Diabetes Mellitus

Diabetes Mellitus, simply stated as Diabetes, is a syndrome characterized by disordered metabolism and inappropriately high blood sugar (hyperglycemia) resulting from either low levels of the hormone insulin or from abnormal resistance to insulin's effects coupled with inadequate levels of insulin secretion to compensate.[1] The characteristic symptoms are excessive urine production (polyuria), excessive thirst and increased fluid intake (polydipsia), and blurred vision; these symptoms are likely absent if the blood sugar is only mildly elevated.

The World Health Organization recognizes three main forms of Diabetes Mellitus: Type 1, Type 2, and gestational diabetes (occurring during pregnancy),[2] which have similar signs, symptoms, and consequences, but different causes and population distributions.  While, ultimately, all forms are due to the beta cells of the pancreas being unable to produce sufficient insulin to prevent hyperglycemia, the causes are different.[3]  Type 1 diabetes is usually due to autoimmune destruction of the pancreatic beta cells.  Type 2 diabetes is characterized by insulin resistance in target tissues, which causes a need for the body to produce abnormally high amounts of insulin and diabetes develops when the beta cells cannot meet this demand.  Gestational diabetes is similar to type 2 diabetes in that it involves insulin resistance; the hormones of pregnancy can cause insulin resistance in women genetically predisposed to developing this condition.

Gestational diabetes typically resolves with delivery of the child, however types 1 and 2 diabetes are chronic conditions.[4]  All types have been treatable since insulin became medically available in 1921.  Type 1 diabetes, in which insulin is not secreted by the pancreas, is directly treatable only with injected insulin, although dietary and other lifestyle adjustments are part of management.  Type 2 may be managed with a combination of dietary treatment, tablets and injections and, frequently, insulin supplementation.  While insulin was originally produced from natural sources such as porcine pancreas, most insulin used today is produced through genetic engineering, either as a direct copy of human insulin, or human insulin with modified molecules that provide different onset and duration of action.  Insulin can also be delivered continuously by a specialized pump which subcutaneously provides insulin through a changeable catheter.

Current treatment methodologies, more efficient and effective recommendations, and Insulin will be discussed further throughout the book.

Classification

The term Diabetes, without qualification, usually refers to Diabetes Mellitus, which is associated with excessive sweet urine, (known as “glycosuria”) but there are several rarer conditions also named diabetes.  The most common of these is Diabetes Insipidus in which the urine is not sweet (insipidus meaning "without taste" in Latin); it can be caused by either kidney (nephrogenic DI) or pituitary gland (central DI) damage.

The principal two idiopathic forms of Diabetes Mellitus are known as Types 1 and 2.  The term "Type 1 Diabetes" has universally replaced several former terms, including childhood-onset diabetes, juvenile diabetes, and insulin-dependent diabetes (IDDM).  Likewise, the term "Type 2 Diabetes" has replaced several former terms, including adult-onset diabetes, obesity-related diabetes, and non-insulin-dependent diabetes (NIDDM).  Beyond these two types, there is no agreed-upon standard nomenclature.  Various sources have defined "type 3 diabetes" as, among others, gestational diabetes,[5] insulin-resistant type 1 diabetes (or "double diabetes"), type 2 diabetes which has progressed to require injected insulin, and latent autoimmune diabetes of adults (or LADA or "type 1.5" diabetes).[6]  There is also maturity onset diabetes of the young (MODY) which is a single gene disorder with strong family history that presents as type 2 diabetes before 30 years of age.

Type 1 Diabetes Mellitus

Type 1 diabetes mellitus is characterized by loss of the insulin-producing beta cells of the islets of Langerhans in the pancreas, leading to a deficiency of insulin.  The main cause of this beta cell loss is a T-cell mediated autoimmune attack.[7]  There is no known preventative measure that can be taken against type 1 diabetes, which comprises up to 10% of diabetes mellitus cases in North America and Europe (though this varies by geographical location).  Most affected people are otherwise healthy and of a healthy weight when onset occurs.  Sensitivity and responsiveness to insulin are usually normal, especially in the early stages.  Type 1 diabetes can affect children or adults but was traditionally termed "juvenile diabetes" because it represents a majority of cases of diabetes affecting children.

The principal treatment of type 1 diabetes, even from the earliest stages, is replacement of insulin combined with careful monitoring of blood glucose levels using blood testing monitors.  Without insulin, diabetic ketoacidosis can develop and may result in coma or death.  Emphasis is also placed on lifestyle adjustments (diet and exercise) though these cannot reverse the loss of insulin function.  Apart from the common subcutaneous injections, it is also possible to deliver insulin by a pump, which allows continuous infusion of insulin 24 hours a day at preset levels, and the ability to program doses (a bolus) of insulin as needed at meal times.  An inhaled form of insulin, Exubera, was approved by the FDA in January 2006[8], however, it was subsequently pulled from the market due to lack of demand.

Type 1 treatment must be continued indefinitely.  Treatment does not impair normal activities, if sufficient awareness, appropriate care, and discipline in testing and medication is taken.  The average glucose level for the type 1 patient should be as close to normal[9] (80–120 mg/dl, 4–6 mmol/l) as possible.  Some physicians suggest up to 140–150 mg/dl (7-7.5 mmol/l) for those having trouble with lower values, such as frequent hypoglycemic events.  Values above 200 mg/dl (10 mmol/l) are often accompanied by discomfort and frequent urination leading to dehydration.  Values above 300 mg/dl (15 mmol/l) usually require immediate treatment and may lead to ketoacidosis.  Low levels of blood glucose, called hypoglycemia, may lead to seizures or episodes of unconsciousness.

Type 2 Diabetes Mellitus

Type 2 Diabetes Mellitus is due to insulin resistance or reduced insulin sensitivity, combined with reduced insulin secretion.  The defective responsiveness of body tissues to insulin almost certainly involves the insulin receptor in cell membranes.  In the early stage the predominant abnormality is reduced insulin sensitivity, characterized by elevated levels of insulin in the blood.  At this stage hyperglycemia can be reversed by a variety of measures and medications that improve insulin sensitivity or reduce glucose production by the liver.  As the disease progresses the impairment of insulin secretion worsens, and therapeutic replacement of insulin often becomes necessary.

There are numerous theories as to the exact cause and mechanism in type 2 diabetes.  Central obesity (fat concentrated around the waist in relation to abdominal organs, but not subcutaneous fat) is known to predispose individuals for insulin resistance.  Abdominal fat is especially active hormonally, secreting a group of hormones called adipokines that may possibly impair glucose tolerance.  Obesity is found in approximately 55% of patients diagnosed with type 2 diabetes.[10]  Other factors include aging (about 20% of elderly patients in North America have diabetes) and family history (type 2 is much more common in those with close relatives who have had it).  In the last decade, type 2 diabetes has increasingly begun to affect children and adolescents, likely in connection with the increased prevalence of childhood obesity seen in recent decades in some places.[11]

Type 2 diabetes may go unnoticed for years because visible symptoms are typically mild, non-existent or sporadic, and usually there are no ketoacidotic episodes.  However, severe long-term complications can result from unnoticed type 2 diabetes, including renal failure due to diabetic nephropathy, vascular disease (including coronary artery disease), vision damage due to diabetic retinopathy, loss of sensation or pain due to diabetes neuropathy, and liver damage from non-alcoholic steatohepatitis.

Type 2 diabetes is usually first treated by increasing physical activity, decreasing carbohydrate intake, and losing weight.  These can restore insulin sensitivity even when the weight loss is modest, for example around 5 kg (10 to 15 lb), most especially when it is in abdominal fat deposits.  It is sometimes possible to achieve long-term, satisfactory glucose control with these measures alone.  However, the underlying tendency to insulin resistance is not lost, and so attention to diet, exercise, and weight loss must continue.  The usual next step, if necessary, is treatment with oral antidiabetic drugs.  Insulin production is initially only moderately impaired in type 2 diabetes, so oral medication (often used in various combinations) can be used to improve insulin production (e.g., sulfonylureas), to regulate inappropriate release of glucose by the liver and attenuate insulin resistance to some extent (e.g., metformin), and to substantially attenuate insulin resistance (e.g., thiazolidinediones).  According to one study, overweight patients treated with metformin compared with diet alone, had relative risk reductions of 32% for any diabetes endpoint, 42% for diabetes related death and 36% for all cause mortality and stroke.[12]  Oral medication may eventually fail due to further impairment of beta cell insulin secretion.  At this point, insulin therapy is necessary to maintain normal or near normal glucose levels.

Gestational diabetes

Gestational diabetes mellitus (GDM) resembles type 2 diabetes in several respects, involving a combination of inadequate insulin secretion and responsiveness.  It occurs in about 2%–5% of all pregnancies and may improve or disappear after delivery.  Gestational diabetes is fully treatable but requires careful medical supervision throughout the pregnancy.  About 20%–50% of affected women develop type 2 diabetes later in life.

Even though it may be transient, untreated gestational diabetes can damage the health of the fetus or mother.  Risks to the baby include macrosomia (high birth weight), congenital cardiac and central nervous system anomalies, and skeletal muscle malformations.  Increased fetal insulin may inhibit fetal surfactant production and cause respiratory distress syndrome.  Hyperbilirubinemia may result from red blood cell destruction.  In severe cases, perinatal death may occur, most commonly as a result of poor placental profusion due to vascular impairment.  Induction may be indicated with decreased placental function.  A cesarean section may be performed if there is marked fetal distress or an increased risk of injury associated with macrosomia, such as shoulder dystocia.

Other types

There are several rare causes of diabetes mellitus that do not fit into type 1, type 2, or gestational diabetes; attempts to classify them remain controversial.  Genetic mutations (autosomal or mitochondrial) can lead to defects in beta cell function.  Abnormal insulin action may also been genetically determined in some cases.  Any disease that causes extensive damage to the pancreas may lead to diabetes (for example, chronic pancreatitis and cystic fibrosis).  Diseases associated with excessive secretion of insulin-antagonistic hormones can cause diabetes (which is typically resolved once the hormone excess is removed).  Many drugs impair insulin secretion and some toxins damage pancreatic beta cells. The ICD-10 (1992) diagnostic entity, malnutrition-related diabetes mellitus (MRDM or MMDM, ICD-10 code E12), was deprecated by the World Health Organization when the current taxonomy was introduced in 1999.[13]

Brittle diabetes, also called labile diabetes, is a term used to describe uncontrolled type 1 diabetes.  People with brittle diabetes frequently experience large swings in glucose levels.  These cause either hypoglycemia  or hyperglycemia, which is more common and sometimes extreme.  Brittle diabetes can be caused by gastrointestinal absorption problems, including delayed stomach emptying (gastroperesis), drug interactions, problems with insulin absorption, or hormonal malfunction.

People who have severely low blood sugar levels may also have problems with their thyroid (hypothyroidism) and adrenal glands (adrenal insufficiency).  Treatment of these conditions often leads to the resolution of brittle diabetes.

Gastroperesis can affect relative absorption rates of food, glucose and insulin into the bloodstream.  The problem can be a side effect of damage to the nerves that control internal organs.  This is a condition that sometimes occurs in people with diabetes.  Medications such as Reglan (metoclopramide) do help to encourage more normal stomach emptying.  Studies have found, though, that treating gastroperesis does not lead to improvements in overall control of the diabetes or its related complications.

Psychological problems, including depression and stress, are also often associated with brittle diabetes.  The person with brittle diabetes is frequently hospitalized, misses work and often has to contend with psychological problems. All of these factors place additional emotional and financial stress on family members.

Brittle diabetes is relatively rare.  Less than 1 of people who have insulin-dependent diabetes patients experience brittle diabetes.  However, those who do are often troubled by frequent medical problems and hospital admissions.  Overall, three in 1,000 (0.3%) people with type 1 diabetes will develop brittle diabetes.

People with psychological problems, such as stress and depression, are at highest risk of experiencing brittle diabetes. In some cases, these psychological problems lead them to neglect self-care for their diabetes. For example, they may stop maintaining a healthy diet or may not manage their blood sugar). As blood sugar control wanes, metabolic imbalances further complicate and often worsen the underlying psychological problems, causing a repetitive cycle of brittle diabetes.

One small study documented that people with brittle diabetes have a greater hormonal response to stress than those whose diabetes is not brittle.  This psychological-hormonal connection may influence the development of brittle diabetes.  Brittle diabetes is more common in young women, with overweight women more likely to be affected. Most people with brittle diabetes tend to be between the ages of 15 and 30.[14]

Signs and symptoms

The classical triad of diabetes symptoms is polyuria, polydipsia and polyphagia, which are, respectively, frequent urination; increased thirst and consequent increased fluid intake; and increased appetite.  Symptoms may develop quite rapidly (weeks or months) in type 1 diabetes, particularly in children.  However, in type 2 diabetes the symptoms develop much more slowly and may be subtle or completely absent.  Type 1 diabetes may also cause weight loss (despite normal or increased eating) and irreducible fatigue.  These symptoms can also manifest in type 2 diabetes in patients whose diabetes is poorly controlled.

When the glucose concentration in the blood is raised beyond the renal threshold, reabsorption of glucose in the proximal renal tubuli is incomplete, and part of the glucose remains in the urine (glycosuria).  This increases the osmotic pressure of the urine and inhibits the reabsorption of water by the kidney, resulting in increased urine production (polyuria) and increased fluid loss.  Lost blood volume will be replaced osmotically from water held in body cells, causing dehydration and increased thirst.

Prolonged high blood glucose causes glucose absorption, which leads to changes in the shape of the lenses of the eyes, resulting in vision changes.  Blurred vision is a common complaint leading to a diabetes diagnosis; type 1 should always be suspected in cases of rapid vision change whereas type 2 is generally more gradual, but should still be suspected.

Patients (usually with type 1 diabetes) may also present with diabetic ketoacidosis (DKA), an extreme state of metabolic dysregulation characterized by the smell of acetone on the patient's breath; a rapid, deep breathing known as Kussmaul breathing; polyuria; nausea; vomiting and abdominal pain; and any of many altered states of consciousness or arousal (such as hostility and mania or, equally, confusion and lethargy).  In severe DKA, coma may follow, progressing to death.  Diabetic ketoacidosis is a medical emergency and requires hospital admission.

A rarer but equally severe possibility is hyperosmolar nonketotic state, which is more common in type 2 diabetes and is mainly the result of dehydration due to loss of body water.  Often, the patient has been drinking extreme amounts of sugar-containing drinks, leading to a vicious circle in regard to the water loss.