Lentil Barley Stew

A bowl of this stew satisfies hunger and helps stabilize blood sugar levels.  It is also high in protein and water soluble fiber. 

• 8 cups water
• 1 cup dry lentils
• 1/2 cup pearl barley
• 2 carrots, scrubbed and cut into large chunks
• 2 stalks celery, chopped
• 1 large yellow onion, chopped
• 1 clove garlic, pressed or chopped fine
• 2 bay leaves
• 2 1/2 tsp. ground cumin
• 1 1/2 tsp. ground thyme
• 1 1/2 tsp. salt
• 1/2 tsp. cinnamon
• 1/4 tsp. black pepper

Combine all ingredients in a large heavy stew pot.

Cover and simmer for about 1 1/2 hours over low heat, stirring occasionally.

Adjust seasonings to suit your taste.

Makes 4 servings
Per serving:

270 calories
50 g carbohydrate
20 g fiber
0 g fat
16 g protein
Mixed Vegetable Stir-Fry

• 1 tablespoon sesame oil
• 2 teaspoons finely chopped ginger root
• 1/2 teaspoon finely chopped garlic
• 1 1/2 cups small broccoli flowerets
• 1 cup thinly sliced carrots
• 1 small onion, chopped
• 3/4 cup vegetable broth
• 1 tablespoon cornstarch
• 1 tablespoon cold water
• 1 can (8 ounces) sliced water chestnuts, drained 
• 1 cup sliced mushrooms (about 3 ounces)
• 2 tablespoons oyster sauce 
Heat sesame oil in wok or large skillet until hot.  Add ginger root and garlic.  Stir-fry about 1 minute or until light brown.  Add broccoli, carrots and onion; stir-fry 1 minute.  Stir in vegetable broth.  Cover and cook about 3 minutes or until carrots are tender. 
Mix cornstarch and cold water; stir into vegetable mixture.  Cook and stir about 10 seconds or until thickened.  Add water chestnuts, mushrooms and oyster sauce.  Cook and stir 30 seconds.
Serve over brown rice or whole grain noodles if desired. 
Makes 4 servings
Per serving (without rice or noodles):
• 95 calories
• 3 g protein
• 18 g carbohydrate
• 1 g fat
• 4 g fiber 
Roasted Pumpkin Seeds

This crunchy snack is so easy and delicious there's no need to only make them at Halloween! Pumpkin seeds are a great source of magnesium, iron, zinc, essential fatty acids, and protein. They are also low in carbohydrate. 
• 2 cups whole raw pumpkin seeds
• 1 tablespoon melted butter or oil
• salt to taste
Scrape seeds from the inside of a pumpkin. Rinse the pumpkin pulp off as well as you can and pat dry. 
Preheat oven to 150 degrees F (75 degrees C). Roasting on this lower heat helps to maintain more of the healthy essential fatty acids.
Combine all ingredients in bowl; stir to coat all the seeds.
Spread the seeds in a single layer on a baking sheet. Bake until seeds are golden brown (about 20 minutes), stirring occasionally.
Adjust seasonings to suit your taste. Experiment: try adding a bit of brown sugar for sweet and salty seeds or paprika and celery salt for a spicy batch.
Makes 4 servings
Per 1/4 cup serving:
186 calories
6 g carbohydrate
1.5 g fiber
15 g fat
8 g protein
Baked Spinach

Ingredients:
• 1 Tbsp butter
• 1/2 cup chopped onions
• 2 - 10oz. packages of frozen chopped spinach (thawed & drained)
• 2 Tbsp parmesan cheese
• 3/4 cup low fat ricotta cheese
• 1/4 tsp. ground nutmeg
• 1/8 tsp garlic powder
• salt and pepper (to taste)
• 1 - 8 oz can tomato sauce
• 1/2 tsp. dried oregano
• 1/2 tsp. dried basil
Directions:
Melt butter in a large skillet over medium-high heat. Add onions and sauté until golden. Remove from heat.
Stir in spinach, parmesan cheese, ricotta cheese, nutmeg, garlic powder, salt and pepper.
Spoon into a 9-inch pie pan that has been sprayed with non-stick cooking spray.
Combine tomato sauce, oregano and basil. Spread evenly over spinach mixture.
Bake uncovered at 350 for 25 minutes.
Let stand for 5 minutes before serving.
Makes 4 servings
Per serving:
• 195 calories
• 14 g protein
• 15 g carbohydrate
• 10 g fat
 

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. It is a noninfectious disease. Among the body systems affected are the nerve, digestive, circulatory, endocrine and urinary systems.

The World Health Organization projects that the number of diabetics will exceed 350 million by 2030. Governments and other healthcare providers around the world are investing in health education, diagnosis and treatments for this chronic, debilitating - but controllable - disorder

The term "type 1 diabetes" has universally replaced several former terms, including childhood-onset diabetes, juvenile diabetes, and insulin-dependent diabetes mellitus (IDDM). Likewise, the term "type 2 diabetes" has replaced several former terms, including adult-onset diabetes, obesity-related diabetes, and non-insulin-dependent diabetes mellitus (NIDDM). Beyond these two types, there is no agreed-upon standard nomenclature. Various sources have defined "type 3 diabetes" as, among others, gestational diabetes,^[6] 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.^[7]) There is also maturity onset diabetes of the young (MODY) which is a group of several single gene (monogenic) disorders with strong family histories that present as type 2 diabetes before 30 years of age.

Gene Therapy Approach

Technology for gene therapy is advancing rapidly such that there are multiple pathways possible to support endocrine function, with potential to practically cure diabetes.^[19]

• Gene therapy can be used to manufacture insulin directly: an oral medication, consisting of viral vectors containing the insulin sequence, is digested and delivers its genes to the upper intestines. Those intestinal cells will then behave like any viral infected cell, and will reproduce the insulin protein. The virus can be controlled to infect only the cells which respond to the presence of glucose, such that insulin is produced only in the presence of high glucose levels. Due to the limited numbers of vectors delivered, very few intestinal cells would actually be impacted and would die off naturally in a few days. Therefore by varying the amount of oral medication used, the amount of insulin created by gene therapy can be increased or decreased as needed. As the insulin producing intestinal cells die off, they are boosted by additional oral medications.^[20]
• Gene therapy might eventually be used to cure the cause of beta cell destruction, thereby curing the new diabetes patient before the beta cell destruction is complete and irreversible.^[21]
• Gene therapy can be used to turn duodenum cells and duodenum adult stem cells into beta cells which produce insulin and amylin naturally. By delivering beta cell DNA to the intestine cells in the duodenum, a few intestine cells will turn into beta cells, and subsequently adult stem cells will develop into beta cells. This makes the supply of beta cells in the duodenum self replenishing, and the beta cells will produce insulin in proportional response to carbohydrates consumed.^[22]

Yonsei University

Scientists in the South Korean university of Yonsei have, in 2000, succeeded in reversing diabetes in mice and rats. Using a viral vector, a DNA encoding the production of an insulin analog was injected to the animals, which remained non-diabetic for at least the eight months duration of the study.^[23]

Prevention

"Immunization" approach

If a biochemical mechanism can be found that prevents the immune system from attacking beta cells, it may be administered to prevent commencement of diabetes type 1. Several groups are trying to achieve this by causing the activation state of the immune system to change from Th1 state (“attack” by killer T Cells) to Th2 state (development of new antibodies). This Th1-Th2 shift occurs via a change in the type of cytokine signaling molecules being released by regulatory T-cells. Instead of pro-inflammatory cytokines, the regulatory T-cells begin to release cytokines that inhibit inflammation.^[24] This phenomenon is commonly known as "acquired immune tolerance".

DiaPep277

A substance designed to cause lymphocyte cells to cease attacking beta cells, DiaPep277 is a peptide fragment of a larger protein called HSP60. Given as a subcutaneous injection, its mechanism of action involves a Th1-Th2 shift. Clinical success has been demonstrated in prolonging the "honeymoon" period for people who already have type 1 diabetes.^[25] The product is currently being tested in people with latent autoimmune diabetes of adults (LADA). Ownership of the drug has changed hands several times over the last decade. In 2007, Clal Biotechnology Industries (CBI) Ltd., an Israeli investment group in the field of life sciences, announced that Andromeda Biotech Ltd., a wholly owned subsidiary of CBI, signed a Term Sheet with Teva Pharmaceutical Industries Ltd. to develop and commercialize DiaPep277.^[26]

Intra-nasal insulin

There is pre-clinical evidence that a Th1-Th2 shift can be induced by administration of insulin directly onto the immune tissue in the nasal cavity. This observation has led to a clinical trial, called INIT II, which began in late 2006, based in Australia and New Zealand.

BCG research

Tumor necrosis factor-alpha, or TNF-a, is part of the immune system. It helps the immune system distinguish self from non-self tissue. People with type 1 diabetes are deficient in this substance. Dr. Denise Faustman theorizes that giving Bacillus Calmette-Guérin (BCG), an inexpensive generic drug, would have the same impact as injecting diabetic mice with Freund's Adjuvant, which stimulates TNF-a production. TNF-a kills the white blood cells responsible for destroying beta cells, and thus prevents, or reverses diabetes.^[27] She has reversed diabetes in laboratory mice with this technique, but was only able to receive funding for subsequent research from The Iaccoca Foundation, founded by Lee Iacocca in honor of his late wife, who died from diabetes complications. Human trials are set to begin in 2008.

Diamyd

Diamyd is the name of a vaccine being developed by Diamyd Medical. Injections with GAD65, an autoantigen involved in type 1 diabetes, has in clinical trials delayed the destruction of beta cells for at least 30 months, without serious adverse effects. Patients treated with the substance showed higher levels of regulatory cytokines, thought to protect the beta cells.^[28] Phase III trials are under way in the USA ^[29] and in Europe^[30].^[31][32] Two prevention studies, where the vaccine is given to persons who have not yet developed diabetes, will start in 2009^[33][34].

Entities involved in research

This section is an incomplete list of mainly commercial companies but also other entities, namely governmental institutions and individual persons, actively involved in research towards finding a cure to diabetes type 1.
It does not list research funds, hospitals in which research is undertaken, etc., but only the industrious, actual developers of such products.

Entities are listed alphabetically along with their status of research in that field, so that also entities which ceased research into finding a cure to diabetes type 1 may be listed.

• Amylin Pharmaceuticals – is working toward finding a cure, and has a drug on the market called Symlin (pramlintide acetate) that helps in treating Type 1 diabetes
• Cerco Medical [1] – Present status: Unknown
• Denise Faustman [2] – Present status: Working on immune modification
• DeveloGen [3] – Present status: Developing DiaPep 277
• Diamyd Medical [4] – Present status: Developing GAD65-based vaccine (phase III trial started)
• Tolerx, Inc. [www.defendagainstdiabetes.com] - Present status: Now (4/2009) in Phase 3 clinical study of otelixizumab, an Fc-disabled, anti-CD3 monoclonal antibody in patients with new onset (diagnosis within last 10 weeks) type 1 diabetes.

See also

• Richard K. Bernstein (low-carb diabetes diet)
• The Kara Neumann case – "treatment" by prayers case resulting in death

Further reading

• National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) - Diabetes in America Textbook (PDFs)

References

External links

• Beta Cell Biology Consortium - Team science with the aim of developing a cell-based therapy for type 1 diabetes
• Summary of Current Research in Type-1 Diabetes Cures
• Diabetes Section of The Hormone Foundation
• Juvenation a social network for people with type 1 diabetes created by the Juvenile Diabetes Research Foundation
• Online Diabetes Support Team at the Juvenile Diabetes Research Foundation
• Children with Diabetes
• Young Diabetics
• Type 1 Diabetes TrialNet
• Type 1 Diabetes at the American Diabetes Association
• National Diabetes Information Clearinghouse

   

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 symptoms usually develop much more slowly and may be subtle or completely absent. Type 1 diabetes may also cause a rapid yet significant weight loss (despite normal or even increased eating) and irreducible mental fatigue. All of these symptoms except weight loss can also manifest in type 2 diabetes in patients whose diabetes is poorly controlled.

When the glucose concentration in the blood is raised beyond its 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 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 and other body compartments, 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; sustained sensible glucose control usually returns the lens to its original shape. Blurred vision is a common complaint leading to a diabetes diagnosis; type 1 should always be suspected in cases of rapid vision change, whereas with type 2 change is generally more gradual, but should still be suspected.

Patients (usually with type 1 diabetes) may also initially 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 asKussmaul 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 immediate hospitalization.

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.

[edit]Genetics

Both type 1 and type 2 diabetes are at least partly inherited. Type 1 diabetes appears to be triggered by some (mainly viral) infections, or less commonly, by stress or environmental exposure (such as exposure to certain chemicals or drugs). There is a genetic element in individual susceptibility to some of these triggers which has been traced to particular HLA genotypes (i.e., the genetic "self" identifiers relied upon by the immune system). However, even in those who have inherited the susceptibility, type 1 diabetes mellitus seems to require an environmental trigger. A small proportion of people with type 1 diabetes carry a mutated gene that causes maturity onset diabetes of the young(MODY).

There is a stronger inheritance pattern for type 2 diabetes. Those with first-degree relatives with type 2 have a much higher risk of developing type 2, increasing with the number of those relatives. Concordance among monozygotic twins is close to 100%, and about 25% of those with the disease have a family history of diabetes. Genes significantly associated with developing type 2 diabetes, include TCF7L2, PPARG, FTO, KCNJ11, NOTCH2, WFS1, CDKAL1, IGF2BP2, SLC30A8, JAZF1, and HHEX.^[16] KCNJ11(potassium inwardly rectifying channel, subfamily J, member 11), encodes the islet ATP-sensitive potassium channel Kir6.2, and TCF7L2 (transcription factor 7–like 2) regulatesproglucagon gene expression and thus the production of glucagon-like peptide-1.^[3] Moreover, obesity (which is an independent risk factor for type 2 diabetes) is strongly inherited.^[17]

Monogenic forms, e.g. MODY, constitute 1-5 % of all cases.^[18]

Various hereditary conditions may feature diabetes, for example myotonic dystrophy and Friedreich's ataxia. Wolfram's syndrome is an autosomal recessive neurodegenerative disorder that first becomes evident in childhood. It consists of diabetes insipidus, diabetes mellitus, optic atrophy, and deafness, hence the acronym DIDMOAD.^[19]

Pathophysiology

Insulin is the principal hormone that regulates uptake of glucose from the blood into most cells (primarily muscle and fat cells, but not central nervous system cells). Therefore deficiency of insulin or the insensitivity of its receptors plays a central role in all forms of diabetes mellitus.

Most of the carbohydrates in food are converted within a few hours to the monosaccharide glucose, the principal carbohydrate found in blood and used by the body as fuel. The most significant exceptions arefructose, most disaccharides (except sucrose and in some people lactose), and all more complex polysaccharides, with the outstanding exception of starch. Insulin is released into the blood by beta cells (ß-cells), 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.

Insulin is also the principal control signal for conversion of glucose to glycogen for internal storage in liver and muscle cells. Lowered glucose levels result both in the reduced release of insulin from the beta cells and in the reverse conversion of glycogen to glucose when glucose levels fall. This is mainly controlled by the hormone glucagon which acts in an opposite manner to insulin. Glucose thus recovered by the liver re-enters the bloodstream; muscle cells lack the necessary export mechanism.

Higher insulin levels increase some anabolic ("building up") processes such as cell growth and duplication, protein synthesis, and fat storage. Insulin (or its lack) is the principal signal in converting many of the bidirectional processes of metabolism from a catabolic to an anabolic direction, and vice versa. In particular, a low insulin level is the trigger for entering or leaving ketosis (the fat burning metabolic phase).

If the amount of insulin available is insufficient, if cells respond poorly to the effects of insulin (insulin insensitivity or resistance), or if the insulin itself is defective, then glucose will not be absorbed properly by those body cells that require it nor will it be stored appropriately in the liver and muscles. The net effect is persistent high levels of blood glucose, poor protein synthesis, and other metabolic derangements, such as acidosis.

Diagnosis

The diagnosis of type 1 diabetes, and many cases of type 2, is usually prompted by recent-onset symptoms of excessive urination (polyuria) and excessive thirst (polydipsia), often accompanied by weight loss. These symptoms typically worsen over days to weeks; about a quarter of people with new type 1 diabetes have developed some degree of diabetic ketoacidosis by the time the diabetes is recognized. The diagnosis of other types of diabetes is usually made in other ways. These include ordinary health screening; detection of hyperglycemia during other medical investigations; and secondary symptoms such as vision changes or unexplainable fatigue. Diabetes is often detected when a person suffers a problem that is frequently caused by diabetes, such as a heart attack, stroke, neuropathy, poor wound healing or a foot ulcer, certain eye problems, certainfungal infections, or delivering a baby with macrosomia or hypoglycemia.

Diabetes mellitus is characterized by recurrent or persistent hyperglycemia, and is diagnosed by demonstrating any one of the following:^[4]

• fasting plasma glucose level at or above 126 mg/dL (7.0 mmol/l).
• plasma glucose at or above 200 mg/dL (11.1 mmol/l) two hours after a 75 g oral glucose load as in a glucose tolerance test.
• symptoms of hyperglycemia and casual plasma glucose at or above 200 mg/dL (11.1 mmol/l).

A positive result, in the absence of unequivocal hyperglycemia, should be confirmed by a repeat of any of the above-listed methods on a different day. Most physicians prefer to measure a fasting glucose level because of the ease of measurement and the considerable time commitment of formal glucose tolerance testing, which takes two hours to complete. According to the current definition, two fasting glucose measurements above 126 mg/dL (7.0 mmol/l) is considered diagnostic for diabetes mellitus.

Patients with fasting glucose levels from 100 to 125 mg/dL (6.1 and 7.0 mmol/l) are considered to have impaired fasting glucose. Patients with plasma glucose at or above 140 mg/dL or 7.8 mmol/l, but not over 200, two hours after a 75 g oral glucose load are considered to have impaired glucose tolerance. Of these two pre-diabetic states, the latter in particular is a major risk factor for progression to full-blown diabetes mellitus as well as cardiovascular disease.^[20]

While not used for diagnosis, an elevated level of glucose irreversibly bound to hemoglobin (termed glycosylated hemoglobin or HbA1c) of 6.0% or higher (the 2003 revised U.S. standard) is considered abnormal by most labs; HbA1c is primarily used as a treatment-tracking test reflecting average blood glucose levels over the preceding 90 days (approximately) which is the average lifetime of red blood cells which contain hemoglobin in most patients. However, some physicians may order this test at the time of diagnosis to track changes over time. The current recommended goal for HbA1c in patients with diabetes is <7.0%, which is considered good glycemic control, although some guidelines are stricter (<6.5%). People with diabetes who have HbA1c levels within this range have a significantly lower incidence of complications from diabetes, including retinopathy anddiabetic nephropathy.^[21][22]

Screening

Diabetes screening is recommended for many people at various stages of life, and for those with any of several risk factors. The screening test varies according to circumstances and local policy, and may be a random blood glucose test, a fasting blood glucose test, a blood glucose test two hours after 75 g of glucose, or an even more formal glucose tolerance test. Many healthcare providers recommend universal screening for adults at age 40 or 50, and often periodically thereafter. Earlier screening is typically recommended for those with risk factors such as obesity, family history of diabetes, high-risk ethnicity (Hispanic, Native American, Afro-Caribbean, Pacific Islander).^[23][24]

Many medical conditions are associated with diabetes and warrant screening. A partial list includes: high blood pressure, elevated cholesterol levels, coronary artery disease, past gestational diabetes, polycystic ovary syndrome, chronic pancreatitis, fatty liver, hemochromatosis, cystic fibrosis, several mitochondrial neuropathies and myopathies,myotonic dystrophy, Friedreich's ataxia, some of the inherited forms of neonatal hyperinsulinism. The risk of diabetes is higher with chronic use of several medications, including high-dose glucocorticoids, some chemotherapy agents (especially L-asparaginase), as well as some of the antipsychotics and mood stabilizers (especially phenothiazines and some atypical antipsychotics).

People with a confirmed diagnosis of diabetes are tested routinely for complications. This includes yearly urine testing for microalbuminuria and examination of the retina of the eye for retinopathy.

Prevention

Type 1 diabetes risk is known to depend upon a genetic predisposition based on HLA types (particularly types DR3 and DR4), an unknown environmental trigger (suspected to be an infection, although none has proven definitive in all cases), and an uncontrolled autoimmune response that attacks the insulin producing beta cells.^[25] Some research has suggested that breastfeeding decreased the risk in later life;^[26][27] various other nutritional risk factors are being studied, but no firm evidence has been found.^[28] Giving children 2000 IU of Vitamin D during their first year of life is associated with reduced risk of type 1 diabetes, though the causal relationship is obscure.^[29]

Children with antibodies to beta cell proteins (ie at early stages of an immune reaction to them) but no overt diabetes, and treated with vitamin B-3 (niacin), had less than half the diabetes onset incidence in a 7-year time span as did the general population, and an even lower incidence relative to those with antibodies as above, but who received no vitamin B3.^[30]

Type 2 diabetes risk can be reduced in many cases by making changes in diet and increasing physical activity.^[31][32] The American Diabetes Association (ADA) recommends maintaining a healthy weight, getting at least 2½ hours of exercise per week (several brisk sustained walks appear sufficient), having a modest fat intake, and eating sufficient fiber (eg, from whole grains). The ADA does not recommend alcohol consumption as a preventive, but it is interesting to note that moderate alcohol intake may reduce the risk (though heavy consumption absolutely and clearly increases damage to bodily systems significantly); a similarly confused connection between low dose alcohol consumption and heart disease is termed the French Paradox.

There is inadequate evidence that eating foods of low glycemic index is clinically helpful despite recommendations and suggested diets emphasizing this approach.^[33]

There are numerous studies which suggest connections between some aspects of Type II diabetes with ingestion of certain foods or with some drugs. Some studies have shown delayed progression to diabetes in predisposed patients through prophylactic use of metformin,^[32] rosiglitazone,^[34] or valsartan.^[35] In patients on hydroxychloroquine forrheumatoid arthritis, incidence of diabetes was reduced by 77% though causal mechanisms are unclear.^[36] Breastfeeding may also be associated with the prevention of type 2 of the disease in mothers.^[37] Clear evidence for these and any of many other connections between foods and supplements and diabetes is sparse to date; none, despite secondary claims for (or against), is sufficiently well established to justify as a standard clinical approach.

Treatment and management

Diabetes mellitus is currently a chronic disease, without a cure, and medical emphasis must necessarily be on managing/avoiding possible short-term as well as long-term diabetes-related problems. There is an exceptionally important role for patient education, dietetic support, sensible exercise, self monitoring of blood glucose, with the goal of keeping both short-term blood glucose levels, and long term levels as well, within acceptable bounds. Careful control is needed to reduce the risk of long term complications. This is theoretically achievable with combinations of diet, exercise and weight loss (type 2), various oral diabetic drugs (type 2 only), and insulin use (type 1 and for type 2 not responding to oral medications, mostly those with extended duration diabetes). In addition, given the associated higher risks of cardiovascular disease, lifestyle modifications should be undertaken to control blood pressure^[38] and cholesterol by exercising more, smoking less or ideally not at all, consuming an appropriate diet, wearing diabetic socks, wearing diabetic shoes, and if necessary, taking any of several drugs to reduce blood pressure. Many type 1 treatments include combination use of regular or NPH insulin, and/or synthetic insulin analogs (eg, Humalog, Novolog or Apidra) in combinations such as Lantus/Levemir and Humalog, Novolog or Apidra. Another type 1 treatment option is the use of the insulin pump (eg, from Deltec Cozmo, Animas, Medtronic Minimed, Insulet Omnipod, or ACCU-CHEK). A blood lancet is used to pierce the skin (typically of a finger), in order to draw blood to test it for sugar levels.

In countries using a general practitioner system, such as the United Kingdom, care may take place mainly outside hospitals, with hospital-based specialist care used only in case of complications, difficult blood sugar control, or research projects. In other circumstances, general practitioners and specialists share care of a patient in a team approach.Optometrists, podiatrists/chiropodists, dietitians, physiotherapists, nursing specialists (eg, DSNs (Diabetic Specialist Nurse)), nurse practitioners, or Certified Diabetes Educators, may jointly provide multidisciplinary expertise. In countries where patients must provide their own health care (i.e., in the developed world, the US, and in much of the undeveloped world), the impact of out-of-pocket costs of adequate diabetic care can be very high. In addition to the medications and supplies needed, patients are often advised to receive regular consultation from a physician (e.g., at least every three to six months).

Peer support links people living with diabetes. Within peer support, people with a common illness share knowledge and experience that others, including many health workers, do not have. Peer support is frequent, ongoing, accessible and flexible and can take many forms—phone calls, text messaging, group meetings, home visits, and even grocery shopping. It complements and enhances other health care services by creating the emotional, social and practical assistance necessary for managing disease and staying healthy.

Cure

Cures for type 1 diabetes

There is no practical cure, at this time, for type 1 diabetes. The fact that type 1 diabetes is due to the failure of one of the cell types of a single organ with a relatively simple function (i.e. the failure of the beta cells in the Islets of Langerhans) has led to the study of several possible schemes to cure this form of diabetes mostly by replacing the pancreas or just the beta cells.^[39] Only those type 1 diabetics who have received either a pancreas or a kidney-pancreas transplant (often when they have developed diabetic kidney disease (ie, nephropathy) and become insulin-independent) may now be considered "cured" from their diabetes. A simultaneous pancreas-kidney transplant is a promising solution, showing similar or improved survival rates over a kidney transplant alone.^[40] Still, they generally remain on long-term immunosuppressive drugs and there is a possibility that the immune system will mount a host versus graft response against the transplanted organ.^[39]

Transplants of exogenous beta cells have been performed experimentally in both mice and humans, but this measure is not yet practical in regular clinical practice partly due to the limited number of beta cell donors. Thus far, like any such transplant, it has provoked an immune reaction and long-term immunosuppressive drugs have been needed to protect the transplanted tissue.^[41] An alternative technique has been proposed to place transplanted beta cells in a semi-permeable container, isolating and protecting them from the immune system. Stem cell research has also been suggested as a potential avenue for a cure since it may permit regrowth of Islet cells which are genetically part of the treated individual, thus perhaps eliminating the need for immuno-suppressants.^[39] This new method, autologous nonmyeloablative HSTC, was recently developed by a research team comprised of scientists from the US and Brazil. This was originally tested in mice and in 2007 there was the first trial with fifteen patients. Recently this trial was continued and 8 more patients were added. In the trial, the researchers implanted diabetes type 1 patients with their own stem cells raised from their own bone marrow. The stem cell transplant led to an appreciable repopulation of functioning insulin-producing beta cells in the pancreas so the patients became insulin free. Most of these patients became insulin independent for a mean period of 18.8 months. At the present time, autologous nonmyeloablative HSCT remains the only treatment capable of reversing type 1 DM in humans.^[42]

Microscopic or nanotechnological approaches are under investigation as well, in one proposed case with implanted stores of insulin metered out by a rapid response valve sensitive to blood glucose levels. At least two approaches have been demonstrated in vitro. These are, in some sense, closed-loop insulin pumps.

Cures for type 2 diabetes

Type 2 has had no definitive cure, although recently it has been shown that a type of gastric bypass surgery can normalize blood glucose levels in 80-100% of severely obese patients with diabetes. The precise causal mechanisms are being intensively researched; its results are not simply attributable to weight loss, as the improvement in blood sugars precedes any change in body mass. This approach may become a standard treatment for some people with type 2 diabetes in the relatively near future.^[43] This surgery has the additional benefit of reducing the death rate from all causes by up to 40% in severely obese people.^[44] A small number of normal to moderately obese patients with type 2 diabetes have successfully undergone similar operations.^[45][46]

Prognosis

Patient education, understanding, and participation is vital since the complications of diabetes are far less common and less severe in people who have well-controlled blood sugar levels.^[47][48] Wider health problems accelerate the deleterious effects of diabetes. These include smoking, elevated cholesterol levels, obesity, high blood pressure, and lack of regular exercise. According to a study, women with high blood pressure have a threefold risk of developing diabetes.

Anecdotal evidence suggests that some of those with type 2 diabetes who exercise regularly, lose weight, and eat healthy diets may be able to keep some of the disease or some of the effects of the disease in 'remission.' Certainly these tips can help prevent people predisposed to type 2 diabetes and those at pre-diabetic stages from actually developing the disorder as it helps restore insulin sensitivity. However patients should talk to their doctors about this for real expectations before undertaking it (esp. to avoid hypoglycemia or other complications); few people actually seem to go into total 'remission,' but some may find they need less of their insulin medications since the body tends to have lower insulin requirements during and shortly following exercise. Regardless of whether it works that way or not for an individual, there are certainly other benefits to this healthy lifestyle for both diabetics and nondiabetics.

The way diabetes is managed changes with age. Insulin production decreases because of age-related impairment of pancreatic beta cells. Additionally, insulin resistance increases because of the loss of lean tissue and the accumulation of fat, particularly intra-abdominal fat, and the decreased tissue sensitivity to insulin. Glucose tolerance progressively declines with age, leading to a high prevalence of type 2 diabetes and postchallenge hyperglycemia in the older population.^[49] Age-related glucose intolerance in humans is often accompanied by insulin resistance, but circulating insulin levels are similar to those of younger people.^[50] Treatment goals for older patients with diabetes vary with the individual, and take into account health status, as well as life expectancy, level of dependence, and willingness to adhere to a treatment regimen.^[51]

Acute complications

Diabetic ketoacidosis

Diabetic ketoacidosis (DKA) is an acute and dangerous complication that is always a medical emergency. Low insulin levels cause the liver to turn to fat for fuel (ie, ketosis);ketone bodies are intermediate substrates in that metabolic sequence. This is normal when periodic, but can become a serious problem if sustained. Elevated levels of ketone bodies in the blood decrease the blood's pH, leading to DKA. On presentation at hospital, the patient in DKA is typically dehydrated, and breathing rapidly and deeply. Abdominal pain is common and may be severe. The level of consciousness is typically normal until late in the process, when lethargy may progress to coma. Ketoacidosis can easily become severe enough to cause hypotension, shock, and death. Urine analysis will reveal significant levels of ketone bodies (which have exceeded their renal threshold blood levels to appear in the urine, often before other overt symptoms). Prompt, proper treatment usually results in full recovery, though death can result from inadequate or delayed treatment, or from complications (eg, brain edema). DKA is always a medical emergency and requires medical attention. Ketoacidosis is much more common in type 1 diabetes than type 2.

Hyperglycemia hyperosmolar state

Hyperosmolar nonketotic state (HNS) is an acute complication sharing many symptoms with DKA, but an entirely different origin and different treatment. A person with very high (usually considered to be above 300 mg/dl (16 mmol/l)) blood glucose levels, water is osmotically drawn out of cells into the blood and the kidneys eventually begin to dump glucose into the urine. This results in loss of water and an increase in blood osmolarity. If fluid is not replaced (by mouth or intravenously), the osmotic effect of high glucose levels, combined with the loss of water, will eventually lead to dehydration. The body's cells become progressively dehydrated as water is taken from them and excreted. Electrolyte imbalances are also common and are always dangerous. As with DKA, urgent medical treatment is necessary, commonly beginning with fluid volume replacement. Lethargy may ultimately progress to a coma, though this is more common in type 2 diabetes than type 1.

Hypoglycemia

Hypoglycemia, or abnormally low blood glucose, is an acute complication of several diabetes treatments. It is rare otherwise, either in diabetic or non-diabetic patients. The patient may become agitated, sweaty, and have many symptoms of sympathetic activation of the autonomic nervous system resulting in feelings akin to dread and immobilized panic. Consciousness can be altered or even lost in extreme cases, leading to coma, seizures, or even brain damage and death. In patients with diabetes, this may be caused by several factors, such as too much or incorrectly timed insulin, too much or incorrectly timed exercise (exercise decreases insulin requirements) or not enough food (specifically glucose containing carbohydrates). The variety of interactions makes cause identification difficult in many instances.

It is more accurate to note that iatrogenic hypoglycemia is typically the result of the interplay of absolute (or relative) insulin excess and compromised glucose counterregulation in type 1 and advanced type 2 diabetes. Decrements in insulin, increments in glucagon, and, absent the latter, increments in epinephrine are the primary glucose counterregulatory factors that normally prevent or (more or less rapidly) correct hypoglycemia. In insulin-deficient diabetes (exogenous) insulin levels do not decrease as glucose levels fall, and the combination of deficient glucagon and epinephrine responses causes defective glucose counterregulation.

Furthermore, reduced sympathoadrenal responses can cause hypoglycemia unawareness. The concept of hypoglycemia-associated autonomic failure (HAAF) in diabetes posits that recent incidents of hypoglycemia causes both defective glucose counterregulation and hypoglycemia unawareness. By shifting glycemic thresholds for the sympathoadrenal (including epinephrine) and the resulting neurogenic responses to lower plasma glucose concentrations, antecedent hypoglycemia leads to a vicious cycle of recurrent hypoglycemia and further impairment of glucose counterregulation. In many cases (but not all), short-term avoidance of hypoglycemia reverses hypoglycemia unawareness in affected patients, although this is easier in theory than in clinical experience.

In most cases, hypoglycemia is treated with sugary drinks or food. In severe cases, an injection of glucagon (a hormone with effects largely opposite to those of insulin) or anintravenous infusion of dextrose is used for treatment, but usually only if the person is unconscious. In any given incident, glucagon will only work once as it uses stored liver glycogen as a glucose source; in the absence of such stores, glucagon is largely ineffective. In hospitals, intravenous dextrose is often used.

Chronic complications

Vascular disease

Chronic elevation of blood glucose level leads to damage of blood vessels (angiopathy). The endothelial cells lining the blood vessels take in more glucose than normal, since they don't depend on insulin. They then form more surface glycoproteins than normal, and cause the basement membrane to grow thicker and weaker. In diabetes, the resulting problems are grouped under "microvascular disease" (due to damage to small blood vessels) and "macrovascular disease" (due to damage to the arteries).

Image of fundus showing scatterlaser surgery for diabetic retinopathy

The damage to small blood vessels leads to a microangiopathy, which can cause one or more of the following:

• Diabetic retinopathy, growth of friable and poor-quality new blood vessels in the retina as well as macular edema (swelling of the macula), which can lead to severe vision loss or blindness. Retinal damage (from microangiopathy) makes it the most common cause of blindness among non-elderly adults in the US.
• Diabetic neuropathy, abnormal and decreased sensation, usually in a 'glove and stocking' distribution starting with the feet but potentially in other nerves, later often fingers and hands. When combined with damaged blood vessels this can lead to diabetic foot (see below). Other forms of diabetic neuropathy may present as mononeuritis or autonomic neuropathy. Diabetic amyotrophy is muscle weakness due to neuropathy.
• Diabetic nephropathy, damage to the kidney which can lead to chronic renal failure, eventually requiring dialysis. Diabetes mellitus is the most common cause of adult kidney failure worldwide in the developed world.
• Diabetic cardiomyopathy, damage to the heart, leading to diastolic dysfunction and eventually heart failure.

Macrovascular disease leads to cardiovascular disease, to which accelerated atherosclerosis is a contributor:

• Coronary artery disease, leading to angina or myocardial infarction ("heart attack")
• Stroke (mainly the ischemic type)
• Peripheral vascular disease, which contributes to intermittent claudication (exertion-related leg and foot pain) as well as diabetic foot.
• Diabetic myonecrosis ('muscle wasting')

Diabetic foot, often due to a combination of sensory neuropathy (numbness or insensitivity) and vascular damage, increases rates of skin ulcers and infection and, in serious cases, necrosis and gangrene. It is why diabetics are prone to leg and foot infections and why it takes longer for them to heal from leg and foot wounds. It is the most common cause of non-traumatic adult amputation, usually of toes and or feet, in the developed world.

Carotid artery stenosis does not occur more often in diabetes, and there appears to be a lower prevalence of abdominal aortic aneurysm. However, diabetes does cause higher morbidity, mortality and operative risks with these conditions.^[52]

Diabetic encephalopathy^[53] is the increased cognitive decline and risk of dementia observed in diabetes. Various mechanisms are proposed, including alterations to the vascular supply of the brain and the interaction of insulin with the brain itself.^[54].

Epidemiology

In 2000, according to the World Health Organization, at least 171 million people worldwide suffer from diabetes, or 2.8% of the population.^[55] Its incidence is increasing rapidly, and it is estimated that by the year 2030, this number will almost double.^[55] Diabetes mellitus occurs throughout the world, but is more common (especially type 2) in the more developed countries. The greatest increase in prevalence is, however, expected to occur in Asia and Africa, where most patients will probably be found by 2030.^[55] The increase in incidence of diabetes in developing countries follows the trend of urbanization and lifestyle changes, perhaps most importantly a "Western-style" diet. This has suggested an environmental (i.e., dietary) effect, but there is little understanding of the mechanism(s) at present, though there is much speculation, some of it most compellingly presented.^[55]

For at least 20 years, diabetes rates in North America have been increasing substantially. In 2008 there were about 24 million people with diabetes in the United States alone, from those 5.7 million people remain undiagnosed. Other 57 million people are estimated to have pre-diabetes.^[56]

The Centers for Disease Control has termed the change an epidemic.^[57] The National Diabetes Information Clearinghouse estimates that diabetes costs $132 billion in the United States alone every year. About 5%–10% of diabetes cases in North America are type 1, with the rest being type 2. The fraction of type 1 in other parts of the world differs; this is probably due to both differences in the rate of type 1 and differences in the rate of other types, most prominently type 2. Most of this difference is not currently understood. The American Diabetes Association cite the 2003 assessment of the National Center for Chronic Disease Prevention and Health Promotion (Centers for Disease Control and Prevention) that 1 in 3 Americans born after 2000 will develop diabetes in their lifetime.^[58][59]

According to the American Diabetes Association, approximately 18.3% (8.6 million) of Americans age 60 and older have diabetes.^[60] Diabetes mellitus prevalence increases with age, and the numbers of older persons with diabetes are expected to grow as the elderly population increases in number. The National Health and Nutrition Examination Survey (NHANES III) demonstrated that, in the population over 65 years old, 18% to 20% have diabetes, with 40% having either diabetes or its precursor form of impaired glucose tolerance.^[49]

Indigenous populations in first world countries have a higher prevalence and increasing incidence of diabetes than their corresponding non-indigenous populations. In Australia the age-standardised prevalence of self-reported diabetes in Indigenous Australians is almost 4 times that of non-indigenous Australians.^[61] Preventative community health programs such as Sugar Man (diabetes education) are showing some success in tackling this problem.

History

The term diabetes (Greek: d?aß?t??, diabetes) was coined by Aretaeus of Cappadocia. It was derived from the Greek verb d?aßa??e??, diabaínein, itself formed from the prefix dia-, "across, apart," and the verb bainein, "to walk, stand." The verb diabeinein meant "to stride, walk, or stand with legs asunder"; hence, its derivative diabetes meant "one that straddles," or specifically "a compass, siphon." The sense "siphon" gave rise to the use of diabetes as the name for a disease involving the discharge of excessive amounts of urine. Diabetes is first recorded in English, in the form diabete, in a medical text written around 1425. In 1675, Thomas Willis added the word mellitus, from the Latin meaning "honey", a reference to the sweet taste of the urine. This sweet taste had been noticed in urine by the ancient Greeks, Chinese, Egyptians, Indians, and Persians. In 1776,Matthew Dobson confirmed that the sweet taste was because of an excess of a kind of sugar in the urine and blood of people with diabetes.^[62]

Diabetes mellitus appears to have been a death sentence in the ancient era. Hippocrates makes no mention of it, which may indicate that he felt the disease was incurable. Aretaeus did attempt to treat it but could not give a good prognosis; he commented that "life (with diabetes) is short, disgusting and painful."^[63]

Sushruta (6th century BCE) identified diabetes and classified it as Medhumeha.^[64] He further identified it with obesity and sedentary lifestyle, advising exercises to help cure it.^[64] The ancient Indians tested for diabetes by observing whether ants were attracted to a person's urine, and called the ailment "sweet urine disease" (Madhumeha). The Korean, Chinese, and Japanese words for diabetes are based on the same ideographs (???) which mean "sugar urine disease". In medieval Persia, Avicenna (980-1037) provided a detailed account on diabetes mellitus in The Canon of Medicine, "describing the abnormal appetite and the collapse of sexual functions and he documented the sweet taste of diabetic urine." Like Aretaeus before him, Avicenna recognized a primary and secondary diabetes. He also described diabetic gangrene, and treated diabetes using a mixture of lupine, trigonella (fenugreek), and zedoary seed, which produces a considerable reduction in the excretion of sugar, a treatment which is still prescribed in modern times. Avicenna also "described diabetes insipidus very precisely for the first time", though it was later Johann Peter Frank (1745-1821) who first differentiated between diabetes mellitus and diabetes insipidus.^[65]

Although diabetes has been recognized since antiquity, and treatments of various efficacy have been known in various regions since the Middle Ages, and in legend for much longer, pathogenesis of diabetes has only been understood experimentally since about 1900.^[66] The discovery of a role for the pancreas in diabetes is generally ascribed toJoseph von Mering and Oskar Minkowski, who in 1889 found that dogs whose pancreas was removed developed all the signs and symptoms of diabetes and died shortly afterwards.^[67] In 1910, Sir Edward Albert Sharpey-Schafer suggested that people with diabetes were deficient in a single chemical that was normally produced by the pancreas—he proposed calling this substance insulin, from the Latin insula, meaning island, in reference to the insulin-producing islets of Langerhans in the pancreas.^[66]

The endocrine role of the pancreas in metabolism, and indeed the existence of insulin, was not further clarified until 1921, when Sir Frederick Grant Banting and Charles Herbert Best repeated the work of Von Mering and Minkowski, and went further to demonstrate they could reverse induced diabetes in dogs by giving them an extract from the pancreatic islets of Langerhans of healthy dogs.^[68] Banting, Best, and colleagues (especially the chemist Collip) went on to purify the hormone insulin from bovine pancreases at theUniversity of Toronto. This led to the availability of an effective treatment—insulin injections—and the first patient was treated in 1922. For this, Banting and laboratory director MacLeod received the Nobel Prize in Physiology or Medicine in 1923; both shared their Prize money with others in the team who were not recognized, in particular Best and Collip. Banting and Best made the patent available without charge and did not attempt to control commercial production. Insulin production and therapy rapidly spread around the world, largely as a result of this decision. Banting is honored by World Diabetes Day which is held on his birthday, November 14.

The distinction between what is now known as type 1 diabetes and type 2 diabetes was first clearly made by Sir Harold Percival (Harry) Himsworth, and published in January 1936.^[69]

Despite the availability of treatment, diabetes has remained a major cause of death. For instance, statistics reveal that the cause-specific mortality rate during 1927 amounted to about 47.7 per 100,000 population in Malta.^[70]

Other landmark discoveries include:^[66]

• identification of the first of the sulfonylureas in 1942
• reintroduction of the use of biguanides for Type 2 diabetes in the late 1950s. The initial phenformin was withdrawn worldwide (in the U.S. in 1977) due to its potential for sometimes fatal lactic acidosis and metformin was first marketed in France in 1979, but not until 1994 in the US.
• the determination of the amino acid sequence of insulin (by Sir Frederick Sanger, for which he received a Nobel Prize)
• the radioimmunoassay for insulin, as discovered by Rosalyn Yalow and Solomon Berson (gaining Yalow the 1977 Nobel Prize in Physiology or Medicine)^[71]
• the three-dimensional structure of insulin (PDB 2INS)
• Dr Gerald Reaven's identification of the constellation of symptoms now called metabolic syndrome in 1988
• demonstration that intensive glycemic control in type 1 diabetes reduces chronic side effects more as glucose levels approach 'normal' in a large longitudinal study,^[72] and also in type 2 diabetics in other large studies
• identification of the first thiazolidinedione as an effective insulin sensitizer during the 1990s

In 1980, U.S. biotech company Genentech developed human insulin. The insulin is isolated from genetically altered bacteria (the bacteria contain the human gene for synthesizing human insulin), which produce large quantities of insulin. Scientists then purify the insulin and distribute it to pharmacies for use by diabetes patients.

Social issues

The 1990 "St Vincent Declaration"^[73][74] was the result of international efforts to improve the care accorded to those with diabetes. Doing so is important both in terms of quality of life and life expectancy but also economically - expenses due to diabetes have been shown to be a major drain on health - and productivity-related resources for healthcare systems and governments.

Several countries established more and less successful national diabetes programmes to improve treatment of the disease.^[75]

A study shows that diabetic patients with neuropathic symptoms such as numbness or tingling in feet or hands are twice more likely to be unemployed than those without the symptoms.^[76]

See also

• Neuropathic ulcer
• List of terms associated with diabetes
• Blood sugar

References