Saturday, March 12, 2011

Association of Cytotoxic T Lymphocyte Antigen-4 Gene Polymorphisms

Association of Cytotoxic T Lymphocyte Antigen-4 Gene Polymorphisms and HLA Class II Alleles with the Development of Type 1 Diabetes in Korean Children and Adolescents
Min Ho Jung,1 Jeesuk Yu,2 Choong Ho Shin, 3 Muhammad arshad,1 Sei Won Yang,3 and Byung Churl Lee1

Abstract
We studied the association of cytotoxic T lymphocyte antigen-4 gene (CTLA4) polymorphisms with the development of type 1 diabetes (T1D) in Korean children and adolescents. A total of 176 Korean subjects (92 females and 84 males) with childhood-onset T1D were studied. The A/G polymorphism at position 49 in CTLA4 exon 1 and the C/T polymorphism at position -318 in the CTLA4 promoter were analyzed by PCR-RFLP methods. The genotype and allele frequencies of the CTLA4 polymorphisms in the T1D patients were not different from those in the controls. These polymorphisms were not associated with the clinical characteristics or the development of autoimmune thyroid disease in the T1D patients. The frequency of the A allele was significantly higher in the patients that did not have two out of the three susceptible HLA-DRB1 alleles, which were DRB1*0301, *0405 and *09012, compared to the controls (P<0.05). These results suggest that CTLA4 polymorphisms do not directly confer any susceptibility to T1D. However, a CTLA4-mediated susceptibility effect on the development of T1D might be significant in children and adolescents that do not have susceptible HLA class II alleles.
Keywords: Diabetes Mellitus, Type 1; Genes; Cytotoxic T-lymphocyte Antigen 4; HLA

INTRODUCTION
Type 1 diabetes (T1D) is an organ-specific autoimmune disease that is characterized by infiltration of lymphocytes into the pancreatic islets and pancreas-specific autoantibodies in the serum (1). A variety of genetically predisposed factors and contributing factors have been known to influence the pathogenesis of T1D. Some evidence has suggested that the susceptible genes to T1D are associated with the amplification of the immune response and the rate of progression of the disease; the role of these genes appear to be more important during childhood than during adult life (2).
The association of HLA alleles and the development of T1D has been shown by studies on diverse ethnic groups. However, a genetic predisposition solely conferred by the HLA is not sufficient to explain the mechanism that leads to the development of T1D. Therefore, it has been hypothesized that several genes are involved in the development of T1D (3).
The cytotoxic T lymphocyte antigen-4 gene (CTLA4) and the gene encoding CD28 have been mapped to chromosome 2q33. CTLA-4 is a glycoprotein receptor expressed on activated T cells and CD28 is involved in the regulation process of the activation of T cells by antigen-presenting cells and subsequent cellular immunity (4). CTLA4 has been considered to be a permissive candidate gene involved in the etiology of autoimmune diseases; this is because CTLA-4 plays a role in the regulation of the activation of T cells and as well as T cell and B cell interactions (5).
According to prior studies on the association of the development of various autoimmune diseases and the CTLA4 gene, the 49 A/G polymorphism in CTLA4 exon 1 has been reported to be involved in the development of Graves' disease (6), Hashimoto thyroiditis (7), a portion of Addison's disease and rheumatoid arthritis (8). A significant association of T1D with the CTLA4 polymorphisms was reported by Nistico et al. (9) for the first time; this association has been additionally reported by other studies in a variety of ethnic groups (10, 11). However, in studies conducted in Japan (12) and other countries (13, 14), the association of the CTLA4 polymorphisms with the development of T1D has not been confirmed.
The primary purpose of this study was to investigate whether the CTLA4 gene was associated with the development of T1D in Korean children and adolescents. Furthermore, we studied whether interactions between the CTLA4 gene and susceptible HLA class II alleles had a role in the pathogenesis of T1D.
MATERIALS AND METHODS
This study included 176 patients (92 females, 84 males) with T1D, who were diagnosed during childhood and adolescence (mean age, 7.5±4.0 yr) from 1992 to 2002 at diabetes clinic of Seoul National University Children's Hospital. In addition, 90 healthy individuals were recruited as a control group. The study was explained to all patients, and their written consent was obtained. The diagnosis of T1D was based on the blood glucose level according to the World Health Organization diagnostic guidelines, clinical symptoms, absolute insulin-dependency, and pancreas-specific autoantibodies.
We reviewed the clinical characteristics, such as diabetic ketoacidosis at the initial presentation, age of onset, family history of T1D, pubertal status at the onset of diabetes, and presence of concomitant autoimmune thyroid disease to determine whether there was an association between the CTLA4 polymorphisms and the clinical characteristics. Among the study subjects, there were 31 patients (17.6%) with autoimmune thyroid disease that were diagnosed by thyroid function tests, anti-thyroid autoantibodies, and/or TSH receptor stimulating antibodies.
Genomic DNA was extracted from peripheral mononuclear cells using the Wizard DNA purification kit (Promega, Maison, WI, U.S.A.), and quantified by spectrophotometer. HLA-DRB1 alleles were analyzed by grouping of DRB1 using a Dynal RELI SSO HLA-DRB1 typing kit (Dynal Biotech Inc., Lake Success, NY, U.S.A.) and primers described previously (15). Each HLA-DRB1 allele was determined by the single strand conformation polymorphism (SSCP) method. HLA-DQB1 alleles were analyzed by applying PCR-RFLP and PCR-SSCP methods as described previously (16). The subjects were classified according to the known susceptible DRB1 alleles (17).
For the analysis of the A/G polymorphism at position 49 in the CTLA4 exon 1, the PCR-RFLP method was used as described previously (7). The primers used were 5'-GCTCTACTTCCTGAAGACCT-3'(forward) and 5'-AGTCTCACTCACCTTTGCAG-3'(reverse). Amplified samples were digested with the specific restriction enzyme BbvI (New England BioLabs, Beverly, MA, U.S.A.) at 37℃ for 2 hr, electrophoresed on a 3% agarose gel for 30 min, stained with ethidium bromide, and evaluated. A 162 bp band was determined to be the A allele and the 88 bp and 74 bp bands were determined to be the G allele.
The C/T polymorphism at position -318 in the CTLA4 promoter was analyzed by PCR-RFLP methods using known primers 5'-AAATGAATTGGACTGGATGGT-3'(forward) and 5'-TTACGAGAAAGGAAGCCGTG-3'(reverse) as described previously (18). The amplified DNA products were treated with the MseI restriction enzyme (New England BioLabs) at 37℃ for 2 hr. The formation of 132/115 bp fragments was determined to be the T allele and the detection of the complete 247 bp fragment was identified as the C allele.
The measured values are presented as mean±standard deviation. The comparisons of the HLA genotypes of the patients and the controls were performed using the two-tailed Fisher's exact test. The corrected P value (Pc) was obtained by multiplying the number of all genotypes included. The odds ratio (OR) was calculated by the Woolf method, and the 95% confidence interval (CI) was applied. For the cases with 0 variables, a Haldane's modification method was used. A P<0.05 was considered statistically significant.

RESULTS

The genotype and allele frequencies of the CTLA4 exon 1 polymorphism in T1D patients were not different from those in the control subjects (Table 1). The distribution of the CTLA4 exon 1 polymorphsims in patients with T1D and autoimmune thyroid disease (n=31) was not different from that in the control subjects. There was no relationship of the CTLA4 exon 1 polymorphism with the clinical characteristics of the patients, such as presence of ketoacidosis, age of disease onset, gender, pubertal status at initial presentation, and concomitant autoimmune thyroid disease.



Table 1
Distribution of the polymorphism at position 49 in exon 1 of the CTLA4 gene in patients with type 1 diabetes and controls
We analyzed the distribution of the CTLA4 exon 1 polymorphism according to the presence or absence of susceptible HLA-DRB1 alleles (DRB1*0301, *0405 and *09012). In the patients without the HLA-DRB1*0301 allele, the frequency of the A allele was significantly higher than in the control subjects (43.6% vs. 31.7%; P<0.05).
We analyzed the distribution of the CTLA4 exon 1 polymorphism in a subgroup of patients that did not have two out of the three susceptible DRB1 alleles. According to the analysis of the genotype frequency, the frequency of the A/A genotype in the patients without the DRB1*0301 and *09012 alleles was significantly higher compared to the control subjects (36.0% vs. 14.4%; P<0.05) (Table 2). According to the analysis of the allele frequency, the frequency of the A allele in the patients without the DRB1*0301 and *0405 alleles was significantly higher than in the control subjects (45.5% vs. 31.7%; P<0.05). In addition, the frequency of the A allele was significantly higher in the patients without the DRB1*0301 and *09012 alleles (52.0% vs. 31.7%; P<0.01), and the patients without the DRB1*0405 and *09012 alleles (54.2% vs. 31.7%; P<0.05), compared to the control subjects.



Table 2
Distribution of the polymorphism at position 49 in exon 1 of the CTLA4 gene in type 1 diabetic patients according to susceptible HLA-DRB1 alleles
The genotype and allele frequencies of the CTLA4 promoter polymorphism were not different in the comparison between the T1D patients and the control subjects (Table 3). The distribution of the CTLA4 promoter polymorphism in patients with both T1D and autoimmune thyroid disease was not different from that in the control subjects. When the patients were divided into subgroups based on the presence of the susceptible HLA-DRB1 alleles, the distribution of the CTLA4 promoter polymorphism was not different in the patients and the control subjects.



Table 3
Distribution of the C/T polymorphism at position -318 in the promoter of the CTLA4 gene in patients with type 1 diabetes and controls

DISCUSSION
It has been reported that the intracellular transduction signals formed by the complex of T cell receptor molecules and CTLA-4 molecules suppress the activation of T cells (19). The CTLA-4 molecule encodes the T cell receptor that plays a role in the control of the proliferation of T cells, as well as mediating apoptosis of T cells. Therefore, it has been considered to be a strong candidate molecule involved in the development of T cell-mediated autoimmune disease. However, the functional relationship of the CTLA-4 protein with human disease has not been elucidated to date.
The distribution of the CTLA4 exon 1 polymorphism among Asians and Caucasians shows a clear difference. The frequency of the G allele of CTLA4 exon 1 has been reported to be 68% among Koreans (20), 57.5% (21) and 63% (22) among Japanese, and 34.2% (10) and 36% (7) among Caucasians. On the other hand, the frequency of the T allele in the CTLA4 promoter region has been reported to be 7-14% among Asians and Caucasians (23), without a marked ethnic difference noted to date.
Our results showed that the distribution of the CTLA4 exon 1 polymorphism and the the CTLA4 promoter polymorphism in patients with T1D were not different from those in control subjects. Recent studies on the association of the CTLA4 polymorphisms and susceptibility to T1D in various ethnic populations showed inconsistent results. According to the studies that included Japanese populations, the distribution of the CTLA4 exon 1 polymorphisms in patients with T1D was not different from that in normal individuals (21, 22). By contrast, Steck et al. (24) observed that the frequency of the C/C genotype at position -318 in the CTLA4 promoter was significantly lower in patients with T1D compared to controls, and they concluded that this polymorphism was associated with T1D.
Meanwhile, a clear association was detected between the CTLA4 genotype and the degree of expression of the CTLA-4 protein (25). According to this study, in individuals with thymidine (-318T) in CTLA4 promoter region, after the stimulation of cells, the expression of CTLA-4 on the cell surface and the expression of CTLA4 mRNA in unstimulated cells were significantly increased. In a recent study, Ueda et al. (26) reported that a reduction in the level of a soluble isoform of CTLA-4 (sCTLA-4) mRNA, associated with the disease-susceptible haplotype of CTLA4, could lead to reduced blocking of CD80/CD86, causing increased activation through CD28, or to less stimulation of CD80/CD86. In order to verify the association of the CTLA4 polymorphisms with the pathogenesis of T1D, distinctive difference in the distribution of CTLA4 genotypes between patients and controls should be identified. However, this has not been consistently demonstrated to date.
The results of recent studies suggest that CTLA4 polymorphisms are associated with the clinical characteristics of patients with T1D. Abe et al. (22) reported a patient group with initial diabetic ketoacidosis and positive for the ICA512 antibody had a different distribution of the CTLA4 polymorphisms compared to control subjects. Other studies showed that the frequency of the G allele of CTLA4 exon 1 was higher in patients with a high titer of GAD antibodies and high residual function of β-cells compared to the control subjects (21, 27). Such results may indicate that CTLA4 polymorphisms are involved in the more potent immune response and specific clinical characteristics of patients with T1D. In addition, Takara et al. (28) reported that the frequency of the G allele of CTLA4 exon 1 was significantly higher in patients with both T1D and autoimmune thyroid disease concomitantly, compared to the controls. However, the results of our study showed no association of CTLA4 polymorphisms and the clinical characteristics of patients with T1D. Therefore, further study is needed to clarify the association of CTLA4 polymorphisms with specific clinical characteristics of patients with T1D.
We analyzed the relationship between the CTLA4 exon 1 polymorphism and HLA-DRB1 alleles to determine whether their interactions had a role in the pathogenesis of T1D. In the diabetic patients that did not have two out of the three susceptible DRB1 alleles, that is DRB1*0301, *0405 and *09012, the frequency of the A allele of CTLA4 exon 1 was significantly higher than that in the control subjects. This finding suggests that the CTLA4 polymorphism was associated with the development of T1D only in the patients that had no specific susceptible HLA-DRB1 alleles.
There have been several reports regarding the association of CTLA4 polymorphisms with HLA-DRB1 allele in the pathogenesis of T1D. Djilali-Saiah et al. (29) reported that in diabetic patients with the DR4 haplotype, the frequency of the G allele of CTLA4 exon 1 was significantly higher. Mochizuki et al. (21) reported that in children with T1D that did not have susceptible DRB1*0405 allele, there was a higher frequency of G allele of CTLA4 exon 1 compared to normal children. On the other hand, Donner et al. (30) conducted a combined transmission analysis of the CTLA4 polymorphisms and HLA DQA1-DQB1 and reported that in patients with T1D that had susceptible haplotypes, such as HLA DQA1*0301-DQB1*0302 or DQA1*0501-DQB1*0201, the protective 84-bp allele of the (AT)n repeat of CTLA4 polymorphism was not protective against the development of T1D. Therefore, when patients do not have susceptible HLA class II alleles, the CTLA4 polymorphism appears to play some role in the pathogenesis of T1D.
Mochizuki et al. (21) explained that the sensitivity of T-cell activation to the CTLA4 mediated pathway after the initiation of the T-cell receptor and DR molecule-antigen complex may be decreased in the absence of susceptible HLA-DRB1 alleles. However, because the distribution of both CTLA4 and the HLA class II alleles vary in different ethnic populations; further study of the association of these two genes is needed.
In conclusion, the results of this study suggest that HLA-DRB1 and DQB1 alleles play a primary role in pathogenesis of T1D and that the CTLA4 exon 1 polymorphism is a genetic factor that mediates the disease associated susceptibility in patients that do not have specific susceptible HLA class II alleles. This concept requires further study and confirmation among different ethnic groups.

Muhammad Arshad > arshad2356@live.com > PAK 707-1

Wednesday, March 9, 2011

Diabetes Mellitus

(Muhammad Arshad Malik > arshad2356@live.com)

Diabetes mellitus is a disorder in which blood sugar (glucose) levels are abnormally high because the body does not produce enough insulin to meet its needs.
· Urination and thirst are increased, and people lose weight when they are not trying to.
· Diabetes damages the nerves and causes problems with sensation.
· Diabetes damages blood vessels and increases the risk of heart attack, stroke, and kidney failure.
· Doctors diagnose diabetes by measuring blood sugar levels.
· People with diabetes need to follow a low-sugar, low-fat diet, exercise, and usually take drugs.
Insulin, a hormone released from the pancreas, controls the amount of sugar in the blood. When people eat or drink, food is broken down into materials, including the simple sugar glucose, that the body needs to function. Sugar is absorbed into the bloodstream and stimulates the pancreas to produce insulin. Insulin allows sugar to move from the blood into the cells. Once inside the cells, it is converted to energy, which is either used immediately or stored as fat or glycogen until it is needed.
The levels of sugar in the blood vary normally throughout the day. They rise after a meal and return to normal within about 2 hours after eating. Once the levels of sugar in the blood return to normal, insulin production decreases. The variation in blood sugar levels is usually within a narrow range, about 70 to 110 milligrams per deciliter (mg/dL) of blood. If people eat a large amount of carbohydrates, the levels may increase more. People older than 65 years tend to have slightly higher levels, especially after eating.
If the body does not produce enough insulin to move the sugar into the cells, the resulting high levels of sugar in the blood and the inadequate amount of sugar in the cells together produce the symptoms and complications of diabetes.
Doctors often use the full name diabetes mellitus, rather than diabetes alone, to distinguish this disorder from diabetes insipidus, a relatively rare disorder that does not affect blood sugar
TypesPrediabetes: Prediabetes is a condition in which blood sugar levels are too high to be considered normal but not high enough to be labeled diabetes. People have prediabetes if their fasting blood sugar level is between 101 mg/dL and 126 mg/dL or if their blood sugar level 2 hours after glucose tolerance test is between 140 mg/dL and 200 mg/dL. Identifying people with prediabetes is important because the condition carries a higher risk for future diabetes as well as heart disease. Decreasing body weight by 5 to 10 % through diet and exercise can significantly reduce the risk of developing future diabetes.
Type 1: In type 1 diabetes (formerly called insulin-dependent diabetes or juvenile-onset diabetes), more than 90% of the insulin-producing cells of the pancreas are permanently destroyed. The pancreas, therefore, produces little or no insulin. Only about 10% of all people with diabetes have type 1 disease. Most people who have type 1 diabetes develop the disease before age 30.
Scientists believe that an environmental factor—possibly a viral infection or a nutritional factor in childhood or early adulthood—causes the immune system to destroy the insulin-producing cells of the pancreas. A genetic predisposition may make some people more susceptible to the environmental factor.
Type 2: In type 2 diabetes (formerly called non-insulin-dependent diabetes or adult-onset diabetes), the pancreas continues to produce insulin, sometimes even at higher-than-normal levels. However, the body develops resistance to the effects of insulin, so there is not enough insulin to meet the body's needs.
Type 2 diabetes was once rare in children and adolescents but has recently become more common. However, it usually begins in people older than 30 and becomes progressively more common with age. About 15% of people older than 70 have type 2 diabetes. People of certain racial and ethnic backgrounds are at increased risk of developing type 2 diabetes: blacks, Native Americans, and Hispanics who live in the United States have a twofold to threefold increased risk. Type 2 diabetes also tends to run in families.
Obesity is the chief risk factor for developing type 2 diabetes, and 80 to 90% of people with this disorder are overweight or obese. Because obesity causes insulin resistance, obese people need very large amounts of insulin to maintain normal blood sugar levels.
Certain disorders and drugs can affect the way the body uses insulin and can lead to type 2 diabetes. High levels of corticosteroids (from Cushing's disease or from taking corticosteroid drugs) and pregnancy (gestational diabetes are the most common causes of altered insulin use. Diabetes also may occur in people with excess production of growth hormone (acromegaly) and in people with certain hormone-secreting tumors. Severe or recurring pancreatitis and other disorders that directly damage the pancreas can lead to diabetes.
Symptoms
The two types of diabetes have very similar symptoms. The first symptoms are related to the direct effects of high blood sugar levels. When the blood sugar level rises above 160 to 180 mg/dL, sugar spills into the urine. When the level of sugar in the urine rises even higher, the kidneys excrete additional water to dilute the large amount of sugar. Because the kidneys produce excessive urine, people with diabetes urinate large volumes frequently (polyuria). The excessive urination creates abnormal thirst (polydipsia). Because excessive calories are lost in the urine, people lose weight. To compensate, people often feel excessively hungry. Other symptoms include blurred vision, drowsiness, nausea, and decreased endurance during exercise.
Type 1: In people with type 1 diabetes, the symptoms often begin abruptly and dramatically. A condition called diabetic ketoacidosis may quickly develop. Without insulin, most cells cannot use the sugar that is in the blood. Cells still need energy to survive, and they switch to a back-up mechanism to obtain energy. Fat cells begin to break down, producing compounds called ketones. Ketones provide some energy to cells but also make the blood too acidic (ketoacidosis). The initial symptoms of diabetic ketoacidosis include excessive thirst and urination, weight loss, nausea, vomiting, fatigue, and—particularly in children—abdominal pain. Breathing tends to become deep and rapid as the body attempts to correct the blood's acidity. The breath smells like nail polish remover, the smell of the ketones escaping into the breath. Without treatment, diabetic ketoacidosis can progress to coma and death, sometimes within a few hours.
Type 2: People with type 2 diabetes may not have any symptoms for years or decades before they are diagnosed. Symptoms may be subtle. Increased urination and thirst are mild at first and gradually worsen over weeks or months. Eventually, people feel extremely fatigued, are likely to develop blurred vision, and may become dehydrated.
Sometimes during the early stages of diabetes, the blood sugar level is abnormally low, a condition called hypoglycemia.
Because people with type 2 diabetes produce some insulin, ketoacidosis does not usually develop. However, the blood sugar levels can become extremely high (often exceeding 1,000 mg/dL). Such high levels often happen as the result of some superimposed stress, such as an infection or drug use. When the blood sugar levels get very high, people may develop severe dehydration, which may lead to mental confusion, drowsiness, and seizures, a condition called nonketotic hyperglycemic-hyperosmolar coma.
Complications
People with diabetes may experience many serious, long-term complications. Some of these complications begin within months of the onset of diabetes, although most tend to develop after a few years. Most of the complications are progressive. The more strictly people with diabetes are able to control the levels of sugar in the blood; the less likely it is that these complications will develop or become worse.
Most complications are the result of problems with blood vessels. High sugar levels over a long time cause narrowing of both the small and large blood vessels. The narrowing reduces blood flow to many parts of the body, leading to problems. There are several causes of blood vessel narrowing. Complex sugar-based substances build up in the walls of small blood vessels, causing them to thicken and leak. Poor control of blood sugar levels also tends to cause the levels of fatty substances in the blood to rise, resulting in atherosclerosis and decreased blood flow in the larger blood vessels. Atherosclerosis is between 2 and 6 times more common in people with diabetes than in people who do not have diabetes and tends to occur at younger ages.
Over time, elevated levels of sugar in the blood and poor circulation can harm the heart, brain, legs, eyes, kidneys, nerves, and skin, resulting in angina, heart failure, strokes, leg cramps on walking (claudication), poor vision, kidney failure, damage to nerves (neuropathy), and skin breakdown. Heart attacks and strokes are more common among people with diabetes.
Poor circulation to the skin can lead to ulcers and infections and causes wounds to heal slowly. People with diabetes are particularly likely to have ulcers and infections of the feet and legs. Too often, these wounds heal slowly or not at all, and amputation of the foot or part of the leg may be needed.
People with diabetes often develop bacterial and fungal infections, typically of the skin. When the levels of sugar in the blood are high, white blood cells cannot effectively fight infections. Any infection that develops tends to be more severe.
Damage to the blood vessels of the eye can cause loss of vision (diabetic retinopathy. Laser surgery can seal the leaking blood vessels of the eye and prevent permanent damage to the retina. Therefore, people with diabetes should have yearly eye examinations to check for damage.
The kidneys can malfunction, resulting in kidney failure that may require dialysis or kidney transplantation. Doctors usually check the urine of people with diabetes for abnormally high levels of protein (albumin), which is an early sign of kidney damage. At the earliest sign of kidney complications, people are often given angiotensin-converting enzyme (ACE) inhibitors, drugs that slow the progression of kidney damage.
Damage to nerves can manifest in several ways. If a single nerve malfunctions, an arm or leg may suddenly become weak. If the nerves to the hands, legs, and feet become damaged (diabetic polyneuropathy), sensation may become abnormal, and tingling or burning pain and weakness in the arms and legs may develop.Damage to the nerves of the skin makes repeated injuries more likely because people cannot sense changes in pressure or temperature.
The Foot in DiabetesDiabetes causes many changes in the body. The following changes in the feet are common and difficult to treat.
· Damage to the nerves (neuropathy) affects sensation to the feet, so that pain is not felt. Irritation and other forms of injury may go unnoticed. An injury may wear through the skin before any pain is felt.
· Changes in sensation alter the way people with diabetes carry weight on their feet, concentrating weight in certain areas so that calluses form. Calluses (and dry skin) increase the risk of skin breakdown.
· Diabetes can cause poor circulation in the feet, making ulcers more likely to form when the skin is damaged and making the ulcers slower to heal.
Because diabetes can affect the body's ability to fight infections, a foot ulcer, once it forms, easily becomes infected. Because of neuropathy, people may not feel discomfort from the infection until it becomes serious and difficult to treat, leading to gangrene. People with diabetes are more than 30 times more likely to require amputation of a foot or leg than are people without diabetes.
Foot care is critical.The feet should be protected from injury, and the skin should be kept moist with a good moisturizer. Shoes should fit properly and not cause areas of irritation. Shoes should have appropriate cushioning to spread out the pressure caused by standing. Going barefoot is ill advised. Regular care from a podiatrist, such as having toenails cut and calluses removed, may also be helpful. Also, sensation and blood flow to the feet should be regularly evaluated by doctors.
Spotlight on Aging
Older people need to follow the same general principles of diabetes management—education, diet, exercise, and drugs—as younger people. However, risking hypoglycemia by strictly controlling blood sugar levels may not be beneficial for people with a short life expectancy, such as those with advanced cancer. Also, managing diabetes can be more difficult for older people. Poor eyesight may make it hard for them to read glucose meters and dose scales on insulin syringes. They may have problems manipulating the syringe because they have arthritis or Parkinson's disease or have had a stroke. When older people have hypoglycemia, their symptoms may be less obvious. If they have hypoglycemia but have difficulty communicating, dementia or both, they may not be able to let anyone know they are having symptoms.
Education:In addition to learning about diabetes itself, older people may have to learn how to fit management of diabetes in with their management of other disorders. Learning about how to avoid complications, such as dehydration, skin breakdown, and circulation problems, and to manage factors that can contribute to diabetes, such as high blood pressure and high cholesterol levels, is especially important. Such problems become more common as people age, whether they have diabetes or not.
Diet:
Many older people have difficulty following a healthy, balanced diet that can control blood sugar levels and weight. Changing long-held food preferences and dietary habits may be hard. Some older people have other disorders that can be affected by diet and may not understand how to integrate the dietary recommendations for their various disorders.
Some older people cannot control what they eat because someone else is cooking for them―at home or in a nursing home or other institution. When people with diabetes do not do their own cooking, the people who shop and prepare meals for them must also understand the diet that is needed. Older people and their caregivers usually benefit from meeting with a dietitian to develop a healthy, feasible eating plan.
Exercise:
Older people may have a difficult time adding exercise to their daily life, particularly if they have not been active or if they have a disorder that limits their movement, such as arthritis. However, they may be able to add exercise to their usual routine. For example, they can walk instead of drive or climb the stairs instead of take the elevator. Also, many community organizations offer exercise programs designed for older people.
Drugs:
Taking the drugs used to treat diabetes, particularly insulin, may be difficult for some older people. For those with vision problems or other problems that make accurately filling a syringe difficult, a caregiver can prepare the syringes ahead of time and store them in the refrigerator. People whose insulin dose is stable may purchase pre-filled syringes. Prefilled insulin pen devices may be easier for people with physical limitations to use. Some of these devices have large numbers and easy-to-turn dials.
Monitoring blood sugar levels:
Poor vision, limited manual dexterity due to arthritis, tremor, or stroke, or other physical limitations may make monitoring blood sugar levels more difficult for older people. However, special monitors are available. Some have large numerical displays that are easier to read. Some provide audible instructions and results. Some monitors read blood sugar levels through the skin and do not require a blood sample. People can consult a diabetes educator to determine which meter is most appropriate.
Complications of treatment:
The most common complication of treating high blood sugar levels is low blood sugar levels. The risk is greatest for older people who are frail, who are sick enough to require frequent hospital admissions, or who are taking several drugs. Of all available drugs to treat diabetes, long-acting sulfonylurea drugs are most likely to cause low blood sugar levels in older people. When they take these drugs, they are also more likely to have serious symptoms, such as fainting and falling, and to have diffculty thinking or using parts of the body due to low blood sugar levels.
Although urine can also be tested for the presence of sugar, checking urine is not a good way to monitor treatment or adjust therapy. Urine testing can be misleading because the amount of sugar in the urine may not reflect the current level of sugar in the blood. Blood sugar levels can get very low or reasonably high without any change in the sugar levels in the urine.
Doctors can monitor treatment using a blood test called hemoglobin A1C. When the blood sugar levels are high, changes occur in hemoglobin, the protein that carries oxygen in the blood. These changes are in direct proportion to the blood sugar levels over an extended period. Thus, unlike the blood sugar measurement, which reveals the level at a particular moment, the hemoglobin A1C measurement demonstrates whether the blood sugar levels have been controlled over the previous few months. People with diabetes aim for a hemoglobin A1C level of less than 7%. Achieving this level is difficult, but the lower the hemoglobin A1C level, the less likely people are to have complications. Levels above 9% show poor control, and levels above 12% show very poor control. Most doctors who specialize in diabetes care recommend that hemoglobin A1C be measured every 3 to 6 months. Fructosamine, an amino acid that has bonded with glucose, is also useful for measuring blood sugar control over a period of a few weeks.
Diagnosis
The diagnosis of diabetes is made when people have abnormally high levels of sugar in the blood. Blood sugar levels are often checked during a routine physical examination. Checking the levels of sugar in the blood annually is particularly important in older people, because diabetes is so common in later life. People may have diabetes, particularly type 2 diabetes, and not know it. Doctors may also check blood sugar levels in people who have symptoms of diabetes such as increased thirst, urination, or hunger. Doctors may also check blood sugar levels in people who have disorders that can be complications of diabetes, such as frequent infections, foot ulcers, and yeast infections.
To measure the blood sugar levels, a blood sample is usually taken after people have fasted overnight. However, it is possible to take blood samples after people have eaten. Some elevation of blood sugar levels after eating is normal, but even after a meal the levels should not be very high. Fasting blood sugar levels should never be higher than 126 mg/dL. Even after eating, blood sugar levels should not be higher than 200 mg/dL.
Doctors can also measure the level of a protein in the blood, hemoglobin A1C (also called glycosylated or glycolated or hemoglobin). Glycosylated hemoglobin forms when the blood has been exposed to high blood sugar levels over a period of time. Doctors do not usually use this test to diagnose diabetes, but the test can help confirm the diagnosis when blood sugar levels are not extremely high. The test demonstrates long-term trends in blood sugar levels.
Another kind of blood test, an oral glucose tolerance test, may be done in certain situations, such as in routine screening of pregnant women for gestational diabetes or in older people who have symptoms of diabetes but normal glucose levels when fasting. However, it is not routinely used for testing for diabetes, including in pregnant women at very low risk. In this test, people fast, have a blood sample taken to determine the fasting blood sugar level, and then drink a special solution containing a large, standard amount of glucose. More blood samples are then taken over the next 2 to 3 hours and are tested to determine whether the level of sugar in the blood rises abnormally high.
Treatment
Treatment of diabetes involves diet, exercise, education, and, for most people, drugs. If people with diabetes strictly control blood sugar levels, complications are less likely to develop. The goal of diabetes treatment, therefore, is to keep blood sugar levels within the normal range as much as possible. Treatment of high blood pressure and cholesterol levels can prevent some of the complications of diabetes as well. A low dose of aspirin taken daily is also helpful.
People with diabetes benefit greatly from learning about the disorder, understanding how diet and exercise affect their blood sugar levels, and knowing how to avoid complications. A nurse trained in diabetes education can provide information about managing diet, exercising, monitoring blood sugar levels, and taking drugs.
People with diabetes should always carry or wear medical identification (such as a bracelet or tag) to alert health care practitioners to the presence of diabetes. This information allows health care practitioners to start life-saving treatment quickly, especially in the case of injury or altered mental status.
Diet management is very important in people with both types of diabetes. Doctors recommend a healthy, balanced diet and efforts to maintain a healthy weight. Some people benefit from meeting with a dietitian to develop an optimal eating plan.
People with type 1 diabetes who are able to maintain a healthy weight may be able to avoid the need for large doses of insulin. People with type 2 diabetes may be able to avoid the need for all drugs by achieving and maintaining a healthy weight. Some people who have been unsuccessful in losing weight through diet and exercise may take drugs to help them lose weight or may even undergo stomach reduction surgery.
In general, people with diabetes should not eat much sweet food. They should also try to eat meals on a regular schedule. Long periods between eating should be avoided. People with diabetes also tend to have high levels of cholesterol in the blood, so limiting the amount of saturated fat in the diet is important. Drugs may also be needed to help control the level of cholesterol in the blood.
Appropriate amounts of exercise can also help people control their weight and maintain blood sugar levels within the normal range. Because blood sugar levels go down during exercise, people must be alert for symptoms of low blood sugar. Some people need to eat a small amount of food with sugar during prolonged exercise, decrease their insulin dose, or both. People with diabetes should stop smoking and consume only moderate amounts of alcohol (up to one drink per day for women and two for men).
Diabetic ketoacidosis is a medical emergency, because it can cause coma and death. Hospitalization, usually in an intensive care unit, is necessary. Large amounts of fluids are given intravenously along with electrolytes, such as sodium, potassium, chloride, and phosphate, to replace those fluids and electrolytes lost through excessive urination. Insulin is generally given intravenously so that it works quickly and the dose can be adjusted frequently. Blood levels of sugar, ketones, and electrolytes are measured every few hours. Doctors also measure the blood's acid level. Sometimes, additional treatments are needed to correct a high acid level. However, controlling the levels of sugar in the blood and replacing electrolytes usually allow the body to restore the normal acid-base balance.
Nonketotic hyperglycemic-hyperosmolar coma is treated much like diabetic ketoacidosis. Fluids and electrolytes must be replaced. The levels of sugar in the blood must be restored to normal levels gradually to avoid sudden shifts of fluid into the brain. The blood sugar levels tend to be more easily controlled than in diabetic ketoacidosis, and blood acidity problems are not severe.
Insulin Replacement Therapy
Insulin is injected under the skin into the fat layer, usually in the arm, thigh, or abdominal wall. Small syringes with very thin needles make the injections nearly painless. An air pump device that blows the insulin under the skin can be used for people who cannot tolerate needles. An insulin pen, which contains a cartridge that holds the insulin, is a convenient way for many people to carry insulin, especially for people who take several injections a day outside the home. Another device is insulin
Pump, which pumps insulin continuously from a reservoir through a small needle left in the skin. Additional doses of insulin can be released at programmed times, or release can be triggered as needed. The pump more closely mimics the way the body normally produces insulin. For some people, the pump offers an added degree of control, whereas others find wearing the pump annoying or develop sores at the needle site.
Insulin is available in three basic forms, divided by speed of onset and duration of action:
· Rapid-acting insulin, such as regular insulin, is fast and short acting. Regular insulin reaches its maximum activity in 2 to 4 hours and works for 6 to 8 hours. Lispro, aspart, and glulisine insulins, special types of regular insulin, are the fastest of all, reaching maximum activity in about 1 hour and working for 3 to 5 hours. Rapid-acting insulin is often used by people who take several daily injections and is injected 15 to 20 minutes before meals or just after eating.
· Intermediate-acting insulin (such as insulin zinc suspension, lente, or isophane insulin suspension) starts to work in 1 to 3 hours, reaches its maximum activity in 6 to 10 hours, and works for 18 to 26 hours. This type of insulin may be used in the morning to provide coverage for the first part of the day or in the evening to provide coverage during the night.
· Long-acting insulin (such as extended insulin zinc suspension, ultra- lente, or glargine) has very little effect in the first few hours but provides coverage for 20 to 36 hours depending on which of these types is used.
Insulin preparations are stable at room temperature for months, allowing them to be carried, brought to work, or taken on a trip. Insulin should not, however, be exposed to extreme temperatures.
The choice of insulin is complex. The following factors are considered before deciding which insulin is best:
· How willing and able people are to monitor their blood sugar levels and adjust the insulin dosage
· How varied daily activity is
· How adept people are at learning about and understanding the disorder
· How stable blood sugar levels are during the day and from day to day
The easiest regimen to follow is a single daily injection of intermediate-acting insulin. However, such a regimen provides the least control over blood sugar levels and is, therefore, rarely the best approach. Stricter control may be achieved by combining two insulins—a rapid-acting and an intermediate-acting insulin —in one morning dose. This combination requires more skill, but it offers people greater opportunity to adjust the blood sugar levels. A second injection of one insulin or both may be taken at dinner or at bedtime. Strictest control is usually achieved by injecting rapid-acting and intermediate-acting insulin in the morning and evening along with several additional injections of rapid-acting insulin during the day. Adjustments can be made as insulin needs change. Measuring blood sugar levels at various times during the day helps determine the adjustment. Although this regimen requires the most knowledge of the disorder and attention to the details of treatment, it is considered the best option for most people who are treated with insulin, especially people with type 1 diabetes.
Some people, especially older people, take the same amount of insulin every day. Other people adjust the insulin dose daily depending on their diet, exercise, and blood sugar patterns. In addition, insulin
Needs may change if people gain or lose weight or experience emotional stress or illness, especially infection.
Over time, some people develop resistance to insulin. Because the injected insulin is not exactly like the insulin the body manufactures, the body can produce antibodies to the insulin. Although this is less common with newer insulin preparations, these antibodies may interfere with the insulin’s activity, requiring very large doses.
Insulin injections can affect the skin and underlying tissues. An allergic reaction, which occurs rarely, produces pain and burning, followed by redness, itchiness, and swelling around the injection site for several hours. More commonly, the injections either cause fat deposits, making the skin look lumpy, or destroy fat, causing indentation of the skin. Many people rotate the injection sites, for example, using the thigh one day, the stomach another, and an arm the next, to avoid these problems.
Monitoring Treatment
Monitoring blood sugar levels is an essential part of diabetes care. People with diabetes must adjust their diet, exercise, and take drugs to control blood sugar levels. Monitoring blood sugar levels provides the information needed to make those adjustments. Waiting until symptoms of low or high blood sugar levels develop is a recipe for disaster.
Many things cause blood sugar levels to change:
· Diet
· Exercise
· Stress
· Illness
· Drug
· Time of day
The blood sugar levels may jump after people eat foods they did not realize were high in carbohydrates. Exercise may cause the levels of sugar in the blood to fall low, requiring that additional sugar be eaten. Emotional stress, an infection, and many drugs tend to increase blood sugar levels. Blood sugar levels increase in many people in the early morning hours because of the normal release of hormones (growth hormone and corticosteroids), a reaction called the dawn phenomenon. And blood sugar may shoot too high if the body releases sugar in response to low blood sugar levels (Somogyi effect).and move to domestics,black papper is found to be helpful in cure of disease.
Blood sugar levels can be measured easily at home or anywhere. Most blood sugar monitoring devices use a drop of blood obtained by pricking the tip of the finger with a small lancet. The lancet holds a tiny needle that can be jabbed into the finger or placed in a spring-loaded device that easily and quickly pierces the skin. Most people find the pricking nearly painless. Then, a drop of blood is placed on a reagent strip. In response to sugar, the reagent strip undergoes some chemical changes. A machine reads the changes in the test strip and reports the result on a digital display. Most of these machines time the reaction and read the result automatically. Some devices allow the blood sample to be obtained from other sites, such as the palm, forearm, upper arm, thigh, or calf. The machines are smaller than a deck of cards.
A newer device reads blood sugar through the skin without needing a sample of blood. The device is worn like a wristwatch and can measure the level of sugar in the blood every 15 minutes. Alarms on the device can be set to sound when blood sugar levels drop too low or climb too high. Disadvantages of this device are that it must be calibrated periodically with a blood test, it may irritate the skin, and it is somewhat large. Other devices can monitor glucose continuously. However, these devices are not routinely used, as they are expensive and have not been shown to be better than glucose meters. In certain circumstances, these devices are less reliable, such as in severe hypoglycemia.
Most people with diabetes should keep a record of their blood sugar levels and report them to their doctors or nurses for advice in adjusting the dose of insulin or the oral antihyperglycemic drug. Many people can learn to adjust the insulin dose on their own as necessary.
Complications of treatment:
The most common complication of treating high blood sugar levels is low blood sugar levels. The risk is greatest for older people who are frail, who are sick enough to require frequent hospital admissions, or who are taking several drugs. Of all available drugs to treat diabetes, long-acting sulfonylurea drugs are most likely to cause low blood sugar levels in older people. When they take these drugs, they are also more likely to have serious symptoms, such as fainting and falling, and to have difficulty thinking or using parts of the body due to low blood sugar levels.
Although urine can also be tested for the presence of sugar, checking urine is not a good way to monitor treatment or adjust therapy. Urine testing can be misleading because the amount of sugar in the urine may not reflect the current level of sugar in the blood. Blood sugar levels can get very low or reasonably high without any change in the sugar levels in the urine.
Doctors can monitor treatment using a blood test called hemoglobin A1C. When the blood sugar levels are high, changes occur in hemoglobin, the protein that carries oxygen in the blood. These changes are in direct proportion to the blood sugar levels over an extended period. Thus, unlike the blood sugar measurement, which reveals the level at a particular moment, the hemoglobin A1C measurement demonstrates whether the blood sugar levels have been controlled over the previous few months. People with diabetes aim for a hemoglobin A1C level of less than 7%. Achieving this level is difficult, but the lower the hemoglobin A1C level, the less likely people are to have complications. Levels above 9% show poor control, and levels above 12% show very poor control. Most doctors who specialize in diabetes care recommend that hemoglobin A1C be measured every 3 to 6 months. Fructosamine, an amino acid that has bonded with glucose, is also useful for measuring blood sugar control over a period of a few weeks.
Hypoglycemia:
Keeping blood sugar levels from getting too high is difficult. The main difficulty with trying to strictly control the levels of sugar in the blood is that low blood sugar levels (hypoglycemia) may occur. Recognizing the presence of low blood sugar is important because treatment of hypoglycemia is an emergency. Symptoms may include hunger pangs, racing heart beat, shakiness, sweating, and inability to think clearly. Sugar must get into the body within minutes to prevent permanent harm and relieve symptoms. Most of the time, people can eat sugar. Almost any form of sugar will do, although glucose works more quickly than table sugar (typical table sugar is sucrose). Many people with diabetes carry glucose tablets or foil packets of a glucose-containing liquid. Other options are to drink a glass of milk (which contains lactose, a type of sugar), sugar water, or fruit juice or to eat a piece of cake, some fruit, or another sweet food. In more serious situations, it may be necessary for emergency medical practitioners to inject glucose into a vein.
Another treatment for hypoglycemia involves the use of glucagon. Glucagon can be injected into the muscle and causes the liver to release large amounts of glucose within minutes. Small transportable kits containing a syringe filled with glucagon are available for people with diabetes to use in emergency situations.
Experimental Treatments
Experimental treatments are also showing promise for the treatment of type 1 diabetes. In one such treatment, insulin-producing cells are transplanted into body organs. This procedure is not yet routinely done, however, because immunosuppressant drugs must be given to prevent the body from rejecting the transplanted cells. Newer techniques may make suppression of the immune system unnecessary.