to measuring ICA, as 43% of ICA-positive, first-degree relatives also have elevated GAD Ab. Children less than 14 years of age can be screened for Type I diabetes using ICA, IAA and GAD Ab. Because of a strong association of IDDM with autoimmune thyroid disease (AITD), testing AITD patients for diabetes mellitus autoantibodies could be a useful means of predicting progression to Type I diabetes.

Tests Offered Test Name

Sample

Test Code

Antiislet cell antibodies

Serum

1166

Antiislet cell antibodies with titre

Serum

1166T

Glutamic acid decarboxylase (GAD) IgG antibodies

Serum

3193

Insulin

Serum Fasting

3192

Anti insulin antibodies

Serum

3191

Microalbuminuria

• Early detection of microalbuminuria through screening allows interventions aimed at preventing diabetic nephropathy. • Patients with diabetes are at risk of microalbuminuria if they have any of the following factors: – – – –

the urine albumin excretion is in the upper range of normal (20–30 mg/d); the systolic blood pressure is greater than 130 mm Hg; the glycosylated hemoglobin level is greater than 9; or the total cholesterol level is greater than 5.24 mmol/L.

Test Code: 3441 UD RANDOM/12 HRS OR 24 HRS URINE SAMPLE CAN BE ACCEPTED

Guideline for Screening for Diabetic nephropathy

HbA1c: A Gold Standard Marker for Diabetes Monitoring Glycosylated hemoglobin (HbA1c) Hemoglobin in erythrocytes combines with glucose in the blood to form HbA1c. The amount of stable HbA1c increases with the average concentration of glucose in the blood.

The level of HbA1c at any time is contributed by all circulating erythrocytes, from the oldest to the youngest. As a result, HbA1c reflects the blood glucose level during the preceding two to three months.

The amount of HbA1c in the blood is thus a Gold Standard marker to monitor long-term blood glucose control in individuals with diabetes mellitus.

Normal HbA1c Levels The normal range of HbA1c is 4 to 5.9% of the total hemoglobin. In diabetics the higher the average blood glucose levels over a two to three month period, the higher the percentage of HbA1c. Each 1% increase in HbA1c corresponds to an increase in mean plasma glucose level of approximately 35 mg/dL (2 mmol/L). Increased HbA1c is closely linked to risk of long-term microvascular diabetic complications. Whereas, decreased HbA1c levels may sometime lead to hypoglycemia.

Factors affecting HbA1c test results A number of factors may confound the interpretation of the test result: Any condition that shortens the erythrocyte lifespan, such as hereditary spherocytosis, hemolysis, sickle cell anemia, thalassemias, etc. would lead to falsely low and inaccurate HbA1c level. Conversely, any condition which lengthens the erythrocyte lifespan, such as iron deficiency anemia, vitamin B12 deficiency anemia, or folate deficiency anemia, would lead to falsely high and inaccurate HbA1c level.

Clinical Significance of HbA1c in management of diabetes Concentration of HbA1c is an indicator of average blood glucose concentration over the preceding 2-3 months. HbA1c is used as a measure of risk for the development of diabetes complications. A study by Diabetes Control and Complications Trial (DCCT) has demonstrated that the 10% stable reduction in HbA1c determines a 35% risk reduction for retinopathy, a 25-44% risk reduction for nephropathy and a 30% risk reduction for neuropathy. Note: With HbA1c as a guideline, the physician can monitor glucose control and can continue or modify the therapy as per the requirement. Test Name Glycosylated Hemoglobin

Sample

Test Code

EDTA Whole Blood

3179

Haptoglobin Genotyping Cardiovascular disease (CVD) is the most frequent, severe, and costly complication of diabetes. Patients with diabetes have a three- to fivefold increase in risk of atherosclerotic CVD compared with nondiabetic individuals. Studies have also suggested that, among diabetic patients, genetic factors could contribute to differences in susceptibility to CVD. One such factor is a functional allelic polymorphism in the Haptoglobin gene.

Haptoglobin Haptoglobin - a serum protein - functions as an antioxidant - prevents the oxidative tissue damage

Two classes of alleles - class 1 and class 2, And, three potential genotypes denoted Hp 1-1, Hp 21, and Hp 2-2.

All three types of haptoglobin proteins bind free hemoglobin equally well with high affinity. The haptoglobin-hemoglobin complex binds with high affinity to the CD163 scavenger. This results in rapid clearance of Hp-Hb complex from blood as well as release of antiinflammatory cytokines like IL-10 and IL-6.

Haptoglobin in Diabetic Cardiovascular Complications Free Hb enters into the subendothelial space. Intravascular free Hb will be rapidly bound by Hp, preventing Hb-induced oxidation. This ability of Hp is lost when hemoglobin becomes heavily glycosylated. Diabetic individuals with Hp 1-1 are exposed to less hemoglobin-driven oxidative stress than diabetic Hp 2-2 individuals.

Haptoglobin Genotyping

Haptoglobin genotyping is performed by polymerase chain reaction and three genotypes of Haptoglobin (Hp 1-1, 2-1 & 2-2) are identified.

Clinical Significance of Haptoglobin Genotyping Haptoglobin genotyping is indicated in diabetic patients to predict higher risk for cardiovascular disease. Patients who are homozygous for the Hp 1 allele (Hp 1-1) are at a lower risk of developing both microvascular and macrovascular complications associated with diabetes. Diabetic patients with the Hp 2-2 genotype have up to 5 fold increased risk of cardiovascular disease and therefore, should be more aggressively managed.

How Haptoglobin genotyping will benefit the patient? Haptoglobin testing may help physicians tailor optimal therapy for patients with diabetes who are at high risk for cardiovascular events. There is almost 50% decrease in cardiovascular events in patients with Hp 2-2 taking Vitamin E. Arteriosclerosis, Thrombosis and Vascular Biology March 2008 Test Name

Sample

Test Code

Haptoglobin Genotyping

EDTA- Whole Blood

7375

Note: Hp genotyping is not currently recommended in the assessment of cardiovascular risk for Non-diabetics, as there is no proven correlation between the genotype and cardiovascular risk.

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