New drug for treatment of insulin‐resistant complication?

Diabetes is an increasing epidemic and more than 500 million people are expected to have diabetes within the nearest 20 years (Whiting et al., 2011). The disease is poly-factorial, and both genetic and life-style factors contribute to the risk of developing the disease. The pathogenesis involves impaired insulin secretion and insulin resistance and is associated with both macroand microvascular complications. In the work by Zhou et al. (2013) in this issue of ACTA Physiologia, the therapeutic effects of adrenomedullin (ADM) on vascular calcification in fructose-induced insulin resistance rats have been investigated. Calcification of the media of the arterial wall is a common feature in patients with increased glucose levels and is associated with increased risk of nephropathy, retinopathy, coronary heart disease and mortality (Jeffcoate et al., 2009). The process includes active ossification and bone formation. The bone formation is initiated by bone morphogenetic proteins (BMPs) secreted from mesenchymal stem cells that activate transcription factors such as transcription factor core-binding protein (Cbafa1). BMPs belong to the TGF-beta family of proteins, and BMP-2 and BMP-4 are the BMPs suggested to be associated with vascular calcification. Calcification of the arterial wall also involves the cytokine osteopontin (OPN). Type 2 diabetes patients with calcification-related complications have been demonstrated to have higher circulating levels of OPN (Jeffcoate et al., 2009). Moreover, it was recently demonstrated that hyperglycaemia increases the level of OPN in smooth muscle cells (Nilsson-Berglund et al., 2010). In agreement with current published work, Zhou et al. (2013) demonstrate that increased calcification through fructose-induced insulin resistance and hyperglycaemia is accompanied by increased protein levels of BMP2, OPN and Cbfa-1. They further demonstrate that the levels of BMP2 and Cbfa-1 are reduced after addition of ADM, whereas levels of OPN continue to increase. Adrenomedullin is a member of the calcitonin gene– related peptide (CGRP)/amylin family. It is widely distributed in peripheral tissue and in the brain, where it has been shown to have both autocrine and paracrine effects. In type 2 diabetes, ADM has been associated with the pathogenesis of diabetic vasculopathy (Lim et al., 2007). Levels of ADM are increased in patients with heart failure and the precursor of ADM, proADM, has been investigated as a possible biomarker of cardiac heart disease (CHD) (Melander et al. 2009). In line with previous studies, Zhoe et al. demonstrate an increased level of ADM due to fructose-induced insulin resistance. This study further contributes by demonstrating direct beneficial effects of ADM on the levels of key proteins in the bone formation associated by arterial calcification. The work by Zhou is one of the first studies demonstrating the positive effects of exogenous added ADM on vascular calcification associated with insulin resistance. In addition, earlier studies have demonstrated that ADM reduces fructose-induced insulin resistance and associated myocardial hypertrophy (Zhang et al., 2011). Thus, the multiple positive effects make administration of ADM a most likely and favourable therapeutic approach for patients with diabetes, at least insulin resistance associated. The multiple positive effects make ADM reminiscent of incretins, such as GLP-1 and GIP. These endogenous produced hormones increase insulin secretion in beta cells and glucose uptake in target tissue. In addition, GLP-1 has been proven to increase cardio protection and cardiac function (Baggio and Drucker, 2007). Agonist of GLP-1 and antagonists of DPPIV (the enzyme that breaks down GLP-1 and GIP) are today widely used in the treatment of type 2 diabetes due to their effects on both insulin secretion and complications. Most of the genetic risk variants of type 2 diabetes discovered today is associated with insulin secretion and it remains to be investigated whether ADM, as the incretins, has beneficial effects also on insulin secretion. The work by Zhou et al. (2013) has added one piece to the large puzzle of ADM as a possible treatment for diabetes and its complications.