User:Johnsad/Insulin-resistance type B

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Insulin-resistance type B (TBIR) is a rare autoimmune disorder that is characterized by the action of anti-insulin receptor autoantibodies (AIRA) against insulin receptors, leading to severe insulin resistance.[1][2] It is responsible for one of the most severe forms of diabetes mellitus.[1][2] Common symptoms include transient hyperglycemia, acanthosis nigricans and weight loss, with other autoimmune disorders such as systemic lupus erythematosus (SLE) as underlying conditions.[1][2] Hyperglycemia is caused by the competition between endogenous insulin and anti-insulin receptor autoantibodies, thus reducing the effect of insulin. Episodes of hypoglycemia may also result from lowered dependence on insulin therapy, which is associated with around 50% of the fatalities.[1]

There are three concurrent treatments to this condition. The first treatment is to administer copious amounts of insulin treat hyperglycemia; the second uses a combinatory immunosuppressive therapy of rituximab, cyclophosphamide and pulse glucocorticoids to inhibit the production of anti-insulin receptor autoantibodies by lymphocytes; and the third is to make dietary adjustments, which are crucial in tackling hypoglycemia.[1][3]

Insulin-resistance type B predominantly affects middle-aged females in a relatively large NIH cohort; otherwise, the exact prevalence of the disease is currently unknown due to its rarity.[1][4] The term "insulin-resistance type B" is first coined by researchers in the 1970s when an immunological condition is found to be responsible for extreme cases of insulin resistance.[1][5]

Signs and symptoms[edit]

The signs and symptoms of insulin-resistance type B can be classified into 3 types: endocrine-related, skin and autoimmune-related. The most prevalent symptoms of insulin-resistance type B include hyperglycemia, hypoglycemia, hyperandrogenism, acanthosis nigricans and systemic lupus erythematosus.[2]

Endocrine-related[edit]

Hyperglycemia and hypoglycemia are the most prevalent clinical signs of insulin-resistance type B.[2] Most patients experience hyperglycemia which is accompanied by a significant weight loss.[1]

Certain patients develop hypoglycemia spontaneously after a hyperglycemic phase.[1] There are also cases where hypoglycemia evolves without the appearance of hyperglycemia.[1]

Acanthosis nigricans on axilla

Severe type II diabetes is the direct effect of hyperglycemia.[6] It is also notable that conventional exogenous insulin therapy is ineffective to alleviate diabetic symptoms in these patients.[1][6]

Hyperandrogenism is common among affected premenopausal females.[1][6] Enlarged polycystic ovaries, hirsutism and other associated signs can be observed.[2]

Other abnormalities include fasting hyperinsulinemia, hypotriglyceridemia and hyperadiponectinemia, which are very common among patients.[1][6]

Skin[edit]

Acanthosis nigricans is another common clinical feature of insulin-resistance type B.[1][6] Brown-to-black hyperpigmentation with poorly defined borders and thickening of the skin (hyperkeratosis) are present in intertriginous areas, including the back of the neck, axilla and groin.[7] This is a common feature associated with endocrine dysfunction, such as diabetes mellitus and hypothyroidism.[7]

Autoimmune-related[edit]

Insulin-resistance type B is often associated with other underlying autoimmune diseases, with systemic lupus erythematosus being the most common concurrent autoimmune condition.[2] The presence of anti-nuclear antibodies or nephritis, are common SLE-associated signs.[2]

Other common clinical features include abnormal blood leptin concentration, increased serum testosterone level, hypoalbuminemia and decreased serum complement factor B.[2]

Insulin-resistance type B has similar clinical features to other insulin-related conditions such as insulinoma.[1] Hence, erroneous diagnoses are common due to the rarity of the disease.[1]

Pathophysiology[edit]

Hyperglycemia and hypoglycemia[edit]

Insulin-resistance type B is caused by the presence of anti-insulin receptor autoantibodies, which are polyclonal autoantibodies produced by plasma cells that act against the insulin receptor.[1] These antibodies have a high affinity for insulin receptors, and they have both stimulation and inhibition effects on insulin receptors, depending on their concentration.[1] Inhibition of insulin receptors leads to insulin resistance and hyperglycemia, while their stimulation leads to hypoglycemia.[1]

Anti-insulin receptor autoantibodies act as antagonists to the insulin receptors when in high concentration.[1] They compete with insulin to bind to the insulin receptors, reducing the effect of insulin.[1] This causes severe insulin resistance.[1][8] On the other hand, anti-insulin receptor autoantibodies act as agonists at low concentration.[1][8] Binding of a small amount of anti-insulin receptor autoantibodies activate these receptors, causing a mild hypoglycemic effect similar to insulin.[1] Hence, different concentrations of anti-insulin receptor autoantibodies lead to different degrees of hyperglycemia or hypoglycemia.[1]

The initial hyperglycemic phase of insulin-resistance type B can be explained by the high concentration of autoantibodies present in the blood, leading to the blocking effect of the receptors.[1] The concentration of autoantibodies decreases with exogenous insulin therapy and the administration of immunosuppressants.[1] This stimulates insulin receptors and hypoglycemia is induced.[1] Failure to adjust the dosage of exogenous insulin may further promote hypoglycemia.[1]

Hyperinsulinemia[edit]

Hyperinsulinemia is a result of insulin resistance.[9] The blocking effect of the anti-insulin receptor autoantibodies leads to the insensitivity of the insulin receptors.[9] Hence, the beta cells in the pancreas produce and release more insulin to the bloodstream in an attempt to lower the blood glucose level, resulting in an elevated level of insulin.[9] However, due to severe insulin resistance, insulin receptors are not able to respond to insulin, and hyperglycemia persists.[1] This negative feedback mechanism of insulin release ultimately leads to hyperinsulinemia.[1][9]

Weight loss[edit]

Significant weight loss is another sign caused by insulin resistance.[2] The insulin resistance in fat cells promotes the hydrolysis of stored triglycerides and reduces cell uptake of circulating lipids.[10] Hence, there is a depletion of the stored fat and will cause weight loss in patients.[10]

Acanthosis nigricans[edit]

Acanthosis nigricans, a common feature of insulin-resistance type B, is caused by hyperinsulinemia.[1][7][6] The elevated concentration of insulin will lead to the binding of insulin to an insulin-like growth factor receptor (IGF-1 receptors).[7] Activation of these receptors will cause proliferative effects on fibroblasts and enhance the stimulation of the epidermal keratinocytes, leading to acanthosis nigricans.[7]

Diagnosis[edit]

As insulin-resistance type B is extremely rare, clinical suspicion is raised through identifying several atypical diabetic symptoms, including extremely abnormal insulin responses and the presence of underlying immune disorders.[1][2] Typical symptoms of insulin resistance, for instance acanthosis nigricans and hyperandrogenism, is also present in many cases.[1][2] Ultimately, serological tests such as radioreceptor assays are performed to confirm the presence of anti-insulin receptor autoantibodies.[3][11][12][13][14]

The determination of blood insulin levels is identical to other diabetic tests, in which the patient is required to fast overnight and then undergo a standard glucose tolerance test.[1] However, patients with insulin-resistance type B are found to have a fasting insulin concentration of more than 150pmol/L, and a peak insulin concentration of more than 1500pmol/L after a glucose tolerance test, indicating hyperinsulinemia.[1]

In some cases, patients may be insulin-deficient similar to normal cases of diabetes, but a dose of more than 3 units per kg a day of exogenous insulin may still result in persistent, albeit transient, episodes of hyperglycemia.[1] The consequent weight loss can be indicated with a typical BMI under 30.[1]

Patients often have underlying autoimmune disorders and the most predominant of which would be systemic lupus erythematosus, which is detected by indirect immunofluorescence anti-nuclear antibody test.[2][15] Clinical suspicion of insulin-resistance type B would be raised if diabetic symptoms and autoimmune disorders concur.[1]

Other symptoms of insulin-resistance type B include acanthosis nigricans, which is evaluated clinically; and hyperandrogenism, which is clinically manifested in the form of hirsutism.[16][17]

Competitive immunoassay; similar to radioreceptor assay, except the IM-9 lymphocyte receptors, anti-insulin receptor antibodies and [125I]‐insulin are replaced by capture antibody, analyte and labelled antigen respectively.

As anti-insulin receptor autoantibodies are diagnostic of insulin-resistance type B, the disease is ultimately confirmed by the presence of anti-insulin receptor autoantibodies in the serum of the patient by radioreceptor assay.[2][3][11][12][13][14] This technique involves the binding of radioactive-labelled insulin to receptors on cultured IM‐9 lymphocytes, which are similar to insulin receptors found on adipose cells and hepatocytes.[11] IM-9 lymphocytes are first exposed to the serum of the patient; after washing off the excess serum, [125I]‐insulin is allowed to bind to the receptors on the lymphocytes.[11] [125I]‐insulin is used in this test as a marker to detect the ratio between bound and unbound insulin.[11] The presence of anti-insulin receptor autoantibodies is indicated if the binding between [125I]‐insulin and IM-9 lymphocyte receptors is significantly low after exposure to a serum sample of a patient.[11][14]

Treatment[edit]

There are three goals in the treatment of insulin-resistance type B: to treat hyperglycemia, to minimize autoimmune responses by anti-insulin receptor autoantibodies, and to potentially treat hypoglycemia in the remission period of the patient.[1]

Treatment of hyperglycemia[edit]

Hyperglycemia and weight loss are the predominant symptoms of insulin resistance, which are addressed by the administration of exogenous insulin.[1] Extremely large doses of exogenous insulin in patients with insulin-resistance type B are required; therefore, U-500 insulin is considered as a more therapeutically effective alternative to obtain relatively normal fasting blood glucose levels.[1] When this is achieved, U-500 insulin doses should be gradually reduced to avoid fasting hypoglycemia.[1]

Immunosuppression[edit]

Rituximab acting against the CD20 cell surface protein on malignant B cells

The immunosuppressive therapy of rituximab, cyclophosphamide and pulse glucocorticoids has been reported to be effective in targeting the production of anti-insulin receptor autoantibodies by plasma cells.[1][3][18] Rituximab is a monoclonal antibody that acts against the cell-surface protein CD20 found on B-lymphocytes, which triggers cell death and thus prevents their maturation into plasma cells.[3][19] Glucocorticoids can suppress the activity of active plasma cells to reduce anti-insulin receptor autoantibodies production.[1][20][21] However, glucocorticoid therapy often only lasts for a few days and is administered monthly to prevent the exacerbation of hyperglycemia and other common adverse effects of steroid use.[1] Cyclophosphamide intensifies the suppression of B and T lymphocytes; but if the patient demonstrates cyclophosphamide intolerance, cyclosporine is used instead.[1][22][23] Azathioprine is also administered at the onset of the remission period for maintenance purposes.[1]

Treatment of hypoglycemia[edit]

Both exogenous insulin and immunosuppressants work in tandem to tackle hyperglycemia, thus causing its remission.[1][6] However, this remission period has the highest risk for hypoglycemic fatalities.[1][4] The remission of hyperglycemia indicates the concentration of anti-insulin receptor autoantibodies has declined, which may act as an agonist at insulin receptors and promote reactive hypoglycemia.[1][8] It has been reported that the usage of the aforementioned immunosuppressive regimen has significantly reduced the high mortality rates associated with hypoglycemia when compared with using insulin therapy alone.[1][6]

The treatment of hypoglycemia in patients with insulin-resistance type B also involves diet modification and occasionally glucocorticoids.[1] Meals are consumed at regular intervals to maintain blood glucose levels in the normal range.[1] Glucocorticoids are also effective in reversing hypoglycemia when taken in high doses, as it has an active role in the regulation of glucose metabolism.[1][24]

Epidemiology[edit]

Insulin-resistance type B predominantly affects females.[1][2] The onset of the disease is usually between 30 years and 50 years of age, although outliers have been reported.[1] The disease is also frequently associated with other autoimmune disorders, most notably systemic lupus erythematosus; other examples of concurrent autoimmune disorders include scleroderma, primary biliary cirrhosis, dermatomyositis and Hashimoto's thyroiditis.[1] Nevertheless, reports of patients who do not have underlying autoimmune conditions exist.[1][2]

Most descriptions of insulin-resistance type B report isolated cases involving people of different ethnic backgrounds, except for the largest cohort of the disease, which was from the American National Institutes of Health (NIH) and featured 24 patients over the course of 28 years.[1][4] The cohort was largely composed of African-American females.[1][4]

The exact prevalence of insulin-resistance type B is currently unknown because of its rarity.[1]

History[edit]

A “circulating serum factor” which inhibited the binding of endogenous insulin to insulin receptors was first identified in 1975.[1][11] It was hypothesized that the “circulating serum factor” was an antibody that competes with insulin to bind to insulin receptors, resulting in a significantly reduced insulin binding activity.[11] Therefore, insulin receptors were found to form an extreme resistance to both endogenous and exogenous insulin treatment.[1][11]

The same group of researchers that discovered the “circulating serum factor” found conclusive evidence to prove their hypothesis a year later.[1][11] Patients demonstrated certain characteristic features of an immunologic condition (e.g. elevated erythrocyte sedimentation rate), thus proving the condition was largely the work of an antibody.[11] Subsequently, the researchers coined the term “type B insulin resistance”.[1][5]

References[edit]

  1. ^ a b c d e f g h i j k l m n o p q r s t u v w x y z aa ab ac ad ae af ag ah ai aj ak al am an ao ap aq ar as at au av aw ax ay az ba bb bc bd be bf bg bh bi bj bk bl bm bn Willard, Devina L.; Stevenson, Mary; Steenkamp, Devin (August 2016). "Type B insulin resistance syndrome:". Current Opinion in Endocrinology & Diabetes and Obesity. 23 (4): 318–323. doi:10.1097/MED.0000000000000263. ISSN 1752-296X.
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  24. ^ Kuo, Taiyi; McQueen, Allison; Chen, Tzu-Chieh; Wang, Jen-Chywan (2015), Wang, Jen-Chywan; Harris, Charles (eds.), "Regulation of Glucose Homeostasis by Glucocorticoids", Glucocorticoid Signaling, vol. 872, Springer New York, pp. 99–126, doi:10.1007/978-1-4939-2895-8_5, ISBN 978-1-4939-2894-1, retrieved 2020-04-20

Category:Diabetes

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