Syndromic insulin resistance: models for the therapeutic basis of the metabolic syndrome and other targets of insulin resistance

Abstract

Objective: To investigate the link between insulin resistance and the metabolic syndrome how to develop treatment approaches.

Methods: We present 3 cases of extreme syndromic insulin resistance: lipodystrophy, autoantibodies to the insulin receptor, and mutations in the insulin receptor gene, with accompanying discussion of pathophysiology and treatment.

Results: In lipodystrophy, insulin resistance is a direct consequence of leptin deficiency, and thus leptin replacement reverses metabolic syndrome abnormalities, including diabetes and hypertriglyceridemia. The insulin "receptoropathies," including autoantibodies to the insulin receptor and insulin receptor gene mutations, are characterized by extreme insulin resistance and ovarian hyperandrogenism, without dyslipidemia or fatty liver disease. Autoantibodies to the insulin receptor can be treated using an immunosuppressive paradigm adapted from treatment of other autoimmune and neoplastic conditions. Leptin treatment has shown some success in treating hyperglycemia in patients with insulin receptor gene mutations. Treatment for this condition remains inadequate, and novel therapies that bypass insulin receptor signaling, such as enhancers of brown adipose tissue, are needed.

Conclusions: We present a clinical approach to the treatment of syndromic insulin resistance. The study of rare diseases that replicate the metabolic syndrome, with clear-cut pathophysiology, promotes understanding of novel physiology and development of targeted therapies that may be applicable to the broader population with obesity, insulin resistance, and diabetes.

Figure 1

A) Patient with acquired generalized lipodystrophy prior to treatment, demonstrating generalized paucity of subcutaneous fat, eruptive xanthomas, and protuberant abdomen due to enlarged fatty liver. Additional presenting features included insulin resistance and diabetes, severe hypertriglyceridemia, and recurrent pancreatitis. B) The same patient after one year of leptin therapy, demonstrating resolution of eruptive xanthomas, and a significant decrease in liver volume. She also had significant improvement in diabetes and hypertriglyceridemia, with resolution of pancreatitis.

Figure 2

Therapeutic strategy for Type B insulin resistance caused by autoantibodies to the insulin receptor. Elimination of the autoantibody is the goal for this three-pronged approach. Rituximab, an antibody against CD-20, a cell surface molecule expressed by B-cell progenitors, targets antibody-producing B lymphocytes. Pulsed steroids target the pre-existing antibody-producing plasma cells. Non-specific B- and T-cell function suppression is achieved by a low dose immunosuppressive drug, either cyclophosphamide or cyclosporine.