New wine in old bottle: liver and diabetes

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There is a long and intimate relationship between the liver and carbohydrate metabolism; could there be more to this than is already known? Insulin has important effects on carbohydrate metabolism; it suppresses gluconeogenesis and induces glycogenesis and lipogenesis [1]. Recent evidence suggests that the hypothalamus can modulate the secretion of insulin and hepatic glucose flux through the autonomic nervous system [2], and by fatty acid oxidation. There is an intriguing concept that a feed-forward mechanism exists to facilitate weight gain involving the brain, liver and other organs [3]: in conditions of energy excess, hepatic glucose metabolism increases expression of glucokinase and feeds back to the central nervous system through the vagus nerve, leading to inactivation of brown adipose tissue sympathetic nerves. Thereby thermogenesis is decreased and deposition of adipose tissue occurs. This has been called the ‘thrifty mechanism operating on the whole body’ [3]. When excess food is available, this evolutionarily conserved homeostasis favours adiposity. Novel hepatic regulatory pathways involving carbohydrate metabolism are being identified such as solute carrier family 30 member 8 gene (SLC30A8) that influences insulin clearance by the liver [4], Fox01/3/4 transcription factors [5] and mitochondrial exhaustion [6]. Liver disease and diabetes mellitus often coexist. Among 14, 523 adults with chronic hepatitis B, a significantly higher cumulative incidence of cirrhosis (RR=3.43, 95%CI=2.62–4.49) was found among those with newly diagnosed diabetes [7]. Even after adjustment for possible confounding factors, diabetes remained an independent predictor for cirrhosis, suggesting that subjects with chronic hepatitis Bwho develop diabetes are prone to develop cirrhosis of liver. Nonalcoholic fatty liver disease (NAFLD), a common cause of chronic liver disease is associated with metabolic syndrome, and is an independent risk factor for the development of type 2 diabetes mellitus [8]. Insulin resistance plays a role in its pathogenesis. A recent study reported that individuals with NAFLD had higher prevalence of metabolic syndrome and lower levels of [25-(OH)D [9]. Among patients with chronic hepatitis C virus from South-east Asia, increasing age, obesity and HCV genotype 3 independently predicted type 2 diabetes in HCV seropositive patients [10]. How could the two be related? A number of hypotheses were proposed: DNA from the gut microbiota, identified in the liver and adipose tissue could point to the existence of a ‘tissue microbiota’ [11], thereby opening up potential channels for therapy. Recently, mitochondrial biogenesis has been implicated in obesity and insulin resistance [12]. Epigenetic alterations may operate to transmit nutrient and metabolic changes into heritable gene expression. Aberrant metabolism and epigenetic alterations may thus be linked [13]. The association of the enzyme gamma-glutamyltransferase and atherosclerosis is being increasingly recognized [14]. In this issue of the Journal , Ho et al. published a report on the relation of the enzyme GGT and metabolic syndrome in a Taiwanese aboriginal population [15]. GGT is a hepatic enzyme that has an antioxidant role [16]. Earlier studies showed that GGT levels were a risk factor for insulin resistance. In a South African cohort (n:1198) indicators of insulin resistance increasedwith rising levels of GGT, suggesting that the enzyme could be used as a risk factor for development of metabolic syndrome [17]. Elevated levels of γ-glutamyltranspeptidase was associated with death due to cardiovascular and hepatic causes in older subjects from the Rancho Bernardo Study [18]. Similar prognostic value of GGT for metabolic syndrome was reported from China [19]. Increasing GGT even within the G. R. Sridhar (*) Endocrine and Diabetes Centre, Visakhapatnam, India e-mail: grsridhar@hotmail.com