DEFINITION
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 and 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.
Some conditions that are categorized as receptor or postreceptor insulin-resistant states include the following:
EPIDEMIOLOGY
In the United States, the frequency of insulin resistance is observed to be 3% in the general population; a several-fold increase occurs in individuals with glucose intolerance.
A quarter of the world’s adults are considered to have the metabolic syndrome. Worldwide, early studies indicated a more significant association between insulin resistance and the various components of the metabolic syndrome in white persons than in members of other ethnic groups. Prevalence rates of insulin resistance syndrome reported for white populations ranged from 3-16%; a rate of less than 2% was reported among Japanese populations.
Subsequent findings, however, have suggested a similar relationship in many minority populations. Nevertheless, available systematic data apply mainly to white populations. Marked variations exist in methodologies and diagnostic criteria.
Age distribution
Type A insulin resistance typically occurs in younger patients. Women with polycystic ovary syndrome (PCOS) usually present in their mid-20s. Many rare disorders of insulin resistance present in early life (eg, leprechaunism and Rabson-Mendenhall [first year of life]).
The strongest relationship between insulin resistance and cardiovascular risk factors is observed in middle-aged persons rather than in older individuals, although cardiovascular morbidity and mortality increase with age.
Despite the growing obesity epidemic and insulin resistance in children, no clear diagnostic criteria and surrogate markers have been identified. An international consensus group recommended against screening children for insulin resistance in children based on existing methodology and criteria.
Sex distribution
The metabolic syndrome is more evident in middle-aged men. Women tend to assume increased cardiovascular risk after menopause. PCOS is a disease limited to women. Type A syndromes are typically found in women but can occur in men. Hyperandrogenism, insulin resistance, and acanthosis nigricans (HAIR-AN) syndrome has also been proposed as an alternative to type A in describing females with congenital forms of insulin resistance and acanthosis nigricans with ovarian hyperandrogenism but no other phenotypic changes such as growth retardation or lipodystrophy.
Prevalence by race
Insulin resistance syndrome is found in all races. The degree of clustering of the risk variables of the metabolic syndrome is generally considered to be higher among whites. However, prevalence rates of the various components of the metabolic syndrome tend to be higher among nonwhite populations.
Acanthosis nigricans, a common physical sign of insulin resistance syndrome, occurs in all ethnic groups, but the prevalence is higher in Hispanics and blacks than it is in whites.
DIAGNOSIS
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. The presentation of insulin resistance depends on the type and stage of the insulin-resistant state.
Type A insulin-resistance syndrome belongs to the group of extreme insulin-resistance 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 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 or ovarian hyperthecoses) leads to fertility problems.
Leprechaunism, the most severe of these syndromes, is characterized by intrauterine growth restriction, loss of glucose homeostasis,hyperinsulinemia, and dysmorphic features, with prominent eyes, thick lips, upturned nostrils, low-set posteriorly rotated ears, thick skin with lack of subcutaneous fat, distended abdomen, and enlarged genitalia in the male and cystic ovaries in the female. Cells from most patients with leprechaunism have absent insulin binding, although recent exceptions were reported.
Patients with the slightly less severe Rabson–Mendenhall syndrome have different dysmorphic features, with premature or dysplastic teeth and gingival hyperplasia. In addition, they present pineal hyperplasia. In both cases, children have initially postprandial hyperglycemia and fasting hypoglycemia. The paradoxical fasting hypoglycemia is caused by inappropriately elevated insulin levels at the time of fasting, due to the excessive production of insulin by the pancreas of these patients, coupled to the prolonged half-life of the hormone for the inability of peripheral tissues to bind and remove circulating insulin.
Patients with Rabson–Mendenhall syndrome survive beyond 1 year of age and, with time, develop constant hyperglycemia followed by diabetic ketoacidosis and death.
PATHOGENESIS
The human IR is encoded by a 22-exon gene (Ir) spanning 120 kb that is located on chromosome 19.
Although the major insulin target tissues are liver, adipose tissue, and skeletal muscle, IRs have also been found in the brain, heart, kidney, pulmonary alveoli, pancreatic acini, placenta vascular endothelium, monocytes, granulocytes, erythrocytes, and fibroblasts. The observation that IRs are not restricted to insulin target tissues suggests that IRs may be functionally linked to multiple systems, in addition to their known role in the metabolic actions of insulin. The findings of both metabolic and nonmetabolic effects of IRs are supported by the effects of insulin on embryonic development. Briefly, pancreatic islet β-cell secretory granules have been observed in the human fetus at 14 wk gestation, and IRs have been detected in the liver as early as 15 to 18 wk gestation. Furthermore, monocytes and erythrocytes from human cord blood have higher IR content than similar cells harvested from adult individuals. Moreover, the fetal IR is not down-regulated by hyperinsulinemia; rather, hyperinsulinemia is associated with increased IR content in cord blood monocytes. In accordance with the notion that insulin may regulate fetal growth, fetal hyperinsulinemia leads to macrosomia, whereas insulin deficiency leads to growth impairment . After birth, IR expression in monocytes and erythrocytes decreases, remains unchanged until puberty, and then increases in adult life. In accordance with the inhibitory effect of estrogens on Ir promoter activity, monocyte IR content is higher during the luteal phase in adult females. This elevation is abolished by use of oral contraceptives or pregnancy. Moreover, glucocorticoids and thyroid hormones have been reported to enhance IR expression.
The IR protein is a heterotetramer consisting of two extracellular {alpha}-subunits and two transmembrane β-subunits held together by disulfide bonds. The {alpha}-chain and 194 residues of the β-chain form the extracellular portion of the IR; in the β-chain, there is a single transmembrane sequence and a 403-residue cytoplasmic domain containing the tyrosine kinase activity (Fig). Ligand binding to the IR {alpha}-subunit stimulates tyrosine kinase activity intrinsic to the β-subunit of the receptor . The {alpha}- and β-chains are both synthesized from a unique mRNA, which is constituted by 22 exons. Ir mRNA encodes for a protein of 1370 amino acids, indicating a predicted molecular mass of 153,917 Da. The protein is cleaved by furin into {alpha}- and β-subunits. The {alpha}-subunit contains 723 amino acids, with a molecular mass of 130 kDa. The β-subunit contains 620 amino acids, with a molecular mass of 95 kDa. Both subunits are glycosylated, thus accounting for most or all of the molecular mass difference in the observed vs. predicted values in various tissues and cells.
Comparative sequence analyses have shown that the IR family members are composed of a number of different, repeated structural units. The N-terminal half of each ectodomain monomer consists of two homologous leucine-rich repeat domains (L1 and L2) of approximately 150 amino acids each, separated by a cysteine-rich region (CR), consisting of seven smaller repeats, also containing approximately 150 residues, with one or two disulfide bonds (Fig.). The C-terminal half of each ectodomain monomer (approximately 460 residues) consists of three fibronectin type III domains (FnIII-1, FnIII-2, and FnIII-3). They are relatively small (approximately 100 amino acids) and form a seven-stranded β-sandwich. The FnIII-2 domain of IR contains a large, 120-amino acid residue fragment, termed the insert domain (ID), and the furin cleavage site (Fig.).The IR splice variant IR-B differs from IR-A by the presence of a 12-amino acid segment (coded by exon 11) inserted between IR-A residues 716 and 717, three residues before the C-terminus of the {alpha}-chain.The intracellular part of each IR monomer contains a tyrosine kinase domain flanked by two regulatory regions (the juxtamembrane region and the C-tail) that contain the phosphotyrosine binding sites for signaling molecules. In particular, the juxtamembrane region is involved in docking IR substrates (IRS) 1–4 and Shc, as well as in receptor internalization.
Analysis of insulin binding to IR reveals curvilinear Scatchard plots and negative cooperativity , thereby implying the existence of both low-affinity and high-affinity insulin binding sites. These two different ligand-binding regions are termed site 1 (low-affinity site) and site 2 (high-affinity site). Photo-affinity labeling and alanine scanning data indicate that insulin binds to the site composed of the L1 domain and {alpha}-subunit C-terminal peptide sequence (amino acids 704–715, CT domain) (Fig.). A second binding site exists within the C-terminal part of L2 and the first FnIII domain (Fn0). Insulin binds first to the low-affinity site (site 1) on one {alpha}-subunit and then to the second site (site 2) of the other IR {alpha}-subunit . A second insulin molecule bridging both leftover sites 1 and 2 accelerates dissociation of the first bound insulin molecule. This behavior explains the bell-shaped curve and negative cooperativity and provides a molecular basis for receptor tyrosine kinase activation, by approximating the two-kinase domains and permitting transphosphorylation. The biological role of IR-negative cooperativity is an interesting issue. The acceleration of the dissociation rate of the IR complex by increased insulin concentration is important for insulin actions. Indeed, the mitogenic effects of insulin are disproportionately enhanced by insulin analogs that have slower dissociation rates relative to native human insulin, suggesting that the negative cooperativity is important for limiting the mitogenic effects of insulin. Computational Boolean analyses have demonstrated that ligand residence time on the IR may indeed determine choices in branching signaling pathways.
The three-dimensional structure of the IR ectodomain dimer has allowed for better understanding of the localization of insulin binding sites 1 and 2. Each monomer of the IR ectodomain exhibits an inverted-V arrangement relative to the cell membrane, with the L1-CR-L2 domains forming one leg and the three FnIII domains forming the other one. In the dimer, the second monomer is related to the first by a 2-fold rotation around the axis of the inverted V, with the L1-CR-L2 domains of one monomer packed against the three FnIII domains of the other (Fig.). At the apex of the inverted V, the L2 domain of each monomer contacts the FnIII-1 domain of the other, whereas the base of the C terminus of the FnIII-3 domains is oriented in such a way that it is capable of being extended through the cell membrane to the kinase domains of the intact receptor. The first component of site 1 in both {alpha}-subunits is the central β-sheet of L1. The second component of site 1 is formed by the central modules of the CR. The larger size of this module in IR is partly responsible for the lower IR affinity of the bulkier IGF-I and IGF-II ligands compared with its affinity for insulin (Fig.). The third component of site 1 is the CT peptide, as demonstrated by chemical cross-linking. The CT peptide sequence, belonging to the other IR monomer, is closely juxtaposed to the L1 domain of the contralateral IR monomer and contacts amino acid B25 of the insulin molecule (Fig.). It is reasonable to suppose that the exon 11-encoded 12-amino acid peptide present in IR-B may contribute, together with the CR module, to reduce the affinity of IR-B for IGF-II by further restraining the site 1 pocket. Site 2 is formed by the C-terminal loops of FnIII-1 and the N-terminal loops of FnIII-2 that are adjacent to the L1 face. The three-dimensional structure of the IR may explain the contribution of each domain to insulin binding and the complexity of the binding characteristics of the IR isoforms and IR/IGF-IR hybrids.
In the insulin-free state, the inhibitory IR conformation maintains a minimum separation between the two intracellular tyrosine kinases. This distance between the tyrosine kinases prevents the tyrosine kinase activation loop of one tyrosine kinase from reaching the catalytic transphosphorylation site of the other tyrosine kinase (Fig.). Binding of a single insulin molecule joins the two ectodomains with a consequent reduction of separation between the associated tyrosine kinase domains, thereby allowing transphosphorylation of the tyrosine kinase activation loops at the catalytic loci of the opposing tyrosine kinase domains. Phosphopeptide mapping techniques have resolved tyrosine kinase residues (in the juxtamembrane region: amino acids 953, 960, and/or 972; in the catalytic domain: 1146, 1151, and 1152; and in the carboxyterminal domain: 1316 and 1322) (Fig.). The most important domain for auto- and transphosphorylation is the catalytic domain (amino acids 1146, 1151, and 1152). Phosphorylation of these sites correlates with the acquisition of transphosphorylation activity.
Carboxyterminal deletions lacking either 43 amino acids or mutants with tyrosine residues 1316 and 1322 changed to phenylalanines have normal tyrosine kinase activity and diminished autophosphorylation due to loss of the two tyrosine residues. However, these mutant , show diminished or unchanged glucose uptake and glycogen synthase activity. In the juxtamembrane region of the β-subunit, Tyr-960 is important for IRS-1 phosphorylation and for metabolic and mitogenic responses to insulin, whereas Tyr-953 and Tyr-960 play a role in receptor endocytosis because they exist within consensus endocytosis signals for internalization via clathrin-coated pits.
Insulin binding to the IR extracellular {alpha}-subunit induces a conformational change in the receptor molecule, which brings the two β-subunits into close opposition.
Crystallographic studies of the IR kinase domain in the unphosphorylated and phosphorylated states indicate that autophosphorylation activates the IR tyrosine kinase due to a series of alterations in the β-subunit conformation that facilitate ATP binding, β-subunit phosphorylation, recruitment of membrane and cytosolic protein substrates, and their subsequent phosphorylation.The activated IR tyrosine kinase phosphorylates several intracellular substrates, including the most extensively characterized IR substrates (IRS-1, -2, -3, and -4), IRS-5/DOK4, IRS-6/DOK5, Shc, Gab1, Cbl, associate protein substrate (APS), and the signal regulatory protein family members.
Each of these phosphorylated proteins provides specific docking sites for effectors containing Src homology 2 (SH2) domains that specifically recognize different phosphotyrosine residues, including the regulatory subunit p85 of type 1A PI3-kinase (PI3K); the protein tyrosine phosphatase SHP2; the Src family of non-receptor-type tyrosine kinases, including Fyn and Csk; the adaptor proteins Grb2; and the GTPase activating protein of Ras. Some of these molecules contain SH3 domains that bind proline-rich regions with the consensus sequence PXXP and thereby provide additional sites for protein-protein interactions with additional downstream intracellular effectors. In this complex cascade of biochemical signals, two major signaling pathways have been recognized, mediating either prevalent metabolic or mitogenic effects and originating by the activation of PI3K or Ras, respectively.
Insulin exerts a wide range of pleiotropic actions at the target tissue such as cellular metabolism, growth and differentiation, via different signaling pathways. Binding of insulin to extracellular α subunits of insulin receptor (INSR) leads to activation of intrinsic tyrosine kinase and autophosphorylation of its β subunits. Activated INSR phosphorylates a number of substrates like the insulin receptor substrate family (IRS 1-4), Gab-1, Cbl, APS and Shc isoforms, and signal regulatory protein (SIRP) family members which bind to INSR29. Phosphorylated IRS proteins act as docking sites for several intracellular proteins such as Grb2, NcK and the regulatory subunit p85 of phosphatidylinositol 3-Kinase (PI3K), which mediate different actions of insulin. PI3K activation is crucial for metabolic actions, such as GLUT4 translocation, glucose transport, glycogen synthesis and protein synthesis, however the downstream signaling proteins of PI3K pathway is still not clear, probably it activates Akt and atypical PKC isoforms λ and ζ. A substrate of Akt, AS160 is involved in GLUT4 translocation from intracellular vesicles to the plasma membrane, which results in rapid entry of glucose into the cell22. Another pathway leading to GLUT4 translocation involvespathway leading to GLUT4 translocation involves the insulin receptor-mediated phosphorylation of the scaffolding protein CAP (c-Cbl Associated Protein) and formation of the CAP:Cbl:CrkII complex. This complex, through its interaction with flotillin, localizes to lipid rafts facilitating GLUT4 translocation30. The mitogenic action is mediated through binding of phosphorylated IRS1/2 or Shc with Grb-2/SOS complex leading to p21Ras and Raf-1 activation of mitogen-activated protein kinase pathway (MAPK)21. PI3K probably facilitates the mitogenic response as well.
Cells from patients with extreme insulin resistance had defective insulin binding.
This defect was complete in cells from patients with leprechaunism and incomplete (with 18–27% residual binding) in fibroblasts or lymphoblasts from patients with Rabson–Mendenhall syndrome. Sequence analysis and expression studies in CHO cells confirmed that the mutations in the insulin receptor gene identified in these patients affected insulin binding.
Patients whose cells failed to bind insulin were homozygous or compound heterozygous for mutations abolishing insulin binding, either for the premature insertion of a stop codon or for a structural alteration in the insulin receptor preventing insulin binding. All the nonsense mutations identified in some study (E124X, 650X, 665X, 682X and R372X) were associated with greatly reduced insulin receptor mRNA levels. Other mutations in the insulin receptor gene resulting in premature stop codons also reduce insulin receptor mRNA levels. Patients homozygous for nonsense mutations in the insulin receptor gene (855X) had normal mRNA levels . Homozygous for the R786X nonsense mutation had absent PCR amplification of insulin receptor cDNA , while RNA was not evaluated in the third patient homozygous for the K121X nonsense mutation. Thus, reduced mRNA levels are not necessarily associated with nonsense mutations in the insulin receptor gene.
Some nonsense mutations were the result of single nucleotide changes, and others the result of frameshifts or small deletions or insertions. Natural mutations reported in the insulin receptor gene introduce 10 UGA , 5 UAG, and 1 UAA premature termination codons. There was no clear association between specific types of stop codons and effect on mRNA levels. Reduced insulin receptor mRNA or cDNA was associated with E124X, W133X, R372X, 650X, 665X, C682X, R786X, 801X, R897X, R1000X and 1118X mutations. By contrast the presence of normal levels of insulin receptor mRNA or cDNA was reported with the 34X, R86X, Q672X and 855X mutations. Importantly, multiple nonsense mutations within exons 2 (R86X, E124X and W133X) and 10 (665X, Q672X and C682X) had a discordant effect on mRNA levels, with two mutations (R86X and Q672X) not reducing transcript levels. The reduction of mRNA levels with premature termination codons occurs through nonsense-mediated RNA decay and is not expected to result in protein formation. Termination codons located more than 55 nucleotides upstream of the 30- most exon–exon junction usually mediate nonsense-mediated mRNA decay. The recognition of abnormally terminated mRNA is probably mediated by ribonucleoproteins that, at time of splicing, bind close to the exon–exon junction and flag to the mRNA surveillance machinery messages prematurely terminated. The additional nonsense mutations identified in this study, when added to those already known in the insulin receptor gene, indicate that the mechanism seems more complex and that there are other factors, in addition to the location of the premature stop codon, that are important determinants of RNA stability. The study of the effect on RNA stability of these and other natural nonsense mutations can shed light on the nature of these factors. The missense mutations identified in patients with leprechaunism and shorter survival affected the extracellular portion of the insulin receptor and abolished or markedly reduced insulin binding.
The A92V mutation identified is located close to the R86P mutation and one of the major insulin binding sites of the receptor. The DN281 mutation was associated with absent insulin binding to the patient’s cells in one study, but near-normal insulin binding in another study. Insulin-binding studies in fibroblasts can be difficult to interpret given the low levels of expression of the insulin receptor gene. The I898T and R899W mutations are located in the extracellular portion of the b subunit of the insulin receptor and close to the T910M mutation identified in another patient with leprechaunism. The T910M mutation was found to affect insulin binding by impairing receptor processing, and it is likely that the two novel mutations identified in this study reduce insulin binding via a similar mechanism. The R1131W mutation, identified in two unrelated patients with Rabson–Mendenhall syndrome, abolished insulin binding when expressed in CHO cells despite its intracellular location. Three other mutations in intracellular residues (P970T, I1116T and R1174W) reduced insulin binding to about 50% of normal. Therefore, even intracellular mutations in the insulin receptor can reduce insulin signaling by impairing, at least in part, insulin binding. The R1174W mutation was previously identified in a patient with leprechaunism, and was found not to impair insulin binding in transiently transfected CHO cells when binding was normalized to receptor number. However, the R1174W-mutant receptors were degraded more rapidly than normal receptors. This might result in reduced steady-state levels of insulin receptors on the plasma membrane, resulting in the decrease in insulin binding reported here in the patient’s cells and in transfected CHO cells. The P970T, I1116T and R1174W substitutions prevented insulin stimulation of glucose transport, indicating their causative role in the insulin resistance observed. The mechanism by which this occurs has not yet been defined. These substitutions affect conserved domains of the insulin receptor and are predicted to impair either the kinase activity of the receptor or its interaction with intracellular substrates. Specifically, the P970T mutation affects the consensus sequence for the binding of insulin receptor substrate 1 (IRS-1), and is the first natural mutation reported in such an important area of the insulin receptor. The I1116T substitution affects an a-helical region to which the catalytic loop of the insulin receptor kinase is attached. A hydrophobic amino acid is present in this position in a number of tyrosine kinases, including the epidermal growth factor, platelet-derived growth factor and fibroblast growth factor receptors (EGFR, PDGFR and FGFR), and the tyrosine kinases c-Src, c-Abl and cAPK. The R1174W substitution affects the activation loop of the tyrosine kinase domain of the insulin receptor. A positively charged amino acid in this position is conserved among several tyrosine kinases as well. Previous studies of this latter mutation have confirmed that the R1174W substitution abolishes insulin-stimulated receptor autophosphorylation and kinase activity. Taken together, this data indicate that the most severe phenotype with early demise was observed when both mutations completely abolished insulin binding and subsequent insulin action. By contrast, when one mutation retained residual insulin-binding activity, the survival was longer. While the majority of patients reported to date seem to fit within this classification, there are notable exceptions. There are patients with leprechaunism in whom the mutations affect the intracellular portion of the insulin receptor. However, in one case, the mutations identified were not expressed in CHO cells, and an effect on insulin binding cannot be excluded in view of our results with the R1131W mutation. In the second case, the patient was older than 1 year of age at the time of the study and an affected brother died at 7 years of age with the same syndrome, despite a phenotype of leprechaunism. The prolonged survival of patients with leprechaunism within this family indicates that residual insulin binding (and probably action) correlates with survival, rather than the specific phenotype of leprechaunism or Rabson–Mendenhall. Therefore, the two diseases should be considered as a continuous of a spectrum, in which the specific mutation and the degree of impairment of insulin action predicts survival, rather than the type of syndrome.
Type A insulin resistance was initially characterized in young female patients with acanthosis nigricans, ovarian hyperandrogenism and virilization. Over 30 mutations have so far been described in these patients, which are mainly clustered in the tyrosine kinase domain of the insulin receptor. A nonsense mutation was identified in one allele of a patient substituting the termination codon (TGA) for the CGA codon normally encoding Arg331 located in a putative L2 domain, which is a single stranded righthand beta-helix and is suggested to make up the bilobal ligand binding site. The nonsense mutation at codon 331 truncated the C-terminal half of the receptor α subunit as well as the entire β subunit including the transmembrane anchor and the tyrosine kinase domain. Therefore, it is unlikely that this truncated receptor, translated from the mutant allele, would be either functional or located on the cell surface. In fact, extreme insulin resistance was observed in a female leprechaunism patient with homozygous R331X alleles. R331X mutant defects one important domains for endocytosis of insulin-insulin receptor complex. A reduction of endocytosis may also affect recycle of insulin receptor and may cause prolonged low hepatic extraction after glucose oral load observed in subjects having R331X mutation.
Some patients with type A diabetes also haveother mutations in their insulin receptor gene. Siblings from Japan who were products of a consanguineous mating were homozygous for a mutation in bp 2424 which converted Arg735 into Ser. This substitution produced a loss of the proteolytic cleavage site between the a and the β subunit. It generated a defective, unprocessed polypeptide chain. In another consanguineous family, the mutation at bp 1363 of the insulin receptor cDNA converted Phe382 into Val. This substitution caused impaired post-translational receptor processing and markedly reduced the number of insulin receptors on the plasma membrane.
THERAPY
Standard therapies: about Leprechaunism and Rabson-Mendenhall syndrome the treatment is generally supportive. The goal is maintain blood glucose levels as constantly as possible with the use of frequent or continuous feeds and complex carbohydrates. Insulin is not effective at normal doses, minimal effects on glucose levels can be seen with extra large doses of insulin (up to 9 U/kg per hour).
Type A insulin resistant patients diabetes may be managed by diet and/or insulin or other medications, as required. Cosmetic measures (e.g., waxing, electrolysis) can be used to facilitate hair removal. For younger women with PCOS, treatment with an oral contraceptive is the most common therapy, whereas for postmenopausal women, hormone replacement therapy is usually recommended. Antiandrogens have also been used.
Investigational therapies: about Leprechaunism and Rabson-Mendenhall syndrome the the use of insulin sensitizers (thazolidinediones and metformin) to improve residual insulin action is under investigation. Insulinlike growth factor 1 at high doses in divided doses or as continuous subcutaneous infusion has been effective in a few patients.
About Type A insulin resistant patients, insulin-sensitizing agent (i.e., metformin) are being investigated as a treatment for hyperandrogenism accompanying insulin resistance.
