Diabetes Mellitus:- Part 2 – Diabetes Mellitus Diagnosis and Management

September 17, 2020Chemical pathologyLab Tests

Sample for Glucose Estimation

1. This test can be done on Serum. The serum should be separated within 30 minutes of collection.
2. The serum can be stored at 25° C for 8 hours and 72 hours at 4 °C.
3. Oxalate blood can also be used. Preservative sodium fluoride may be added.
4. The plasma can be stored at 25 °C for 24 hours (when there is preservative sodium fluoride).

Stability of sample

1. One ml blood in anticoagulant will be stable for 3 hours with the presence of fluoride.
2. Oxalate plasma is stable at 2 to 8 °C for 48 hours.
3. Mostly serum is used which is stable for 8 hours at 25 °C and 72 hours at 4 °C.
4. For a fasting sample, the fast of 6 to 8 hours is required.

Indications

1. This test is done to diagnose diabetes mellitus.
2. This test is also done to evaluate and monitoring of the patient with diabetes mellitus.

Screening for diabetes is advised in individuals:

1. People over the age of 45 years or older at 3 years interval.
2. Younger individuals should be screened if they are obese,>120% of the desired weight, or body index ≥ 27.
3. Individuals with H/O first degree relatives with diabetes.
4. In the case of high-risk ethnic groups, afro-American, Hispanic American,  Native American, and Asian American.
5. Babies delivered >9 Lbs of weight, and there is a previous H/O GDM.
6. Individuals with hypertension ≥140/90 mm Hg and H/O atherogenic dyslipidemia.
   1. HDH-Cholesterol = ≤35 mg/dL.
   2. Triglycerides         = ≥250 mg/dL.

Definition of diabetes mellitus

• Diabetes mellitus is a group of metabolic disorders of carbohydrates metabolism in which glucose is not properly utilized, leading to hyperglycemia.
• This is not a single disease but is a group of disorders with glucose intolerance in common.
• Diabetes mellitus term is used to describe a syndrome characterized by chronic hyperglycemia and disturbances of carbohydrate. protein and fat metabolism.
• Diabetes Mellitus is a metabolic disorder characterized by hyperglycemia that results from defects in insulin secretion or insulin action or both.
  • This condition is also associated with protein and fat metabolism abnormality.
  • Diagnosis is dependant upon the hyperglycemia and glucosuria.
  • Chronic hyperglycemia leads to:
    • Changes in the retina and lens of the eye.
    • Damage to kidneys.
    • The heart, arterial system, and microcirculation are adversely affected.
      

      Diabetes Mellitus and insulin function

Diabetes Mellitus

Criteria for the diagnosis of diabetes Mellitus:

1. 1. Polyuria, polydipsia, and rapid weight loss.
   2. Fasting glucose level is high.
   3. Insulinopenia has decreased insulin due to the loss of β-cells of the pancreas.
   4. Most patients have autoantibody was called an autoimmune process.
   5. While no cause known is called idiopathic type.
   6. Abnormal Glucose tolerance test.

Type of Diabetes  Mellitus (classification of the diabetes mellitus):

1. Type 1 diabetes mellitus (Insulin-dependent, IDDM). There is β-cell destruction, usually leading to absolute insulin deficiency.
   1. This may be immune-mediated.
   2. Idiopathic.
2. Type 2 diabetes mellitus (Noninsulin dependant, NIDDM). There is predominantly insulin resistance with relative insulin deficiency. OR
   1. There may be predominantly insulin secretion deficiency with insulin resistance.
3. Gestational Diabetes Mellitus (Gestational diabetes mellitus, GDM). It is detected early in the pregnancy. This may be type 1 or type 2.
   1. This is detected in 2nd or 3rd trimester in 4% of the pregnant ladies.
4. Other specific types are:
   1. The genetic defects of β-cell dysfunction.
   2. The genetic defect in insulin action (type A insulin resistance).
   3. Diseases of the pancreas (exocrine glands).
      1. Pancreatitis.
      2. Trauma or pancreatectomy.
      3. Tumor of the pancreas.
   4. Drugs or chemical induced.
      1. Thiazide.
      2. Glucocorticoids.
      3. Nicotinic acid.
   5. Infections.
      1. Cytomegalovirus (CMV).
      2. Congenital rubella.
   6. Endocrinopathies.
      1. Glucagonoma.
      2. Cushing’s syndrome.
      3. Acromegaly.
   7. Immune-mediated diabetes.
   8. Genetic syndrome associated with diabetes mellitus are:
      1. Turner syndrome.
      2. Down’s syndrome.
      3. Myotonic dystrophy.
      4. Friedreich ataxia.

Pathogenesis of diabetes mellitus:

Pathogenesis of type 1 diabetes:

1. The autoimmune phenomenon may be the cause of  type 1 diabetes:
   1. Type 1 diabetes mellitus is due to cell-mediated autoimmunity leading to the destruction of the insulin-secreting cell of the pancreatic β- cells.
   2. While other α, δ, and other islets cells are preserved.
   3. The islet cells have mononuclear cells infiltrate called insulitis.
   4. The autoimmune process for type 1 diabetes begins years before the clinical presentation.
   5. 80 to 90% reduction in the volume of β- cells is needed before clinical diabetes appears.
   6. Destruction of the β- cells is more rapid in the children than the adults.
      

      Insulin production from the pancreas

2. Antibodies may play a role for the type 1 diabetes are:
   1. There is a marker of β-cells autoimmunity where the antibodies in the serum are detected before diabetes appear.
      1. Islet cell cytoplasmic antibodies.
      2. Insulin auto-antibodies.
      3. Glutamic acid decarboxylase antibodies.
3. Genetic  role:
   1. Type 1 diabetes is inherited but the mode is not clear.
4. Environmental factors:
   1. There are various factors reported and one of those is the virus.
   2. Viruses like mumps, Bella, and coxsackievirus B, are blamed.
   3. Another factor like cow’s milk and chemicals.

Pathogenesis of type 2 diabetes:

1. 1. One of the factors is the decreased ability of the insulin to act on the peripheral tissue (insulin resistance).
      

      Insulin role in glucose metabolism

   2. β-cells dysfunction, which is an inability of the pancreas to produce a sufficient amount of insulin to compensate for insulin resistance.
   3. Genetic factors:
      1. These are well known, in identical twins almost 100% in the second twin.
      2. An obese person with diabetic parents has 10 times more chances to develop diabetes than without a diabetic family history.
   4. Environmental factors:
      1. Exercise and diet are well-known factors in type 2 diabetes.
      2. 60 to 80% are obese diabetic in type 2.
   5. Loss of β-cells functions. There is a loss of pulsatile release of insulin and an increased ratio of plasma proinsulin to insulin.
   6. Insulin resistance is found in type 2.
      

      Mechanism of Insulin formation

Type 1 Diabetes Mellitus (Insulin-dependent)

1. 1. This is also called as:
      1. Juvenile-onset diabetes.
      2. Juvenile diabetes.
      3. Ketosis prone diabetes.
      4. Brittle diabetes.
      5. Autoimmune diabetes.
      6. Idiopathic diabetes.
   2. There is a long preclinical period with abrupt onset of clinical manifestations.
   3. Patients are prone to develop ketoacidosis.
   4. There is a dependency on insulin.
   5. This often affects young people around the age of puberty.
      1. The peak age of onset is 11 to 13 years.
      2. The risk in the sibling is 5 to 10% while the risk for the offsprings is 2 to 5%.
   6. There are several syndromes like autoimmune and genetic origin.
   7. Pathophysiology of type 1 diabetes mellitus:
      1. This is because of the severe or absolute absence of insulin caused by the loss of beta cells of the pancreas.
      2. destruction of the islet cells may be due to:
         1. Genetics.
         2. Autoimmunity.
         3. Environmental factors.
      3. There are 80 to 90% of the cases there are islet cells autoantibodies and antibodies to insulin and to glutamic acid decarboxylase which causes the damage to the islet cells.
      4. Non-immune type 1 diabetes occurs secondary to other diseases like pancreatitis.
   8. Pathology: Beta-cell abnormalities are present long before the onset of type 1 diabetes mellitus.
      1. 1. Both beta and alpha cell functions are abnormal with a lake of insulin and relative excess of glucagon which is produced by the alpha-cells.
   9. Signs and symptoms: Glucose accumulates in the blood (hyperglycemia)  and excreted in the urine.
      1. 1. There is weight loss due to the breakdown of the proteins and fats.
         2. There is polyuria, polyphagia, and polydipsia.
         3. there is a wide fluctuation in the blood glucose level.
         4. There may be ketoacidosis because of the breakdown of protein and fat.
            1. There are increased ketone bodies.
         5. The pH drops which triggers the buffer system and leads to metabolic acidosis.
         6. There is a fruity odor in the breath due to volatile ketone body acetone.
   10. The patient may go into a coma.
   11. Clinical manifestation and their explanation:
       

       Clinical manifestation	Explanation
       Weight loss	There is a fluid loss due to osmotic diuresis and loss of body tissue as fat and protein used for energy.
       Fatigue	There are metabolic changes that result in poor utilization of the food, and this will contribute to lethargy and fatigue.
       Polyphagia	This is due to the depletion of the body store of fat, proteins, and carbohydrate leading to cellular starvation and increase hunger
       Polydipsia	This is due to a raised blood sugar level, which osmotically attracts the water from the cells, leading to intracellular dehydration and ultimately stimulates the hypothalamus and thirst.
       Polyuria	Hyperglycemia acts as an osmotic diuretic and leads to Glycosuria which is accompanied by loss of water in the urine.

   12. Treatment: This will need a combination of insulin, food planning, and exercise. More details are discussed at the end of this discussion.

Type 2 Diabetes Mellitus (NON-Insulin dependent NIDDM)

1. This is also called as:
   1. Adult-onset type diabetes.
   2. Maturity-onset diabetes.
   3. Ketosis resistant diabetes.
2. Patients have minimal symptoms.
3. This is not dependent on insulin to prevent ketonuria.
4. The insulin level may be normal or decreased or increased.
5. Most patients have impaired insulin action.
6. There is the interaction of metabolic, genetics, and environmental factors.
7. It affects the people after the age of 40 years and mostly these are obese.
8. Pathophysiology: The cause is unknown.
   1. Genetics may play some role but not clearly defined.
   2. There is no evidence of the autoimmune mechanism.
   3. Cellular resistance is a factor 60 to 80% of the people with type 11 diabetes mellitus.
   4. Insulin resistance increases with obesity.
   5.  There is a decreased response of the β-cell to blood glucose level and abnormal secretion of the glucagon.
9. There may be alteration in the insulin-receptor or post-receptor events.
   1. There may be an increase in the insulin level to compensate for insulin resistance in the peripheral tissue, but still, there is relative insulin deficiency.
   2. The changes in the pancreas are nonspecific.
      1. 10 to 40% of the cases show amyloidosis of the pancreas in type 2 diabetes mellitus.
      2. Pancreatic fibrosis occurs in 33 to 66% of the cases with type 2 diabetes which leads to a decreased number of the β-cells.
      3. Generally, there is a decrease in the weight and number of β-cells, and the cause is unclear.
   3. The most common factor is obesity. It increases 10 times in the obese person. Also, excessive intake of calories also predisposes to diabetes type 2.
      1. The insulin can not facilitate the entry of glucose into the muscle cells, hepatocytes, and fat cells.
10. Signs and symptoms: These are nonspecific.
11. Most patients are obese and overweight.
    1. There is hyperlipidemia.
    2. Onset is slow and mostly not noted which leads to late diagnosis.
    3. Classical symptoms like polydipsia, polyphagia, and polyuria are present.
    4. There may be nonspecific symptoms like pruritus, recurrent infections, paresthesia, and visual changes.
12. Treatment: This is just like type 1 diabetes.  The aim is to keep blood sugar in the normal range.
    1. There is a need to decrease the calorie intake in an overweight person.
    2. Saturated fats and cholesterol are restricted.
    3. Some people recommend a high fiber diet.
    4. Oral hypoglycemic drugs may be needed.
    5. Exercise also helps.
    6. Insulin may also be given.

Factors affecting glucose level:

1. 1. Stress like trauma, general anesthesia, infection, burns, and Myocardial infarction can Increase the glucose level.
   2. Caffeine may increase the level.
   3. Some pregnant women may experience glucose intolerance. In the case of the raised significant level is called Gestational diabetes.
   4. Drugs may increase the glucose level like an antidepressant (tricyclic), Beta-blockers, corticosteroids, I/V glucose, dextrothyroxine, diazoxide, diuretics, estrogen, glucagon, isoniazid, lithium, phenothiazine, phenytoin, and salicylates intoxication.
   5. Drugs may decrease the glucose level like acetaminophen, alcohol, anabolic steroids, insulin, tolbutamide, propranolol, and clofibrate.

American diabetes association standards for Glycemic Control in Diabetes mellitus:

Clinical manifestation and their explanation:

Gestational diabetes mellitus:

1. This is also called as:
   1. Asymptomatic diabetes.
   2. Chemical diabetes.
   3. Border-line diabetes.
   4. latent diabetes.
   5. Subclinical diabetes.
2. Gestational diabetes mellitus develops when glucose intolerance develops during pregnancy, so all pregnant women need to be tested.
3. After the delivery, the glucose becomes normal, or impaired or progresses to diabetes.
4. This is first diagnosed during pregnancy and usually in the third trimester.
5. Already known cases of diabetic women are not included in this group.
6. This occurs in 6 to 8% of the pregnant ladies (another source only 2% of pregnant ladies may have this diabetes).
7. Out of this group, 60% may develop diabetes in 15 years. of gestation.
8. These ladies are at increased risk later on to develop diabetes mellitus (6 to 62% of these ladies).
9. Risk factors to develop gestational diabetes are:
   1. Pregnant ladies with glycosuria.
   2. If there is a family history of diabetes.
   3. In obese ladies.
   4. If the ladies develop pregnancy at a late age.
   5. In multiparity of 5 or more.
   6. In case of previous complicated pregnancy.
10. Treatment should be aggressive to prevent morbidity and fetal mortality.

Impaired glucose tolerance (IGT)

1. This group has less fasting glucose than required for diabetes mellitus.
2. An oral glucose tolerance test is needed to diagnose this group.
3. The overt case develops 1 to 5% per year.
   1. 10 to 20% will convert to type 11 diabetes within 10 years.
4. Microvascular diseases are very uncommon in this group.
5. Many of them are obese.

Impaired fasting glucose (IFG)

1. There is an abnormal response to an oral glucose tolerance test.
   1. 2 hours of glucose = ≥ 140 mg/dL.
      1. <200 mg/dL.
2. This is diagnosed by fasting glucose values between normal and diabetics individuals.
3. This is a metabolic stage between normal glucose and diabetes mellitus.
4. There is an increased risk for the development of diabetes and cardiovascular disease.

Latest classification criteria for diabetes mellitus

1. Diabetes mellitus:
   1. Presence of classical symptoms.
   2. If fasting glucose level 126 mg/dl (>7.0 mmol/L) or above should be labeled as D. Mellitus (when this value is found two times).
   3. One random glucose level of more >200 mg/dl  (11.1 mmol/L) with symptoms of polyuria, polydipsia, and polyphagia are considered diagnostic of diabetes.
   4. HbA1c more than 6.5 % diagnostic for Diabetes.
   5. The 2-hour postprandial glucose level of  ≥200 mg/dl  (11.1 mmol/L) during OGTT.
2. Impaired fasting glucose = > 126 mg/dl. (fasting glucose level 110 to 125 mg/dL (6.1 to 7.0 mmol/L).
3. Impaired glucose tolerance when:
   1. Fasting glucose < 126 mg/dl (7 mmol/L).
   2. OGTT 2 hours sample is 140 mg to 199 mg/dl (7.8 to 11.1 mmol/L).

Criteria for the diagnosis of diabetes mellitus:

1. Fasting blood glucose level:
   1. 126 mg/dL (7.0 mmol/L) or higher is considered diagnostic.
2. Random/ non fasting blood glucose level:
   1. 200 mg/dL (11.1 mmol/L) is diagnostic.
3. Oral glucose tolerance test with 75 G of glucose:
   1. 2-hour sample 200 mg/dL  (11.1 mmol/L) or higher value is diagnostic.

Values in diabetic patients and normal person:

Difference between the Diabetes Mellitus type 1 and 2

Normal

The normal fasting glucose level

Source 1

•  To convert to SI units x 0.0555 = mmol/L
• Values vary from the biochemical method used.

Source 6

Source Tietz

Plasma/ serum level

• Adult = 74 to 106 mg/dL (4.5 to 5.9 mmol/L)
• Children = 60 to 100 mg/dL (3.5 to 5.6 mmol/L)
• Premature neonates = 20 to 60 mg/dL (1.1 to 3.3 mmol/L)
• Term neonates = 30 to 60 mg/dL (1.7 to 3.3 mmol/L)

Whole blood 

• 65 to 95 mg/dL (3.5 to 5.3 mmol/L)

CSF

• 40 to 70 mg/dL (2.2 to 3.9 mmol/L)
  • 60% of the plasma

Urine 24 hours

1 to 15 mg/dL (0.1 to 0.8 mmol/L)

Normal value from another source

1. Usually, glucose between 70 to 110 mg/dl is considered normal.
2. Fasting glucose = < 100 mg/dl.
   1. Cord blood = 45 to 96 mg/dL  (2.5 to 5.3 mmol/L)
   2. premature baby = 20 to 60 mg/dL.  (1.1 to 3.3 mmol/L).
   3. Neonates = 30 to 60 mg/dL  (1.7 to 3.3 mmol/L).
3. Infants = 40 to 90 mg/dL  (2.2 to 5.0 mmol/L).
4. Child <2 years = 60 to 100 mg/dL  (3.3 to 5.5 mmol/L).
   1. Child >2 years = like adult level.
5. Adult fasting = 70 to 110 mg/dL  (<6.1 mmol/L).
6. Adult random = <160 mg/dL  (11.1 mmol/L).

Various types of diabetes mellitus and glucose values:

Diabetes mellitus pattern in different people

Glucose values in whole blood and serum:

Diabetes Mellitus classification on the basis of  oral 75 G Glucose overload:

Critical values of Glucose:

Raised glucose level (Hyperglycemia) seen in:

1. Diabetes mellitus, adult, and juvenile.
2. Physiological causes.
   1. Strenuous exercise.
   2. Strong emotions.
   3. Shock and burns.
   4. Infections.
3. Endocrine disorders.
   1. Thyrotoxicosis
   2. Acromegaly and gigantism.
   3. Pheochromocytoma.
   4. Cushing’s syndrome.
4. Pancreatic diseases.
   1. Acute and chronic pancreatitis.
   2. Pancreatitis due to mumps.
   3. Cystic fibrosis.
   4. Hemochromatosis.
   5. Pancreatic cancers.
5. other causes are:
   1. Cerebrovascular accident.
   2. Chronic liver disease.
   3. Chronic renal disease.
   4. Acanthosis nigricans.

Decreased glucose level (Hypoglycemia) seen in:

1. Pancreatic disorders.
   1. Islet Cell Tumor.
   2. Glucagon deficiency.
2. Tumors.
   1. Adrenal gland carcinoma.
   2. carcinoma of the stomach.
   3. Fibrosarcoma.
3. Liver diseases.
   1. In poisoning e.g. arsenic, chloroform, carbon tetrachloride, phosphorus, salicylates, antihistamines, phenformin, and alcohol.
4. Endocrine disorders.
   1. Hypopituitarism.
   2. Addison’s disease.
   3. hypothyroidism.
5. Functional disorders.
   1. Postgastrectomy.
   2. Gastroenterostomy.
   3. Autonomic nervous system disorders.
6. Pediatric causes.
   1. Prematurity.
   2. Infant diabetic mothers.
   3. Idiopathic leucine sensitivity.
7. Enzyme deficiency.
   1. Galactosemia.
   2. Fructose intolerance.
   3. Von Gierke’s syndrome.

The complication of Diabetes Mellitus:

Acute complications are:

1. There may be hypoglycemia.
2. In patients with hyperglycemia of Type I left uncontrolled, they may develop life-threatening complications like diabetic Ketoacidosis.
   1. Without treatment, the patient may become acidotic and dehydrated and may lose consciousness.
3. Type II may develop hyperosmolar coma.

Chronic complications are:

1. Peripheral neuropathy.
2. Diabetic retinopathy and cataract formation.
3. Cardiovascular microangiopathy.
   1. Coronary atherosclerosis.
   2. Myocardial infarction is 3 to 5 times more common in diabetic patients.
   3. AMI is the leading cause of death in patients with diabetes mellitus type 2.
4. Peripheral vascular diseases like ischemia of lower extremities, erectile dysfunction, and intestinal ischemia.
   1. Gangrene of the foot.
5. Diabetic kidney diseases (diabetic nephropathy), and may lead to end-stage renal disease.
6. Chronic pyogenic skin infection.
   1. Candidal infection of the skin.
7. Bone and joints show contracture.
   

   Diabetes mellitus complications

Monitoring of diabetes mellitus:

1. In the newly diagnosed patient check glucose frequently.
2. The best timings are:
   1. Before meals.
   2. At bedtime.
3. The goal of therapy is:
   1. To maintain euglycemia.
   2. Avoid hypoglycemia.
   3. Prevent cardiovascular diseases.
   4. Prevent neurological complications.

Treatment of Diabetes mellitus:

1. it requires number modalities to treat diabetic patients like:
2. Diet control.
   1. 1. This includes dietary fibers in the diet.
      2. Eat low glycemic index foods which will not raise the blood glucose. This glycemic index is 55 or low and it includes vegetables, fruits, pasta, grainy bread, and legumes.
      3. High glycemic index foods have a value above 77 or greater. This will include potatoes, white bread, and white rice.
      4. The Glycemic index can be lowered by the addition of protein and fats.
      5. Artificial sweeteners can be used in cooking and baking.
      6. fructose is a natural sweetener and does not increase much glucose levels.
3. Medications to lower the hyperglycemia are:
   1. 1. The first-generation sulphonylureas are tolbutamide, tolazamide, acetohexamide, and chlorpropamide.
      2. Second generation sulphonylureas are glyburide, glipizide, gliclazide, and glimepiride.
      3. Repaglinide.
      4. Nateglinide.
   2. Drugs that lower the glucose level by their action on the liver, muscle, and adipose tissue are:
      1. Metformin.
      2. Thiazolidinediones.
   3. Medications that affect the absorption of the glucose are:
      1. Acarbose.
      2. Miglitol.
   4. Incretins are oral insulin stimulator are:
      1. GLP-1 receptor antagonists.
      2. DPP-4 inhibitors.
   5. Sodium-glucose co-transporter 2 inhibitors.
4. Insulin has various preparations.
5. Transplant of the pancreatic tissue.

Functions of various Hormones related to glucose produced by the pancreas: