Severe Insulin Resistance SyndromesChapter 1

The concept of “insulin resistance” was proposed as early as 1936 to describe diabetic patients requiring high doses of insulin. Insulin resistance can be broadly defined as a subnormal biological response to normal insulin concentrations, either endogenous or exogenous. By this definition, it may pertain to many biological actions of insulin in many tissues of the body; however, in clinical practice, insulin resistance refers to a state of decreased sensitivity and/or responsiveness to insulin-mediated glucose disposal (ideally performed using a hyperinsulinemic-euglycemic clamp method).¹ While the most common cause of insulin resistance is metabolic syndrome and obesity, cases of severe insulin resistance are rare. The categories of disorders causing severe or extreme insulin resistance can be grouped as:2

A 4-month-old female baby was evaluated for dysmorphic features and hypoglycemia. She was the product of a third degree consanguineous marriage and delivered at term by cesarean section, and had normal APGAR scores at birth. She had intrauterine growth retardation and birth weight was 1.35 kg. Family history was significant for early death of three siblings. A pedigree chart is included (Fig. 1.1).

A diagnosis of Donohue syndrome (Leprechaunism) was made. Unfortunately, the child was lost to follow-up and was not known to have survived beyond infancy.4

Severe insulin resistance is generally suspected in individuals with clinical signs of insulin resistance and present with uncontrolled hyperglycemia, requiring more than 2–3 units/kg/day of insulin.² In rare instances, as in the case mentioned, hyperglycemia may not be an initial feature but develops if the child survives infancy. If patient does not have hyperglycemia and is non-obese, severe insulin resistance is suspected when the fasting insulin level is over 50 pmol/L or a post-oral glucose tolerance test (OGTT) insulin level is greater than 1,500 pmol/L.³

The genetic insulin receptoropathies (Fig. 1.3) are due to mutations in the insulin receptor gene leading to defects in insulin action.³ In contrast to the commonly occurring insulin resistance associated with metabolic syndrome, these patients with proximal insulin receptor defect have low serum triglyceride levels and elevated sex hormone binding globulin (SHBG), insulin-like growth factor binding protein 1 (IGFBP1), and adiponectin (Fig. 1.4).⁴ The insulin receptoropathies can be divided into three groups: (i) type A, (ii) type B, and (iii) type C. There is a female preponderance for all these syndromes.

Type A insulin resistance is defined by the triad of insulin resistance, acanthosis nigricans, and hyperandrogenism in the absence of obesity or lipoatrophy or insulin receptor antibodies. Many of these patients are homozygous or heterozygous for mutations in the insulin receptor gene, especially in the tyrosine kinase domain of the receptor.^1–3,5–8 The syndrome typically has its onset during adolescence, and reproductive-aged females present with oligomenorrhea and infertility. A variant of this disorder with an earlier onset, which typically presents during early childhood, characterized by growth retardation, dysmorphisms, lack of subcutaneous fat, acanthosis nigricans, enlarged genitalia, hypertrichosis, premature and dysplastic dentition, coarse facial features, precocious pseudopuberty, paradoxical fasting hypoglycemia, postprandial hyperglycemia, extreme hyperinsulinemia, protracted course, and eventual development of ketoacidosis, is known as the Rabson–Mendenhall syndrome.^9–11 Advanced microvascular complications or diabetic ketoacidosis are the commonest modes of death, usually in the second or third decade.⁸ Another variant with congenital onset is seen only in infants, as few live beyond the first year of life, under the phenotype of leprechaunism also known as Donohue syndrome caused by biallelic severe loss-of-function mutations in the insulin receptor and is autosomal recessive. As seen in the index case, this syndrome 6is characterized by severe intrauterine and postnatal growth retardation, failure to thrive, lipoatrophy, dysmorphic features (globular eyes, large ears and micrognathia), and acanthosis nigricans.¹² These infants have massive hyperinsulinemia, often associated with glucose intolerance or frank diabetes mellitus, in addition to fasting hypoglycemia. Additionally, affected female infants commonly have hirsutism and clitoromegaly, whereas affected males commonly present with penile enlargement. Other features of this syndrome include dysmorphic lungs, renal disease (nephromegaly, nephrocalcinosis, and medullary sponge kidney), and cardiomyopathy. When β-cells decompensate, hyperglycemia may become refractory to treatment and death usually occurs during intercurrent infection in infancy. The occurrence of hypoglycemia and lack of ketoacidosis even in those with no functional insulin receptor is unclear and hypothesis include continued action of extremely elevated insulins on persisting hepatic insulin-like growth factor-I (IGF-I) receptors in the immature liver or deficiency of growth hormone (GH) secretion or action.¹³

The type B insulin resistance syndrome is a manifestation of autoantibodies to the insulin receptor, predominantly occurring in middle aged women. In addition to the common features of severe insulin resistance (i.e., abnormal glucose homeostasis, acanthosis nigricans, and ovarian hyperandrogenism), these patients have a characteristic distribution of their acanthosis nigricans involving their periocular, perioral, and labial regions. These patients may have coexisting¹⁴ autoimmune disorders, commonly systemic lupus erythematosus. Rarely, the syndrome has been described as part of a paraneoplastic syndrome associated with multiple myeloma or Hodgkin disease. The disease causes a spectrum of abnormalities in glucose homeostasis, ranging from extreme insulin resistance with or without hyperglycemia to fasting hypoglycemia, and in some other cases a change from extreme insulin resistance to intractable hypoglycemia. In addition, the abnormalities in glucose homeostasis may remit in association with the disappearance of the antibody to the insulin receptor. In addition to nonspecific laboratory findings, including elevated erythrocyte sedimentation rate, leukopenia, hypergammaglobulinemia, serum anti-nuclear antibodies, and proteinuria, these patients demonstrate the presence of anti-insulin receptor (anti-IR) antibodies in the plasma. Commonly, anti-IR antibody titers are in proportion to the magnitude of insulin resistance. The type B syndrome is quite distinct from the resistance to exogenous insulin or Hirata syndrome, which occurs as a result of anti-insulin antibodies that bind insulin and prevent its interaction with insulin receptors.¹⁵7

Although grouped under the insulin receptoropathies, the exact etiology for the insulin resistance is unknown. The triad of hyperandrogenism, insulin resistance and acanthosis nigricans constitutes HAIR-AN syndrome.^16,17 The phenotype of the syndrome of severe insulin resistance type A is very similar, but most patients with HAIR-AN syndrome are obese. This syndrome is known by some as the syndrome of severe insulin resistance type C. Obesity alone, does not explain the resistance to insulin found in HAIR-AN, and type C insulin resistance is said to be found in 5% of patients with polycystic ovary syndrome (PCOS).¹⁶ The distinction between HAIR-AN and PCOS is defined by the presence of severe insulin resistance and hyperinsulinemia, determined by an arbitrary cutoff value, which currently is represented by a post-glucose-challenge insulin level of more than 300–500 pU/mL.¹⁸

Lipodystrophy is a heterogeneous disorder characterized by pathological adipose tissue deficiency.¹⁹ The lack of fat may be partial or generalized, and inherited or acquired in origin. These syndromes are characterized by severe insulin resistance, associated with severe hypertriglyceridemia leading to pancreatitis, and fatty liver leading to cirrhosis, in addition to selective, variable loss of adipose tissue. These syndromes have been sub-classified according to the extent and location of lipodystrophy and age of onset. The main subtypes of familial lipodystrophies are congenital generalized lipodystrophy (Berardinelli–Seip syndrome), an autosomal recessive disorder characterized by near complete lack of metabolically active adipose tissue from birth, and familial partial lipodystrophy, Dunnigan type, an autosomal dominant disorder characterized by loss of subcutaneous fat from the extremities at puberty and excess fat accumulation in the face and neck.

Physiological states including puberty and pathological states including uremia, liver disease, sepsis syndrome, acute myocardial infarction, diabetic ketoacidosis usually result in high insulin requirement, which settles down once the primary condition resolves.

This is a rare syndrome characterized by severe resistance to subcutaneous insulin with normal intravenous insulin sensitivity, although its actual existence remains controversial. Its pathophysiology is unknown, though an increased insulin-degrading activity has been reported in the subcutaneous adipose tissue by some²⁰ but not agreed by others.²¹

Management of severe insulin resistance is a major clinical challenge in those with proven or suspected genetic defects in the insulin receptor or downstream signaling. Optimal management of these complex disorders depends on early diagnosis and appropriate targeting of both high and low glucose levels. In newborns, continuous nasogastric feeding may reduce harmful glycemic fluctuations. Insulin sensitization, initially with metformin but later with trials of additional agents such as thiazolidinediones, is the mainstay of early therapy, but insulin replacement, eventually with very high doses, is required once diabetes has supervened.²²

The authors profusely thank Dr Sujatha Jagadeesh, Consultant Geneticist and Dysmorphologist, Mediscans, Chennai for her help in providing the case details as well as photographs.