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

December 20, 2021Chemical pathologyLab Tests

Diabetes Mellitus

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 (with preservative sodium fluoride).

Stability of sample

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

Indications for Diabetes Mellitus patients

1. This test is done to diagnose diabetes mellitus.
2. This test is also done to evaluate and monitor 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

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

      Diabetes mellitus and insulin action

Diabetes Mellitus

Criteria for the Diagnosis of Diabetes Mellitus:

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 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 the 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 chemicals 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 mellitus:

1. The autoimmune phenomenon may be the cause of  type 1 diabetes mellitus:
   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 infiltrated 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 children than adults.
      

      Insulin functions

2. Antibodies that may play a role in type 1 diabetes are:
   1. There is a marker of β-cells autoimmunity where the antibodies in the Serum are detected before Diabetes appears.
      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. Other factors like cow’s milk and chemicals.

Pathogenesis of type 2 diabetes:

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

   Insulin functions

2. β-cells dysfunction is the pancreas’ inability to produce a sufficient amount of insulin to compensate for insulin resistance.
3. Genetic factors:
   1. In identical twins, these are well known, 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.
   1. Insulin resistance is found in type 2.
      

      Insulin formation

Type 1 Diabetes Mellitus (Insulin-dependent)

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 offspring 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. 1. Genetics.
         2. Autoimmunity.
         3. Environmental factors.
      2. There are 80 to 90% of the cases. There are islet cells autoantibodies and antibodies to insulin and glutamic acid decarboxylase, which causes damage to the islet cells.
      3. Non-immune type 1 diabetes occurs secondary to other diseases like pancreatitis.
   3. 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 lack of insulin and relative excess of glucagon produced by the alpha-cells.
   4. Signs and symptoms: Glucose accumulates in the blood (hyperglycemia)  and is excreted in the urine.
      1. 1. There is weight loss due to the breakdown of 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.
   5. The patient may go into a coma.
   6. 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 are used for energy.
      Fatigue	There are metabolic changes that result in poor food utilization, which will contribute to lethargy and fatigue.
      Polyphagia	This is due to the depletion of the body’s fat, proteins, and carbohydrate leading to cellular starvation and increased 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 stimulating the hypothalamus and thirst.
      Polyuria	Hyperglycemia acts as an osmotic diuretic and leads to Glycosuria which is accompanied by water loss in the urine.

   7. 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 of diabetes mellitus:
   1. The cause is unknown.
   2. Genetics may play some role but not clearly defined.
   3. There is no evidence of the autoimmune mechanism.
   4. Cellular resistance is a factor 60 to 80% of people with type 11 diabetes mellitus.
   5. Insulin resistance increases with obesity.
   6.  There is a decreased response of the β-cell to blood glucose level and abnormal glucagon secretion.
9. There may be alterations 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, leading to a decreased number of 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 obese people. Also, excessive intake of calories 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:
    1. These are nonspecific.
    2. Most patients are obese and overweight.
    3. There is hyperlipidemia.
    4. Onset is slow and mostly not noted, which leads to late diagnosis.
    5. Classic symptoms like polydipsia, polyphagia, and polyuria are present.
    6. There may be nonspecific symptoms like pruritus, recurrent infections, paresthesia, and visual changes.
11. 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 in Diabetes mellitus:

Gestational diabetes mellitus:

1. This is also called as:
   1. Asymptomatic Diabetes.
   2. Chemical Diabetes.
   3. Borderline 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, 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 pregnant women (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. Later on, these ladies are at increased risk of developing diabetes mellitus (6 to 62% of these ladies).
9. Risk factors in developing 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 the case of previous complicated pregnancies.
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 diabetic 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 classic 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 people:

Difference between the Diabetes Mellitus type 1 and 2

Normal Glucose level

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 for glucose level

Source Tietz

Plasma/ serum glucose 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 glucose level

• 65 to 95 mg/dL (3.5 to 5.3 mmol/L)

CSF glucose level

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

Urine 24 hours glucose level

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

Normal value of glucose 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:

Glucose level in various conditions

Glucose values in whole blood and Serum:

Diabetes Mellitus classification based on 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. Patients with hyperglycemia of Type I left uncontrolled may develop life-threatening complications like diabetic Ketoacidosis.
   1. Without treatment, the patient may become acidotic and dehydrated and 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 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) 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

   

   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 a number of modalities to treat diabetic patients like:
2. Diet control.
   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, including 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 addition of protein and fats can lower the Glycemic index.
   5. Artificial sweeteners can be used in cooking and baking.
   6. Fructose is a natural sweetener and does not increase glucose levels.
3. Medications to lower the hyperglycemia are:
   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.
4. Drugs that lower the glucose level by their action on the liver, muscle, and adipose tissue are:
   1. Metformin.
   2. Thiazolidinediones.
5. Medications that affect the absorption of glucose are:
   1. Acarbose.
   2. Miglitol.
6. Incretins are oral insulin stimulators:
   1. GLP-1 receptor antagonists.
   2. DPP-4 inhibitors.
   3. Sodium-glucose co-transporter 2 inhibitors.
7. Insulin has various preparations.
8. Transplant of the pancreatic tissue.

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