Diabetes Mellitus | Pathophysiology Science

Insulin is the principal hormone that regulates the uptake of glucose from the blood into most cells of the body, especially 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 for 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 in the opposite manner 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 occurs 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 amount 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 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 On Body And Further Complications Caused

Poor Control of Diabetes can lead to an Increased Risk of Following Diseases:

Ketoacidosis: 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 causes blood pH to fall, a condition is known as Ketoacidosis, unless treated quickly, ketoacidosis can cause death.

Cardiovascular disease: 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 multitude of cardiovascular problems, including cerebrovascular insufficiency (excess acid is potent poison for brain), ischemic heart disease, peripheral vascular disease and gangrene.

Blindness: 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 complication include: Gum disease, foot and leg infections, sexual dysfunction and complications of pregnancy.

Diagnosis Of Diabetes In Any Person 

Elevated blood glucose level is often the fundamental basis for the diagnosis of diabetes mellitus. Regular checking of fasting and post meal blood glucose level 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): Testing 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 results is shown in

Oral Glucose Tolerance Test (OGTT): Test done to confirm the diagnosis in doubtful cases (i.e. cases were FPG and/or PPG are in the borderline range). In this test, one has to drink 75 g glucose (sugar) in water on empty stomach and blood sugar is to be tested after 2 hours. The interpretation of the results is shown in above table

• 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. 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 other form of glycosuria.

Test for ketones: Presence of ketone bodies in urine (ketonuria) is used to assess the severity of diabetes mellitus.

Management and Treatment for Diabetes

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 the diabetes along with drugs.

1. Type I diabetes is treated with insulin, exercise, and a diabetic diet.
2. Type II diabetes is treated first with weight reduction, a diabetic diet, andexercise.

Patients with type I diabetes mellitus require lifelong insulin therapy. Most require 2 or more injections of insulin daily, with doses adjusted on the basis of 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:

Metformin: Generally, metformin is the first medication prescribed for type II diabetes. It works by improving the sensitivity of body tissues to insulin so that, body uses insulin more effectively. Metformin also lowers glucose production in the liver.

Sulfonylureas: These medications help body secrete more insulin. e.g. Glyburide,
glipizide, and glimepiride.

Meglitinides: 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.

Thiazolidinediones: 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 (Glucogon 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 level. e.g. Canagliflozin, and dapagliflozin.

Insulin therapy: Some people who have type II diabetes need insulin therapy as well.
In the past, insulin therapy was used as 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 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.