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Type a Insulin Resistance Syndrome and HAIR-AN

"Type A insulin resistance" [Fig. 1, case 2] encompasses lean women presenting

with SIR, manifesting as acanthosis nigricans, oligo/amenorrhoea, hirsutism and

acne, polycystic ovaries and often very high testosterone levels (sometimes above10 nmol/l).[24]They may exhibit postprandial hypoglycaemia without diabetes, or, if

diabetes is manifest, they may present as insulin dependent lean patients requiring

more than 200 units of insulin per day. Around 1020% of such patients have

identifiable insulin receptor mutations, which are often heterozygous with autosomal-

dominant inheritance.[8]Patients in whom receptor defects cannot be detected are

presumed to have as yet unidentified defects in postreceptor signalling.

Without genetic testing of all patients, it has been difficult to discriminate those with

insulin receptor mutations from the wider SIR group. It has recently been suggestedthat Sex Hormone Binding Globulin (SHBG), IGFBP1 and particularly adiponectin

have utility in identifying patients with receptoropathies biochemically prior to

targeted genetic screening.[25]These proteins are suppressed in other insulin-

resistant states but are normal or elevated in insulin receptoropathies.[26,27]A further

clue is the absence of dyslipidaemia and hepatic steatosis despite SIR. Insulin

receptor signalling may be essential for the development of these complications and,

to some extent, those with insulin receptoropathies are protected.[28]Nevertheless,

type A insulin resistance is far from benign, for as well as the cosmetic distress of

acanthosis nigricans and hyperandrogenism, subfertility is a major feature, and

insulin-resistant diabetes often eventually leads to microvascular complications and

early death.

The commonly used term "HAIR-AN", denoting hyperandrogenism, insulin

resistance and acanthosis nigricans, is a generic description of the features of SIR.

We have come to use it to refer to patients with SIR who are also obese and in

whom the rate of diagnosis of single-gene defects is much lower than in lean type A

patients. Obese patients with HAIR-AN syndrome are likely to harbour insulin

signalling defects, but the milder phenotype suggests that combinations of genes

may be involved requiring more sophisticated approaches to molecular resolution.

Low rates of genetic diagnosis in adult patients with SIR means that there is a

paucity of clinical trial data exploring optimal management in pathologically

homogeneous groups of patients. Clinical experience indicates that the sequence of

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metabolic compromise is similar to those in infants, albeit much less severe. Early

after presentation, postprandial hypoglycaemia may be the most intrusive symptom,

and acarbose may be effective in diminishing postprandial glucose excursion and

hypoglycaemia secondary to slow insulin clearance. Later, insulin sensitization is the

key treatment strategy, either pre-emptively to delay onset of diabetes or oncediabetes has supervened. Regular exercise and maintenance of a healthy weight

may improve glucose homoeostasis and reduce ovarian dysfunction. Metformin

should be introduced early if severe hyperinsulinaemia persists and can be

beneficial at high doses. Reports of thiazolidinedione use in SIR have been

inconsistent, and further data are required.[29,30]

If these preliminary strategies fail and diabetes develops, treatment with exogenous

insulin is required. Rapid escalation to high doses may be required and transition to

U500 insulin and possibly continuous subcutaneous insulin infusion should beconsidered.

It remains unclear whether the characteristically benign lipid profile of patients with

insulin receptor defects translates into a lower burden of macrovascular disease

than in other SIR groups, but it is clear that they suffer high rates of morbidity and

mortality related to complications of hyperglycaemia. Recent data suggest that

recombinant IGF-1 may reduce HbA1c levels and possibly improve beta cell function

in these patients in the short term, but longer-term studies are required [Fig.

2].[31]Similarly, alternative approaches to improving beta cell function with glucagon-like peptide-1 agonists or dipeptidyl peptidase-IV inhibitors are attractive on

theoretical grounds, but await formal evaluation in this setting.