Current Diabetes Reviews - Volume 2, Issue 1, 2006

This issue of CDR contains a range of interesting, well-crafted and insightful reviews on diabetes mellitus and its complications by highly respected groups of investigators. At the level of the pancreatic acinar cells, Bouwens examines the ability of beta cells to regenerate, and considers recent data such as the use of combinations of growth factors to promote regeneration or replacement by precursor cell neogenesis, which may eventually contribute to a therapeutic approach to insulindependent diabetes. Kim et al. reviews research on the transcriptional regulation of glucose sensors (GLUT2 and glucokinase) in beta cells and liver and the potential role for these mechanisms in the development of insulin resistance in type 2 diabetes. Two papers examine the links between obesity, insulin resistance, pro-inflammatory changes and cardiovascular disease in type 2 diabetes. Bulcao et al. review patterns of cytokine production by adipose tissue, including adiponectin and leptin, which promote insulin sensitivity and other cytokines such as tumor necrosis factor alpha that promote to proinflammatory changes and insulin resistance. You and Nicklas focus on the beneficial consequences of lifestyle modifications to cause weight loss and their effects on inflammatory changes and adipose tissue pro- and anti-inflammatory cytokine production. A broadly related review by Garcia-Romero and Escobar-Morreale considers the relation between polycystic ovary syndrome, insulin resistance and compensatory hyperinsulinemia, and hyperandrogen disorders in women with type 2 diabetes. They also examine the notion that insulin resistance and hyperinsulinemia resulting from insulin injection are important in the development of hyperandrogenism in type 1 diabetes. For these women, the combination of hyperandrogenism and insulin resistance exacerbates cardiovascular risk. The important vascular actions of insulin, and their potential consequences for diabetic complications, are considered. Duncan et al., review the effects of insulin on vascular endothelium, with particular regard to insulin signaling and the endothelial nitric oxide (NO) system. For macrovascular function, insulin-stimulated NO production has an antiatherogenic effect, however, insulin resistance reveals adverse effects; NO production is reduced and the proatherogenic effects may be apparent, possibly stimulated by activation of MAPkinase cascades, endothelin production and reactive oxygen species. Rattigan et al address the hemodynamic and metabolic effects of insulin in skeletal muscle, particularly in terms of microvascular effects, capillary recruitment and the role of the NO and endothelin systems. The potentially important causative relationship between vascular factors and insulin resistance is reviewed. This issue contains two papers on diabetic retinopathy. Simo et al. critically review the changes in angiogenic and antiangiogenic factors that are important in the etiology and control of proliferative retinopathy. The former include vascular endothelial growth factor, insulin-like growth factor, and the latter, which may have therapeutic implications, include pigment epithelium derived factor and somatostatin. Gomez-Ulla et al. examine the problem of diabetic macular edema, with particular regard to therapeutic application by intravital injection of the anti-inflammatory glucocorticosteroid, triamcinolone, emphasizing safety and efficacy data. Finally, De Block et al. consider the important problem of diabetic gastroporesis, which has a 30-50% prevalence in patients with type 1 or type 2 diabetes. They review current understanding of gastroporesis, including epidemiology, diagnosis, clinical consequences, the roles of potential mechanisms such as autonomic neuropathy, hyperglycemia, and altered gastrointestinal neuropeptides, as well as current therapeutic approaches. I hope readers find these reviews as stimulating, informative and enjoyable as I did.

Beta cell replacement and regeneration therapies seem promising approaches to the treatment of insulindependent diabetes. The short supply in beta cells from cadaveric organ donors and the very low replication capacity of human beta cells have spurred efforts to find robust ways of (re-)generating beta cells in vitro and in vivo. In the pancreas, both the capacity of regeneration and the mechanism involved can differ significantly depending on the experimental model, as it has also been found in other organs like the liver. Robust expansion of the beta cell mass in adult rodent pancreas doesn't normally occur after partial (50-70%) pancreatectomy nor after beta cell destruction by streptozotocin or alloxan. However, extensive tissue injury and treatment with certain gastrointestinal hormones, like gastrin and growth factors from the EGF-family can stimulate beta cell regeneration. Whereas a slow rate of beta cell mass expansion can result from beta cell replication, more robust regeneration depends largely on neogenesis from precursor cells. Precursor cells can be derived from stem cells or from pancreatic exocrine cells which are known to retain phenotypic plasticity and can transdifferentiate into, amongst others, endocrine cells. Identifying the conditions involved in the regulation of cellular plasticity and regenerative growth may lead to new pharmacological strategies for the treatment of diabetes.

Derangement of glucose metabolism is a key feature of T2DM, with the liver and pancreatic β-cells playing a key role in glucose homeostasis. In the postprandial state, glucose is transported into hepatocytes and either metabolized to fatty acids or CO2, or stored as glycogen. Glucose also acts as a key signal in pancreatic β-cells for regulating insulin secretion. Because GLUT2 and GK expressed in liver and β-cells are responsible for sensing glucose levels in the blood, studies on the regulation of these biomolecules are important in understanding glucose homeostasis in vivo. These molecules are known to be regulated either transcriptionally or post-transcriptionally, and recent studies on the structure and function of promoters of these genes have revealed the involvement of various transcriptional factors in their regulation. Here, we review recent progress in elucidating the transcriptional regulation of glucose sensors in the liver and pancreatic β-cells and the relevance to T2DM.

Obesity is a well-known risk factor for the development of insulin resistance, type 2 diabetes, dyslipidemia, hypertension, and cardiovascular disease. Rather than the total amount of fat, central distribution of adipose tissue is very important in the pathophysiology of this constellation of abnormalities termed metabolic syndrome. Adipose tissue, regarded only as an energy storage organ until the last decade, is now known as the biggest endocrine organ of the human body. This tissue secretes a number of substances - adipocytokines - with multiple functions in metabolic profile and immunological process. Therefore, excessive fat mass may trigger metabolic and hemostatic disturbances as well as CVD. Adipocytokines may act locally or distally as inflammatory, immune or hormonal signalers. In this review we discuss visceral obesity, the potential mechanisms by which it would be related to insulin resistance, methods for its assessment and focus on the main adipocytokines expressed and secreted by the adipose tissue. Particularly, we review the role of adiponectin, leptin, resistin, angiotensinogen, TNF-α , and PAI-1, describing their impact on insulin resistance and cardiovascular risk, based on more recent findings in this area.

Chronic inflammation has been linked with an increased risk of type 2 diabetes and cardiovascular disease. As an endocrine and inflammatory organ, adipose tissue is an important source of circulating pro-inflammatory cytokines. Current evidence strongly supports that chronic inflammation is associated with enlarged body fat mass. Moreover, inflammation is independently linked with abdominal, especially visceral fat mass, possibly due to the regional variation in adipose tissue cytokine production. In addition to pharmacological approaches, lifestyle modifications have been advocated for the treatment of chronic inflammation. A number of studies have indicated that either weight loss via energy restriction, or energy restriction plus other strategies (aerobic exercise, behavioral counseling, and liposuction), could reduce chronic inflammation. While the amount of weight loss tends to be important, exercise and other strategies may have additional effects. A few studies have reported weight loss effects on adipose tissue cytokine production. Weight loss reduces subcutaneous adipose tissue production of pro-inflammatory cytokines (i.e. interleukin 6, tumor necrosis factor alpha) and increases adipose expression of anti-inflammatory cytokines (i.e. interleukin 10, interleukin 1 receptor antagonist). More studies are needed to investigate the role of regional adipose tissue cytokine production in regulation of inflammation and the modulating effects of weight loss.

The polycystic ovary syndrome (PCOS) and hyperandrogenism are some of the most common endocrine disorders in women of fertile age. Insulin resistance is present in a significant proportion of hyperandrogenic patients, yet also, impaired ß-cell function, even in absence of clinically evident glucose intolerance, is a frequent finding, especially in patients with familial history of type 2 diabetes mellitus. Therefore, it is not surprising that hyperandrogenism, PCOS, and disorders of carbohydrate metabolism are associated frequently. This association was first reported 75 years ago and, although the mechanisms responsible are not precisely understood, insulin resistance plays an important role in the development of both disorders. PCOS patients develop type 2 diabetes mellitus more frequently than non-hyperandrogenic women and, conversely, women with type 2 diabetes have a greater risk of having PCOS compared with the normal population. Although type 1 diabetes mellitus is a disease characterized by complete abolition of endogenous insulin secretion, a certain degree of hyperinsulinism may exist, resulting from the relatively excessive insulin doses needed to maintain a strict metabolic control. This exogenous hyperinsulinism may increase ovarian androgen secretion, and it has been reported that there is an increased prevalence of hyperandrogenic disorders in type 1 diabetic women. Considering that insulin resistance, hyperinsulinemia and androgen excess may collaborate in increasing the risk for CVD in these women, the identification of hyperandrogenic symptoms in diabetic women, and the identification of disorders of glucose tolerance in hyperandrogenic patients, may have important consequences for the correct management of these women.

A number of population studies have suggested that hyperinsulinaemia is an independent risk factor for the development of cardiovascular atherosclerosis. Furthermore, there is an emerging body of evidence supporting a role for insulin as both a vasoregulatory and glucoregulatory peptide. Principal amongst insulin's putative vascular effects is to stimulate release of the anti-atherosclerotic signalling molecule nitric oxide (NO) from endothelial cells. Moreover, there is data demonstrating that in parallel to insulin mediated glucose uptake, stimulation of NO release by insulin is blunted in insulin resistant conditions. A number of in-vitro studies have begun to dissect and define the pathway by which insulin stimulates release of NO from endothelial cells and complimentary studies in gene-modified murine models of abnormal insulin signalling and/or hyperinsulinaemia have begun to elucidate the role of hyperinsulinaemia in NO release in-vivo. It is emerging that the effects of insulin on endothelial function are complex and in part dependent on the physiological/pathophysiological environment present when insulin binds to its receptor on the endothelial cell surface. The present article reviews the evidence for insulin being a pro-atherosclerotic and anti-atherosclerotic peptide with particular reference to endothelial cell derived NO bioavailability. In the present review we attempt to clarify the complex relationship between insulin, endothelial function and the risk of atherosclerosis by using data from in-vivo and ex-vivo models.

Insulin mediates its own access and that of glucose to muscle by capillary recruitment and an increase in bulk blood flow. In addition, insulin resistance of muscle may result in part from an impaired hemodynamic action of insulin. The present review examines some of the factors that influence the effects of insulin both at the level of hemodynamics and metabolism in muscle. Factors include fatty acids, the inflammatory cytokine TNFα , vasodilators that relax the blood vessels and increase bulk flow, and elevated blood pressure that may be mediated by endothelin, a potent locally released vasoconstrictor, or other vasoconstrictor influences.

Diabetic retinopathy continues to be the leading cause of legal blindness among working-age individuals. The earliest histological features of diabetic retinopathy include neuroretinal damage, capillary basement membrane thickening, loss of pericytes and loss of endothelial cells. At advanced stages, neovascularization, the hallmark of proliferative diabetic retinopathy (PDR) occurs, and blindness can result from relentless abnormal fibrovascular proliferation with subsequent bleeding and retinal detachment. Macular oedema is another retinal complication of diabetes that is responsible for a major part of vision loss, particularly in type 2 diabetes. The breakdown of the blood retinal barrier and the consequent vascular leakage and thickening of retina are the main events involved in its pathogenesis. Although a tight control of both blood glucose levels and hypertension are essential to prevent or arrest progression of the disease, the recommended goals are difficult to achieve in many patients. Laser photocoagulation treatment soon after the onset of PDR significantly reduces the incidence of severe vision loss. However, the optimal timing for laser treatment is frequently passed and, in addition, it is not uniformly successful in halting visual decline. For all these reasons, new pharmacological treatments based on the understanding of the pathophysiological mechanisms of diabetic retinopathy have been developed in recent years. There is mounting evidence to suggest that angiogenic factors play a crucial role in PDR development, vascular endothelial growth factor (VEGF) being the most relevant. Other growth factors or cytokines such as insulin-like growth factor I (IGF-1), hepatocyte growth factor (HGF), basic fibroblast growth factor (b-FGF), platelet derived growth factor (PDGF), pro-inflammatory cytokines and angiopoetins, are also involved in the pathogenesis of PDR. However, the intraocular synthesis of angiogenic factors is counterbalanced by the synthesis of antiangiogenic factors. Therefore, the balance between the angiogenic and antiangiogenic factors rather than angiogenic factors themselves will be crucial in determining the progression of PDR. The main antiangiogenic factor is the pigment epithelium derived factor (PEDF) but the transforming growth factor beta (TGF-β ), thrombospondin (TSP) and somatostatin are also among the intraocullary synthesized antiangiogenic factors.

Diabetic macular edema is one of the leading causes of visual loss in first world countries and the first cause in diabetic retinopathy. The Early Treatment Diabetic Retinopathy Study showed a significant benefit in using focal laser photocoagulation for the treatment of macular edema, more specifically defined as clinically significant macular edema. Nevertheless, progressive visual loss is found in the 26% of patients with diabetic macular edema treated with photocoagulation. The failure of laser treatment and the destructive nature of the therapy has forced researchers to pursue new alternatives including vitrectomy with or without internal limiting membrane peels, the use of proteinkinase C inhibitors, intravitreal injections of antibodies that inhibit the vascular endothelial growth factor, somatostatin analog, or the intravitreal injection with corticosteroids. Triamcinolone acetonide is glucocoticosteroid with antiangiogenic and antiedematous properties. Publications evaluating the safety and efficacy of intravitreal injection of triamcinolone in the treatment of diabetic macular edema show varying outcomes with respect to the increases of visual acuity and decreases in foveal thickness. Despite this, intravitreal triamcinolone is a treatment that has evolved quickly and is considered increasingly useful.

This review addresses the current concepts in our understanding of the epidemiology, mechanisms, symptoms, clinical consequences, diagnosis and treatment of delayed gastric emptying in patients with diabetes. Upper gastrointestinal symptoms, particularly postprandial fullness, nausea, vomiting and abdominal bloating, occur in 30-50% of patients with diabetes. The use of scintigraphic techniques, and more recently breath test, has shown that as many as 50% of diabetic patients have gastroparesis. Diabetic gastroparesis comprises a decrease in fundic and antral motor activity, a reduction or a lack of the interdigestive migrating motor complex, gastric dysrhythmias, and pylorospasms. The mechanisms involved include: autonomic neuropathy, acute hyperglycaemia, and abnormalities in gastrointestinal hormones and neuropeptides. Other possible contributing factors such as hypothyroidism and H. pylori infection are discussed as well. Because treatment is possible by means of dietary advise, prokinetics or surgical procedures, it is important to identify risk factors for and to diagnose gastroparesis to prevent morbidity by controlling gastrointestinal symptoms, and to enhance glucoregulation. Understanding the current advances is key to the development of novel therapeutic strategies and for making rational choices in the management of diabetic gastroparesis.