Insulin resistance syndromes
Insulin resistance is widely thought to account for the tight association between obesity and type 2 diabetes. Obesity is the major driving force behind the burgeoning prevalence of insulin resistance, and in some obese patients this is severe; a small minority of patients have severe insulin resistance without obesity. These often harbour pathogenic single gene defects affecting insulin signalling or adipose tissue function. Clinical history and examination may suggest the presence of severe insulin resistance, but laboratory confirmation is generally required. The clinical presentation of severe insulin resistance is with hyperglycaemia associated with very high circulating endogenous or exogenous insulin levels, sometimes preceded by hypoglycaemia in the prediabetic period. Acanthosis nigricans and skin tags form at skin creases, and insulin resistance may present with oligomenorrhoea or amenorrhoea in women. Monogenic disorders fall into two types: the "insulin receptoropathies" characterized by defects in canonical insulin signalling components, and the lipodystrophies characterized by primary defects in adipose tissue. Treatment includes include early and intensive lifestyle modification as well as the use of insulin sensitising agents (particularly metformin). Dietary measures are of particular importance in ameliorating dyslipidaemia and diabetes associated with the lipodystrophies.
Biochemical diagnostic thresholds for severe insulin resistance (IR) are arbitrary, and should ideally be defined relative to BMI-adjusted population normal ranges, however one set of approximate diagnostic criteria is as follows:
- Non-diabetic and B.M.I. <30 kg/m2
- Fasting insulin above 150 pmol/l OR
- Peak insulin on oral glucose tolerance testing above 1,500 pmol/l
- Absolute insulin deficiency and B.M.I. <30 kg/m2
- Exogenous insulin requirement > 3U/kg/day.
- Partial beta cell decompensation and/or B.M.I. >30 kg/m2
Insulin levels are more difficult to interpret in the context of obesity or pre-existing diabetes, where glucotoxicity, and mixtures of endogenous and exogenous insulin in the circulation confuse the biochemical picture. In these settings the clinical history and features such as acanthosis nigricans are particularly useful in making a diagnosis of likely monogenic severe IR. Subjective clinical judgement is also required.
Generic clinical features of severe insulin resistance
Figure 1: Axillary acanthosis nigricans and skin tags in a patient with severe insulin resistance.Severe insulin resistance (IR) usually presents in one of three ways:
Persistent hyperglycaemia despite large doses of insulin in patients with diabetes - Note, however, that many cases are unrecognised in the prediabetic phase. Indeed, a very common early feature of severe IR is spontaneous and symptomatic postprandial hypoglycaemia which may require medical intervention. This may dominate the clinical picture for years before hyperglycemia supervenes, which only occurs in the face of beta cell decompensation.
Acanthosis Nigricans - The commonest presentation of monogenic severe IR is with the skin condition acanthosis nigricans (Figure 1).
Ovarian hyperandrogenism, or “Polycystic Ovary Syndrome” - This may be severe, and oligo- or amenorrhoea are frequently the first sign of severe IR in young women.
These clinical problems are common to all known forms of severe insulin resistance. The degree of IR in an individual with a monogenic defect can vary considerably in response to physiological or pathological influences that typically induce a degree of insulin resistance in healthy people. Thus weight gain, puberty and the later stages of pregnancy as well as intercurrent infection or illness may exacerbate the problem. These patients also tend to be exquisitely sensitive to dietary indiscretion and can manifest dramatic metabolic deterioration (particularly dyslipidaemia) in response to high calorie and high fat meals.
KNOWN GENETIC CAUSES OF SEVERE INSULIN RESISTANCE
Monogenic syndromes can be broadly categorised as those syndromes related to defects in canonical insulin signalling components (predominantly the insulin receptor itself, for which we tend to use the term ‘insulin receptoropathy’) or to i.e. lipodystrophies. This classification is largely based on currently defined disorders and may well be revised as further syndromes are linked to specific gene defects.
Genetic mutations in the INSR gene that impair function of the insulin receptor produce a range of clinical problems : the most severe are autosomal recessive disorders with infant or childhood mortality. The historical labels Donohue  or Rabson Mendenhall  Syndromes are still commonly used, based on the initial clinical descriptions long before the insulin receptor was identified, but in truth insulin receptor disorders produce a continuous range of insulin resistance, of which these are only two “snapshots” at the severe end.
Both feature dysmorphism and impaired linear growth. There is poor development of adipose tissue and muscle, which rely on insulin-stimulated glucose uptake, but marked overgrowth of many other soft tissues. Hypertrichosis and exaggerated growth of androgen-dependent tissues may be particularly striking. More difficult to diagnose clinically are the milder autosomal dominant insulin receptor defects leading to Type A IR, HAIR-AN (hyperandrogenism, insulin resistance – acanthosis nigricans) or their male equivalents. These are most commonly caused by heterozygous mutations in the INSR gene with dominant negative activity towards the co-expressed wild type allele .
Table 1. Clinical and biochemical features of common forms of insulin resistance (IR) compared to what is typically seen in patients with either ‘insulin receptoropathies’ or lipodystrophy.Traditionally it has been difficult to discriminate patients with type A IR due to INSR mutations from those with other forms of non lipodystrophic severe IR. However the biochemical differences between receptor defects and other forms of severe IR can now be used to preselect patients for genetic testing with a high degree of accuracy (see Table 1).
This speeds up genetic diagnosis and avoids unnecessary and expensive sequencing of the large INSR gene. Although insulin-responsive proteins such as SHBG and IGFBP-1 can also be used for this purpose, levels of the fat-derived protein adiponectin are the most reliable marker of receptoropathy . In INSR defects normal or elevated adiponectin levels are usually found in the face of extreme IR, unlike the suppressed levels seen in other insulin resistant states . A further clinical clue to insulin receptoropathy is the absence of dyslipidaemia and hepatic steatosis despite severe IR .
Primary lipodystrophic syndromes
Lipodystrophies are a heterogeneous group of conditions characterized by partial or complete absence of adipose tissue . They may be genetic or acquired (not discussed herein – see reference  for more detail on these disorders), and are further classified according to the anatomical distribution of the lipodystrophy. IR is a feature of most, but not all, of these disorders and may be severe, with the clinical features of the Type A IR syndrome in postpubertal patients. As with all forms of IR the clinical expression is more pronounced in women and the disease is readily overlooked in men with partial LD. The presence of dyslipidaemia in a patient with severe insulin resistance is a useful prompt to at least carefully consider the possibility of lipodystrophy. Diagnosis remains largely clinically based but assessment of fat mass and distribution by either dual energy X-ray absorptiometry (DEXA) or magnetic resonance imaging (MRI) may be helpful in documenting fat mass and distribution.
Congenital generalised lipodystrophy (CGL), also known as Berardinelli-Seip congenital lipodystrophy (BSCL) is an autosomal recessive condition characterized by a generalized absence of adipose tissue from birth, increased appetite due to leptin deficiency, accelerated growth and advanced bone age. Skeletal muscles and peripheral veins 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 (although some children have presented with diabetes within their first year). Hepatomegaly is often prominent and caused by severe non-alcoholic fatty liver which generally progresses to non-alcoholic 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 (BSCL2), an endoplasmic reticulum protein. AGPAT2 is an essential enzyme in glycerophospholipid and triacylglycerol synthesis. The mechanistic link between seipin and lipodystrophy, however, remains more obscure. Biallelic mutations in CAV1 and PTRF have also recently been linked to CGL phenotypes.
It is currently not possible to confidently distinguish clinically between these genetic subgroups, 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 BSCL2 mutations . Adiponectin levels are also reported to be higher in patients with BSCL2 mutations than in those with AGPAT2 mutations .
Familial partial lipodystrophies (FPLD) are both milder and more common than CGL. Indeed, patients with these conditions may exhibit normal or even increased fat mass. Consequently crude indices such as the B.M.I. have very limited utility in diagnosing FPLD. The abnormality instead lies in the fat distribution. These disorders most commonly present in peri- or postpubertal women, in whom 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 T2DM and severe dyslipidaemia, eruptive xanthomata and pancreatitis. NAFLD/ NASH is also very common. The FPLDs have been subclassified into three groups:
FPLD1 is characterised 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, and clinical observation suggests that additional factors such as the menopause and hyperandrogenism may be contributory. No specific genetic defects have been reported in this sizable group.
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. 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. Some patients manifest overlapping features of these different ‘laminopathies’. Detailed understanding of the mechanisms underlying the tissue-selective phenotypes associated with LMNA mutations is currently lacking.
FPLD3 also features a paucity of limb and gluteal fat, however abdominal fat is generally preserved, and facial fat often normal. Insulin resistance and lipodystrophy have been described in prepubertal children, although peri-pubertal presentation is most common. Early onset hypertension may help to discriminate FPLD3 from FPLD2 but is not always present in FPLD3 and can be a feature of FPLD2. Loss-of-function mutations in the gene encoding 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 .
Heterozygous mutations in AKT2, ZMPSTE24 and PLIN1 (FPLD4) have also been reported in patients with autosomal dominant FPLD and one patient with autosomal recessive PLD was found to have a homozygous premature stop mutation in CIDEC.
Complex syndromes featuring severe insulin resistance
In addition to these conditions where severe IR is the dominant clinical feature, there is a group of syndromes which may exhibit severe IR as part of a more generalised disorder. These include Alstrom’s syndrome, various forms of primordial dwarfism, Mandibulo-acral dysplasia (MAD), and some forms of progeria. In these conditions acanthosis nigricans is often the key clinical clue, and it is important that genetecists and others recognise its clinical significance.
Principles of management of severe insulin resistance
The principles of managing severe insulin resistance include early and intensive lifestyle modification as well as the use of insulin sensitising agents (particularly metformin). Dietary measures are particularly important in lipodystrophies where they are crucial/ essential in ameliorating dyslipidaemia and diabetes. Personal experience suggests that without strict dietary compliance most patients with lipodystrophy will struggle to control their dyslipidaemia and diabetes. Other syndromes of severe IR also appear to be particularly responsive to dietary modification. Dietary management in lipodystrophic patients needs to emphasize both total calorie- and fat restriction. The former is frequently inadequately emphasized by specialist dieticians, presumably in response to the ‘lean’ appearance of these patients. In addition to diet, dyslipidaemia management should follow conventional guidelines in most patients.
Where postprandial hypoglycaemia is symptomatic, acarbose may be efficacious. More recently use of subcutaneous leptin in patients who have secondary leptin deficiency due to lipodystrophy 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, this requires further study.
^ Semple RK, Savage DB, Cochran EK, Gorden P, O'Rahilly S. Genetic syndromes of severe insulin resistance. Endocr Rev. 2011 Aug;32(4):498-514.
^ Taylor SI, Cama A, Accili D, Barbetti F, Quon MJ, de la Luz Sierra M, et al. Mutations in the insulin receptor gene. Endocr Rev. 1992 Aug;13(3):566-95.
^ Donohue WL, Uchida I. Leprechaunism: a euphemism for a rare familial disorder. J Pediatr. 1954 Nov;45(5):505-19.
^ Rabson SM, Mendenhall EN. Familial hypertrophy of pineal body, hyperplasia of adrenal cortex and diabetes mellitus; report of 3 cases. Am J Clin Pathol. 1956 Mar;26(3):283-90.
^ Semple RK, Cochran EK, Soos MA, Burling KA, Savage DB, Gorden P, et al. Plasma adiponectin as a marker of insulin receptor dysfunction: clinical utility in severe insulin resistance. Diabetes Care. 2008 May;31(5):977-9.
^ Semple RK, Soos MA, Luan J, Mitchell CS, Wilson JC, Gurnell M, et al. Elevated plasma adiponectin in humans with genetically defective insulin receptors. J Clin Endocrinol Metab. 2006 Aug;91(8):3219-23.
^ Semple RK, Sleigh A, Murgatroyd PR, Adams CA, Bluck L, Jackson S, et al. Postreceptor insulin resistance contributes to human dyslipidemia and hepatic steatosis. J Clin Invest. 2009 Feb;119(2):315-22.
^ Garg A. Acquired and inherited lipodystrophies. The New England journal of medicine. 2004 Mar 18;350(12):1220-34.
^ Simha V, Garg A. Phenotypic heterogeneity in body fat distribution in patients with congenital generalized lipodystrophy caused by mutations in the AGPAT2 or seipin genes. J Clin Endocrinol Metab. 2003 Nov;88(11):5433-7.
^ Antuna-Puente B, Boutet E, Vigouroux C, Lascols O, Slama L, Caron-Debarle M, et al. Higher adiponectin levels in patients with Berardinelli-Seip congenital lipodystrophy due to seipin as compared with 1-acylglycerol-3-phosphate-o-acyltransferase-2 deficiency. J Clin Endocrinol Metab. 2010 Mar;95(3):1463-8.
^ Semple RK, Chatterjee VK, O'Rahilly S. PPAR gamma and human metabolic disease. J Clin Invest. 2006 Mar;116(3):581-9.
^ Chong AY, Lupsa BC, Cochran EK, Gorden P. Efficacy of leptin therapy in the different forms of human lipodystrophy. Diabetologia. 2010 Jan;53(1):27-35.