Classification of Diabetes Mellitus

Classification of Diabetes Mellitus

Diabetes, the Greek word for siphon, in early days, referred to the disease that caused siphoning of the structural components of body into urine. The term "Diabetes Mellitus" (Greek for honey) has been given as urine of a diabetic patient is sweet. Clinically, diabetes mellitus is a heterogeneous primary disorder of carbohydrate metabolism with various etiologic factors, generally involving absolute or relative insulin deficiency or resistance or both. One hallmark of the disease is that it ultimately leads to chronic hyperglycemia. The disease most commonly characterized by frequent urination of the patient, is a complex syndrome that affects multiple organ systems.

Classification
Insulin Dependent Diabetes Mellitus (IDDM) - Type I: Formerly called juvenile-onset or ketosis-prone diabetes and is present in patients with little or no endogenous insulin secretory capacity. These patients develop extreme hyperglycemia, ketosis, and associated symptomatology unless treated with insulin, and they are therefore entirely dependent on exogenous insulin therapy for immediate survival.

Non-Insulin Dependent Diabetes Mellitus (NIDD,V) - Type II : Formerly known as adult-onset, maturity-onset, or nonketotic diabetes. It occurs in patients who retain significant endogenous insulin secretory capacity. Although treatment with insulin may be necessary to control hyperglycemia, these patients do not develop ketosis in absence of insulin therapy and are not dependent on exogenous insulin for immediate survival. Obesity is a frequent feature of NIDDM (obese - 80 per cent, and non-obese -20 per cent), which itself leads to insulin resistance and predisposes or exacerbates the NIDDM state.

Secondary Diabetes :
Many secondary forms of diabetes exist when some other readily identi-fiable primary disease entity or pathophysiologic state is strongly associated with the diabetic state.

  1. Pancreatic diseases (e.g., pancreatectomy, pancreatic insufficiency, hemochromatosis)
  2. Hormonal (excess counter insulin hormones, e.g., Cushing's syndrome, acromegaly, pheochro-mocytoma)
  3. Drug-induced (e.g., thiazide diuretics, steroids, phenytoin)
  4. Specific genetic syndromes (lipodystrophy, myotonic dystrophy, ataxia-telangiectasia)

Impaired Glucose Tolerance:
Formerly called chemical, latent, borderline, or subclinical diabetes.

Gestational Diabetes :
Glucose intolerance with onset during pregnancy.

Etiology
The etiology of diabetes is far from completely understood. Numerous factors are associated with the development of diabetes. While genetic factors are important in IDDM, they are only predisposing and must interact with environmental influences if diabetes is to develop. If one parent has IDDM, the risk to the offspring of developing IDDM is on the order of 2 to 5 percent. If one child has IDDM, the average risk for another sibling is 5-10 per cent. Genetic susceptibility to IDDM appears to be linked to 2 genes on chromosome 6 that control the production of human lymphocyte antigens (HLA) DR3 and DR4. 95 per cent of IDDM patients have one or both of these antigens compared with 40 per cent of non-diabetic patients. Conversely, patients who carry HLA- DQA1° 0102 or HLA - DQB1° 0602 seem to be protected from the development of IDDM. Emotional and physiologic stress may contribute as precipitating factors in the development of diabetes. Type I patients have a defect in pancreatic b cell function that may be attributed to several causes. Genetic defects in production of certain macro-molecules may interfere with proper insulin synthesis or release, or b cells may not recognize glucose signals or replicate normally. Extrinsic factors that affect b cell function include damage caused by viruses like mumps or Coxsackie B4, by destructive cytotoxins and antibodies released by sensitized lymphocytes, or by autodigestion in the course of an inflammatory disorder involving adjacent exocrine pancreas.

Unlike IDDM, Type II is relatively common in all populations enjoying an affluent life style. This type of diabetes may be present in a subclinical form for years before diagnosis, and the incidence increases markedly with age and degree of obesity. A reduced number of insulin receptors and the problem of insulin binding are major factors in the etiology of NIBDM.

Blood glucose level can be elevated by some hormones and drugs that influence the regulation of blood glucose.

Epidemiology
The prevalence of diabetes differs widely among different populations, depending on ethnic group, age, economical conditions, and other environmental factors. Diabetes mellitus and its complications are now the third leading cause of death in the USA.

Overall, in the USA the prevalence of diabetes is probably between 2 and 4 per cent, with IDDM comprising 7-10 per cent of all cases. Indians, particularly after emigrating from their country, have a higher rate of diabetes than other ethnic groups. Thus, Indians living in South Africa, Trinidad, Singapore, Malayasia, and Fiji exhibit a higher prevalence of diabetes than the local population and than those living in the Indian subcontinent. A low prevalence has been noted in Escimos, Athabascan Indians (Alaska), and Chinese. The proportion of IDDM to NIDDM also differs widely among different populations; IDDM is extremely rare in Pima Indians, Micronesians, and Eskimos, but is more common in Caucasians.2 According to a small group rural study the prevalence of NIDDM in Bangladesh is 2.1 per cent.

Pathophysiology
Insulin is produced in the pancreatic b cell. The regulation of insulin release is extremely complex, being influenced by glucose, amino acids, gut insulinogenic hormones, glucagon, neural influences, and other factors. Insulin exerts its major effects on carbohydrate homeostasis by stimulating peripheral glucose disposal and inhibiting hepatic glucose production. A variety of abnormalities in insulin biosynthesis, secretion, and action can lead to diabetes.

IDDM:
Autoimmunity plays a major role in the etiology of IDDM. Up to 90 per cent of patients with new-onset IDDM have demonstrable serum titers of islet cell antibodies. These antibodies are heterogeneous- some binding to cvtoplasmic antigens common wall islet cells and others directed against the P cell surface. The latter lyse b cells in culture in the presence of complement, consistent with a pathophysioloeic role in vivo. In humans, islet cell and anti-insulin antibodies can be detected at least several years prior to IDDM onset. Titers of these antibodies fall after the onset of clinical disease. A strong genetic component is involved in the etiology of IDDM, but several lines of evidence suggest a role for viruses in IDDM: (1) Autopsies of IDDM patients have revealed round cell infiltration of islet tissue, (2) Seasonal variation in the incidence of IDDM has been noted in some studies, (3) History of preceding viral-type illness, particularly coxsackie B and mumps, is often reported at the onset of IDDM, (4) Increased viral titers including coxsackie virus B, have been reported at or near the time of onset of disease, (5) Certain diabetogenic viruses (encephalomyocarditis M, coxsackie virus B, and rheovirus) can cause diabetes when inoculated into rodents, (6) Diabetogenic viruses can also directly infect b cells in culture, causing cell lysis and death.

NIDDM :
Abnormalities of insulin and to a lesser extent, glucagon secretion and action are central to the pathogenesis of NIDDM. Beyond familial hyperproinsulinemia and mutations in the structural gene for insulin, insulin biosynthesis is qualitatively normal in NIDDM. Majority of patients with NIDDM are both insulin deficient and insulin resistant. b cell dysfunction may be characterised by a defect in glucose recognition by islet cells. Insulin deficiency tends to be more severe in patients with longstanding disease. Although a receptor defect (decreased number) is present in most insulin-resistant NIDDM patients, this does not appear to be the major abnormality. Several postbinding defects have also been described in NIDDM ; e. g., these patients exhibit decreased b subunit tyrosine kinase activity, decreased rates of cellular glucose transport, and diminished activity. In addition, hepatic glucose production rates are also increased. This hepatic abnormality is, at least partially, due to resistance to insulin's normal restraining effect on liver glucose production. Additionally, glucagon levels are often elevated, either absolutely or relatively, and it is possible that excess glucagon stimulation also contributes to the increase in glucose production. Thus, insulin deficiency, insulin resistance, and accelerated hepatic glucose production contribute to the hyperglycemia in NIDDM.

Investigations

Oral Glucose Tolerance Test (OGTT) :
This diagnostic test, although controversial is a quite reliable test for diabetes. Several factors including infections stress, pregnancy, metabolic abnormalities, and certain drugs can impair glucose tolerance and produce abnormal results. One should screen for the possibility of these factors when using the OGTT.

Fasting Plasma Glucose /FPG) :
It a the simplest test in which blood is dravm from the patient after an overnight fast Hoaevm a normal FPG does not rule out diabetes. This test is used in nonpregnant adult patients who are neither receiving drugs nor have other diseases that could be responsible for the abnormal results.

Two-hour Postprandial Blood Glucose (2HPP) :
The 2HPP is used as a screening test in which a blood glucose level is measured two hours after the patient ingests a 100-g glucose load.

Glycosylated Hemoglobin (Hemoglobin A1) Measurements :
Glycosylated hemoglobin is abnormally high in diabetics with chronic hyperglycemia and reflects their metabolic control. In patients monitoring their own blood glucose levels, glycohemoglobin values provide a valuable check on the accuracy of monitoring. Glycohemoglobin values are also essential for adjusting therapy.

Self-monitoring of Blood Glucose and Urinalysis :
Monitoring of blood glucose by patients has allowed greater flexibility in management while achieving improved glycemic control. It involves educating the patient to perform 3 essential steps : (1) The obtaining of a drop of capillary blood from the fingertip. (2) Application of the sample to the test strip and removal at the proper time. (3) Accurate quantitation of the color developed. Patient-performed urinalysis tests are used for the evaluation of urine glucose, urine ketones, and urine protein.

Clinical Features

IDDM :
These patients usually present with relatively abrupt clinical symptoms of polyuria, polydipsia, and polyphagia. Weight loss, fatigue, and infection can often accompany the initial presentation. Because of the extreme hvpoinsulinemia and hyperglucagonemia, these patients readily develop ketosis, and the initial onset of this disease may be clinically evident as full-blown ketoacidosis. When vomiting occurs in response to worsening ketoacidosis, dehydration progresses and compensatory mechanisms become inadequate to keep serum osmolality below 320-330 mosm/1. Under these circumstances, stupor or even coma may occur. In occasional patients with slow, insidious onset of insulin deficiency, subcutaneous fat may be considerably depleted. An enlarged liver, eruptive xanthomas on the flexor surface of the limbs and on the buttocks, and lipemia retinalis indicate that chronic insulin deficiency has resulted in chylomicronemia.

NIDDM :
It typically presents with polyuria and polydipsia of several weeks' to months' duration. Polyphagia can occur but is less common, whereas weight loss, weakness, and fatigue are frequent. Dizziness, headache, and blurry vision are common accompanying complaints. In many patients no symptoms are apparent and the disease is diagnosed by routine blood or urine testing. In others, diabetes is advanced, and the presenting complaints are related to neuropathic, retinopathic, or vascular complaints. Chronic skin infections are common. Generalised pruritus and symptoms of vaginitis are frequently the initial complaints of women with NIDDM. Abdominal or upper body obesity is more closely associated with NIDDM than is lower body obesity. Ketosis is rare?

Complications
Most diabetic patients eventually experience one or more of the long-term complications of the disease. These complications arise from chronic hyperglycemia, which causes damage to small-and large-caliber blood vessels and peripheral nerves, greatly increasing the risk of heart attack, stroke, blindness, amputation, and kidney failure. Exactly how hyperglycemia causes these complications has been debated for years. Ishii and co-workers provide new support for the hypothesis that activation of the b2 isoform of protein kinase C (PKC) in vascular tissue is a key step in the cascade of events through which glucose triggers diabetic complications.

Diabetic Retinopathy :
Diabetic retinopathy is a specific microvascular complication of chronic hyperglycemia. In patients who have had diabetes for 20 years, some degree of diabetic retinopathy is found in nearly all with IDDM and in more than 60 per cent with NIDDM.

Diabetic Nephropathy :
Diabetic nephropathy accounts for nearly one third of all new cases of end-stage renal disease. The incidence of this disease is about 30 per cent in patients with IDDM and 40 per cent to 20 per cent in those with NIDDM. Although hyperglycemia appears to be an important risk factor for diabetic nephropathy, other factors have also been identified. Genetic factors, excessive protein intake, systemic hypertension, and certain metabolic abnormalities (e.g., lipoprotein abnormalities, nonenzymatic glycosylation) have been implicated in the pathogenesis of diabetic renal disease. Because of the consensus regarding the benefit of ACE inhibitors for early diabetic nephropathy, these agents should be started when microalbuminuria is confirmed and the effects of glycemic control are noted.

Diabetic Neuropathy :
The most common diabetic neuropathy is distal symmetric sensorimotor polyneuropathy. Other neuropathies, which may coexist or occur independently, include cranial mononeuropathy, isolated peripheral neuropathy, proximal motor neuropathy and autonomic neuropathy. Hyperglycemia is one of the major risk factors in development of distal symmetric sensorimotor polyneuropathy and autonomic dysfunction. Others include tallness, male sex, older age, hypertension, elevated cholesterol levels, and smoking.

The High-Risk Foot :
Advanced distal sensory, motor, and autonomic deficits are involved in the pathogenesis of most foot ulcers and resultant amputations in patients with diabetes. Typical complaints include pins-and-needles pain, shooting pain, and nocturnal exacerbations preventing sleep. Patients should be advised to refrain from walking barefoot and taught to inspect the feet and interdigital spaces daily. Shoes should accommodate any deformities and provide cushioning at the points of contact.

Diabetic Ketoacidosis :
It is a state of uncontrolled catabolism associated with insulin deficiency. In absence of insulin, hepatic glucose production accelerates and peripheral uptake by tissues is reduced. Rising glucose levels lead to an osmotic diuresis, loss of fluid and electrolytes, and dehydration. Plasma osmolality rises and renal perfusion falls. The features of ketoacidosis are those of uncontrolled diabetes with acidosis, and include prostration, hyperventilation, nausea, vomiting and abdominal pain. Diagnosis is con-firmed by demonstrating hyperglycemia with ketonemia or heavy ketonuria, and acidosis. The goals of therapy are to increase the rate of glucose utilisation by insulin-dependent tissues, to reverse ketonemia and acidosis, and to correct the depletion of water and electrolytes.

Management
Management of diabetes consists of diabetes education; nutrition and exercise plan; pharmacologic approach and insulin therapy.

Diabetes Education :
From 12 different trials it has been found that diabetes-related hospitalisations were reduced significantly in patients receiving instruction regarding self management. It is important that the educational process be well organised according to the individual patients' need and be periodically evaluated for their competence in performing urine or blood tests, mixing and injecting insulin, rotating injection sites, using the diet exchange system, and following an exercise prescription. Information should be provided about the identification of complication and their handling especially of hypoglycemic and hyperglycemic episodes. Improvement of life-style is another area where educational guidelines should be developed.

Nutritionl Diet :
Diet is the cornerstone of treatment of both Type I and Type II diabetes. It is estimated that upto 80 per cent of type II diabetes are over-weight and even a modest weight reduction of 10 pounds can markedly improve glucose tolerance. Behavioral changes in choosing and preparing food are essential for long term success. Daily calorie intake would be 30-35 kcal/kg depending upon the physical activity. It should be tailored in overweight patient. The total amount of carbohydrate in the diet should provide 50-55 per cent of total calories with fat 30-35 per cent and protein 15 per cent. Carbohydrate should be unrefined rather than simple sugars such as sucrose. Dietary fiber intake should be at least 20-35 g/day. Of fat intake, saturated, monounsaturated, polyunsaturated and cholesterol content would be daily

Exercise :
The exercise programme should be individualized and appropriate for the patient's age, coexisting medical conditions, and lifestyle. Exercise produces an improvement in insulin sensitivity or the ability of insulin to be used to drive glucose into the cell, and improves circulation. It also helps to maintain normal body weight and aids in breathing, digestion, and metabolism. Exercise may also reduce cardiovascular risk factors, such as hypertension and dyslipidemia. However, pre-exercise evaluation for silent ischemia may be necessary.

Oral Hypoglycemic Agents :
Unfortunately, in some patients, blood glucose levels continue to worsen even with diet and exercise. Causes may include noncompliance, diminishing endogenous insulin reserve, and glucose toxicity. Several agents may be considered in pharmacologic treatment of NIDDM. The choice depends on such factors as cost, side-effect profile, ease of administration, and patient age. The most recent consensus statement of the American Diabetes Association asserts that "Sulphonylureas are a rational choice to begin pharmacological intervention because almost all patients with Type II diabetes are relatively insulin deficient." Suphonylureas are inexpensive, many can be taken once daily, and have few side effects. The main concerns with their use are hypoglycemia and a tendency toward weight gain. Biguanides can also be used in NIDDM. Mortality associated with lactic acidosis necessitated removal of Phenphormin from the market. But Metformin appears to be safer with the incidence of lactic acidosis in 0.03 cases for 1,000 patients, and it usually occurs in patients with renal disease or other risk factors. It should not be given in men and women with creatinine level 1.5 mg/dl or more and 1.4 mg/dl or more respectively and in patients with a history of acute or chronic metabolic acidosis. It should also be avoided in clinical situations associated with renal dysfunction, myocardial infarction, shock and sepsis. Other disadvantages include cost and gastrointestinal side effects. But as it does not cause hypoglycemia or weight gain, it has a favourable effect on dyslipidemia. Studies have shown that combined therapy with Metformin and Sulphonylurea have synergistic effect on glucose control. Metformin can also be used in patients who require extremely high doses of exogenous insulin, so that relatively low doses of insulin is required. Another agent recently available, Acarbose competitively inhibit intestinal brush-border alphaglucosidase required for breakdown of starches and sucrose to absorbable monosaccharides. Acarbose-Sulphonylurea combination has been found to be more effective than Sulphonylurea therapy alone. Disadvantages of Acarbose include flatulence and abdominal discomfort. Many reports have recorded the use of a class of drugs referred to as Thiazolidinediones. These agents have been shown to have an insulin-sensitising effect by improving glucose tolerance while lowering insulin levels. But their use is limited because of observed side effects. Recently, the Thiazolidinedione troglitazone has been shown to have a peripheral tissue insulin-sensitising effect with greatly reduced side effects, so the agent holds promise for future use.

A possible approach when oral therapy for NIDDM begins to fail is bedtime insulin-daytime Sulfonvlurea therapy, known as BIDS. The regimen is usually started with 0.1 to 0.2 U/kg of an intermediate-acting insulin at bedtime. The dose is increased until a fasting blood glucose level of 150 mg/dl or less is achieved. A Sulfonylurea is given during the day time. Although clinical improvement is usually seen sooner, a 4 to 6 weeks observation period may be needed to determine whether the therapy has been successful.

Appetite Suppressants :
Agents currently used to suppress appetite and promote weight loss include Phentermine HCI, Fenfluramine HCI, Fluoxetine HCl and Dexfenfluramine. These can be used in NIDDM. Ongoing studies are evaluating the potential of these agents for long-term use.

Exogenous Insulin :
Insulin is the primary mode of therapy in all patients with IDDM, and in many with NIDDM when other treatment modalities fail. In NIDDM regimens that provide 24 hour insulin should be considered with intermediate or short-acting insulin. More aggressive strategies include use of an insulin pump or long-acting insulin preparation combined with regular insulin at meals.

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