Accumulation of excessive fat in the liver is the common denominator underlying the two most common and emerging causes of chronic liver disease, alcoholic liver disease (ALD) and non-alcoholic fatty liver disease (NAFLD), that are emerging public health issues globally. The burden of both ALD and NAFLD are increasing worldwide (1,2). ALD occur as a component of a broader perspective of alcohol abuse disorders, is frequently associated with psychiatric comorbidities and is the most frequent cause of morbidity, health care utilization and mortality in alcohol use disorders (3)(4)(5)(6). This is in contrast to NAFLD that occurs as an essential component of metabolic disorders that are associated with insulin resistance as the pathophysiological hallmark and is clinically manifest as hepatic, pancreatic, cardiac endothelial cell dysfunction and disease. In NAFLD, death is most commonly due to cardiovascular disease and often nonhepatic cancers apart from liver disease (7,8). The current global march of NAFLD as a public health challenge parallels the global upsurge for food intake, increase in per capita income, sedentary lifestyle, increasing body mass index and finally is an expression of an excess of caloric

Nonalcoholic fatty liver disease (NAFLD) is an independent predictor of systemic insulin resistance and type 2 diabetes mellitus (T2DM). However, converse correlates between excess liver fat content and β-cell function remain equivocal. Specifically, how the accumulation of liver fat consequent to the enhanced de novo lipogenesis (DNL) leads to pancreatic β-cell failure and eventually to T2DM is elusive. Here we have identified lowmolecular-weight calcium-binding protein S100A6 or calcyclin inhibits glucose-stimulated insulin secretion (GSIS) from β-cells through activation of the receptor for the advanced glycation end product (RAGE) and diminution of mitochondrial respiration. Serum S100A6 level is elevated both in human NAFLD patients and in a high-fat diet (HFD) induced mouse model of NAFLD. While serum S100A6 levels are negatively associated with β-cell insulin secretory capacity in human patients, depletion of hepatic S100A6 improves GSIS and glycemia in mice suggesting that S100A6 contributes to the pathophysiology of diabetes in NAFLD. Moreover, transcriptional induction of hepatic S100A6 is driven by the potent regulator of DNL, carbohydrate response element-binding protein (ChREBP), and ectopic expression of ChREBP in the liver suppresses GSIS in a S100A6 sensitive manner. Together, these data suggest elevated serum levels of S100A6 may serve as a biomarker in identifying NAFLD patients with a heightened risk of developing β-cell dysfunction. Overall, our data, implicate S100A6 as a hitherto unknown hepatokine to be activated by ChREBP and participates in the hepato-pancreatic communication to impair insulin secretion and drive the development of T2DM in NAFLD.

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<p>Nonalcoholic fatty liver disease (NAFLD) is an independent predictor of systemic insulin resistance and type 2 diabetes mellitus (T2DM). However, converse correlates between excess liver fat content and β-cell function remain equivocal. Specifically, how the accumulation of liver fat consequent to the enhanced <em>de novo</em> lipogenesis (DNL) leads to pancreatic β-cell failure and eventually to T2DM is elusive. Here we have identified low-molecular-weight calcium-binding protein S100A6 or calcyclin inhibits glucose-stimulated insulin secretion (GSIS) from β-cells through activation of the receptor for the advanced glycation end product (RAGE) and diminution of mitochondrial respiration. Serum S100A6 level is elevated both in human NAFLD patients and in a high-fat diet (HFD) induced mouse model of NAFLD. While serum S100A6 levels are negatively associated with β-cell insulin secretory capacity in human patients, depletion of hepatic S100A6 improves GSIS and glycemia in mice suggesting that S100A6 contributes to the pathophysiology of diabetes in NAFLD. Moreover, transcriptional induction of hepatic S100A6 is driven by the potent regulator of DNL, carbohydrate response element-binding protein (ChREBP), and ectopic expression of ChREBP in the liver suppresses GSIS in a S100A6 sensitive manner. Together, these data suggest elevated serum levels of S100A6 may serve as a biomarker in identifying NAFLD patients with a heightened risk of developing β-cell dysfunction. Overall, our data, implicate S100A6 as a hitherto unknown hepatokine to be activated by ChREBP and participates in the hepato-pancreatic communication to impair insulin secretion and drive the development of T2DM in NAFLD. </p>

Systemic lupus erythematosus (SLE) is an autoimmune disease with multisystem involvement and most commonly affects women of childbearing age. Most of the patients, if not all, have positive antinuclear antibody (ANA) in their serum. ANA-negative SLE is extremely rare. Here, we present a case of a 15-yearold girl presenting with pancreatitis due to ANA-negative SLE.