INHIBITION OF THROMBIN ACTION IMPROVES INSULIN SENSITIVITY IN AN OBESE PATIENT WITH TYPE 2 DIABETES

Program: Abstracts - Orals, Featured Poster Presentations, and Posters
Session: SAT 758-785-Diabetes Case Reports: Type 1, Type 2, MODY & Complications
Clinical
Saturday, June 15, 2013: 1:45 PM-3:45 PM
Expo Halls ABC (Moscone Center)

Poster Board SAT-777
Ravi Kant*1, Hillary Barnes Loper2, Rana Malek2 and Kashif M Munir2
1Endocrinology, University of Maryland School of Medicine, Baltimore, MD, 2University of Maryland School of Medicine, Baltimore, MD
INTRODUCTION: Several pharmacological agents target insulin resistance to improve glycemic control in patients with type 2 diabetes (T2DM). Chronic inflammation in adipose tissue plays a central role in the development of obesity-related insulin resistance. Thrombin has been shown to stimulate inflammatory cytokines leading to insulin resistance, particularly in obese patients with diabetes. We report the first case of improved insulin sensitivity in an obese patient with T2DM by inhibition of thrombin action with argatroban (AG), a direct thrombin inhibitor.

CLINICAL CASE:  A 67 year-old Caucasian man presented with acute bilateral lower extremity pain after plasmapheresis for hypertriglyceridemia (> 9000 mg/dL). He was diagnosed with acute bilateral lower limb ischemia. Past medical history included, T2DM, hypertriglyceridemia, hypertension, peripheral vascular disease, COPD and chronic pain syndrome. Medications for T2DM were insulin glargine 60 units BID and aspart 40 units TID with meals.

Axillary-femoral bypass grafting was performed and an intravenous heparin infusion was initiated. Hyperglycemia was managed with an insulin infusion. His insulin requirements were 129 units on day 1 (over 16 hours) and 144 units on day 2. Heparin was changed to an AG infusion on day 3 due to inability to achieve adequate anticoagulation. After starting AG, the patient only required 56 units of insulin in the first 24 hours. The insulin infusion was discontinued within 14 hours of starting AG. Subcutaneous insulin requirements progressively decreased to 16-20 units/day over the next week. A transition to enoxaparin 100 mg subcutaneous every 12 hours was made for outpatient administration. The patient was maintained on glargine 20 units daily. Five weeks after hospitalization fasting glucose was in the 160-200 mg/dl.

CONCLUSION:  Obesity and T2DM are associated with increased inflammatory cytokines, likely resulting in impaired insulin sensitivity. We hypothesize that AG, by inhibiting thrombin mediated inflammatory cytokines, ameliorated insulin resistance, resulting in significantly decreased requirements of insulin in our patient, from 240 to 20 units/day. This finding is supported by results showing reduced fasting plasma glucose and improved insulin sensitivity in obese diabetic db/db mice by inhibition of thrombin action with administration of AG (1). Enoxaparin, which potentiates inhibition of factor Xa leading to decreased production of thrombin, may be responsible for maintenance of improved insulin sensitivity in our patient. Our case illustrates the importance of thrombin action in development of insulin resistance and possibly identifies a novel therapeutic target for management of T2DM.

(1)  Mihara M., Aihara K., Ikeda Y., Yoshida S., Kinouchi M., Kurahashi K., Fujinaka Y., Akaike M., Matsumoto T. Inhibition of Thrombin Action Ameliorates Insulin Resistance in Type 2 Diabetic db/db Mice.  Endocrinology. 2010;151(2):513-519.

Nothing to Disclose: RK, HBL, RM, KMM

*Please take note of The Endocrine Society's News Embargo Policy at http://www.endo-society.org/endo2013/media.cfm