Data Availability StatementData and materials related to this work are available upon request. resistance and T2D in both human being and mice. Moreover, MAP4K4 solitary nucleotide polymorphisms and epigenetic changes are associated with T2D individuals. Relationships between MAP4K4 gene variants and environmental factors may contribute to MAP4K4 attenuation in T cells, leading to nonobese T2D. SAG inhibition Long term investigations of the pathogenesis of non-obese T2D shall lead to development of precision medicine for non-obese T2D. reported in 2015. We ought to not ignore that numerous non-obese or thin people suffer from T2D. To date, most attention and resources have been directed toward studying obesity-induced T2D. However, the pathogenesis of non-obese T2D cannot be readily revealed using samples from human subjects from North America due to the small sample sizes of non-obese T2D individuals. SAG inhibition It also cannot be demonstrated from the platinum standard high-fat-diet (HFD)-fed animal model, which is not suitable for studying non-obese T2D. In some cases, studies from Western countries reported potential risk factors (such as solitary nucleotide polymorphisms (SNPs) of insulin receptor substrate 1 (IRS-1)) for T2D ; however, the association between these risk factors and T2D could not become reproduced using mostly nonobese T2D individuals from Asian countries such as Turkey , Japan, India, and Taiwan . Therefore, it becomes obvious that disease mechanism of non-obese T2D is different from that of obese T2D [9, 10]. Furthermore, the cause-effect human relationships of the risk factors in non-obese T2D cannot be demonstrated due to the lack of relevant non-obese T2D animal models. These limitations lead to slow progress in our understanding of the pathogenesis of non-obese T2D. The controversy of visceral extra fat accumulation in non-obese T2D Central obesity as determined by increased visceral extra fat accumulation was thought to be a risk of T2D in both Europeans and Asians . The data derived from 290?second-generation Japanese Americans having a mean age of 61.8 indicate that intra-abdominal fat is only SAG inhibition slightly correlated with the T2D incidence (odds percentage?=?1.5), while the fasting glucose, impaired glucose tolerance (IGT) at baseline, woman sex, or family history of diabetes is correlated with T2D incidence (odds percentage?=?2.3, 3.8, 3.1, and 1.9, respectively) under the same multivariate model . In India, both central abdominal fat and SAG inhibition visceral extra fat accumulation are very slightly correlated with T2D (odds percentage?=?1.001 and 1.011, respectively) . Over the past decade, it is controversial whether visceral extra fat accumulation is the only explanation for the high prevalence of non-obese T2D in Asia and Europe [11, 14]. In earlier studies explained above [12, 13], obese or non-obese individuals from Japan or India were not subgrouped for analyses; consequently, the very minor correlation (odds percentage?=?1.001, 1.011, or 1.5) between visceral adiposity and T2D may be due to the enrolled individuals also include some obese T2D individuals. Importantly, a medical study of a consortium of 18,565 Western normal-weight/obese/obese individuals from eight European countries demonstrates the association between insulin resistance and T2D event is self-employed of central obesity (waist circumferences) and obesity (BMI) . Remarkably, insulin resistance of normal-weight T2D subjects is not positively (but inversely) correlated with central obesity (gynoid extra fat mass, measured by dual-energy X-ray absorptiometry (DAX)), as well as BMI . Consistently, another group also reported the BMI, waist circumferences, and extra fat mass of non-obese T2D individuals from Europe are not significantly increased compared to control individuals . Therefore, visceral extra fat accumulation is not associated with non-obese T2D. In addition, insulin resistance of all the 18,565 enrolled individuals in the above study is definitely correlated with increased alanine transaminase or -glutamyltransferase levels, suggesting that insulin resistance Col4a3 is associated with fatty liver (hepatic steatosis) . Moreover, another group analyzed extra fat deposition of the slim T2D (BMI?=?23) or obese T2D (BMI?=?33) individuals from United Kingdom by magnetic resonance imaging (MRI). They found that actually slim T2D individuals possess an increased hepatic steatosis . Collectively,.