Genetic types of extreme insulin resistance include type A insulin resistance syndrome, leprechaunism, congenital generalized lipodystrophy, and Rabson-Mendelhall syndrome (1). Acanthosis nigricans and ovarian masculinization are frequently associated with these syndromes. Genetic defects in insulin action at the receptor or postreceptor levels are responsible for insulin resistance. Since thiazolidinediones enhance insulin sensitivity in patients with insulin resistance, we administered pioglitazone to an insulin-resistant patient with a mutation of the insulin receptor.

A 15-year-old Japanese female was referred to the hospital for an evaluation of hirsutism. Acanthosis nigricans was present in the axillary area and on the neck. She had been amenorrheic since menarche at the age of 12 years. She had two elder sisters, one of whom had the same phenotype. The other sister and the mother of this individual appeared to be unaffected. The father died from laryngiocarcinoma at the age of 45 years after being on hemodialysis due to diabetic renal failure. The patient was normoglycemic (glucose 69 mg/dl) and hyperinsulinemic (immunoreactive insulin [IRI] 148 μU/ml) under fasting conditions. The homeostasis model assessment of insulin resistance was 25.21, and the serum testosterone level was elevated (1.23 ng/ml). A 75-g oral glucose tolerance test generated the following values: glucose 59, 161, 195, and 184 mg/dl and IRI 109, 300, 450, and 695 μU/ml at 0, 30, 60, and 120 min, respectively. Thus, insulin resistance was marked, and hyperandrogenemia was evident. We determined partial DNA sequences of the insulin receptor gene of this patient and found heterogeneous triplet basic deletion from exon 17 of the human insulin receptor gene that resulted in a leucine deletion at amino acid 1,026.

We administered 15 mg/day of pioglitazone. Although fasting glucose levels were not changed, fasting IRI decreased from 148 to 104 μU/ml and HbA1c (A1C) decreased from 6.0 to 4.5% after 5 months. We continued pioglitazone (15 mg/day), and after another 5 months, fasting IRI decreased to 73 μU/ml and A1C to 4.4%. The serum testosterone level decreased from 1.23 to 0.97 ng/ml after 5 months and normalized to 0.68 ng/ml after 10 months. Menstruation recovered after pioglitazone for 2 months. Before treatment, plasma leptin and adiponectin levels were elevated to 15.9 ng/ml and 19.8 μg/ml, respectively. Serum adiponectin increased to 30.5 μg/ml after pioglitazone for 5 months, while the leptin level remained similar.

A number of studies suggest an important link between adiponectin and insulin resistance (2). Although its physiological and pathophysiological role has not been fully elucidated, its low levels in insulin-resistant states suggest that therapeutic modulation of adiponectin may provide a novel treatment modality for insulin resistance (2). Interestingly, the level of adiponectin in this case was not low, but pioglitazone further increased the serum adiponectin level. Thus, pioglitazone might have been beneficial to this patient via both adiponectin-dependent and -independent pathways (3).

The mutation in this patient was situated in the ATP binding site of the insulin receptor β subunit (4). This might disturb the intrinsic tyrosine kinase activity that is essential for signal transduction. However, the means by which the heterogeneous mutation caused insulin resistance remains to be elucidated. Pioglitazone attenuated insulin resistance and ameliorated masculinization. Thus, thiazolidinediones should be considered for treating patients with extreme insulin resistance syndrome. Coadministration of pioglitazone with IGF-1 (5) might be a more optimal treatment strategy for patients with such extreme syndromes.

Goldfine AB, Moses AC: Syndrome of extreme insulin resistance. In
Joslin’s Diabetes Mellitus
. 14th ed. Kahn CR, Weir GC, King GL, Jacobson AM, Moses AC, Smith RJ, Eds. Philadelphia, Lippincott Williams & Wilkins,
, p.
Pittas AG, Joseph NA, Greenberg AS: Adipocytokines and insulin resistance.
J Clin Endocrinol Metab
Kubota N, Terauchi Y, Kubota T, Kumagai H, Itoh S, Satoh H, Yano W, Ogata H, Tokuyama K, Takamoto I, Mineyama T, Ishikawa M, Moroi M, Sugi K, Yamauchi T, Ueki K, Tobe K, Noda T, Nagai R, Kadowaki T: Pioglitazone ameliorates insulin resistance and diabetes by both adiponectin-dependent and -independent pathways.
J Biol Chem
Ullrich A, Bell JR, Chen EY, Herrera R, Petruzzelli LM, Dull TJ, Gray A, Coussens L, Liao YC, Tsubokawa M, Mason A, Seeburg PH, Grunfeld C, Rosen OM, Ramachandran J: Human insulin receptor and its relationship to the tyrosine kinase family of oncogenes.
Kuzuya H, Matsuura N, Sakamoto M, Makino H, Sakamoto Y, Kadowaki T, Suzuki Y, Kobayashi M, Akazawa Y, Nomura M, Yoshimasa Y, Kasuga M, Goji K, Nagataki S, Oyasu H, Imura: Trial of insulinlike growth factor I therapy for patients with extreme insulin resistance syndromes.