Introduction of Diabetes mellitus:
Diabetes mellitus is a metabolic disorder, in which glucose level in the blood is much higher than normal (hyperglycemia) and hence this condition is also commonly referred to as sugar disease. The defect in this condition is that either the pancreas does not produce enough insulin or it produces sufficient insulin, but the cells of the body are unable to use the insulin properly. Insulin, a hormone released from the pancreas, controls the amount of glucose in the blood. Glucose in the bloodstream stimulates the pancreas to produce insulin. Insulin allows glucose to move from the blood into the cells. Once inside the cells, glucose is converted to energy, which is used immediately, or the glucose is stored as fat or glycogen until it is needed. The levels of glucose in the blood vary normally throughout the day. They rise after a meal and return to normal within about 2 hours after eating. Once the levels of glucose in the blood return to normal, insulin production decreases. The variation in blood glucose levels is usually within a narrow range, about 70 to 110 milligrams per deciliter (mg/dL) of blood in healthy people. If people eat a large number of carbohydrates, the levels may increase more. People older than 65 years tend to have slightly higher levels, especially after eating. Insulin is like a key that opens the body’s cell doors to allow glucose to enter. In the absence of enough insulin, glucose cannot enter the cells and remains in the bloodstream in high amounts (hyperglycemia). If the body does not produce enough insulin to move the glucose into the cells, or if the cells stop responding normally to insulin, the resulting high levels of glucose in the blood and the inadequate amount of glucose in the cells together produce the symptoms and complications of diabetes.
A multitude of Mechanisms:
The body’s response to blood sugar requires the coordination of an array of mechanisms. Failure of any one component involved in insulin regulation, secretion, uptake, or breakdown can lead to the build-up of glucose in the blood.
β-cells damage: Destruction or damage to the β-cells, lead to increased levels of blood glucose.
Classification of Diabetes mellitus:
There are two major types of diabetes: Primary and Secondary
[I] Primary or Idiopathic Diabetes Mellitus:
It is most common with unknown causes of diabetes. It is further divided into
- Type 1 Diabetes (5-10%)
- Type 2 Diabetes (90-95%)
- Gestational Diabetes.
Type I Diabetes mellitus (Insulin-dependent diabetes mellitus (IDDM) or Juvenile diabetes):
It results from the body’s failure of insulin production by β-cells of the islets of Langerhans in the pancreas, leading to insulin deficiency. This type can be further classified as immune-mediated or idiopathic. Most type 1 diabetes is of an immune-mediated nature, in which a T-cell mediated autoimmune attack leads to the loss of β-cells and thus insulin. Only about 10% of all people with diabetes have type 1 disease. Onset most often occurs in childhood, but most people who have type 1 diabetes develop the disease before age 30, although it can develop later in life.
The exact cause is not known but attributed to an environmental factor; possibly a viral infection or a nutritional factor during childhood or early adulthood causes the immune system to destroy the insulin-producing β-cells of the pancreas. A genetic predisposition may make some people more susceptible to environmental factors.
Type II Diabetes mellitus (non– insulin-dependent diabetes mellitus, or Adult/maturity-onset diabetes mellitus):
This form of diabetes, which accounts for 90% of those with diabetes, encompasses individuals who have insulin resistance, diminished tissue sensitivity to insulin, impaired β-cell function (delayed or inadequate insulin release), and excessive or inappropriate glucagon secretion. Type II diabetes may occur at any age but more common in people older than the age 40.
There are probably many different causes of this form of diabetes. Although the specific etiologies are not known, autoimmune destruction of β-cells does not occur but it is attributed to typical genetic makeup, familial history, obesity, and defect in insulin receptors. Type II diabetes also tends to run in families.
Obesity is the chief risk factor for developing type II diabetes, and 80 to 90% of people with this disorder are overweight or obese. Because obesity causes some degree of insulin resistance, obese people need very large amounts of insulin to maintain normal blood glucose levels.
Certain disorders and drugs can affect the way the body uses insulin and can lead to type II diabetes. High levels of corticosteroids (due to Cushing’s disease or taking corticosteroid drugs) and pregnancy are the most common causes of altered insulin use. Diabetes also may occur in people with excess production of growth hormone (acromegaly) and people with certain hormone-secreting tumors. Severe or recurring pancreatitis and other disorders that directly damage the pancreas can lead to diabetes.
Diabetes can occur temporarily during pregnancy, and it occurs in 2% to 10% of all pregnancies. Significant hormonal changes during pregnancy can lead to blood sugar elevation in genetically predisposed individuals. Blood sugar elevation during pregnancy is called gestational diabetes.
Gestational diabetes usually resolves once the baby is born. However, 35% to 60% of women with gestational diabetes will eventually develop type II diabetes over the next 10 to 20 years, especially in those who require insulin during pregnancy and those who remain overweight after their delivery.
[II] Secondary Diabetes:
It is the type of diabetes mellitus and has a definite cause of hyperglycemia.
Secondary diabetes refers to elevated blood sugar levels from another medical condition. Secondary diabetes may develop when the pancreatic tissue responsible for the production of insulin is destroyed by diseases, such as chronic pancreatitis (inflammation of the pancreas by toxins like excessive alcohol), trauma, or surgical removal of the pancreas.
Diabetes can also result from other hormonal disturbances, such as excessive growth hormone production (acromegaly) and Cushing’s syndrome. In acromegaly, a pituitary gland tumor at the base of the brain causes excessive production of growth hormone, leading to hyperglycemia. In Cushing’s syndrome, the adrenal glands produce an excess of cortisol, which promotes blood sugar elevation.
In addition, certain medications may worsen diabetes control, or “unmask” latent diabetes. This is seen most commonly when steroid medications (such as prednisone) are taken and also with medications used in the treatment of HIV infection (AIDS).
Pathophysiology of Diabetes mellitus:
Insulin is the principal hormone that regulates the uptake of glucose from the blood into most cells of the body, especially the liver, muscle, and adipose tissue. Therefore, deficiency of insulin or the insensitivity of its receptor plays a central role in all forms of diabetes mellitus.
The body obtains glucose from three main places: the intestinal absorption of food, the breakdown of glycogen; the storage form of glucose found in the liver, and gluconeogenesis, the generation of glucose from non-carbohydrate substrates in the body.
Insulin plays a critical role in balancing glucose levels in the body. Insulin can inhibit the breakdown of glycogen or the process of gluconeogenesis, it can stimulate the transport of glucose into fat and muscle cells, and it can stimulate the storage of glucose in the form of glycogen.
Insulin is released into the blood by βcells, found in the islets of Langerhans in the pancreas, in response to rising levels of blood glucose, typically after eating. Insulin is used by about two-thirds of the body’s cells to absorb glucose from the blood for use as fuel, for conversion to other needed molecules, or storage. Lower glucose levels result in decreased insulin release from the β-cells and in the breakdown of glycogen to glucose. This process is mainly controlled by the hormone glucagon, which acts oppositely to insulin.
If the amount of insulin available is insufficient, if cells respond poorly to the effects of insulin (insulin sensitivity or insulin resistance) or if the insulin itself is defective, then glucose will not be absorbed properly by the body cells that require it, and it will not be stored appropriately in the liver and muscles. The net effect is persistently high levels of blood glucose, poor protein synthesis, and other metabolic derangements, such as acidosis.
Clinical Manifestations Of Diabetes Mellitus:
People with type II diabetes often do not have any symptoms. When symptoms do occur, they are often ignored because they may not seem serious. Symptoms in type I diabetes usually occur much more suddenly and are often severe.
Common symptoms of diabetes include:
- The early symptoms of untreated diabetes are related to elevated blood sugar levels, and loss of glucose in the urine (glycosuria).
- In response to glycosuria, kidneys excrete additional water to dilute the excessive glucose, called polyuria.
- High amounts of glucose in the urine can cause increased urine output and lead to dehydration. Dehydration causes increased thirst (polydipsia) and water consumption.
- The inability of insulin to perform normally has effects on protein, fat, and carbohydrate metabolism. Insulin is an anabolic hormone, that is, one that encourages the storage of fat and protein.
- Excessive loss of calories in urine results in weakness. The loss of energy, in turn, causes excessive hunger called polyphagia.
- A relative or absolute insulin deficiency eventually leads to weight loss despite an increase in appetite.
- Patients with diabetes are prone to developing infections of the bladder, skin, and vaginal areas.
- Fluctuations in blood glucose levels can lead to blurred vision. Extremely elevated glucose levels can lead to lethargy and coma.
- Itching skin, especially in the groin or vaginal area.
- Slow-healing sores or cuts.
Other symptoms of untreated diabetes patients include drowsiness, fatigue, renal failure, various opportunistic infections, nausea, and vomiting.
Effects of Diabetes:
Poor Control of Diabetes can lead to an Increased Risk of Following Diseases:
The cellular metabolism of untreated type I diabetes is similar to that of a starving person. Because insulin is not present to aid the entry of glucose into body cells, most cells use fatty acids to produce ATP. Stores of triglycerides in adipose tissue are catabolized to yield fatty acids and glycerol. The by-product of fatty acid breakdown is organic acid called ketones and ketone bodies. Accumulation and buildup of ketones cause blood pH to fall, a condition is known as Ketoacidosis, unless treated quickly, ketoacidosis can cause death.
The breakdown of stored triglycerides also causes weight loss. As lipids are transported by the blood from storage depots to cells, lipid particles are deposited on the walls of blood vessels, leading to atherosclerosis and a multitude of cardiovascular problems, including cerebrovascular insufficiency (excess acid is potent poison for the brain), ischemic heart disease, peripheral vascular disease, and gangrene.
A major complication of diabetes is loss of vision either due to cataracts (excessive glucose attaches to lens proteins, causing cloudiness) or due to damage to blood vessels of the retina.
Kidney and bladder failure:
Severe kidney problems also may result from damage to renal blood vessels.
Other complications include:
Gum disease, foot and leg infections, sexual dysfunction, and complications of pregnancy.
Elevated blood glucose level is often the fundamental basis for the diagnosis of diabetes mellitus. Regular checking of fasting and post-meal blood glucose levels is a standard method of diagnosis. A random plasma glucose concentration above 250mg/dL is also an indication of diabetes mellitus.
Blood sugar estimation using a glucometer can be done at different times and the three common time points are:
Fasting Plasma Glucose (FPG):
Testing blood sugar levels after 8 hours of fasting, usually overnight fasting.
Postprandial Plasma Glucose (PPG):
blood sugar levels 2 hours after a meal (usually it is breakfast).
Random or casual sugar: Any time of the day irrespective of meal intake. The interpretation of the results is shown in table 1.
Oral Glucose Tolerance Test (OGTT):
The test is done to confirm the diagnosis in doubtful cases (i.e. cases where FPG and/or PPG are in the borderline range). In this test, one has to drink 75 g glucose (sugar) in water on an empty stomach and blood sugar is to be tested after 2 hours.
The interpretation of the results is shown in table 1.
Table 1: The tests commonly done and their interpretation
|2 hr. PPG||Up to 140||140-199||>200|
Table 2: OGTT and its interpretation
|Result (2 hour value) (mg/dl) |
|>140 but <200 |
NGT = Normal Glucose Tolerance; IFG = Impaired Fasting Glucose (Pre diabetes); IGT = Impaired Glucose Tolerance (Pre diabetes); DM = Diabetes Mellitus; 25 – 40% patients with IGT progress to DM
Urine sugar testing alone is not recommended for diagnosis. The presence of glucose in urine (glycosuria) is also a diagnostic criterion for diabetes but may be false positive or false negative. Since diabetes glycosuria is differentiated from another form of glycosuria.
Test for ketones:
The presence of ketone bodies in urine (ketonuria) is used to assess the severity of diabetes mellitus.
Table 3: Comparison of BSL in normal and diabetic patients
|Blood sugar test||Normal||Diabetes mellitus|
|Fasting blood glucose||80- 100 mg/dl||> 120 mg/dl|
|2 hours Post lunch||130-160 mg/dl||> 180 mg/dl|
Management and Treatment of Diabetes mellitus:
The major goal in treating diabetes is to keep blood sugar (glucose) levels as close to normal as possible, without causing abnormally low levels of blood sugar (hypoglycemia).
Lifestyle modifications are the cornerstone of management of diabetes mellitus and include the healthy diet (high protein and low carbohydrate and fat diet), management of stress, avoidance of alcohol and tobacco, etc. are found to be effective to control diabetes along with drugs.
Type I diabetes is treated with insulin, exercise, and a diabetic diet.
Type II diabetes is treated first with weight reduction, a diabetic diet, and exercise.
Patients with type I diabetes mellitus require lifelong insulin therapy. Most require 2 or more injections of insulin daily, with doses adjusted based on self-monitoring of blood glucose levels.
Early initiation of pharmacologic therapy is associated with improved glycemic control and reduced long-term complications in type II diabetes.
Drug classes used for the treatment of type II diabetes include the following:
Generally, metformin is the first medication prescribed for type II diabetes. It works by improving the sensitivity of body tissues to insulin so that, the body uses insulin more effectively. Metformin also lowers glucose production in the liver.
These medications help the body secrete more insulin. e.g. Glyburide, glipizide, and glimepiride.
These medications work like sulfonylureas by encouraging the body to secrete more insulin, but they are faster acting, and they do not stay active in the body for as long. e.g. Repaglinide and nateglinide.
Like metformin, these medications make the body’s tissues more sensitive to insulin. e.g. Rosiglitazone and pioglitazone.
Selective Dipeptidyl Peptidase-4 Inhibitors (DPP-4 inhibitors):
These medicines help to keep blood sugar in a target range without causing low blood sugar or weight gain but tend to have a modest effect. e.g. Sitagliptin, saxagliptin, and linagliptin.
GLP (Glucagon-like peptide)-1 receptor agonists:
These medications slow digestion and help lower blood sugar levels, though not as much as sulfonylureas. e.g. Exenatide and liraglutide.
Sodium-glucose co-transporter 2 (SGLT2) inhibitors (SGLT2 inhibitors):
These are a new class of diabetic medications indicated only for the treatment of type II diabetes. In conjunction with exercise and a healthy diet, they can improve glycemic control. They work by preventing the kidneys from reabsorbing sugar in the blood. Instead, the sugar is excreted in the urine and it lowers blood glucose levels. e.g. Canagliflozin, and dapagliflozin.
Some people who have type II diabetes need insulin therapy as well. In the past, insulin therapy was used as a last resort, but today it is often prescribed sooner because of its benefits.
Regular monitoring of the blood and urine glucose level, during treatment, is an essential part of management. These results indicate the appropriate change required in the treatment.
The overdose of insulin or hypoglycemic agent may result in hypoglycemia. Symptoms of hypoglycemia include Anxiety, confusion, extreme hunger, fatigue, irritability, sweating or clammy skin, and trembling hands which need immediate treatment. If sugar levels continue to fall during an insulin overdose, serious complications such as seizures, unconsciousness, and pale skin can occur. Untreated hypoglycemia may cause permanent brain damage and hypoglycemic coma.
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