Current Diabetes Reviews - Volume 8, Issue 4, 2012

Diabetic mellitus is the leading cause of blindness in working aged patients in developing nations. Due to the buildup of abnormal metabolites from several overactive biochemical pathways, chronic hyperglycemia causes oxidative stress in the retina which upregulates vascular endothelial growth factor (VEGF). Together with other growth factors and metabolites, VEGF causes endothelial cell proliferation, vasodilation, recruitment of inflammatory cells, and increased vascular permeability, leading to breakdown of the blood-retinal barrier. This allows trans-cellular exudation into the interstitial space resulting in diabetic macular edema (DME). For over 3 decades the standard treatment for DME has been laser photocoagulation. Though laser reduces the incidence of vision loss by 50%, few eyes with diffuse edema experience improved vision. This has led physicians to use the VEGF-binding drugs pegaptanib, ranibizumab, and aflibercept, each of which has been approved for the treatment of exudative macular degeneration, and bevacizumab which is commonly used off-label for a variety of chorioretinal disorders. Intravitreal administration of each drug frequently causes rapid improvement of DME with sustained improvement in vision through 2 years. Though these drugs significantly outperform laser photocoagulation over treatment periods of 1 year of less, the advantages appear to lessen when trials approach 2 years. Further studies to better determine relative efficacies of anti-VEGF drugs and laser photocoagulation are continuing.

The incidence of gestational diabetes is increasing, with higher obesity in the pregnant population, lifestyle changes and migration thought to underlie this. Recent large studies, such as the MiG, HAPO and ACHOIS trials, have furthered our understanding of both the implications of the disease and the management options available. Previous CEMACH (Confidential Enquiries into Maternal and Child Health) studies of diabetes in pregnancy have shown a significant proportion of patients receiving sub-optimal care. We aim to summarise the current standard of management strategies in pregnancy, whilst acknowledging controversies and limitations in the existing evidence. Antenatal management involves service organisation to provide multi-disciplinary team reviews to address glycaemic control, fetal monitoring and associated conditions such as obesity and hypertensive disorders of pregnancy. The use of diet, exercise, oral hypoglycaemic agents and insulins will be discussed, along with specific considerations for the management of preterm labour and administration of corticosteroids for fetal lung maturity. The timing and management of labour, including mechanisms of delivery, will be covered, including neonatal considerations and the use of breast feeding. Finally, a discussion of appropriate post delivery care will consider the prevention of, and screening for, the development of type 2 diabetes.

With growing awareness that long-term hyperglycemia is directly implicated in the tissue damage characteristic of diabetes, there has been a corresponding increase in clinicians’ willingness to employ intensive treatment to achieve euglycemia, which may require diabetes drugs in combination. The expanding array of drugs with different mechanisms of action calls for a clear method of classification to guide rational combination therapy. Contemporary and historical literature was surveyed to document changes in awareness of toxicity from hyperglycemia and consequent changes in treatment strategy. References were selected for clinical applicability and explanation of drug mechanisms of action, with the goal of proposing a useful schema for classification. Diabetes drugs may be classified in the following categories: insulin providers, which increase the supply of insulin through administration of exogenous human insulin or analogues or drugs that stimulate endogenous insulin secretion (sulfonylureas and meglitinides are direct insulin secretagogues, whereas glucagon- like peptide-1 analogues and dipeptidyl peptidase-4 inhibitors act to increase the supply of insulin); insulin sensitizers (metformin, thiazolidinediones), which offset the effects of insulin resistance; and insulin-independent drugs, which work in the gut to impede intestinal absorption of glucose into the circulation (α-glucosidase inhibitors) or in the kidney to prevent renal reabsorption of glucose back into the circulation (sodium-glucose cotransporter 2 inhibitors, currently investigational). Awareness of these categories facilitates rational combinations of drugs with differing mechanisms of action to address hyperglycemia from separate directions, in accordance with current treatment guidelines.

An elevated risk of cardiovascular events is present in patients with mild-to-moderate renal function impairment. Similar to patients with end-stage renal disease, this elevated risk can be accounted for by high prevalence of classic and emergent cardiovascular risk factors and additional conditions that are more specifically related to the organ failure, such as anemia and electrolyte disturbances. Among emergent cardiovascular risk factors, insulin resistance has been demonstrated to contribute significantly to the cardiovascular risk in the general population and it is known that abnormalities of glucose metabolism and hyperinsulinemia due to insulin resistance are present in patients with renal failure. Because patients with more advanced disease stage have several abnormalities that might affect the cellular action of insulin acting as important confounders, the relationship between insulin sensitivity and renal function should be better evaluated in the early stages of renal failure. This article overviews the evidence supporting the presence of increased cardiovascular morbidity and mortality in patients with early stages of renal disease, and examines the potential for insulin resistance to contribute to cardiovascular risk in these patients.

Purpose: To present the state-of-the-art of subthreshold diode laser micropulse photocoagulation (SDM) as invisible retinal phototherapy for diabetic macular edema (DME). Method: To review the role and evolution of retinal laser treatment for DME. Results: Thermal laser retinal photocoagulation has been the cornerstone of treatment for diabetic macular edema for over four decades. Throughout, laser induced retinal damage produced by conventional photocoagulation has been universally accepted as necessary to produce a therapeutic benefit, despite the inherent risks, adverse effects and limitations of thermally destructive treatment. Recently, SDM, performed as invisible retinal phototherapy for DME, has been found to be effective in the absence of any retinal damage or adverse effect, fundamentally altering our understanding of laser treatment for retinal disease. Summary: The discovery of clinically effective and harmless SDM treatment for DME offers exciting new information that will improve our understanding of laser treatment for retinal disease, expand treatment indications, and improve patient outcomes.

Fibroblast growth factor 21 (FGF21) is emerging as a key regulator of energy homeostasis and presents a novel target for the development of therapies for the treatment of diabetes, cardiovascular disease and obesity. Recent publications have demonstrated that FGF21 resides downstream of a complex network of transcriptional regulators which modulate its expression in response to a wide array of physiological stimuli or pharmacologic agents. The manner in which these mechanisms are integrated to regulate FGF21 transcription, production and subsequent secretion is poorly understood. While FGF21 is detected in many metabolically active tissues and is regulated by several of the known transcription factors involved in metabolic control little is known about how these pathways are integrated. In this review, we discuss the data presented to date on regulation of FGF21 by a wide array of transcription factors and explore how it relates to metabolic regulation in vivo.

Diabetes mellitus is a major disease worldwide, and the prevalence of diabetes has risen significantly in the past several decades. Although one of the major complications of diabetic eyes is diabetic retinopathy (DR), corneal diseases can not only develop in diabetic patients but are also difficult to manage. Diabetic neurotrophic keratopathy is a component of diabetic polyneuropathy and is recognized to be the cause of the morbidity of the cornea in diabetic patients. In addition, corneal endothelial cell damage can cause disturbances in the management of proliferative DR before and after surgeries because of endothelial decompensation with bullous keratopathy. However, there have been only a limited number of studies that have focused on the importance of corneal diseases in diabetic patients. This review describes the pathophysiological roles of different factors that have been found to be causative factors of diabetic corneal keratopathy and endothelial cell dysfunction in diabetic patients. In addition, the clinical features of the corneal changes in diabetic patients and recent studies related to the development of therapies for the management of corneal diseases are presented.

As understanding of the mechanisms driving and regulating insulin secretion from pancreatic beta cells grows, there is increasing and compelling evidence that nitric oxide (•NO) and other closely-related reactive nitrogen species (RNS) play important roles in this exocytic process. •NO and associated RNS, in particular peroxynitrite, possess the capability to effect signals across both intracellular and extracellular compartments in rapid fashion, affording extraordinary signaling potential. It is well established that nitric oxide signals through activation of guanylate cyclase-mediated production of cyclic GMP. The intricate intracellular redox environment, however, lends credence to the possibility that •NO and peroxynitrite could interact with a wider variety of biological targets, with two leading mechanisms involving 1) Snitrosylation of cysteine, and 2) nitration of tyrosine residues comprised within a variety of proteins. Efforts aimed at delineating the specific roles of •NO and peroxynitrite in regulated insulin secretion indicate that a highly-complex and nuanced system exists, with evidence that •NO and peroxynitrite can contribute in both positive and negative regulatory ways in beta cells. Furthermore, the ultimate biochemical outcome within beta cells, whether to compensate and recover from a given stress, or not, is likely a summation of contributory signals and redox status. Such seeming regulatory dichotomy provides ample opportunity for these mechanisms to serve both physiological and pathophysiologic roles in onset and progression of diabetes. This review focuses attention upon recent accumulating evidence pointing to roles for nitric oxide induced post-translational modifications in the normal regulation as well as the dysfunction of beta cell insulin exocytosis.