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Contents

New-Onset Posttransplantation Diabetes Mellitus: Insulin Resistance or Insulinopenia? Impact of Immunosuppressive Drugs, Cytomegalovirus and Hepatitis C Virus Infection Pp.1-10
Joran Hjelmesaeth, Anders Asberg, Fredrik Muller, Anders Hartmann and Trond Jenssen
[Abstract] [Full text article]

Cardiac Mitochondrial Alterations Observed in Hyperglycaemic Rats -What Can We Learn From Cell Biology? Pp.11-21
Paulo J. Oliveira
[Abstract] [Full text article]

Will Long Acting Insulin Analogs Influence the Use of Insulin Pump Therapy in Type 1 Diabetes? Pp.23-26
J. Hans DeVries
[Abstract] [Full text article]

Insight on the Pathogenesis of Diabetic Nephropathy from the Study of Podocyte and Mesangial Cell Biology Pp.27-40
Gabriella Gruden, Paolo C. Perin and Giovanni Camussi
[Abstract] [Full text article]

Endothelial Progenitor Cells and Vascular Biology in Diabetes Mellitus: Current Knowledge and Future Perspectives Pp.41-58
Gian P. Fadini, Carlo Agostini and Angelo Avogaro
[Abstract] [Full text article]

Endothelial Dysfunction in Hyperglycemia as a Trigger of Atherosclerosis Pp.59-63
Hironori Nakagami, Yasufumi Kaneda, Toshio Ogihara and Ryuichi Morishita
[Abstract] [Full text article]

Oxidative Stress and the JNK Pathway in Diabetes Pp.65-72
Hideaki Kaneto, Taka-aki Matsuoka, Yoshihisa Nakatani, Dan Kawamori, Munehide Matsuhisa and Yoshimitsu Yamasaki
[Abstract] [Full text article]

Role of Cytokines and Trophic Factors in the Pathogenesis of Diabetic Retinopathy Pp.73-81
Yoshinori Mitamura, Chikako Harada and Takayuki Harada
[Abstract] [Full text article]

The Utility of Oral Diabetes Medications in Type 2 Diabetes of the Young Pp.83-92
Michael P. Kane, Asim Abu-Baker and Robert S. Busch
[Abstract] [Full text article]

Advanced Glycation End Products (AGEs) and Diabetic Vascular Complications Pp.93-106
Sho-ichi Yamagishi, Kazuo Nakamura and Tsutomu Imaizumi
[Abstract] [Full text article]

Anaemia in Diabetes: An Emerging Complication of Microvascular Disease Pp.107-126
Merlin Thomas, Con Tsalamandris, Richard MacIsaac and George Jerums
[Abstract] [Full text article]

Abstracts

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New-Onset Posttransplantation Diabetes Mellitus: Insulin Resistance or Insulinopenia? Impact of Immunosuppressive Drugs, Cytomegalovirus and Hepatitis C Virus Infection
Joran Hjelmesaeth, Anders Asberg, Fredrik Muller, Anders Hartmann and Trond Jenssen
[Full text article]

Restoration of renal function may ameliorate uremia induced insulin resistance. Therefore it seems a paradox that new-onset posttransplantation diabetes mellitus (PTDM) is a frequently observed complication after renal transplantation. The incidence varies between 2 and 50% depending on the population under study, criteria for the diagnosis of diabetes and the time of follow up.

This review addresses recent findings on transplant specific risk factors and pathogenesis of PTDM after solid organ transplantation, and we focus on the following issues:

1. The relative impact of insulin resistance and insulinopenia in the pathogenesis of PTDM.

2. The role of immunosuppressive drugs with special emphasis on calcineurin inhibitors (cyclosporine A, tacrolimus) and steroids.

3. The possible roles of cytomegalovirus and hepatitis C infections.

Conclusions: New-onset PTDM is characterized by a variety of clinical manifestations, ranging from predominantly insulin resistance which can be handled with lifestyle intervention, to b-cell failure requiring insulin treatment. The etiology is multi-factorial, but diabetogenic immunosuppressive drugs are of major importance. Future studies should therefore address the effects of different immunosuppressive regimens on the incidence of PTDM. In addition, the impact of cytomegalovirus infection and hepatitis C on PTDM needs further evaluation.

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Cardiac Mitochondrial Alterations Observed in Hyperglycaemic Rats -What Can We Learn From Cell Biology?
Paulo J. Oliveira
[Full text article]

Diabetes mellitus is one of the most common metabolic diseases in the world. The complications associated with this disease are often responsible for a decreased quality of life in many patients. For example, the diabetic population has a greater probability to suffer from cardiovascular problems and heart failure than the general population.

Due to the importance heart mitochondria have in the context of the bioenergetics of the myocardium, it appears logical to explore mitochondrial dysfunction as an important link between hyperglycaemia and heart alterations observed during diabetes. One important factor that can lead to mitochondrial dysfunction is the mitochondrial permeability transition (MPT), caused by the formation of poly-protein pores (MPT pores), occurring with mitochondrial calcium overload and increased oxidative stress, conditions already described to exist in myocytes exposed to hyperglycaemia. The MPT has been involved as determinant in the survival of myocytes after anoxia and reoxigenation, as well as in triggering cell death.

The present review deals with cardiac mitochondrial alterations observed in drug-induced hyperglycaemic animals or in the GK rat, a hereditary model of hyperglycaemia. Respiration rates, susceptibility to oxidative stress, protein expression and MPT induction are altered in hyperglycaemic animals, which in extreme conditions can alter the bioenergetics of the diabetic myocardium and even cause myocardial cell death. The study of the cardiac mitochondrial function of hyperglycaemic animals offer an important insight, not only to explain cardiac alterations found in diabetic patients, but also in the design of new therapeutic approaches to reduce mitochondrial dysfunction and cell death typically associated with diabetes.

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Will Long Acting Insulin Analogs Influence the Use of Insulin Pump Therapy in Type 1 Diabetes?
J. Hans DeVries
[Full text article]

Insulin pump therapy enjoys a steadily growing number of users and is associated with an approximately 0.5% lower A1c as compared to flexible insulin injection therapy in type 1 diabetes patients. An important question is whether superiority of insulin pump therapy persists in the era of rapid acting analogs and will persist in the era of long acting analogs. Pooled data of three randomized clinical trials using rapid acting analogs in both arms shows a 0.35% lower A1c when on the pump. Treatment effect was shown to be larger in those with higher baseline A1c’s. Results of three trials comparing insulin pump therapy with regimens consisting of both rapid acting and long acting analogs are inconsistent, probably indicating the advantage of pump therapy at group level is likely to have become relatively small. Therefore, the challenge for the treatment team is to identify those patients who benefit most from insulin pump treatment. Poor glycemic control merits a trial of insulin pump therapy in the motivated patient. Other indications for insulin pump therapy include the need for several basal rates, a life style characterized by unpredictable physical activity and patient preference.

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Insight on the Pathogenesis of Diabetic Nephropathy from the Study of Podocyte and Mesangial Cell Biology
Gabriella Gruden, Paolo C. Perin and Giovanni Camussi
[Full text article]

Diabetic nephropathy is characterised by increased glomerular permeability to proteins, thickening of the glomerular basement membrane, and excessive extracellular matrix accumulation in the mesangium. Both mesangial cells and podocytes play a pivotal role in the pathogenesis of these alterations. Recent studies have cast light on both the mediators and the intracellular signalling molecules whereby high glucose and stretch, mimicking glomerular capillary hypertension, induce an abnormal extracellular matrix deposition. Furthermore, they have provided a better understanding of the mechanisms by which multiple pathways of hyperglycaemia- and hypertension-induced damage may converge at the cellular level. Glomerulosclerosis only partially explains the development of proteinuria and in recent years there has been a growing interest on the potential role of podocytes. The discovery of nephrin, a key molecule of the slit-diaphragm, has stressed the importance of podocytes in maintaining the glomerular size-selective barrier. Nephrin is lost in both human and experimental diabetic nephropathy and studies on cultured podocytes have shown that insults relevant to diabetes, such as high glucose, AGE, angiotensin II, and stretch, have important deleterious effects on podocyte survival and adhesion. This review focuses on the most significant advances in understanding the pathophysiology of both mesangial cells and podocytes, and their potential impact on diabetic nephropathy future treatments.

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Endothelial Progenitor Cells and Vascular Biology in Diabetes Mellitus: Current Knowledge and Future Perspectives
Gian P. Fadini, Carlo Agostini and Angelo Avogaro
[Full text article]

A growing amount of evidence demonstrates that Endothelial Progenitor Cells (EPCs) are involved in adult neovasculogenesis and maintenance of vascular integrity. EPC decrease and dysfunction are related to atherosclerosis and cardiovascular disease (CVD), and it has been proposed that the level of circulating EPCs may be used as a surrogate index of cumulative cardiovascular risk.

Moreover, many experimental approaches reveal that exogenous EPC injection stimulates blood flow recovery in critical limb and myocardial ischemia, providing a new therapeutic tool for CVD.

Diabetes Mellitus is a clinical condition characterized by a high incidence of CVD and is indeed associated with alterations in EPC physiology.

In this review we focus on the relationships between EPCs and vascular biology, with particular regard to Diabetes Mellitus and future therapeutical implications.

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Endothelial Dysfunction in Hyperglycemia as a Trigger of Atherosclerosis
Hironori Nakagami, Yasufumi Kaneda, Toshio Ogihara and Ryuichi Morishita
[Full text article]

Type 2 diabetes is associated with a two to fourfold increased risk of both coronary heart disease and stroke. Dysfunction of endothelial cells (EC) is known to promote abnormal vascular growth such as that in atherosclerosis and arteriosclerosis and has been postulated as an initial trigger of the progression of atherosclerosis in patients with diabetes mellitus, and hyperglycemia is an independent risk factor for the development of cardiovascular disease. We and others have previously demonstrated that high D-glucose induced apoptosis through activation of the bax-caspase proteases pathway in human EC and the potential contribution of hepatocyte growth factor, as an anti-apoptotic factor, to the pathogenesis of endothelial dysfunction. The antiapoptotic action of HGF was due to bcl-2-upregulation and the phosphatidylinositol 3-kinase pathway, which is involved in Akt activation. Although it has been known for years that cardiovascular tissues can release a large amount ROS, including superoxide, hydrogen peroxide, and nitric oxide, the role of oxidative stress in atherogenesis has received increasing attention in recent years. Recent work strongly suggests that NADPH oxidase is a major source of superoxide in cardiovascular cells, and oxidative stress can be involved in the process of endothelial dysfunction. NADPH oxidase can be activated in hyperglycemia through the protein kinase C pathway. From the viewpoint of these molecular mechanisms, HMG-CoA reductase inhibitors (statins) might inhibit the high glucose-induced NADPH oxidase activation through inhibition of Rac activity and finally prevent the increase in ROS production in diabetes. A recent clinical trial suggested that statins prevent several vascular events in patients with type 2 diabetes without a high concentration of LDL-cholesterol. These pleiotropic effects of statins can be expected to improve endothelial dysfunction through nitric oxide production and/or an anti-oxidant effect in diabetic patients.

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Oxidative Stress and the JNK Pathway in Diabetes
Hideaki Kaneto, Taka-aki Matsuoka, Yoshihisa Nakatani, Dan Kawamori, Munehide Matsuhisa and Yoshimitsu Yamasaki
[Full text article]

Under diabetic conditions, oxidative stress is induced and the JNK pathway is activated, which is involved in deterioration of pancreatic β-cell function found in diabetes. Oxidative stress and/or activation of the JNK pathway suppress insulin gene expression, accompanied by reduction of PDX-1 DNA binding activity. Treatment with antioxidants and/or suppression of the JNK pathway protect β-cells from some of the toxic effects of hyperglycemia. The JNK pathway is also involved in the progression of insulin resistance; suppression of the JNK pathway in obese diabetic mice markedly improves insulin resistance and ameliorates glucose tolerance. The phosphorylation state of key molecules for insulin signaling is altered upon modification of the JNK pathway. Taken together, the JNK pathway plays a crucial role in progression of insulin resistance as well as β-cell dysfunction found in diabetes and thus could be a potential therapeutic target for diabetes.

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Role of Cytokines and Trophic Factors in the Pathogenesis of Diabetic Retinopathy
Yoshinori Mitamura, Chikako Harada and Takayuki Harada
[Full text article]

Diabetic retinopathy (DR) is one of the most frequent complications of diabetes and the leading cause of acquired blindness in developed countries. A note worthy problem in DR is the formation of fibrovascular epiretinal membranes (ERMs) which can cause tractional retinal detachment in the progressed stage of DR. Ocular vitreous fluid and ERMs, which can be obtained during vitrectomy, allow laboratory studies investigating the pathogenesis of DR. Recent studies have shown a significant association between clinical grades of DR and the expression levels of specific cytokines, such as vascular endothelial growth factor (VEGF), in the intraocular fluid. In addition, expression of various trophic factors and their receptors are reported in ERMs. ERM is composed of many cell types including endothelial cells, which is the primary target of glucose-induced dysfunction in the retina. However, some trophic factor receptors are observed in other cell types such as the glial cells, and their role in ERMs is unclarified. These findings may uncover the detailed pathogenesis of DR, which may lead to new therapeutic strategies. This review briefly summarizes recent research regarding the clinical and laboratory findings of DR.

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The Utility of Oral Diabetes Medications in Type 2 Diabetes of the Young
Michael P. Kane, Asim Abu-Baker and Robert S. Busch
[Full text article]

Background: An estimated two-thirds of medications prescribed for use in pediatric patients have not been proven safe or effective for this patient population. Since 1995 a dozen orally administered diabetes medications or combination of medications for the management of type 2 diabetes mellitus have been approved by the Food and Drug Administration. Of these, only one (metformin) is approved for use in pediatrics. As the prevalence of children diagnosed with type 2 diabetes continues to rise, the need for adequate information regarding the safety, efficacy, and appropriate dosing of oral diabetes medications in the pediatric population likewise increases.

Objective: The purpose of this paper is to present the data available regarding the use of oral diabetes medications in a pediatric type 2 diabetes population.

Methods: A computerized literature search was performed using Medline and the Cochrane Database of Systematic Reviews.

Results: The Table consists of a summary of data regarding the use of oral antidiabetic agents in pediatric patients. These data include information regarding drug safety and efficacy and/or drug pharmacokinetic and drug dosing information.

Conclusions: Data concerning the safety and efficacy of oral diabetes medications to treat type 2 diabetes of the young is limited. Data currently available support the use of metformin as first-line drug therapy. Results of prospective studies over the next three to five years will better define the role of thiazolidinedione use as initial therapy in pediatric type 2 diabetes patients.

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Advanced Glycation End Products (AGEs) and Diabetic Vascular Complications
Sho-ichi Yamagishi, Kazuo Nakamura and Tsutomu Imaizumi
[Full text article]

Diabetic vascular complication is a leading cause of acquired blindness, end-stage renal failure, a variety of neuropathies and accelerated atherosclerosis, which could account for disabilities and high mortality rates in patients with diabetes. Chronic hyperglycemia is essentially involved in the development and progression of diabetic micro- and macroangiopathy. Among various metabolic derangements implicated in the pathogenesis of diabetic vascular complication, advanced glycation end product (AGE) hypothesis is most compatible with the theory of ‘hyperglycemic memory’. In this review, we discuss the molecular mechanisms of diabetic vascular complication, specially focusing on AGEs and their receptor (RAGE) system. Several types of AGE inhibitors and their therapeutic implications in this devastating disorder are also discussed here.

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Anaemia in Diabetes: An Emerging Complication of Microvascular Disease
Merlin Thomas, Con Tsalamandris, Richard MacIsaac and George Jerums
[Full text article]

Diabetes as the dominant cause of ESRD is also the major cause of renal anaemia. However, most patients with diabetic kidney disease will succumb to co-morbid vascular disease or heart failure before developing severe renal impairment. In these patients, anaemia is also common finding, with a 2-3 times greater prevalence and earlier onset than in patients with renal impairment from other causes. We have recently shown that at least one in five outpatients with type 1 or type 2 diabetes in tertiary referral clinics have anaemia, in whom it constitutes a significant additional burden. Impaired renal erythropoietin release in response to declining haemoglobin levels appears to be the major contributor to anaemia in diabetes. This may be due to the predominance of damage to cells and vascular architecture of the renal tubulointerstitium associated with diabetic nephropathy that may be apparent, like albuminuria, before demonstrable changes in renal function. In addition, systemic inflammation, autonomic neuropathy and reduce red cell survival may also compound anaemia in diabetes. While anaemia may be considered a marker of diabetic kidney disease, reduced haemoglobin levels, even within the normal range, identify diabetic patients with an increased risk of hospitalisation and mortality. Anaemia may also be significant in determining the outcome of heart failure and hypoxia–induced organ damage in patients with diabetes. Upcoming studies will determine whether correction of anaemia in diabetes will lead to improved outcomes in these patients.