Extreme subcutaneous insulin resistance is a very rare syndrome characterized by severe resistance to subcutaneous insulin together with normal or near normal intravenous insulin sensitivity. The pathophysiology is unknown. An increased insulin-degrading activity has been reported in the subcutaneous adipose tissue fraction (1). The proposed treatments are disappointing. We report such a case that was successfully treated by intraperitoneal insulin.

A 36-year-old male patient was admitted for acute pancreatitis of unknown etiology associated with diabetes. His mother had type 2 diabetes. The patient’s BMI was 31 kg/m2. After the onset of acute pancreatitis, the patient discontinued his antidiabetic treatment. Five years later, he was admitted in a hyperosmolar state (fasting blood glucose of 1,000 mg/dl) without ketoacidosis. His BMI was 28 kg/m2. Subcutaneous insulin was resumed, using multi-injections, followed by subcutaneous treatment with an insulin pump. Despite a dramatic increase in the insulin dose (up to 1,800 units/day), metabolic control was bad (HbA1c 11%; high-performance liquid chromatography <6% [normal]). Intravenous insulin infusion was then attempted through an implanted venous access port. Continuous insulin was given with an external insulin pump through a Port-A-Cath (Braun, Boulogne Billancourt, France), whereby the catheter was connected to a subcutaneous reservoir. After initial success, this treatment was withdrawn because the metabolic state was deteriorated in a septic context (catheter infection). Continuous subcutaneous infusion was resumed with freeze-dried insulin (endopancrine; Organon Eragny/Epte, France), up to 4,000 units/day, and then with lispro insulin (Lilly), up to 420 units/day. Then, a protease inhibitor, aprotinin (Iniprol 8 million units/day for 4 days; Laboratoire Choay, Gentilly, France) was mixed with insulin, but >1,500 units/day insulin was needed to achieve euglycemia. Corticosteroid therapy (dexamethasone [Soludecadron; MSD Chibret, Clermond-Ferrand, France] 40 mg for 3 days, then prednisolone [Solupred, Houde, Paris-Defense, France] 60 mg/day for 3 days) and intravenous immunoglobulin therapy were also ineffective. For 8 years, blood glucose remained very high, between 300 and 400 mg/dl and, consequently, diabetic complications appeared: retinopathy (macular edema), painful neuropathy with neuropathic ulcer, nephropathy, and sepsis. Then, an intraperitoneal insulin infusion with an implantable pump (MIP 2001; Minimed, Sylman, CA) was started. After implantation, the metabolic state dramatically improved; weight increased from 65 to 70 kg (BMI from 21.2 to 22.8 kg/m2), insulin requirement decreased to 40 units/day, and HbA1c dropped from 10 to 6%. Sixteen months later, the good metabolic state was maintained.

Abdominal tomodensitometry was normal, and there was no alteration of exocrine pancreatic function. There were no islet cell antibodies, GAD autoantibodies, or anti-insulin and anti-insulin–receptor antibodies. Insulin secretion was preserved (basal C-peptide before glucagon: 5 ng/ml; after glucagon: 10 ng/ml). Levels of glucagon, vasoactive intestinal peptide, and somatostatin were normal. The euglycemic clamp study showed a decrease in both sensitivity (ED50 = 1.13 vs. 0.62 mU · kg–1 · min–1 in control subjects) and responsiveness (mean maximal glucose disposal: 10.2 mg · kg–1 · min–1, or 73% of the control subjects) to intravenous insulin.

Insulin binding was normal on the patient’s erythrocytes. Insulin receptor number and phosphorylation, studied on skin-cultured fibroblasts, were not altered. We did not find any coding mutation in the insulin receptor or the lamin A/C genes (2). Finally, plasma insulin measurements showed subcutaneous malabsorption of insulin; plasma free insulin was 26 mU/l when 3,600 units/day insulin was subcutaneously infused and 7 mU/l when 30 units/day was intraperitoneally infused.

We have described a case of severe subcutaneous insulin resistance that was treated by intraperitoneal insulin therapy. Such cases have already been described. For some of them, an insulin-degrading activity has been found in muscle or adipose tissue (1,3). Therefore, some patients were successfully treated with a protease inhibitor, aprotinin (1,3,4,5). Other patients did not respond to this treatment (6). Intramuscular insulin therapy was successfully attempted in some cases (7,8). All of these treatments were ineffective in our patient. Intraperitoneal insulin therapy, through a subcutaneous access device, was proposed in some cases (9,10,11) with good results. We tried the same route of insulin therapy using an implantable pump (MIP 2001). As a result, glycemic control dramatically improved with good efficiency for 1 year.

Therefore, extreme subcutaneous insulin resistance is a new indication of implantable pump use. The pathophysiology of this syndrome remains unexplained.

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Address correspondence to Jean-Pierre Riveline, MD, 59 Bd Henri Dunand, 91100 Corbeil-Essonnes, France. E-mail: jpriveline@hotmail.com.