Other Specific Types of Diabetes Mellitus*

I. Maturity-onset diabetes of the young (MODY)

This subgroup is a relatively rare monogenic disorder characterized by non–insulin-dependent diabetes with autosomal dominant inheritance and an age at onset of 25 years or younger. Patients are nonobese, and their hyperglycemia is due to impaired glucose-induced secretion of insulin. Six types of MODY have been described. Except for MODY 2, in which a glucokinase gene is defective, all other types involve mutations of a nuclear transcription factor that regulates islet gene expression.

MODY 2 is quite mild, associated with only slight fasting hyperglycemia and few if any microvascular diabetic complications. It generally responds well to hygienic measures or low doses of oral hypoglycemic agents. MODY 3—the most common form—accounts for two-thirds of all MODY cases. The clinical course is similar to that of idiopathic type 2 diabetes in terms of microangiopathy and failure to respond to oral agents with time.

II. Diabetes due to mutant insulins

This is a very rare subtype of nonobese type 2 diabetes, with no more than ten families having been described. Since affected individuals were heterozygous and possessed one normal insulin gene, diabetes was mild, did not appear until middle age, and showed autosomal dominant genetic transmission. There is generally no evidence of clinical insulin resistance, and these patients respond well to standard therapy.

III. Diabetes due to mutant insulin receptors

Defects in one of their insulin receptor genes have been found in more than 40 people with diabetes, and most have extreme insulin resistance associated with acanthosis nigricans. In very rare instances when both insulin receptor genes are abnormal, newborns present with a leprechaun-like phenotype and seldom live through infancy.

IV. Diabetes mellitus associated with a mutation of mitochondrial DNA

Since sperm do not contain mitochondria, only the mother transmits mitochondrial genes to her offspring. Diabetes due to a mutation of mitochondrial DNA that impairs the transfer of leucine or lysine into mitochondrial proteins has been described. Most patients have a mild form of diabetes that responds to oral hypoglycemic agents; some have a nonimmune form of type 1 diabetes. Two-thirds of patients with this subtype of diabetes have a hearing loss, and a smaller proportion (15%) had a syndrome of myopathy, encephalopathy, lactic acidosis, and stroke-like episodes (MELAS).

V. Wolfram's syndrome

Wolfram's syndrome is an autosomal recessive neurodegenerative disorder first evident in childhood. It consists of diabetes insipidus, diabetes mellitus, optic atrophy, and deafness, hence the acronym DIDMOAD. It is due to mutations in a gene named WFS1, which encodes a 100.3 KDa transmembrane protein localized in the endoplasmic reticulum. The function of the protein is not known. The diabetes mellitus, which is nonimmune and not linked to specific HLA antigens, usually presents in the first decade together with the optic atrophy. Cranial diabetes insipidus and sensorineural deafness develop during the second decade in 60–75% of patients. Ureterohydronephrosis, neurogenic bladder, cerebellar ataxia, peripheral neuropathy, and psychiatric illness develop later in many patients.

*Text/Info/Stats from CMDT 2008

Type 2 Diabetes Mellitus*

This represents a heterogeneous group of conditions that used to occur predominantly in adults, but it is now more frequently encountered in children and adolescents. More than 90% of all diabetic persons in the United States are included under this classification. Circulating endogenous insulin is sufficient to prevent ketoacidosis but is inadequate to prevent hyperglycemia in the face of increased needs owing to tissue insensitivity (insulin resistance).

Pathophysiology**

Hyperglycemia is produced by lack of endogenous insulin, which is either absolute, as in type 1 diabetes mellitus, or relative, as in type 2 diabetes mellitus. Relative insulin deficiency usually occurs because of resistance to the actions of insulin in muscle, fat, and the liver and an inadequate response by the pancreatic beta cell. This pathophysiologic abnormality results in decreased glucose transport in muscle, elevated hepatic glucose production, and increased breakdown of fat.

The genetics of type 2 diabetes are complex and not completely understood, but presumably this disease is related to multiple genes (with the exception of maturity-onset diabetes of the young [MODY]). Evidence supports inherited components for both pancreatic beta cell failure and insulin resistance. Considerable debate exists regarding the primary defect in type 2 diabetes mellitus. Most patients have both insulin resistance and some degree of insulin deficiency. However, insulin resistance per se is not the sine qua non for type 2 diabetes mellitus because many people with insulin resistance (particularly patients who are obese) do not develop glucose intolerance. Therefore, insulin deficiency is necessary for the development of hyperglycemia. Patients may have high insulin levels, but the insulin concentrations are inappropriately low for the level of glycemia.

MODY is associated with autosomal dominant inheritance and is characterized by onset in at least 1 family member younger than 25 years, correction of fasting hyperglycemia without insulin for at least 2 years, and absence of ketosis. At least 6 genetically different types of MODY have been described. Some patients ultimately require insulin to control glycemia.

Recent work has suggested that elevated free fatty acids may be the driving force behind insulin resistance and perhaps even beta cell dysfunction. If this defect is more proximal than defects specifically related to glycemia, then therapies aimed at correcting this phenomenon would be highly beneficial.

Presumably, the defects of type 2 diabetes mellitus occur when a diabetogenic lifestyle (ie, excessive calories, inadequate caloric expenditure, obesity) is superimposed upon a susceptible genotype. The extent of excess weight may vary with different groups. For example, overweight patients from Asia may not be overweight by Western standards, but excess weight is often much more pronounced in these ethnic groups. Recent work suggests that in utero environment resulting in low birth weight may predispose some individuals to develop type 2 diabetes mellitus.

Hyperglycemia appears to be the determinant of microvascular and metabolic complications. However, glycemia is much less related to macrovascular disease. Insulin resistance with concomitant lipid (ie, small dense low-density lipoprotein [LDL] particles, low high-density lipoprotein-cholesterol [HDL-C] levels, elevated triglyceride-rich remnant lipoproteins) and thrombotic (ie, elevated type-1 plasminogen activator inhibitor [PAI-1], elevated fibrinogen) abnormalities, as well as conventional atherosclerotic risk factors (eg, family history, smoking, hypertension, elevated low-density lipoprotein-cholesterol [LDL-C], low HDL-C), determine cardiovascular risk.

Increased cardiovascular risk appears to begin prior to the development of frank hyperglycemia, presumably because of the effects of insulin resistance. Stern in 1996 and Haffner and D'Agostino in 1999 developed the "ticking clock" hypothesis of complications, asserting that the clock starts ticking for microvascular risk at the onset of hyperglycemia, while the clock starts ticking for macrovascular risk at some antecedent point, presumably with the onset of insulin resistance.

Genetic and environmental factors combine to cause both the insulin resistance and the beta cell loss. Most epidemiologic data indicate strong genetic influences, since in monozygotic twins over 40 years of age, concordance develops in over 70% of cases within a year whenever type 2 diabetes develops in one twin. Attempts to identify genes for type 2 diabetics that cause the insulin resistance and the beta cell failure have as yet been unsuccessful, although linkage to a gene on chromosome 2 encoding a cysteine protease, calpain-10, has been reported in a Mexican-American population. However, its association with other ethnic populations and any role it plays in the pathogenesis of type 2 diabetes remain to be clarified.

Early in the disease process, hyperplasia of pancreatic B cells occurs and probably accounts for the fasting hyperinsulinism and exaggerated insulin and proinsulin responses to glucose and other stimuli. With time, chronic deposition of amyloid in the islets may combine with inherited genetic defects progressively to impair B cell function.

Obesity is the most important environmental factor causing insulin resistance. The degree and prevalence of obesity varies among different racial groups with type 2 diabetes. While obesity is apparent in no more than 30% of Chinese and Japanese patients with type 2, it is found in 60–70% of North Americans, Europeans, or Africans with type 2 and approaches 100% of patients with type 2 among Pima Indians or Pacific Islanders from Nauru or Samoa.

Visceral obesity, due to accumulation of fat in the omental and mesenteric regions, correlates with insulin resistance; subcutaneous abdominal fat seems to have less of an association with insulin insensitivity. Exercise may affect the deposition of visceral fat as suggested by CT scans of Japanese wrestlers, whose extreme obesity is predominantly subcutaneous. Their daily vigorous exercise program prevents accumulation of visceral fat, and they have normal serum lipids and euglycemia despite daily intakes of 5000–7000 kcal and development of massive subcutaneous obesity. Several adipokines, secreted by fat cells, can affect insulin action in obesity. Two of these, leptin and adiponectin, seem to increase sensitivity to insulin, presumably by increasing hepatic responsiveness. Two others—tumor necrosis factor-a, which inactivates insulin receptors, and the newly discovered peptide, resistin—interfere with insulin action on glucose metabolism and have been reported to be elevated in obese animal models. Mutations or abnormal levels of these adipokines may contribute to the development of insulin resistance in human obesity.

Hyperglycemia per se can impair insulin action by causing accumulation of hexosamines in muscle and fat tissue and by inhibiting glucose transport (acquired glucose toxicity). Correction of hyperglycemia reverses this acquired insulin resistance.

While many patients with type 2 diabetes present with increased urination and thirst, many others have an insidious onset of hyperglycemia and are asymptomatic initially. This is particularly true in obese patients, whose diabetes may be detected only after glycosuria or hyperglycemia is noted during routine laboratory studies. Occasionally, type 2 patients may present with evidence of neuropathic or cardiovascular complications because of occult disease present for some time prior to diagnosis. Chronic skin infections are common. Generalized pruritus and symptoms of vaginitis are frequently the initial complaints of women. Diabetes should be suspected in women with chronic candidal vulvovaginitis as well as in those who have delivered large babies (> 9 lb, or 4.1 kg) or have had polyhydramnios, preeclampsia, or unexplained fetal losses.

Obese diabetics may have any variety of fat distribution; however, diabetes seems to be more often associated in both men and women with localization of fat deposits on the upper segment of the body (particularly the abdomen, chest, neck, and face) and relatively less fat on the appendages, which may be quite muscular. Standardized tables of waist-to-hip ratio indicate that ratios of "greater than 0.9" in men and "greater than 0.8" in women are associated with an increased risk of diabetes in obese subjects. Mild hypertension is often present in obese diabetics. Eruptive xanthomas on the flexor surface of the limbs and on the buttocks and lipemia retinalis due to hyperchylomicronemia can occur in patients with uncontrolled type 2 diabetes who also have a familial form of hypertriglyceridemia.

*Text/Info/Stats from CMDT 2008

**by KPL Ligaray, MD from WebMD

Type 1 Diabetes Mellitus*

This form of diabetes is immune-mediated (i.e. caused by the immune system destroying pancreatic B cells) in over 90% of cases and idiopathic (i.e. from unknown cause) in less than 10%. The rate of pancreatic B cell destruction is quite variable, being rapid in some individuals and slow in others. Type 1 diabetes is usually associated with ketosis in its untreated state. It occurs at any age but most commonly arises in children and young adults with a peak incidence before school age and again at around puberty. It is a catabolic disorder in which circulating insulin is virtually absent, plasma glucagon is elevated, and the pancreatic B cells fail to respond to all insulinogenic stimuli. Exogenous insulin is therefore required to reverse the catabolic state, prevent ketosis, reduce the hyperglucagonemia, and reduce blood glucose.

Pathophysiology**

Insulin is essential to process carbohydrates, fat, and protein. Insulin reduces blood glucose levels by allowing glucose to enter muscle cells and by stimulating the conversion of glucose to glycogen (glycogenesis) as a carbohydrate store. Insulin also inhibits the release of stored glucose from liver glycogen (glycogenolysis) and slows the breakdown of fat to triglycerides, free fatty acids, and ketones. It also stimulates fat storage. Additionally, insulin inhibits the breakdown of protein and fat for glucose production (gluconeogenesis) in both liver and kidneys.

Hyperglycemia (ie, random blood glucose concentration more than 200 mg/dL or 11 mmol/L) results when insulin deficiency leads to uninhibited gluconeogenesis and prevents the use and storage of circulating glucose. The kidneys cannot reabsorb the excess glucose load, causing glycosuria, osmotic diuresis, thirst, and dehydration. Increased fat and protein breakdown leads to ketone production and weight loss. Without insulin, a child with IDDM wastes away and eventually dies from diabetic ketoacidosis (DKA).

An excess of insulin prevents the release of glucose into the circulation and results in hypoglycemia (blood glucose concentrations of less than 60 mg/dL or 3.5 mmol/L). Glucose is the sole energy source for erythrocytes, kidney medulla, and the brain.

I . Immune-mediated type 1 diabetes mellitus

The highest incidence of immune-mediated type 1 diabetes mellitus is in Scandinavia and northern Europe, where the annual incidence is as high as 37 per 100,000 children aged 14 years or younger in Finland, 27 per 100,000 in Sweden, 22 per 100,000 in Norway, and 19 per 100,000 in the United Kingdom. The annual incidence of type 1 diabetes decreases across the rest of Europe to 10 per 100,000 in Greece and 8 per 100,000 in France. The island of Sardinia has as high an annual incidence as Finland (37 per 100,000) even though in the rest of Italy, including the island of Sicily, it is only 10 per 100,000 per year. In the United States, the annual incidence of type 1 diabetes averages 15 per 100,000, with higher rates in states more densely populated with persons of Scandinavian descent such as Minnesota. Worldwide, the lowest incidence of type 1 diabetes (less than 1 case per 100,000 per year) is in China and parts of South America. The global incidence of type 1 diabetes is increasing (approximately 3% each year).

Approximately one-third of the disease susceptibility is due to genes and two-thirds to environmental factors. Genes that are related to the HLA locus contribute about 40% of the genetic risk. About 95% of patients with type 1 diabetes possess either HLA-DR3 or HLA-DR4, compared with 45–50% of white controls. HLA-DQ genes are even more specific markers of type 1 susceptibility, since a particular variety (HLA-DQB1*0302) is found in the DR4 patients with type 1, while a "protective" gene (HLA-DQB1*0602) is often present in the DR4 controls. The other important gene that contributes to about 10% of the genetic risk is found at the 5' polymorphic region of the insulin gene. This polymorphic region affects the expression of the insulin gene in the thymus and results in depletion of insulin-specific T lymphocytes. In linkage studies, 16 other genetic regions of the human genome have been identified as being important to pathogenesis but less is known about them.

Most patients with type 1 diabetes mellitus have circulating antibodies to islet cells (ICA), insulin (IAA), glutamic acid decarboxylase (GAD65), and tyrosine phosphatases (IA-2 and IA2- ) at the time the diagnosis is made. These antibodies facilitate screening for an autoimmune cause of diabetes, particularly screening siblings of affected children, as well as adults with atypical features of type 2 diabetes . Antibody levels decline with increasing duration of disease. Also, low levels of anti-insulin antibodies develop in almost all patients once they are treated with insulin.

Family members of diabetic probands are at increased lifetime risk for developing type 1 diabetes. A child whose mother has type 1 diabetes has a 3% risk of developing the disease and a 6% risk if the child's father has it. The risk in siblings is related to the number of HLA haplotypes that the sibling shares with the diabetic proband. If one haplotype is shared, the risk is 6% and if two haplotypes are shared, the risk increases to 12–25%. The highest risk is for identical twins, where the concordance rate is 25–50%.

Some patients with a milder expression of type 1 diabetes mellitus initially retain enough B cell function to avoid ketosis, but as their B cell mass diminishes later in life, dependence on insulin therapy develops. Islet cell antibody surveys among northern Europeans indicate that up to 15% of "type 2" diabetic patients may actually have this mild form of type 1 diabetes (latent autoimmune diabetes of adulthood; LADA). Evidence for environmental factors playing a role in the development of type 1 diabetes include the observation that the disease is more common in Scandinavian countries and becomes progressively less frequent in countries nearer and nearer to the equator. Also, the risk for type 1 diabetes increases when individuals who normally have a low risk emigrate to the Northern Hemisphere. For example, it was recently shown that Pakistani children born and raised in Bradford, England have a higher risk for developing type 1 diabetes compared with children who lived in Pakistan all their lives.

Which environmental factor is responsible for the increased risk is not known. There have been a number of different hypotheses including infections with certain viruses (rubella, Coxsackie B4) and consumption of cow's milk. Also, in developed countries, childhood infections have become less frequent and so perhaps the immune system becomes dysregulated with development of autoimmunity and conditions such as asthma and diabetes. This theory is referred to as the hygiene hypothesis. None of these factors has so far been confirmed as the culprit. Part of the difficulty is that autoimmune injury undoubtedly starts many years before clinical diabetes mellitus develops.

II. Idiopathic type 1 diabetes mellitus

Less than 10% of subjects have no evidence of pancreatic B cell autoimmunity to explain their insulinopenia and ketoacidosis. This subgroup has been classified as "idiopathic type 1 diabetes" and designated as "type 1B." Although only a minority of patients with type 1 diabetes fall into this group, most of these are of Asian or African origin. It was recently reported that about 4% of the West Africans with ketosis-prone diabetes are homozygous for a mutation in PAX-4 (Arg133Trp)—a gene that is essential for the development of pancreatic islets.

*Text/Info/Stats from CMDT 2008

**by WH Lamb, MD from WebMD

This is a very broad subject so I plan to write this in several parts. For starters, I'm going to write down the nomenclature generally followed by clinicians at present so that it would be easier to follow the subject matter as the article goes along. The present classification of diabetes follows the etiological classification of disorders of glycemia. Simply put, that means your doctors will call it according to its pathological cause. As a side note, this was adopted because the previous way of categorizing the disease into insulin dependent and non-insulin dependent was deemed confusing. This is due to the fact that patients with any form of diabetes may require insulin treatment at some stage of their disease.

So to start off, we start with Type 1 diabetes. Type 1 (formerly known as IDDM or insulin dependent diabetes mellitus in the previous nomenclature) is the type of diabetes that is generally due to beta-cell destruction that usually leads to absolute insulin deficiency. Type 2 (formerly known as NIDDM or non-insulin dependent diabetes mellitus in the previous nomenclature) is the type that has an etiological cause ranging from predominantly insulin resistance with relative insulin deficiency to a predominantly secretory defect with or without insulin resistance.

The third type is a collective of diabetes mellitus from various known etiologies and is grouped together to form the classification called "other specific types." This group includes persons with genetic defects of beta-cell function (this type of diabetes was formerly called MODY or maturity-onset diabetes in youth) or with defects of insulin action; persons with diseases of the exocrine pancreas, such as pancreatitis or cystic fibrosis; persons with dysfunction associated with other endocrinopathies (e.g., acromegaly); and persons with pancreatic dysfunction caused by drugs, chemicals or infections.

The fourth type is known as gestational diabetes (can usually be read as the acronym GDM or gestational diabetes mellitus). Among the types, this is the only one not following the etiologic basis of diabetes nomenclature. By reason of customary practice, it remained in its operational classification and did not use the etiological basis of nomenclature. Thus, it identifies all women who develop diabetes mellitus during gestation, regardless of pathological etiology, as having GDM. That is to say, women who develop type 1 diabetes mellitus during pregnancy and women with undiagnosed asymptomatic type 2 diabetes mellitus that is discovered during pregnancy are classified as having gestational diabetes mellitus, just the same.

Apart from type 1, type 2, other specific types and GDM, we will sometimes encounter the terms impaired glucose tolerance (IGT) and impaired fasting glucose (IFG). These basically refers to recognized forms of hyperglycemia in an intermediate group of subjects whose glucose levels, although not meeting the criteria for diabetes, are nevertheless too high to be considered normal.

Well, there you have it. These are the nomenclature basics that we need to further delve into DM. I will leave this topic for now and continue next time on this. For my next posting, I plan to go into specifics. So I will most probably go discussing 1 type per post. Until then, ciao for now!

Seeking a second opinion from another doctor is quite common today. This practice is especially wise more so before one undergoes an operation or a special treatment. But the problem with this process is that it can lead to more dilemmas as different doctors can have different ideas that can collide. As patients are now more aware of their capacity to ask their doctors further information regarding what it is they have and the treatment options that they can choose from, seeking a second opinion is more and more becoming common. But with it also comes the situation where we find an increasing number of incidents where we have doctors who have differing opinions regarding the same matter. It is with this in mind that I thus, made this short list of caveats on what patients can do when this situation arises.

The first thing that could be done to resolve the situation is for patients to know the reason why the views of the doctors differed in the first place. Could it be that one was suggesting a surgical approach, as that doctor was a surgeon? Or how about the other one who thought of a medical approach because he, on the other hand, was an internist? Basically, it would be rightfully judicious for patients to consider the reasons why the views of the doctors did not match in the first place. Simultaneously, it would also be prudent for patients to discover the credentials of the doctors making the opinions. Who knows, the other doctor could be the Nobel price genius who was the expert in that field and was actually suggesting the better solution. The bottom line is, patients should also try to find out more about their doctors and not just know their specialties because they can use that in weighing whose option they think would benefit them some more.

The next thing that patients can do is to try and share the information they have with their primary physicians. They should trust their own doctors some more and try to discuss and elaborate with them what they were presented with and the treatment options that were given to them. In this connection, patients must remember that they should stay on top of the situation and must not feel pressured. Of course that could be difficult depending on their situation, but it should be borne in mind that good doctors do take time to explain their diagnosis and treatment options to their patients. Thus, patients should not feel rushed and make hurried decisions in whatever it is their doctors plan to do.

Lastly, patients should always be aware of their comfort levels. This is because in the final analysis, doctors can only just plan ahead and determine what it is that they plan to do, but the final decision will always fall on the patients themselves. Thus, patients should trust their gut feelings too, as the answers could be blurry and only they can tell what it is they feel is good for them.