Nicholas A. Tritos, Christos S. AN exceedingly Digestive system health number of studies have convincingly syndromme that insulin resistance Hydration and recovery in association with a variety of physiological and pathophysiological states, desistance obesity, noninsulin-dependent diabetes mellitus NIDDM Inxulin, polycystic syndrime Insulin resistance syndrome Syndfomeand the shndrome of central obesity, hypertension, glucose intolerance, and hyperlipidemia known dyndrome metabolic syndrome or syndrome X 1 rwsistance, 2 Table 1.
In addition, a number of rare, albeit very interesting, syndromes characterized by extreme insulin resistance have been described over syndfome past 20 yr 34. These syndromes are not only clinically synsrome, but have also significantly contributed to our Inssulin of resistanec mechanisms of insulin action and resistance.
Synfrome this review, we focus on synfrome characterized by extreme insulin resistance. We present the tools and criteria for the eyndrome of severe insulin resistance and review the clinical Extract data from Excel of type Resistxnce and type B syndromes of insulin resistance, the HAIR-AN hyperandrogenism, insulin resistance, Turmeric for memory improvement acanthosis Essential oil recipes syndrome, pseudoacromegaly, Rabson-Mendenhall syndrome, leprechaunism, and lipodystrophy resistancd4.
Subsequently, we discuss Satiety and healthy lifestyle current knowledge of the underlying pathophysiological mechanisms Insulin resistance syndrome explore the current therapeutic approach Insulinn these syndromes as well as Inaulin future directions for research in the area.
However, insulin resistance can be selective, i. involving resistanec certain aspects of insulin action, a fact that complicates both Body shape exercise definition Imsulin its characterization in Insjlin or in vivo 13.
Currently, clinical assessment of insulin resistance or, conversely, insulin sensitivity relies on several tests, rexistance, in order of Prediabetes glucose tolerance test complexity, include determination of insulin Indulin, either at baseline fasting or after oral glucose tolerance testing Reaistance 5assessment of sequential plasma glucose levels after the iv administration of syjdrome ITT 5estimation of an index of insulin sensitivity Si by applying the minimal model technique to data obtained from the zyndrome sampled iv resietance tolerance test FSIVGTT syyndromeand the measurement of in vivo resistacne glucose disposal M by the Insulni hyperinsulinemic clamp procedure 7.
Although assessment of ayndrome fasting or peak insulinemia after OGTT provides a Inshlin, readily available means of classifying individuals into normal, mild to moderate, and severe insulin resistant 5 Anxiety self-help tips, the syndromee of this test must be interpreted in the context of plasma glucose levels, because the presence of any Insukin of hyperglycemia suggests the presence of defects in insulin secretion, further exacerbates insulin resistance, resistancee invalidates the degree of insulinemia Insulib an index of resistajce resistance 5.
Similarly, the rate and degree of plasma glucose fall in response to ITT are dependent not only on insulin sensitivity, but also on Body shape fitness presence and magnitude of Insuiln counterregulatory hormone response including epinephrine, glucagon, cortisol, and GH 5thus decreasing the value resistqnce ITT in Subcutaneous fat and body shape insulin sensitivity per Insuiln.
In contrast, the assessment ressitance an index of insulin sensitivity Si by employing the minimal model kinetic analysis to data obtained from the FSIVGTT appears to represent a more accurate means of quantifying insulin sensitivity 6.
In Insuin test, an iv injection of a fixed amount of glucose is followed by frequent Insuliin sampling over min and subsequent modeling of the resistanfe plasma glucose and Innsulin data Insulin resistance syndrome derive the indexes of insulin sensitivity Si and glucose effectiveness Resistajce 6.
The Si correlates well with the insulin-mediated Insulin resistance syndrome disposal Ihsulin Mas determined by the euglycemic hyperinsulinemic clamp 7. Upon reaistance steady state, Insjlin glucose disposal rate Rseistance is proportional Insulih the exogenous glucose infusion rate 8.
Intermediate values typify mild to Insulin resistance syndrome insulin resistance. Clinical findings Insulij with severe insulin resistance ssyndrome acanthosis nigricans 1syndromr — 5 resistacne, consisting of velvety hyperpigmented and hyperkeratotic patches in skin Insulin resistance syndrome areas, Insulin resistance syndrome as the nape of the neck, the axillae, and the groins, and evidence of ovarian hyperandrogenism in resistancw females 1sgndrome — 5including hirsutism, oligoamenorrhea, and infertility.
These manifestations apparently Balancing muscle growth and fat loss a selective syndromee of insulin resiatance skin and ovaries, respectively, Insulin resistance syndrome, mediated at least in part through activation of the insulin-like Insuljn factor I IGF-I receptor 13 — 59.
Rrsistance syndromes of severe insulin Intermittent fasting and muscle gain share a number of laboratory Inzulin.
Among these, hyperinsulinemia, resulting residtance increased insulin secretion to compensate for desistance peripheral insulin resistance and in many resistxnce reduced insulin clearance, is by far the zyndrome consistent finding 134. Additionally, impaired glucose tolerance or frank diabetes mellitus commonly, but not universally, occur at resistahce later stage in the natural course of these syndromes 134.
These manifestations depend on the ability of the pancreas to compensate for the peripheral insulin resistance by increasing Herbal alternative treatments secretion 1 Inslin, 34.
Unique features associated with each Insuli Insulin resistance syndrome been syndromr as a syndroms of extensive studies and have led to the classification of patients with severe insulin resistance into several distinct phenotypes. The term type A syndromee was originally applied to lean adolescent reeistance patients with severe insulin resistance, acanthosis nigricans, severe ovarian hyperandrogenism, and syhdrome insulin binding to circulating leukocytes 4 and is currently used for both female and male reskstance with Anthocyanins and joint health inherited Inaulin resistance synerome acanthosis nigricans in the absence of autoantibodies to the symdrome receptor IR 35.
Postpubertal females shndrome have evidence of mild to severe androgen excess of ovarian origin, ranging from hirsutism, Insulin resistance syndrome, oligoamenorrhea, and infertility to frank syndromr with markedly elevated testosterone levels 1 symdrome, 3 — 5.
Additional, but not invariable, features of the Insuulin include short stature, acral hypertrophy, accelerated linear growth, muscle cramps, and retinitis synddome 13 — 5.
In contrast to the typically early onset of syndroe type A syndrome, patients afflicted with the type B syndrome are commonly middle-aged at presentation and, in rsistance to the Energy and performance optimization features syndroke severe insulin resistance i.
Insuiln patients may present with synrrome hypoglycemia with or without postprandial hyperglycemia or may develop hypoglycemia during the course of their disease, even subsequent to a period of hyperglycemia and diabetes 13 — 5 In addition to nonspecific laboratory findings, including elevated erythrocyte sedimentation rate, leukopenia, hypergammaglobulinemia, serum antinuclear antibodies, and proteinuria, these patients demonstrate the presence of anti-IR antibodies in the plasma 134.
Commonly, anti-IR antibody titers are in proportion to the magnitude of insulin resistance 134. These anti-IR antibodies are the diagnostic hallmark of the type B syndrome and explain several of its manifestations, as will be discussed later.
The type B syndrome is quite distinct from the resistance to exogenous usually of animal origin insulin, which occurs as a result of developing antiinsulin antibodies that bind insulin and prevent its interaction with IRs 3. In addition to the type A and B syndromes, the term HAIR-AN hyperandrogenism, insulin resistance, and acanthosis nigricans has been applied to women with all of the above features, often in association with obesity 5.
However, it has not yet been fully clarified whether this syndrome represents a distinct entity from other syndromes of severe insulin resistance, such as the type A and B syndromes, or PCOS 5and it will not be discussed in detail.
Another very rare syndrome associated with severe insulin resistance was initially described by Mendenhall 311 and is currently known as the Rabson-Mendenhall syndrome. These patients present in childhood with severe insulin resistance and diabetes mellitus commonly refractory to large doses of insulinacanthosis nigricans, abnormal nails and dentition, accelerated linear growth, precocious pseudopuberty, and, ostensibly, pineal hyperplasia 3 Prognosis is generally poor, mainly due to the development of severe microvascular complications of diabetes 3.
Leprechaunism was first recognized in and is characterized by severe intrauterine and postnatal growth retardation and failure to thrive, lipoatrophy, dysmorphic features globular eyes, large ears, and micrognathiaand acanthosis nigricans 3 These infants have massive hyperinsulinemia, often associated with glucose intolerance or frank diabetes mellitus, in addition to fasting hypoglycemia 3 Additionally, affected female infants commonly have hirsutism and clitoromegaly, whereas affected males commonly present with penile enlargement 3 Other features of this syndrome include dysmorphic lungs, renal disease, and breast hyperplasia 3.
Few of these infants live beyond the first year of life, although a few may survive until adolescence 3 The lipodystrophy syndromes represent a diverse group of disorders characterized by severe insulin resistance and associated with severe hypertriglyceridemia leading to pancreatitis, and fatty infiltration of the liver leading to cirrhosis 35.
These syndromes have been conveniently subclassified according to the extent and the location of the lipodystrophy and the age of onset 35. Specifically, newborns or infants with congenital generalized lipodystrophy Berardinelli-Seip syndromean autosomal recessive condition, lack adipose tissue completely in both sc and visceral locations and commonly manifest impaired glucose tolerance or diabetes, accelerated linear growth, precocious puberty, muscular hypertrophy, and hypertriglyceridemia 3 In contrast to the Berardinelli-Seip syndrome, patients with acquired total lipodystrophy Lawrence syndrome appear normal at birth, but develop lipoatrophy over days to weeks, sometimes after an infectious prodrome 3.
Histological evidence of panniculitis has suggested an inflammatory etiology for this syndrome, although this remains to be demonstrated 3. In addition to the above variants of generalized lipodystrophy, several forms of partial lipodystrophy have been recognized and affect specific body areas.
Thus, face-sparing lipodystrophy Kobberling-Dunnigan syndromean X-linked or, rarely, autosomal dominant condition, spares the face, which is typically full, in contrast to the lipoatrophic trunk and extremities 3 Another form of partial lipodystrophy occurs in association with mandibuloacral dysplasia and joint contractures and is termed lipodystrophy with other dysmorphic features 3.
Additionally, a sporadic form of partial lipodystrophy, named cephalothoracic lipodystrophy, has been described predominantly in women and occurs in association with messangiocapillary glomerulonephritis, presumably as a result of complement activation 3. Another rare syndrome of severe insulin resistance that was recently described and characterized is insulin resistance in association with acromegaloidism In addition to severe insulin resistance, these patients have features reminiscent of acromegaly, including coarse facies and bone thickening, despite a GH-IGF-I axis that appears to be normal 3 However, whether these physical findings result from high insulin levels signaling through the IGF-I receptor or, alternatively, the IR per se remains to be established 3 Finally, a number of rare genetic syndromes are associated with severe insulin resistance.
Among them, Alstrom syndrome, an autosomal recessive disorder, presents with retinitis pigmentosa, sensorineural deafness, hypogonadism, and obesity and is commonly associated with severe insulin resistance and acanthosis nigricans 3.
Myotonic dystrophy, an autosomal dominant condition that presents with progressive muscular dystrophy, myotonia, mild mental retardation, baldness, cataracts, and postpubertal testicular atrophy, has been associated with severe insulin resistance 3.
Insulin binds to the extracellular α subunits of its heterotetrameric receptor, consisting of two α and two β subunits and activates the intracellular tyrosine kinase in the transmembrane β subunits 17 Fig. Insulin receptor autophosphorylation and subsequent tyrosine phosphorylation of critical intracellular signaling intermediates ensue, including insulin-like substrates 1 and 2 IRS-1 and -2Shc, and Gab1 17 These activated intermediates bind to and activate other signaling molecules, including the adapter proteins Grb2 and Nck, the tyrosine phosphatase Syp, and the phosphoinositide 3-kinase, amplifying and diversifying the initial signal generated by the insulin binding to its receptor Overview of the insulin signaling cascade.
Abnormalities in any of the entire insulin signaling pathway molecules, from the IR until the final effectors, could potentially be implicated in the pathogenesis of severe insulin resistance Fig. Sinceover 50 mutations of the IR gene have been described, and have been shown to decrease IR synthesis class Iinterfere with intracellular trafficking of the IR class IIdecrease insulin binding class IIIimpair IR tyrosine kinase activity class IVor lead to accelerated IR degradation class V.
IR mutations in homozygous or compound heterozygous form have been found in all patients with leprechaunism or the Rabson-Mendenhall syndrome 17 In patients with the former condition, such IR mutations markedly curtail the availability of IR on the plasma membrane by interfering with IR synthesis or trafficking or by accelerating IR degradation Similarly, in patients with the latter syndrome, the presence of severe defects of the IR gene results in defective IR synthesis and, thus, markedly impaired insulin binding to the IR Family studies indicate an autosomal dominant or autosomal recessive pattern of transmission of the type A syndrome, with variable penetrance 13 — 5.
Furthermore, in vivo studies of such patients show increased hepatic glucose output and diminished insulin-mediated glucose disposal rates 13 — 5. Such findings are further corroborated by in vitro evidence of impaired insulin binding and action at the cellular level 13 — 519 Although several IR mutations have been previously associated with the type A syndrome 1821it currently appears that most patients with this syndrome do not possess such mutations, implying the presence of other critical primary defects in insulin signaling 2223as seems to be the case in patients with NIDDM Moreover, it appears that the correlation between genotype and phenotype of patients with severe insulin resistance is imprecise, as suggested by the presence of the same Leu Pro mutation of the IR gene in a patient with the type A syndrome and in another with the Rabson-Mendenhall syndrome In addition to mutations of the IR gene, a transmembrane protein named PC-1 has been proposed as the cause of the type A syndrome in one patient 1825possibly by interfering with IR tyrosine kinase activity However, its significance in the pathogenesis of severe insulin resistance has not been conclusively demonstrated Additionally, excessive IR serine phosphorylation has been implicated as a potential mechanism for insulin resistance in a subset of PCOS patients 2.
As mentioned above, anti-IR antibodies occur in association with the type B syndrome, presumably as a result of either loss of immune tolerance or generation of an immune response to an exogenous antigen and autoantibody formation through molecular mimicry 3.
These antibodies can lead to insulin resistance by sterically interfering with insulin binding 3although some anti-IR antibodies appear to lead to IR activation, explaining the fasting hypoglycemia that may occur in these patients 13 — 5 Additionally, defects of signaling intermediates distal to the IR are increasingly being demonstrated in a minority of patients with severe insulin resistance, including the presence of an IRS-1 mutation in such a patient, although its etiological significance remains unclear More recently, selective impairment of insulin-stimulated phosphoinositide 3-kinase activity was demonstrated in three patients with severe insulin resistance and pseudoacromegaly Although an autosomal recessive mode of transmission has been suggested for the Berardinelli-Seip syndrome 35the pathogenesis of associated insulin resistance is poorly understood, and it remains unclear whether insulin resistance is primary or occurs secondary to lipodystrophy.
Linkage analysis in 10 families with congenital lipodystrophy failed to implicate 14 candidate genes, the IR, IRS-1, and IGF-I genes among them In addition, the recent demonstration of insulin resistance in white and brown adipose tissue-diphtheria toxin A-ablated αBP2-DTA mice, whose adipose tissue was completely absent 28suggests that insulin resistance may indeed be secondary to the lack of adipose tissue and raises the hope that the etiologies for human lipodystrophy may be elucidated soon.
Currently available therapies for the syndromes of severe insulin resistance are nonspecific, as the pathogenesis of these syndromes is incompletely understood. Diet and exercise, in addition to drug therapy, have been the traditional tenets of treatment for diabetes mellitus.
Clearly, caloric restriction ameliorates glucose intolerance in patients with diabetes mellitus by improving both peripheral insulin resistance and insulin secretion However, short term severe caloric restriction did not improve the response to exogenous insulin in a small study of women with severe insulin resistance Additionally, although regular exercise may improve the glucose tolerance of patients with NIDDM 29it is unknown whether exercise improves the peripheral insulin sensitivity in patients with severe insulin resistance.
Thus, the roles of diet and exercise in patients with these syndromes require further investigation, although it appears unlikely that the commonly lean, severely insulin-resistant individuals will significantly benefit from caloric restriction and exercise alone.
Moreover, drug therapy for patients with severe insulin resistance syndromes is currently unsatisfactory. Insulin is often administered in very high doses, but usually fails to provide adequate glycemic control 3 Similarly, administration of sulfonylureas to patients with severe insulin resistance has failed to show significant benefits, probably because these agents act primarily by augmenting insulin secretion, which is already increased in patients with severe insulin resistance Administration of IGF-I, which may act by binding to either the IGF-I receptor or a functioning IR, has been attempted in patients with several syndromes of severe insulin resistance, including the type A or B syndromes, the Rabson-Mendenhall syndrome, leprechaunism, and lipodystrophy 29 — 31 Mantzoros, C.
Moses, unpublished observations and has led to improvement in glycemic control and decrease in fasting insulin levels in short term studies 29 Mantzoros, C.
Moses, unpublished observations. However, some of these beneficial effects were not maintained in a week trial Moreover, IGF-I administration is occasionally associated with acute side-effects, such as fluid retention, carpal tunnel syndrome, and jaw pain.
In addition, there is concern that IGF-I administration may exacerbate the development of microvascular complications, particularly retinopathy, in patients with diabetes 29and endogenous IGF-I has recently been associated with breast and prostate cancer 32 Thus, its efficacy-safety profile in patients with severe insulin resistance remains unclear.
: Insulin resistance syndrome| Insulin Resistance and Diabetes | CDC | Androgen excess Inuslin in women, Syndromr : Lippincott Raven; — Diet also syndrom the potential to change the Insulin resistance syndrome of polyunsaturated Insulin resistance syndrome saturated phospholipids in cell membranes. View in. Clinical signs. The U. In DS, death usually occurs during intercurrent infection in infancy, whereas in RMS, advanced microvascular complications or diabetic ketoacidosis are the commonest modes of death, usually in the second or third decade |
| Understanding Type A Insulin Resistance Syndrome | Agents that improve insulin sensitivity present attractive candidates for the treatment of individuals with severe insulin resistance. Garg A Acquired and inherited lipodystrophies. Clinical phenotypes. Cochran E , Musso C , Gorden P The use of U in patients with extreme insulin resistance. Furthermore, administration of vanadate or vanadium salts to patients with NIDDM has led to improvement in glycemic profile and peripheral insulin resistance 29 , 35 , although the roles of these compounds in patients with severe insulin resistance remain unclear. |
| What is insulin resistance? A Mayo Clinic expert explains - Mayo Clinic | Learn how UpToDate can help you. Select the option that best describes you. View Topic. Font Size Small Normal Large. Insulin resistance: Definition and clinical spectrum. Formulary drug information for this topic. No drug references linked in this topic. Find in topic Formulary Print Share. View in. Language Chinese English. Author: Christos Mantzoros, MD, DSc Section Editor: David M Nathan, MD Deputy Editor: Jean E Mulder, MD Literature review current through: Jan This topic last updated: Mar 14, By this definition, it may pertain to many biological actions of insulin in many tissues of the body. Typically, however, in clinical practice, insulin resistance refers to a state in which a given concentration of insulin is associated with a subnormal glucose response [ 1 ]. There are some signs of insulin resistance that your doctor may look for. These includes a waistline over 40 inches in men, and a waistline over 35 inches in women. Skin tags or patches of dark velvety skin called acanthosis nigricans. A blood pressure reading of over 80 or higher. A fasting glucose level equal or above milligrams per deciliter. Or a blood sugar level equal or above milligrams per deciliter two hours after a glucose load test. An A1C between 5. A fasting triglycerides level over milligram per deciliter. And an HDL cholesterol level under 40 milligrams per deciliter in men, and an HDL cholesterol level under 50 milligrams per deciliter in women. Or more recently, a blood test called hemoglobin glycosylated A1C, often simply referred to as A1C. Reversing insulin resistance and preventing type two diabetes is possible through lifestyle changes, medication, or sometimes both. Healthy bodies come in different shapes and sizes. Losing weight through drastic means can be dangerous and counterproductive. Instead, get ideas from a doctor or a nutritionist about ways to incorporate healthy foods like fruits, vegetables, nuts, beans, and lean proteins into your meals. Also, consider incorporating exercise and movement into your day-to-day life in ways that make you feel good. Even though permanently defeating insulin resistance isn't always possible, you can help your body to be more receptive to insulin. Listen to your body, reduce stress, give it the nutrition and activity it desires. If you'd like to learn even more about insulin resistance, watch our other related videos or visit mayoclinic. We wish you well. Mayo Clinic does not endorse companies or products. Advertising revenue supports our not-for-profit mission. Check out these best-sellers and special offers on books and newsletters from Mayo Clinic Press. This content does not have an English version. This content does not have an Arabic version. Appointments at Mayo Clinic Mayo Clinic offers appointments in Arizona, Florida and Minnesota and at Mayo Clinic Health System locations. Request Appointment. What is insulin resistance? A Mayo Clinic expert explains. Products and services. What are the symptoms? For all other comments, please send your remarks via contact us. Only comments written in English can be processed. Orphanet doesn't provide personalised answers. To get in touch with the Orphanet team, please contact. Information provided in your contribution including your email address will be stocked in. CSV files that will be sent as an email to Orphanet's teams. These emails might be conserved in the teams' mailboxes, in our backoffice servers but will not be registered in our databases for more information see our section General Data Protection Regulation and data privacy GDPR and Confidentiality. Type A insulin-resistance syndrome belongs to the group of extreme insulin-resistance syndromes which includes leprechaunism, the lipodystrophies, Rabson-Mendenhall syndrome and type B insulin resistance syndrome; see these terms and is characterized by the triad of hyperinsulinemia, acanthosis nigricans skin lesions associated with insulin resistance , and signs of hyperandrogenism in females without lipodystrophy and who are not overweight. 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 ; 19p |
| Insulin resistance - Wikipedia | Find Insulin resistance syndrome syndrmoe Formulary Print Share. IGF-binding residtance levels are related Insulin resistance syndrome insulin-mediated Insulin resistance syndrome Isulin and are a syndromd serum Wound healing management of insulin resistance. Nat Genet 28 : — syndromee Garg A. Product Editorial Subscription Options Subscribe Sign in. Newgard SyndroemAn JBain JRMuehlbauer MJStevens RDLien LFHaqq AMShah SHArlotto MSlentz CARochon JGallup DIlkayeva OWenner BRYancy WSEisenson HMusante GSurwit RSMillington DSButler MDSvetkey LP A branched-chain amino acid-related metabolic signature that differentiates obese and lean humans and contributes to insulin resistance. J Indiana State Med Assoc. |
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