Potential Usefulness of Intrahepatic Lipid Accumulation and Liver Function Tests to Identify Insulin Resistance Phenotype in Non-Obese Type 2 Diabetes

Abstract

Despite low body mass index (BMI), Asian people often develop type 2 diabetes ^1)-3). In addition to reduced insulin secretion, etiological difference of insulin resistance (IR) between Caucasian and Asian might be involved in this phenomenon ^{4) 5)}. Previous data demonstrated that non-obese Asians easily develop non-alcoholic fatty liver disease (NAFLD) ^6)-8) which is considered as cause and result of IR ^9)-14). As well as fat accumulation in liver, liver enzymes, such as alanine aminotransferase (ALT) and gamma-glutamyl transferase (GGT), are easily elevated by small increase in BMI within normal limits in Asians ¹⁵⁾; however those are less observed in other ethnicities ¹⁶⁾. In addition, both ALT and GGT were correlated to insulin resistance independent of measures of adiposity ^{17) 18)}. These data suggested that intrahepatic lipid (IHL) accumulation and liver dysfunction could be markers of IR in non-obese type 2 diabetes.

To test this hypothesis, we recruited 16 non-obese (BMI<25kg/m²) type 2 diabetes (BMI 21.9±2.0 kg/m², HbA1C 6.8±0.5%, Diet and exercise or take α-glucosidase only). We measured IHL by ¹H-magnetic resonance spectroscopy (MRS) at overnight fasting state. Total body fat content was measured by using the bioimpedance method. We also evaluated visceral fat and subcutaneous fat area by magnetic resonance imaging (MRI). Then, we performed euglycemic hyperinsulinemic clamp to measure insulin sensitivity (IS) in muscle and liver, respectively. We also measured serum liver function tests, such as AST, ALT and γ-GTP. Based on the upper limit of normal IHL level (4%) in general non-obese Japanese cohort, we divided the subjects into low IHL group (n=11; 1.3 (0.46-2.39) %) and high IHL group (n=5; 10.3 (6.26-12.7) %). Our preliminary data showed that compared with low IHL group, high IHL group showed lower muscle IS (6.79 (5.48-7.54) mg/kg/min vs 3.87 (3.84-5.66) mg/kg/min, p=0.06). Correlation analysis in all subjects revealed that IHL was not significantly correlated to IS in muscle and liver, however, all liver function tests are significantly correlated to both hepatic and muscle IS, respectively.

The present study demonstrated that IHL accumulation and elevated liver enzymes were associated with impaired insulin sensitivity in non-obese Japanese type 2 diabetes. These data suggested the usefulness of those hepatic parameters as marker of impaired insulin sensitivity in non-obese Japanese type 2 diabetes. However, this study is preliminary analysis in small number of subjects; further analysis is clearly required to confirm these relationships.