Clinical Significance of Insulin Sensitivity in Adipose Tissue in Apparently Healthy Nonobese Men

Abstract

Increased plasma free fatty acid (FFA) level is reported to be an important cause of obesity-associated insulin resistance in muscle and liver. Increased plasma FFA level in obesity is induced by insufficient suppression of plasma FFA by insulin and this is defined as impaired insulin sensitivity in adipose tissue (Adipo-IS). However, significance of impaired Adipo-IS in non-obese healthy subjects is totally unknown. To clarify this, we studied 49 non-obese (BMI< 25kg/m2) apparently healthy Japanese men without any cardiometabolic risk factors (mean age; 40.2±5.3 y.o, mean BMI; 23.1±1.0 kg/m²). We performed a 2-step hyperinsulinemic euglycemic clamp test (10 and 20 mU/m2 per min, 3h for each) to measure insulin sensitivity in muscle and liver. In addition, plasma FFA levels were also measured at fasting and 2nd step during the glucose clamp. Ectopic fat levels in muscle and liver and visceral fat area (VFA) were measured by 1H-MRS and MRI, respectively. The plasma FFA level was decreased from 530.6±139.1μEq/l to 62.4±64.2μEq/l during hyperinsulinemic euglycemic clamp. Thus, the mean Adipo-IS, defined as %FFA suppression during glucose clamp, was 88.8±10.3%; however, there was a large individual variations in Adipo-IS. Interestingly, Adipo-IS was positively correlated to insulin sensitivity in muscle (r=0.60, p<0.001) and liver (r=0.44, p=0.002) and negatively correlated to fasting plasma glucose (r=-0.33, p=0.019) and fasting insulin concentration (r=-0.46, p=0.001). In contrast, Adipo-IS had no significant correlation with fasting FFA, VFA, adipokines (adiponectin, TNF-alpha, MCP-1 and IL-6), CRP and ectopic fat in muscle and liver, respectively. These data suggested that moderately impaired Adipo-IS may be early functional abnormality in adipose tissue occurred in apparently healthy non-obese men. The impaired Adipo-IS may contribute to slightly reduced insulin sensitivity in muscle and liver and elevated plasma glucose level. Disclosure D. Sugimoto: None. Y. Tamura: None. K. Takeno: None. H. Kaga: None. Y. Someya: None. R. Suzuki: None. S. Kadowaki: None. T. Funayama: None. Y. Furukawa: None. R. Kawamori: None. H. Watada: Advisory Panel; Self; AstraZeneca. Consultant; Self; Astellas Pharma US, Inc., AstraZeneca, Boehringer Ingelheim GmbH, Daiichi Sankyo Company, Limited, Sumitomo Dainippon Pharma Co., Ltd., Eli Lilly and Company, Kissei Pharmaceutical Co., Ltd., Kowa Pharmaceuticals America, Inc., Kyowa Hakko Kirin Co., Ltd., Merck Sharp & Dohme Corp., Mitsubishi Tanabe Pharma Corporation, Novo Nordisk A/S, Novartis AG, Ono Pharmaceutical Co., Ltd., Sanofi, Sanwa Kagaku Kenkyusho Co., Ltd., Takeda Development Center Asia, Pte. Ltd.. Research Support; Self; Abbott, Astellas Pharma US, Inc., AstraZeneca, Bayer AG, Benefit One Health Care Co., Ltd., Boehringer Ingelheim GmbH, Bristol-Myers Squibb Company, Daiichi Sankyo Company, Limited, Sumitomo Dainippon Pharma Co., Ltd., Eli Lilly and Company, Kissei Pharmaceutical Co., Ltd., Kowa Pharmaceuticals America, Inc., Kyowa Hakko Kirin Co., Ltd., Johnson & Johnson Diabetes Institute, LLC., Merck Sharp & Dohme Corp., Mitsubishi Tanabe Pharma Corporation, Mochida Pharmaceutical Co., Ltd., Nitto Boseki Co., Ltd., Novartis AG, Novo Nordisk A/S, Ono Pharmaceutical Co., Ltd., Pfizer Inc., Sanofi, Sanwa Kagaku Kenkyusho Co., Ltd., Taisho Pharmaceutical Co., Ltd., Takeda Development Center Asia, Pte. Ltd., Terumo Medical Corporation.