13.3.5 Genetics of severe insulin resistance

As the prevalence of obesity burgeons, so the prevalence of insulin resistance follows. A small minority of patients have severe insulin resistance without obesity. These patients, while not contributing significantly to the general prevalence of diabetes, often harbour pathogenic single gene defects affecting insulin signalling or adipose tissue function. Clinical history and examination may offer strong clues to the presence of severe insulin resistance, but laboratory confirmation should usually be sought. Biochemical diagnostic thresholds for severe insulin resistance are arbitrary, and should, ideally, be defined relative to BMI-adjusted population normal ranges (Fig. 13.3.5.1). However, one set of approximate diagnostic criteria is as follows:

Insulin resistance is commonly noticed first in patients with persistent hyperglycaemia despite large doses of insulin. However, many cases are unrecognized in the prediabetic phase. Indeed, a very common early feature of severe insulin resistance is spontaneous and symptomatic postprandial hypoglycaemia, which may require medical intervention. This may dominate the clinical picture for years before hyperglycaemia supervenes, which only occurs in the face of β cell decompensation. However, the commonest presentation of monogenic severe insulin resistance is with severe acanthosis nigricans, which is nearly a sine qua non of all forms of severe insulin resistance, ovarian hyperandrogenism, which may be severe, and oligo- or amenorrhoea. Partly for this reason, a large preponderance of presenting patients are female. (Note: Some existing clinical nomenclature relating to severe insulin resistance is cumbersome, reflecting historical descriptions of the syndromes: type A insulin resistance syndrome, so named in the 1970s to discriminate it from the anti-insulin receptor antibody-mediated type B insulin resistance syndrome, refers to acanthosis nigricans, hyperandrogenism, oligo- or amenorrhoea and a BMI <30 kgm². The HAIR-AN syndrome, another commonly used label, denotes ‘HyperAndrogenism, IR and Acanthosis Nigricans’, and is thus essentially identical to the type A insulin resistance syndrome except that it has come to be used by convention only in women with BMI >30 kgm². This distinction is of some use, as there is a great enrichment of monogenic disease in slim very-insulin-resistant patients relative to their obese counterparts, however, there is considerable overlap between the two groups).

These clinical problems are common to all known forms of severe insulin resistance (Fig. 13.3.5.2), but are not generally seen in insulin-deficient forms of diabetes. It is thus concluded that their pathogenesis depends upon severe hyperinsulinaemia, likely leading to ectopic activation of the insulin-like growth factor 1 (IGF-1) receptor, which is closely homologous to the insulin receptor. This may be exacerbated by aberrant expression of both the IGF-1 receptor and some of the IGF1 binding proteins as a consequence of loss of insulin action. This mechanism, while not proven, seems plausible for components of the syndrome that feature cellular hyperproliferation, such as acanthosis nigricans and ovarian hyperthecosis.

No clear prevalence figures exist for monogenic severe insulin resistance. However, experience over 15 years in a single quaternary referral centre suggests that known genetic defects account for around 17% of severe insulin resistance in nonobese individuals presenting after 10 years old, with mutations in INSR and LMNA, encoding the insulin receptor and lamins A and C, respectively, accounting for the largest individual groups in adults (Table 13.3.5.1). The degree of insulin resistance in an individual with a monogenic defect is not invariant, and physiological or pathological influences that lead to insulin resistance often synergise with the inherited defect to exaggerate the clinical problem. Thus, puberty and the later stages of pregnancy, as well as intercurrent infection or illness, may, in some cases, lead to an increase in acanthosis nigricans and hyperandrogenism, and/or hyperglycaemia, which is resistant even to huge doses of exogenous insulin.

Genetic defects in INSR, the gene encoding the insulin receptor, produce a spectrum of clinical syndromes: the most severe are autosomal recessive disorders with infant or childhood mortality (1). Although they form a continuum, the historical labels ‘Donohue’ or ‘Rabson–Mendenhall’ syndromes are still commonly used (2, 3). Both feature characteristic dysmorphism and impaired linear growth. There is notably poor development of adipose tissue and muscle, which both rely on insulin-stimulated glucose uptake, contrasting with pseudoacromegaloid overgrowth of many other soft tissues. Hypertrichosis and exaggerated growth of androgen-dependent tissues may be particularly prominent. More difficult to diagnose clinically are the milder autosomal dominant insulin-receptor defects leading to type A insulin resistance, HAIR-AN (hyperandrogenism, insulin resistance, and acanthosis nigricans) syndrome, or their male equivalents. These are most commonly, though not invariably, caused by heterozygous intracellular mutations with dominant negative activity towards the co-expressed wild type allele (1).

Traditionally, it has been difficult to discriminate patients with type A insulin resistance due to INSR mutations from those with other aetiologies for their insulin resistance. However, by exploiting the biochemical differences between receptoropathies and other forms of severe insulin resistance, it is now possible to undertake biochemical triage with a high degree of accuracy prior to genetic testing, expediting genetic diagnosis of affected patients and avoiding unnecessary and expensive sequencing of the large INSR gene. Although insulin-responsive plasma proteins—such as sex hormone-binding globulin (SHBG) and insulin-like growth factor binding protein 1 (IGFBP-1)—have some utility for this purpose, levels of the adipose tissue-derived protein adiponectin are by far the most discriminating marker of receptoropathy (4). In receptoropathy, normal or elevated adiponectin levels are usually found in the face of extreme insulin resistance, quite unlike the suppressed levels seen in other insulin-resistant states (5) (Table 13.3.5.2). A further clinical clue to insulin receptoropathy is the absence of dyslipidaemia and hepatic steatosis despite severe insulin resistance (6). This interesting observation has also led to the inference that this component of the common ‘insulin resistance syndrome’ actually reflects exposure of intact arms of the insulin signalling pathway to high circulating insulin levels (Fig. 13.3.5.2).

Lipodystrophies are a heterogeneous group of conditions characterized by partial or complete absence of adipose tissue (7). They may be genetic or acquired, and are further classified according to the anatomical distribution of the lipodystrophy (Fig. 13.3.5.3). Insulin resistance is a feature of most, but not all, of these disorders and may be severe, with the clinical features of the type A insulin resistance syndrome in postpubertal patients. As with all forms of insulin resistance, the clinical expression is more pronounced in women.

Congenital generalized lipodystrophy (CGL), also known as Berardinelli–Seip congenital lipodystrophy (BSCL) (8, 9), is an autosomal recessive condition characterized by a generalized absence of adipose tissue from birth, increased appetite due to leptin deficiency (10), accelerated growth and advanced bone age. Skeletal muscles, peripheral veins, and the thyroid gland are particularly prominent, due to the paucity of subcutaneous fat. Hyperinsulinaemia from early childhood leads to organomegaly, acromegaloid features, and acanthosis nigricans. Diabetes tends to develop in the second decade. Hepatomegaly is often prominent and caused by severe nonalcoholic fatty liver disease (NAFLD), which generally progresses to nonalcoholic steatohepatitis (NASH), and, often, eventually to cirrhosis. Severe hypertriglyceridaemia, eruptive xanthomata, and pancreatitis are common.

In the vast majority of cases, BSCL is due to biallelic mutations in either the gene encoding 1-acylglycerol-3-phosphate O-acyltransferase 2 (AGPAT2), or the gene encoding seipin, an endoplasmic reticulum protein. AGPAT2 is an essential enzyme in glycerophospholipid and triacylglycerol synthesis, providing a ready explanation for the failure of adipose tissue development in patients with genetic defects in the AGPAT2 gene. The mechanistic link between seipin and lipodystrophy, however, is more obscure—although, recently, it has been shown to be highly expressed in white adipose tissue and to be essential for adipogenesis in vitro (11).

It is currently not possible to distinguish clinically between these genetic subgroups with confidence. However, adipose tissue loss in mechanical fat pads, such as the palms, soles, orbits, scalp, and periarticular regions, has been reported as a specific feature of BSCL due to seipin mutations (12).

Familial partial lipodystrophies (FPLD) are both milder and more common than CGL. Indeed, patients with these conditions may exhibit normal, or even increased, whole-body adipose stores. Consequently, crude indices such as the BMI have very limited utility in diagnosing FPLD. The abnormality instead lies in the adipose tissue topography, or fat distribution. In particular, head and neck adipose depots are often preserved or increased. Without fully exposing the patient, it is thus possible to form the erroneous impression of normal or increased adiposity. These disorders most commonly present in peri- or postpubertal women, and the loss of femorogluteal fat is particularly visually striking. They are very difficult to detect clinically in men and in prepubertal children. Metabolic abnormalities range from asymptomatic impaired glucose tolerance and mild dyslipidaemia to severe insulin resistance with type 2 diabetes mellitus and severe dyslipidaemia, eruptive xanthomata, and pancreatitis. NAFLD/ NASH is also very common. The FPLDs have been subclassified into three groups, as follows.

FPLD2 predominantly affects the limbs and gluteal fat depots with variable truncal involvement, but with normal or excess fat on the face, neck, and in the labia majora (13). A large majority of patients with FPLD2 have heterozygous loss-of-function mutations in LMNA, encoding lamin A/C, a structural component of the nuclear lamina which is nearly ubiquitously expressed. Remarkably, mutations in this gene have also been convincingly linked to several different disorders, including muscular dystrophy and dilated cardiomyopathy. Detailed understanding of the mechanisms underlying the tissue-selective phenotypes associated with LMNA mutations is lacking, but proposed abnormalities include structural defects in the nuclear envelope and altered binding of the nuclear lamina to chromatin or transcription factors.

FPLD3 also features a paucity of limb and gluteal fat; however, abdominal fat is generally preserved, and facial fat most commonly normal. Insulin resistance and lipodystrophy have been described in prepubertal children, although peripubertal presentation is most common. The very high prevalence of early onset hypertension helps to discriminate FPLD3 from FPLD2 (14). Loss-of-function mutations in the gene encoding peroxisome proliferator-activated receptor γ (PPARγ)—a nuclear hormone receptor critically required for adipose tissue development and targeted by thiazolidinedione insulin sensitizers—have been described in many patients with FPLD3. All pathogenic mutations described to date have been heterozygous, located in the DNA or ligand-binding domains of the protein, and displaying dominant negative activity in vitro (14, 15).

FPLD1 is characterized by loss of limb fat with preserved (and, frequently, increased) truncal fat, in a pattern reminiscent of that seen in Cushing’s syndrome. Whilst some of these patients do have affected family members, many do not, suggesting that not all cases are inherited; clinical observation suggests that additional factors, such as the menopause and hyperandrogenism, may be contributory. No specific genetic defects have been reported in this group.

In addition to these conditions where severe insulin resistance is the dominant clinical feature, there exists a group of syndromes that may exhibit severe insulin resistance which is disproportionate to total fat mass only as part of a more generalized disorder. These include Alström syndrome, various forms of primordial dwarfism, Mandibuloacral dysplasia, and some forms of progeria. Often in these conditions, acanthosis nigricans is the key clinical clue, and it is important that its clinical significance is recognized and that appropriate endocrine assessment is undertaken at an early stage of evaluation.

The principles of managing severe insulin resistance include early and intensive use of insulin sensitising agents, and lifestyle modification to include close adherence to a low-calorie, low-fat diet and as much aerobic exercise as reasonably possible. Dietary measures are particularly important in lipodystrophies, where they are crucial in preventing or delaying dyslipidaemia and diabetes. Where postprandial hypoglycaemia is symptomatic, acarbose may be efficacious. More recently, adjunctive use of subcutaneous leptin in patients who have secondary leptin deficiency due to lack of adipose tissue has proved highly effective, and recombinant IGF1 or composite preparations have some utility in severe insulin resistance. Nevertheless, these therapies should be introduced based on clinical and biochemical criteria, and establishment of the genetic defect should not influence therapeutic decision making significantly. The FPLDs are minor exceptions to this: it is logical to suppose that use of potent thiazolidinedione PPARγ agonists in patients with PPARG mutations may be particularly efficacious; however, despite some limited evidence for this in the case of particular mutations and novel agonists (16), this requires further study.