Making a case for adiponectin in diabetes and its complications

Adiponectin is a protein synthesized and secreted predominantly by adipocytes into the peripheral blood. Low circulating adiponectin concentrations are associated with a variety of metabolic diseases and cancers, with recent studies demonstrating the potential of the protein as various clinical biomarkers and therapeutic targets. Professor Karen Siu Ling Lam shared some insights into the latest development in this area at a recent conference

Hypoadiponectenemia in obese individuals plays a pathogenic role in the development of type 2 diabetes mellitus (T2DM) as well as its complications, which include coronary artery disease, ischemic stroke and nephropathy. Hence, the potential clinical applications of adiponectin as a biomarker for predicting the development of T2DM and its cardiovascular complications, plus the development of therapeutic targets, have been suggested based on cumulative data from multiple studies. These studies were described extensively by Professor Karen Siu Ling Lam, of the Li Ka Shing Faculty of Medicine, University of Hong Kong, at the first plenary session of the recent Diabetes Asia conference in Petaling Jaya, Malaysia.

“In a meta-analysis of 13 prospective studies, which included almost 15,000 subjects, high adiponectin levels were observed to confer a lower risk of T2DM – relative risk of 0.72 per 1-log µg/mL increment in adiponectin levels. This inverse association was consistently observed across all populations,” said Lam. [JAMA 2009; 302(2):179-88] In addition, Lam and her colleagues’ study of non-diabetics in the Hong Kong Cardiovascular Risk Factor Prevalence Study (CRISPS) cohort showed that the combined use of serum adiponectin and tumor necrosis factor-alpha receptor 2 (TNF-α R2) as biomarkers provided added-value over traditional risk factors for T2DM prediction. [PloS one 2012; 7(5):e36868]

The association between adiponectin and insulin sensitivity has also been analyzed at the genetic level, where evidence of a causal relationship was found in a study of Swedish men. [Diabetes 2013; 62(4):1338-44] This corresponds to an earlier study in the CRISPS cohort and a subsequent meta-analysis including 2 European studies, which concluded that the ADIPOQ single nucleotide polymorphism (SNP) T45G (rs2241766) independently predicted persistent hyperglycemia at 5 years and the development of T2DM. [Diabetologia 2006; 49(8):1806-15]

The link between adiponectin and T2DM is taken further with associations found between the protein and T2DM complications. A study of a large Caucasian cohort showed that a variant of the ADIPOQ gene, adipo4 (rs266729), which results in low adiponectin levels, is  associated with increased carotid intima-media thickness (CIMT), a marker of atherosclerosis and a stroke risk factor, suggesting a causal role of adiponectin in carotid atherosclerosis. [Stroke 2011; 42(6):1510-4] This relationship was also observed in a multi-ethnic population and was even more marked in those with T2DM. [Stroke 2012; 43(4):1123-25] Hui et al confirmed this relationship in a prospective study in the CRISPS cohort, whereby low serum adiponectin independently predicted progression of carotid atherosclerosis identified via CIMT increments over the years. [Metab Syndr Relat Disord 2014 Epub ahead of print] All these suggest that adiponectin participates in the development of carotid atherosclerosis. However, this was not the case in ischemic stroke patients, although serum adiponectin was indeed lower compared to controls. A meta-analysis of eight prospective studies showed that in the long term, serum adiponectin levels did not predict incidence, but instead was found to be a good predictor of the 5-year survival rate following the first episode of ischemic stroke. [Stroke 2014; 45(1):10-7; Stroke 2005; 36(9): 1915-9]

“In almost all populations studied, there was a clear indication that a high level of adiponectin is protective against incident myocardial infarction (MI), even after correcting for cholesterol levels. This produced up to a 40% MI risk reduction in the Healthcare Professionals Follow-up Study,” said Lam. “In obese individuals who did not undergo bariatric surgery, a follow-up of 10 years found that a protective effect for the development of T2DM and MI was conferred by adiponectin. This was confirmed by a 16-year longitudinal study in the CRISPS cohort in which the ADIPOQ gene +276G>T (rs1501299) SNP when present even in the heterozygous state, was associated with an increased risk of coronary heart disease in men even after correcting for confounding risk factors,’’ she added.

In diabetic nephropathy, serum adiponectin is inversely related to albumin excretion rates in individuals with ‘normal’ albuminuria. However, once the state of microalbuminuria or albuminuria is reached, the direction of the relationship is changed, with a positive correlation observed between serum adiponectin and urinary albumin concentration (UAC). An inverse relationship is also observed between serum adiponectin levels and glomerular filtration rate (GFR). However, patients with end-stage renal failure have serum adiponectin levels as high as controls, potentially as a result of a secondary phenomenon. [Kidney Int 2013; 83(3):487-94; Nephrol Dial Transplant 2014; doi: 10.1093/ndt/gfu249] These indicate that levels of serum adiponectin differ according to phases of nephropathy. “In a prospective study of a small cohort with relatively well preserved kidney function followed up to 20 months, a low serum adiponectin level was able to predict progression of albuminuria, suggesting that in this selected population, adiponectin is indeed protective against renal failure,” said Lam.

Fatty liver disease is another complication frequently seen among T2DM patients. An inverse relationship is seen between serum adiponectin and serum alanine aminotransferase (ALT), suggesting a protective effect conferred by the protein. The increase in serum adiponectin levels also correlates to improvements in hepatic incidences.  [J Clin Invest (2003); 112(1): 91-100]

It is now commonly known that T2DM increases the risk for the development of certain types of cancers. These include cancer of the pancreas, liver, colorectum, bladder and reproductive tract. Adiponectin, working through various signaling mechanisms, has been shown to decrease cell proliferation in many animal- and cell-based studies. In humans, low adiponectin levels found in diabetes-related cancer patients have been found to have a decreased ability to limit proliferation and metastasis. [Endocr Relat Cancer 2009; 16(4):1103-23; Diabetes Care2010; 33(7):1674-85]

The myriad of studies described show clear potential for the manipulation of adiponectin in diseased states to create therapeutic remedies. Current anti-diabetic and cardiovascular drugs such as agonists of peroxisome proliferator-activated receptor (PPAR) and statins are associated with increased plasma adiponectin in humans. “The recently discovered fibroblast growth factor 21 (FGF21), a metabolic regulator, is the most potent adiponectin stimulator to date,” said Lam. “Many pharmaceutical companies are now developing FGF21 mimetics or analogues to improve the activity as well as the circulating half-life of FGF21. All these are in various stages of clinical trials, one of which has already been used in a phase II clinical trial in humans,’’ she added.

Lam also briefly spoke of the importance of lifestyle measures in improving adiponectin levels, stating that a low-energy Mediterranean diet, combined with increased physical activity, has shown to increase adiponectin levels by 30 percent over two years in individuals who succeeded in losing weight

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