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 above
10 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 suggested
that 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
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 once
diabetes 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 be
considered.
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.