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Severe Insulin Resistance Syndrome

Syndromes Of Severe Insulin Resistance

Syndromes Of Severe Insulin Resistance

Division of Endocrinology, Beth Israel Deaconess Medical Center and Joslin Diabetes Center, Boston, Massachusetts 02215 Search for other works by this author on: Division of Endocrinology, Beth Israel Deaconess Medical Center and Joslin Diabetes Center, Boston, Massachusetts 02215 Address all correspondence and requests for reprints to: Christos S. Mantzoros, M.D., D.Sc., Division of Endocrinology, RN 325, 99 Brookline Avenue, Boston, Massachusetts 02215. Search for other works by this author on: The Journal of Clinical Endocrinology & Metabolism, Volume 83, Issue 9, 1 September 1998, Pages 30253030, Nicholas A. Tritos, Christos S. Mantzoros; Syndromes of Severe Insulin Resistance, The Journal of Clinical Endocrinology & Metabolism, Volume 83, Issue 9, 1 September 1998, Pages 30253030, AN exceedingly large number of studies have convincingly demonstrated that insulin resistance occurs in association with a variety of physiological and pathophysiological states, including obesity, noninsulin-dependent diabetes mellitus (NIDDM), polycystic ovary syndrome (PCOS), and the constellation of central obesity, hypertension, glucose intolerance, and hyperlipidemia known as metabolic syndrome or syndrome X ( 1 , 2 ) ( Table 1 ). In addition, a number of rare, albeit very interesting, syndromes characterized by extreme insulin resistance have been described over the past 20 yr ( 3 , 4 ). These syndromes are not only clinically important, but have also significantly contributed to our knowledge of the mechanisms of insulin action and resistance. In this review, we focus on syndromes characterized by extreme insulin resistance. We present the tools and criteria for the diagnosis of severe insulin resistance and review the clinical phenotypes of type A and type B syndromes of insulin Continue reading >>

Severe Insulin-resistance Hyperandrogenic Syndromes

Severe Insulin-resistance Hyperandrogenic Syndromes

Abstract Insulin resistance is associated with a wide variety of markedly heterogeneous clinical disorders, either inherited or acquired, that may result in acanthosis nigricans, ovarian hyperandrogenism, and ovulatory dysfunction. These include the type A (primarily affecting lean women and resulting from defects of the insulin receptor), type B (resulting from an autoimmune process affecting the insulin receptor), and type C (a variant of type A, the hyperandrogenic, insulin-resistant, and acanthosis nigricans [HAIR-AN] syndrome) insulin resistance syndromes. More rare syndromes include leprechaunism, the Rabson-Mendenhall syndrome, and a heterogeneous group of lipodystrophic syndromes. HAIR-AN is generally present in obese women who do not demonstrate defects of the insulin receptor, although they may exhibit postreceptor defects. Although the type A and B insulin resistance syndromes are rare causes of ovarian hyperandrogenism, type C may affect up to 3% of women with androgen excess. These patients may be treated as other women with ovarian hyperandrogenism, namely using lifestyle modification, oral contraceptives, insulin sensitizers, and antiandrogens, although a few patients may require further suppression of their hypothalamic-pituitary-ovarian axis with a long-acting gona-dotropin-releasing hormone analog. It is likely that HAIR-AN patients are at greater risk for metabolic dysfunction and diabetes mellitus, although long-term studies are lacking. Finally, the distinction between HAIR-AN and the polycystic ovary syndrome (PCOS) is becoming less clear as more patients with PCOS are being recognized as potentially having postreceptor abnormalities in insulin signaling. Better characterization awaits more detailed phenotyping and genotyping studies. Continue reading >>

Type A Insulin Resistance Syndrome

Type A Insulin Resistance Syndrome

Type A insulin resistance syndrome is a rare disorder characterized by severe insulin resistance, a condition in which the body's tissues and organs do not respond properly to the hormone insulin. Insulin normally helps regulate blood sugar levels by controlling how much sugar (in the form of glucose) is passed from the bloodstream into cells to be used as energy. In people with type A insulin resistance syndrome, insulin resistance impairs blood sugar regulation and ultimately leads to a condition called diabetes mellitus, in which blood sugar levels can become dangerously high. Severe insulin resistance also underlies the other signs and symptoms of type A insulin resistance syndrome. In affected females, the major features of the condition become apparent in adolescence. Many affected females do not begin menstruation by age 16 (primary amenorrhea) or their periods may be light and irregular (oligomenorrhea). They develop cysts on the ovaries and excessive body hair growth (hirsutism). Most affected females also develop a skin condition called acanthosis nigricans, in which the skin in body folds and creases becomes thick, dark, and velvety. Unlike most people with insulin resistance, females with type A insulin resistance syndrome are usually not overweight. The features of type A insulin resistance syndrome are more subtle in affected males. Some males have low blood sugar (hypoglycemia) as the only sign; others may also have acanthosis nigricans. In many cases, males with this condition come to medical attention only when they develop diabetes mellitus in adulthood. Type A insulin resistance syndrome is one of a group of related conditions described as inherited severe insulin resistance syndromes. These disorders, which also include Donohue syndrome and Rabson-Me Continue reading >>

Insulin Resistance Syndromes

Insulin Resistance Syndromes

Diagnosis Biochemical diagnostic thresholds for severe insulin resistance (IR) are arbitrary, and should ideally be defined relative to BMI-adjusted population normal ranges, however one set of approximate diagnostic criteria is as follows: A: Non-diabetic and B.M.I. <30 kg/m2 Fasting insulin above 150 pmol/l OR Peak insulin on oral glucose tolerance testing above 1,500 pmol/l B: Absolute insulin deficiency and B.M.I. <30 kg/m2 Exogenous insulin requirement > 3U/kg/day. C: Partial beta cell decompensation and/or B.M.I. >30 kg/m2 Insulin levels are more difficult to interpret in the context of obesity or pre-existing diabetes, where glucotoxicity, and mixtures of endogenous and exogenous insulin in the circulation confuse the biochemical picture. In these settings the clinical history and features such as acanthosis nigricans are particularly useful in making a diagnosis of likely monogenic severe IR. Subjective clinical judgement is also required. Generic clinical features of severe insulin resistance Severe insulin resistance (IR) usually presents in one of three ways: Persistent hyperglycaemia despite large doses of insulin in patients with diabetes - Note, however, that many cases are unrecognised in the prediabetic phase. Indeed, a very common early feature of severe IR is spontaneous and symptomatic postprandial hypoglycaemia which may require medical intervention. This may dominate the clinical picture for years before hyperglycemia supervenes, which only occurs in the face of beta cell decompensation. Acanthosis Nigricans - The commonest presentation of monogenic severe IR is with the skin condition acanthosis nigricans (Figure 1). Ovarian hyperandrogenism, or “Polycystic Ovary Syndrome” - This may be severe, and oligo- or amenorrhoea are frequently the first Continue reading >>

Genetic Syndromes Of Severe Insulin Resistance

Genetic Syndromes Of Severe Insulin Resistance

Genetic Syndromes of Severe Insulin Resistance University of Cambridge Metabolic Research Laboratories (R.K.S., D.B.S., S.O.), Institute of Metabolic Science, Addenbrooke's Hospital, Cambridge CB2 0QQ, United Kingdom; Address all correspondence and requests for reprints to: Dr. R. K. Semple or Dr. D. B. Savage, Metabolic Research Laboratories, Institute of Metabolic Science, University of Cambridge, Addenbrooke's Hospital, Hills Road, Cambridge CB2 0QQ, United Kingdom Search for other works by this author on: University of Cambridge Metabolic Research Laboratories (R.K.S., D.B.S., S.O.), Institute of Metabolic Science, Addenbrooke's Hospital, Cambridge CB2 0QQ, United Kingdom; Address all correspondence and requests for reprints to: Dr. R. K. Semple or Dr. D. B. Savage, Metabolic Research Laboratories, Institute of Metabolic Science, University of Cambridge, Addenbrooke's Hospital, Hills Road, Cambridge CB2 0QQ, United Kingdom Search for other works by this author on: Clinical Endocrinology Branch (E.K.C., P.G.), National Institute of Diabetes, Digestive and Kidney Diseases, Bethesda, Maryland 20892 Search for other works by this author on: Clinical Endocrinology Branch (E.K.C., P.G.), National Institute of Diabetes, Digestive and Kidney Diseases, Bethesda, Maryland 20892 Search for other works by this author on: University of Cambridge Metabolic Research Laboratories (R.K.S., D.B.S., S.O.), Institute of Metabolic Science, Addenbrooke's Hospital, Cambridge CB2 0QQ, United Kingdom; Search for other works by this author on: Endocrine Reviews, Volume 32, Issue 4, 1 August 2011, Pages 498514, Robert K. Semple, David B. Savage, Elaine K. Cochran, Phillip Gorden, Stephen O'Rahilly; Genetic Syndromes of Severe Insulin Resistance, Endocrine Reviews, Volume 32, Issue 4, 1 Augus Continue reading >>

What Is Severe Insulin Resistance?

What Is Severe Insulin Resistance?

Severe insulin resistance and lipodystrophy are rare metabolic disorders. They occur when the body does not use the insulin it produces properly. Insulin is a hormone (a chemical signal that travels in the bloodstream) made by the pancreas.It controls how the body uses sugars and fats and is essential for life. Its absence is the underlying problem in type 1 diabetes. However, from person to person there are significant differences in how sensitive the tissues of the body are to insulin. In other words, in some people a very small amount of insulin produces a large change in the blood levels of glucose and fats (these people are said to be very insulin sensitive), while in others much larger amounts are required to produce the same change (these people are said to be insulin resistant). Those with severe insulin resistance are those whose bodies respond least well to insulin. Although many with severe insulin resistance do go onto develop diabetes, severe insulin resistance is NOT the same as diabetes: as long as the pancreas can produce enough insulin to overcome the insulin resistance diabetes does not develop. However even before diabetes appears, insulin levels in the body may be extremely high, and this can produce a range of different problems in its own right. Rarely, people are born with severe insulin resistance and remain severely insulin resistant throughout their lives. Far more frequently insulin resistance develops only at puberty or in later life, while in some people it is only a temporary condition caused by other situations or illnesses. Most commonly a tendency towards insulin resistance is inherited, but only in the presence of environmental or lifestyle factors does it become a problem. Consequences of severe insulin resistance include development Continue reading >>

What Have We Learned Form Monogenic Forms Of Severe Insulin Resistance Associated With Pcos/hairan? - Em|consulte

What Have We Learned Form Monogenic Forms Of Severe Insulin Resistance Associated With Pcos/hairan? - Em|consulte

What have we learned form monogenic forms of severe insulin resistance associated with PCOS/HAIRAN? Quavons-nous appris des formes monogniques dinsulino-rsistance svre associes au SOPK? aFacult de mdecine Saint-Antoine, universit Paris-6 Pierre-et-Marie-Curie, centre de recherche Saint-Antoine, Inserm UMR_S 938, 27, rue Chaligny, 75571 Paris cedex 12, France bAssistance publique-hpitaux de Paris, service de biochimie et hormonologie, hpital Tenon, 4, rue de la Chine, 75970 Paris cedex 20, France Quelle que soit lorigine dune insulinorsistance svre (dfauts primaires du rcepteur de linsuline ou lipodystrophies), lhyperinsulinisme contribue in vivo promouvoir la croissance ovarienne et la synthse des andrognes indpendamment des gonadotrophines. Dans les syndromes lipodystrophiques, le dficit endocrinien li au dfaut du tissu adipeux joue un rle physiopathologique important dans les altrations mtaboliques. En particulier, la leptine est diminue, contribuant au stockage ectopique des lipides dans des cellules non adipocytaires ce qui va inhiber la signalisation de linsuline (lipotoxicit). Par ailleurs, les caractristiques du syndrome des ovaires polykystiques ne sont pas toujours prsentes dans les syndromes dinsulinorsistance avec lipodystrophie. Cela est en faveur dun rle aggravant, mais non primitif de linsulinorsistance post-rcepteur dans les dysfonctions ovariennes. The full text of this article is available in PDF format. Whatever the origin of severe insulin resistance (primary insulin receptors defects or lipodystrophies), in vivo hyperinsulinemia has been clearly shown to promote ovarian growth and androgen synthesis independently of gonadotropins. In lipodystrophic syndromes, the endocrine deficiency of adipose tissue has been shown to play important pathophysiologi Continue reading >>

Genetic Syndromes Of Severe Insulin Resistance

Genetic Syndromes Of Severe Insulin Resistance

Genetic syndromes of severe insulin resistance Author links open overlay panel AMelvin SORahilly DBSavage Get rights and content Insulin resistance underpins the link between obesity and most of its associated metabolic disorders including type 2 diabetes, fatty liver disease, dyslipidaemia and cardiovascular disease. Despite its importance and extensive scientific endeavour, its precise molecular pathogenesis remains unclear. Monogenic syndromes of extreme insulin resistance, whilst rare in themselves, can provide unique insights into the pathogenesis of human insulin resistance. Severe insulin resistance syndromes are broadly classified into three categories: lipodystrophies, primary insulin signalling defects or complex syndromes including severe insulin resistance. Genetically confirmed classification has facilitated the identification of robust diagnostic biochemical features accelerating accurate clinical diagnosis. Interestingly the biochemical features of lipodystrophies are far more closely aligned to what is seen in prevalent forms of insulin resistance than those of primary insulin signalling defects, suggesting that lipodystrophy could be a relevant model for common disease. This assertion is supported by genome-wide association data indicating that SNPs associated with fasting hyperinsulinemia and metabolic dyslipidaemia, are strongly associated with a subtle reduction in hip fat, suggesting that subtle forms of lipodystrophy are likely to be a significant contributor to prevalent insulin resistance. Continue reading >>

Insulin Resistance: Practice Essentials, Pathophysiology, Etiology

Insulin Resistance: Practice Essentials, Pathophysiology, Etiology

Insulin resistance is a state in which a given concentration of insulin produces a less-than-expected biological effect. Insulin resistance has also been arbitrarily defined as the requirement of 200 or more units of insulin per day to attain glycemic control and to prevent ketosis. The syndromes of insulin resistance actually make up a broad clinical spectrum, which includes obesity, glucose intolerance, diabetes, and the metabolic syndrome, as well as an extreme insulin-resistant state. Many of these disorders are associated with various endocrine, metabolic, and genetic conditions. These syndromes may also be associated with immunological diseases and may exhibit distinct phenotypic characteristics. [ 1 , 2 , 3 , 4 , 5 , 6 , 7 , 8 ] The metabolic syndrome a state of insulin-resistance that is also known as either syndrome X or the dysmetabolic syndromehas drawn the greatest attention because of its public health importance. In addition to hypertension, findings can include central obesity, peripheral arterial disease, type A syndrome, type B syndrome, ancanthosis nigricans, polycystic ovary syndrome, and other insulin-resistant states. In clinical practice, no single laboratory test is used to diagnose insulin resistance syndrome. Diagnosis is based on clinical findings corroborated with laboratory tests. Individual patients are screened based on the presence of comorbid conditions. Lab tests include the plasma glucose level, the fasting insulin level, and a lipid profile, among others. Treatment involves pharmacologic therapy to reduce insulin resistance, along with surgical management of underlying causes if appropriate. Comorbid conditions should be evaluated and addressed; this is generally feasible on an outpatient basis, though some patients will require admis Continue reading >>

Orphanet: Insulin Resistance Syndrome Type A

Orphanet: Insulin Resistance Syndrome Type A

It is a rare disorder of unknown prevalence. It is generally diagnosed in young women with marked signs of hyperandrogenism, but insulin resistance and acanthosis nigricans may be observed in men and in childhood. Acromegaloid facies or muscular cramps are sometimes associated. Hyperinsulinemia, a biological marker for insulin resistance, is often associated with glucose tolerance defects over the course of the disease, and diabetes progressively sets in. Hyperandrogenism (associated with polycystic ovarian syndrome (see this term) or ovarian hyperthecoses) leads to fertility problems. In some cases, the syndrome is caused by heterozygous mutations in the insulin receptor gene (INSR; 19p13.3-p13.2), affecting the region encoding the tyrosine kinase domain. Cases associated with homozygous mutations affecting the insulin-binding domain of the receptor have also been reported. However, only 15 to 20% of female patients with hyperandrogenism, insulin resistance and acanthosis nigricans present mutations in the insulin receptor gene. When such mutations are not found, the disease is of unknown cause and may be considered as an HAIR-AN syndrome (see this term). The differential diagnosis includes the other forms of extreme insulin-resistance, in particular the lipodystrophy syndromes (see these terms), in which the reparation anomaly of the adipose tissue may be clinically minor. The differential diagnosis with type B insulin resistance syndrome is based on the lack of insulin anti-receptor auto-antibodies in patients with the type A syndrome. The treatment consists of dietary changes and/or drugs (metformin, glitazones, or other antidiabetic drugs) to reduce the insulin resistance and treat the diabetes. Expert reviewer(s): Pr Corinne VIGOUROUX - Last update: January 2009 Continue reading >>

Payperview: A Clinical Approach To Severe Insulin Resistance - Karger Publishers

Payperview: A Clinical Approach To Severe Insulin Resistance - Karger Publishers

A Clinical Approach to Severe Insulin Resistance Savage D.a Semple R.a Chatterjee V.a Wales J.b Ross R.c O'Rahilly S.a I have read the Karger Terms and Conditions and agree. Extreme forms of insulin resistance are a rare cause of type 2 diabetes. However, individualswith severe insulin resistance pose unique diagnostic and therapeutic challenges,and have often acted as experiments of nature providing important novel informationregarding endocrine physiology and mechanistic insights relevant to the study of more commondisorders. Progress in understanding the molecular pathogenesis of such syndromes isalso beginning to yield novel therapeutic options. Severe insulin resistance typically presentsin 1 of 3 ways: (1) disordered glucose metabolism including both diabetes and/orparadoxical hypoglycaemia; (2) acanthosis nigricans, a velvety hyperpigmentation of axilliaryand flexural skin often associated with skin tags; or (3) hyperandrogenism in girls (hirsutism,oligo-/amenorrhoea and polycystic ovaries). Lipodystrophy is a major cause ofsevere insulin resistance and needs to be looked for very carefully, particularly in thepatients with significant dyslipidaemia and fatty liver. Specific treatments are now availablefor some forms of severe insulin resistance; for example, leptin replacement in patients withgeneralized lipodystrophy. In the absence of a specific diagnosis and therapy, metformin isa useful insulin sensitizer and should be used in conjunction with aggressive diet and exerciseinterventions. Continue reading >>

Insulin Resistance

Insulin Resistance

What medical conditions are associated with insulin resistance? While the metabolic syndrome links insulin resistance with abdominal obesity, elevated cholesterol, and high blood pressure; several other medical other conditions are specifically associated with insulin resistance. Insulin resistance may contribute to the following conditions: Type 2 Diabetes: Overt diabetes may be the first sign insulin resistance is present. Insulin resistance can be noted long before type 2 diabetes develops. Individuals reluctant or unable to see a health-care professional often seek medical attention when they have already developed type 2 diabetes and insulin resistance. Fatty liver: Fatty liver is strongly associated with insulin resistance. Accumulation of fat in the liver is a manifestation of the disordered control of lipids that occurs with insulin resistance. Fatty liver associated with insulin resistance may be mild or severe. Newer evidence suggests fatty liver may even lead to cirrhosis of the liver and, possibly, liver cancer. Arteriosclerosis: Arteriosclerosis (also known as atherosclerosis) is a process of progressive thickening and hardening of the walls of medium-sized and large arteries. Arteriosclerosis is responsible for: Other risk factors for arteriosclerosis include: High levels of "bad" (LDL) cholesterol Diabetes mellitus from any cause Family history of arteriosclerosis Skin Lesions: Skin lesions include increased skin tags and a condition called acanthosis nigerians (AN). Acanthosis nigricans is a darkening and thickening of the skin, especially in folds such as the neck, under the arms, and in the groin. This condition is directly related to the insulin resistance, though the exact mechanism is not clear. Acanthosis nigricans is a cosmetic condition strongly Continue reading >>

Insulin Resistance

Insulin Resistance

Insulin resistance (IR) is a pathological condition in which cells fail to respond normally to the hormone insulin. The body produces insulin when glucose starts to be released into the bloodstream from the digestion of carbohydrates in the diet. Normally this insulin response triggers glucose being taken into body cells, to be used for energy, and inhibits the body from using fat for energy. The concentration of glucose in the blood decreases as a result, staying within the normal range even when a large amount of carbohydrates is consumed. When the body produces insulin under conditions of insulin resistance, the cells are resistant to the insulin and are unable to use it as effectively, leading to high blood sugar. Beta cells in the pancreas subsequently increase their production of insulin, further contributing to a high blood insulin level. This often remains undetected and can contribute to the development of type 2 diabetes or latent autoimmune diabetes of adults.[1] Although this type of chronic insulin resistance is harmful, during acute illness it is actually a well-evolved protective mechanism. Recent investigations have revealed that insulin resistance helps to conserve the brain's glucose supply by preventing muscles from taking up excessive glucose.[2] In theory, insulin resistance should even be strengthened under harsh metabolic conditions such as pregnancy, during which the expanding fetal brain demands more glucose. People who develop type 2 diabetes usually pass through earlier stages of insulin resistance and prediabetes, although those often go undiagnosed. Insulin resistance is a syndrome (a set of signs and symptoms) resulting from reduced insulin activity; it is also part of a larger constellation of symptoms called the metabolic syndrome. Insuli Continue reading >>

Insulin Resistance Causes And Symptoms

Insulin Resistance Causes And Symptoms

One in three Americans—including half of those age 60 and older1— have a silent blood sugar problem known as insulin resistance. Insulin resistance increases the risk for prediabetes, type 2 diabetes and a host of other serious health problems, including heart attacks, strokes2 and cancer.3 What is Insulin Resistance? Insulin resistance is when cells in your muscles, body fat and liver start resisting or ignoring the signal that the hormone insulin is trying to send out—which is to grab glucose out of the bloodstream and put it into our cells. Glucose, also known as blood sugar, is the body’s main source of fuel. We get glucose from grains, fruit, vegetables, dairy products, and drinks that bring break down into carbohydrates. How Insulin Resistance Develops While genetics, aging and ethnicity play roles in developing insulin sensitivity, the driving forces behind insulin resistance include excess body weight, too much belly fat, a lack of exercise, smoking, and even skimping on sleep.4 As insulin resistance develops, your body fights back by producing more insulin. Over months and years, the beta cells in your pancreas that are working so hard to make insulin get worn out and can no longer keep pace with the demand for more and more insulin. Then – years after insulin resistance silently began – your blood sugar may begin to rise and you may develop prediabetes or type 2 diabetes. You may also develop non-alcoholic fatty liver disease (NAFLD), a growing problem associated with insulin resistance that boosts your risk for liver damage and heart disease. 5 Signs and Symptoms of Insulin Resistance Insulin resistance is usually triggered by a combination of factors linked to weight, age, genetics, being sedentary and smoking. - A large waist. Experts say the be Continue reading >>

Syndromes Of Extreme Insulin Resistance

Syndromes Of Extreme Insulin Resistance

This group of syndromes shares severe insulin resistance and hyperinsulinemia with variable clinical manifestations (Kahn et al., N Engl J Med 294:739745, 1976; Moller and Flier, N Engl J Med 325:938948, 1991). Attention has been paid to these rare disorders because they provide insight into several aspects of insulin action at the molecular level and advance our understanding of the more common insulin-resistant disorders, such as polycystic ovarian syndrome (Barbieri et al., Fertil Steril 50:197202, 1988) and type 2 diabetes mellitus (Barroso et al., Nature 402:880883, 1999). Insulin resistanceHyperinsulinemiaPlasma glucoseGlucose tolerance testSerum insulinHOMAGlucose homeostasisLipoatrophyAcanthosis nigricansLipodystrophicRabson-MendenhallThiazolidinedionesInsulinImmunomodulationChromium This is a preview of subscription content, log in to check access. Kahn CR, Flier JS, Bar RS, et al. The syndrome of insulin resistance and acanthosis nigricans: insulin receptor disorders in man. N Engl J Med. 1976;294:73945. PubMed CrossRef Google Scholar Moller DE, Flier JS. Insulin resistance: mechanisms, syndromes, and implications. N Engl J Med. 1991;325:93848. PubMed CrossRef Google Scholar Barbieri RL, Smith S, Ryan KJ, et al. The role of hyperinsulinemia in the pathogenesis of ovarian hyperandrogenism. Fertil Steril. 1988;50:197202. PubMed CrossRef Google Scholar Barroso I, Curnell M, Crowley VE, et al. Dominant negative mutation in human PPAR gamma associated with severe insulin resistance, diabetes mellitus, and hypertension. Nature. 1999;402:8803. PubMed Google Scholar Borai A, Livingstone C, Ferns GA. The biochemical assessment of insulin resistance. Ann Clin Biochem. 2007;44:32442. PubMed CrossRef Google Scholar Tritos NA, Mantzoros CS. Syndromes of severe insulin res Continue reading >>

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