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Fibroblast Growth Factor 21 as an emerging metabolic regulator: clinical perspectives

Fibroblast growth factor 21 (FGF21), a metabolic hormone predominantly produced by the liver, is also expressed in adipocytes and the pancreas. It regulates glucose and lipid metabolism through pleiotropic actions in these tissues and the brain. In mice, fasting leads to increased PPAR‐α mediated expression of FGF21 in the liver where it stimulates gluconeogenesis, fatty acid oxidation, and ketogenesis, as an adaptive response to fasting and starvation. In the fed state, FGF21 acts as an autocrine factor in adipocytes, regulating the activity of PPAR‐γ through a feed‐forward loop mechanism. Administration of recombinant FGF21 has been shown to confer multiple metabolic benefits on insulin sensitivity, blood glucose, lipid profile and body weight in obese mice and diabetic monkeys, without mitogenic or other side effects. Such findings highlight the potential role of FGF21 as a therapeutic agent for obesity‐related medical conditions. However, in human studies, high circulating FGF21 levels are found in obesity and its related cardiometabolic disorders including the metabolic syndrome, type 2 diabetes, non‐alcoholic fatty liver disease and coronary artery disease. These findings may indicate the presence of FGF21 resistance or compensatory responses to the underlying metabolic stress, and imply the need for supraphysiological doses of FGF21 to achieve therapeutic efficacy. On the other hand, serum FGF21 has been implicated as a potential biomarker for the early detection of these cardiometabolic disorders. This review summarizes recent developments in the understanding of FGF21, from physiological and clinical perspectives.

Adiponectin gene variants and the risk of coronary heart disease: a 16-year longitudinal study.

OBJECTIVE Circulating adiponectin levels have been shown to be associated with a risk of coronary heart disease (CHD). However, its primary role in protecting against the development of CHD remains controversial due to conflicting observations in prospective studies. To gain further insight into the primary role of adiponectin, our major objective was to investigate the relationship between single nucleotide polymorphisms (SNPs) of the adiponectin gene (ADIPOQ) and incident CHD in a population-based cohort with no CHD at baseline. DESIGN AND METHODS We conducted a 16-year longitudinal study in 2196 subjects from the Hong Kong Cardiovascular Risk Factor Prevalence Study (CRISPS). During 33 862 person-years of follow-up, 184 subjects developed CHD (cumulative incidence rate=5.4 per 1000 person-years). Nine ADIPOQ SNPs with potential functional relevance or shown to be associated with adiponectin levels and/or CHD were genotyped. RESULTS Among the nine ADIPOQ SNPs, +276G>T (rs1501299) was independently associated with incident CHD in men but not in women, even after adjustments for traditional cardiovascular risk factors (Padjusted=5.5×10(-3) to 0.023; hazard ratio=1.39-1.54). Furthermore, there was a significant association of the T allele of +276G>T with a lower adiponectin level (P=0.027; β (95% CI)=-0.05 (-0.10, -0.01). CONCLUSIONS This study demonstrated that +276G>T may be an independent predictor of CHD development. Our findings suggest that low adiponectin levels, as may be influenced by +276G>T, confer a higher risk of CHD, in keeping with a role of hypoadiponectinaemia in the development of CHD in the general population.

Obesity, adipokines and cancer: an update

Obesity causes dysfunction of adipose tissue, with resultant chronic inflammation and adverse interplay of various adipokines, sex steroids and endocrine hormones. All these drive tumourigenesis and explain the epidemiological link between obesity and cancer. Over the past decade, the associations among obesity, adipokines and cancer have been increasingly recognized. Adipokines and their respective signalling pathways have drawn much research attention in the field of oncology and cancer therapeutics. This review will discuss the recent advances in the understanding of the association of several adipokines with common obesity‐related cancers and the clinical therapeutic implications.

Which creatinine-based estimated glomerular filtration rate equation best predicts all-cause mortality in Chinese subjects with type 2 diabetes?

AIM In Chinese, ethnicity-based and/or diabetes specific modifications of the Modification of Diet in Renal Disease (MDRD) and the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) equations have been developed for determining estimated glomerular filtrate rate (eGFR). This study aimed to compare the performance of five different creatinine-based eGFR equations in predicting all-cause mortality among Chinese subjects with type 2 diabetes (T2DM). METHODS A total of 6739 Chinese subjects with T2DM were included. Their eGFR was calculated using the MDRD, CKD-EPI, their respective modified equations for Chinese, and the diabetes specific CKD-EPI Chinese T2DM equations. Multiple Cox regression analysis was used to evaluate the associations of eGFR with all-cause mortality. C-statistics, net reclassification index (NRI) and integrated discrimination index (IDI) were applied to assess the discrimination and reclassification of each eGFR equation in predicting mortality outcome. RESULTS Over a follow-up of 5.7years, the incidence of all-cause mortality was 12.9% (N=867). The CKD-EPI equation discriminated all-cause mortality better than the MDRD equation (C-statistics: 0.714 vs. 0.689, p<0.0001), and Chinese modification of their respective equations did not improve discrimination. Among the five eGFR equations evaluated, the CKD-EPI Chinese T2DM equation provided the best discrimination in predicting all-cause mortality among Chinese subjects with T2DM, and was the only equation providing a significantly positive NRI and IDI relative to the CKD-EPI equation. CONCLUSIONS Among Chinese subjects with T2DM, our findings suggested that the CKD-EPI Chinese T2DM equation best predicted all-cause mortality, and relative to the CKD-EPI equation, conferred improved discrimination and reclassification.

OP19 CIRCULATING ADIPOCYTE FATTY ACID BINDING PROTEIN LEVELS PREDICT THE PROGRESSION OF NEPHROPATHY IN TYPE 2 DIABETES MELLITUS

interaction. Lee WJ, Huey-Herng Sheu W, Liu SH, Yi YC, Chen WC, Lin SY, Liang KW, Shen CC, Yeh HY, Lin LY, Tsai YC, Tien HR, Lee MR, Yang TJ, Sheu ML. Free Radic Biol Med. 2014 Jul 8; 74C: 294–306. [2] Advanced glycation end product Ne-carboxymethyllysine induces endothelial cell injury: the involvement of SHP-1regulated VEGFR-2 dephosphorylation. Liu SH, Sheu WH, Lee MR, Lee WJ, Yi YC, Yang TJ, Jen JF, Pan HC, Shen CC, Chen WB, Tien HR, Sheu ML. J Pathol. 2013 Jun; 230(2): 215–27. [3] The advanced glycation end product Nepsilon-(carboxymethyl)lysine is increased in serum from children and adolescents with type 1 diabetes. Berg TJ, Clausen JT, Torjesen PA, Dahl-Jorgensen K, Bangstad HJ, Hanssen KF. Diabetes Care. 1998 Nov; 21(11): 1997–2002.

Plasma Fibrinogen Level as a Predictor of Cardiovascular Diseases, Independent of Diabetes, in a Population-Based 16-Year Prospective Study in Hong Kong

1395-P Does Functional Decline in Older Adults Hasten the Onset of Diabetes? The Health and Retirement Study 1998-2010 BARBARA H. BARDENHEIER, EDWARD GREGG, XIAOHUI ZHUO, YILING J. CHENG, LINDA GEISS, Atlanta, GA Prospective studies have associated diabetes with a high risk of incident disability among older adults. However, the converse association could also occur, with functional decline hastening the onset of diabetes, particularly in those at high risk. 13,134 adults aged over 50 years who entered the longitudinal Health and Retirement Study between 1992 and 2006 with no disability or diabetes were followed to 2010 to determine if those who became disabled would subsequently develop diabetes. Mobility disability was assessed by self-reported diffi culty walking one block; walking several blocks; climbing one fl ight of stairs; stooping, crouching, or kneeling; and pushing or pulling a large object. Participants were classifi ed by disability: none, mild (diffi culty with stooping and walking several blocks or diffi culty with > 2 mobility measures other than climbing), moderate (diffi culty with climbing or diffi culty with > 3 mobility measures), and severe (diffi culty with > 4 mobility measures). 1,955 (14.9%) participants developed diabetes, 8,228 (62.6%) reported incident disability, and 2,482 (18.9%) died by 2010. Among those who did not develop disability, diabetes incidence was 8.67 per 1,000; among those who developed disability and remained disabled at least 50% of the reporting period, diabetes incidence was 13.5 per 1,000. In a generalized estimating equation controlling for body mass index, age, sex, race/ethnicity, net wealth, and year of report, we found a statistically signifi cant dose-response relationship between incident disability and later incident diabetes: severe vs. none (OR: 2.18, 95%CI: 1.82, 2.61); moderate vs. none (OR: 1.50, 95%CI: 1.25, 1.80); mild vs. none (OR: 1.40, 95%CI: 1.26, 1.56). We found those who become mildly disabled are at increased risk of developing diabetes within a few years. These fi ndings raise the question of whether approaches to delay functional decline, an almost ubiquitous aspect of aging, may reduce the risk of diabetes.