Current Diabetes Reviews - Volume 8, Issue 5, 2012

Diabetic nephropathy (DN) is a leading cause of end-stage renal disease. Searching for the perfect biomarker of DN has become the holy grail of nephrology since the burden of this disease is untenable. The only feasible way to tackle this health care crisis is by prevention and treatment in a mechanistically rational approach. Therefore, the discovery of a specific, reliable diagnostic and prognostic biomarker for DN is imperative. Part of the difficulty in finding such a marker is the complex pathogenesis of DN; it is clearly multifactorial and involves multiple genes, proteins, metabolic pathways, and environmental factors. In this review, we will discuss the latest findings in the use of genetic, protein, and metabolic markers of DN. Particular attention will be paid to the urinary biomarker as a noninvasive method to detect either morphological or biochemical changes in DN. Urinary protein and mRNA studies have focused on either the glomerular (podocyte-specific) or tubular components (matrix or injury-related) of the nephron. The virtues and pitfalls of using the podocyte as a biomarker will be discussed. The systems biology approach of biomarker discovery in the studies of genomics, transcriptomics, proteomics, and metabolomics will be explored. Despite significant numbers of new biomarkers described, most studies are limited by either their small sample size or their cross-sectional nature, so that the ability to predict future and severity of DN is lacking. In order to successfully search for the ideal, validated biomarker, we need to conduct large, prospective, multi-center trials enlisting both Type 1 and Type II diabetic patients with and without nephropathy for at least two decades.

Until recently, relaxin and insulin were grouped into the same hormone superfamily because of substantial biochemical homologies. This notion has then changed with the understanding that insulin and relaxin are ligands for different receptors and signal transduction systems, namely, tyrosine kinase and G-protein-coupled receptors respectively. As a matter of fact, relaxin does not mimic the metabolic effects of insulin. The biological effects of insulin are much more clearly delineated than those of relaxin, which is traditionally viewed as a reproductive hormone involved in the maternal adjustments of pregnancy. In the last decade, evidence has been accumulating that relaxin has major effects on the heart, blood vessels and the extracellular matrix within connective tissues. In particular, pertaining to the relationships between relaxin and diabetes, relaxin was shown to promote arterial and microvascular dilation, thereby increasing organ perfusion, counteract ischemic injury, improve adverse cardiac and vascular remodeling, and promote extracellular matrix turn-over, thereby exerting anti-fibrotic effects. Thus, relaxin could blunt or delay the vascular and organ complication of diabetes. Whether relaxin may also synergize with insulin to optimize blood glucose homeostasis remains an unconfirmed issue. However, there are clues in the literature which, if gathered, speak in favor of this perspective. Moreover, preliminary data suggest that exogenous relaxin administration may improve insulin sensitivity in diabetic patients. Considering that human recombinant relaxin is under study as a novel, promising drug for the treatment of heart failure, a broader knowledge of the possible beneficial effects of relaxin in diabetes and its complications can be of interest to the scientific community.

Clinical observations and epidemiological studies have shown that there is familial aggregation of diabetic nephropathy in many ethnic groups, indicating the strong contribution of inherited factors in the development of diabetic nephropathy. Identification of the genes involved in the pathogenesis of diabetic nephropathy may provide better knowledge of its pathophysiology and future therapies. To search for the genes involved in susceptibility, resistance or progression to diabetic nephropathy, candidate gene population association, family-based association and genome wide association studies have been widely used. This article reviews genetic polymorphisms, summarizes the data from genetic association studies of diabetic nephropathy in both type 1 and type 2 diabetes, and discusses about the future genetic analyses in the complex diseases.

The importance of glycaemic variability (GV) as a factor in the pathophysiology of cellular dysfunction and late diabetes complications is currently a matter of debate. However, there is mounting evidence from in vivo and in vitro studies that GV has adverse effects on the cascade of physiological processes that result in chronic ß-cell dysfunctions. Glucose fluctuations more than sustained chronic hyperglycaemia can induce excessive formation of reactive oxygen (ROS) and reactive nitrogen species (RNS), ultimately leading to apoptosis related to oxidative stress. The insulinsecreting ß-cells are particularly susceptible to damage imposed by oxidative stress. Evidence from experiments, using isolated pancreatic islets or ß-cell lines, has linked intermittent high glucose, which mimicks GV under diabetic conditions, to significant impairment of ß-cell function. Several clinical studies reported a close association between GV and ßcell dysfunction, although the deleterious effects are difficult to demonstrate. Notwithstanding, early therapeutic interventions in patients with type 1 as well as type 2 diabetes, using different strategies of optimising glycaemic control, have shown that favourable outcomes on recovery and maintenance of ß-cell function correlated with reduction of GV. The purpose of the present review is to discuss the detrimental effects of GV and associations with ß-cell function as well as upcoming therapeutic strategies directed towards minimising glucose excursions, improving ß-cell recovery and preventing progressive ß-cell loss. Measuring GV has importance for management of diabetes, because it is the only one component of the dysglycaemia that reflects the degree of dysregulation of glucose homeostasis.

Circadian misalignment has been implicated in the development of diabetes mellitus and cardiovascular disease. Circadian rhythms of blood pressure (BP) and heart rate (HR) have long been known and the mechanisms controlling them have been actively investigated in physiology and disease. In this respect, the introduction of 24-hour ambulatory blood pressure monitoring (ABPM) has enabled a more accurate assessment of circadian BP patterns in order to solve diagnostic uncertainty or to establish dipper status. However, attention has been mainly focused on measures of extent (midline estimating statistic of rhythm, MESOR, and amplitude) rather than timing (acrophase) of changes within a cycle. The review summarises 1) evidence for altered characteristics of BP rhythm (in particular, phase shifts along the time axis) in animal and human diabetes mellitus, 2) the mechanisms that have been supposed to underlie the observed changes in cardiovascular function before diabetes onset and during progression of the disease, and 3) the adverse consequences that may result from an altered circadian BP rhythm.

It is well established that glucagon can stimulate adipose lipolysis, myocardial contractility, and hepatic glucose output by activating a GPCR and adenylate cyclase (AC) and increasing cAMP production. It is also widely reported that activation of AC in all three tissues requires pharmacological levels of the hormone, exceeding 0.1 nM. Extensive evidence is presented here supporting the view that cAMP does not mediate metabolic actions of glucagon on adipose, heart, or liver in vivo. Only pharmacological levels stimulate AC, adipose lipolysis, or cardiac contractility. Physiological concentrations of glucagon (below 0.1 nM) duplicate metabolic effects of insulin on the heart by activating a PI3K- dependent signal without stimulating AC. In the liver, glucagon can enhance gluconeogenesis and glucose output - by increasing the expression of PEPCK or inhibiting the activity of PK - at pharmacological concentrations by activating AC coupled to a low-affinity GPCR, but also at physiological concentrations by activating a high affinity receptor without generating cAMP. Plausible AC/cAMP-independent signals mediating the increase in gluconeogenesis include p38 MAPK (PEPCK expression) and IP3/DAG/Ca 2+ (PK activity). None of glucagon's physiological effects can be explained by activation of spare receptors or amplification of the AC/cAMP signal. In a new model proposed here, glucagon antagonizes insulin on the liver but mimics insulin on the heart without activating AC. Confirmation of the model would have broad implications, applicable not only to the general field of metabolic endocrinology but also to the specific role of glucagon in the pathogenesis and treatment of diabetes.

Translational research is necessary for the development of efficient experimental animal models that can be used to develop innovative medical treatments, such as improvements in organ or tissue transplantation. We have developed animal models that produce photogenic proteins in their islet cells: rats models expressing the gene for luciferase or green fluorescent protein (GFP), and pig models expressing the gene for GFP or Kusabira-Orange. We also developed methods for preserving isolated islets in culture and showed that the fluorescence of the islets remains at usable levels for at least seven days. These models will enable transplanted islets to be visualized without the need for chemical reactions, and will be useful for research on the biology of islets as well as for the development of new transplantation methods.

Identifying the causative relationship between the fatty acid composition of cell membranes and type 2 diabetes mellitus fundamentally contributes to the understanding of the basic pathophysiological mechanisms of the disease. Important outcomes of the reviewed studies appear to support the hypotheses that the flexibility of a membrane determined by the ratio of (poly)unsaturated to saturated fatty acyl chains of its phospholipids influences the effectiveness of glucose transport by insulin-independent glucose transporters (GLUTs) and the insulin-dependent GLUT4, and from the prediabetic stage on a shift from unsaturated towards saturated fatty acyl chains of membrane phospholipids directly induces a decrease in glucose effectiveness and insulin sensitivity. In addition, it has become evident that a concomitant increase in stiffness of both plasma and erythrocyte membranes may decrease the microcirculatory flow, leading ultimately to tissue hypoxia, insufficient tissue nutrition, and diabetes-specific microvascular pathology. As to the etiology of type 2 diabetes mellitus, a revised hypothesis that attempts to accommodate the reviewed findings is presented.