Diabetes in the elderly population

Type 2 diabetes mellitus has emerged as an important condition of older patients in which both microvascular and macrovascular complications are a common cause of morbidity and mortality. In contrast to type 1 diabetes mellitus, this endocrinopathy is clustered in minority populations and has both strong genetic and environmental factors that influence disease manifestation. A number of physiological alterations of glucose metabolism including hepatic overproduction of glucose, and reduced glucose utilization by peripheral tissues as a result of insulin resistance contribute to the development of the metabolic manifestations of this disease. Ultimately, pancreatic failure and reduced insulin secretion lead to hyperglycemia and the diabetic state. Frequently, many of these metabolic manifestations, or what has been termed Syndrome X, antecede the development of overt diabetes by many years. This syndrome is manifest clinically by such cardiovascular risk factors as hypertension, dyslipidemia, and coagulation abnormalities. This abnormal metabolic milieu contributes to the high prevalence of macrovascular complications including coronary artery disease as well as more generalized atherosclerosis. Microvascular complications have only more recently been recognized as an important and frequent complication of type 2 diabetes. Among the elderly and minority populations, this has become the single most important cause of end-stage renal failure that necessitates renal replacement therapies. The outcome for these patients on hemodialysis, the modality most frequently selected, is poor, with the majority of these patients dying of cardiovascular causes. Unfortunately, interventional strategies to reduce or prevent the microvascular and macrovascular complications have only recently received the needed attention and will require considerable effort and resources to improve the clinical outcomes and life expectancies for these patients.     

Hyperglycemia and cardiovascular disease in type 2 diabetes.

Cardiovascular disease (coronary heart disease, stroke, peripheral vascular disease) is the most important cause of mortality and morbidity among patients with type 2 diabetes. Conventional risk factors contribute similarly to macrovascular complications in patients with type 2 diabetes and nondiabetic subjects, and therefore, other explanations have been sought for enhanced atherothrombosis in type 2 diabetes. Among characteristics specific for type 2 diabetes, hyperglycemia has recently been a focus of keen research. A recent meta-analysis of 20 studies on nondiabetic subjects has demonstrated that in the nondiabetic range of glycemia (<6.1 mmol/l), increased glucose is already associated with an increased risk for cardiovascular disease. Similarly, 12 recent prospective studies have convincingly indicated that hyperglycemia contributes to cardiovascular complications in patients with type 2 diabetes. The recently published U.K. Prospective Diabetes Study has shown that intensive glucose control reduces effectively microvascular complications among patients with type 2 diabetes, but that its effect on the prevention of cardiovascular complications was limited. Given the fact that in the U.K. Prospective Diabetes Study, none of the treatment modalities was particularly effective in reducing glucose, this underestimates the true potential of the correction of hyperglycemia in the prevention of cardiovascular disease in type 2 diabetes. However, in addition to intensive therapy of hyperglycemia, other conventional risk factors should also be normalized to prevent cardiovascular disease in patients with type 2 diabetes.     

Genetics of diabetes

Diabetes mellitus is a complicated disease characterized by a complex interplay of genetic, epigenetic, and environmental variables. It is one of the world's fastest-growing diseases, with 783 million adults expected to be affected by 2045. Devastating macrovascular consequences (cerebrovascular disease, cardiovascular disease, and peripheral vascular disease) and microvascular complications (like retinopathy, nephropathy, and neuropathy) increase mortality, blindness, kidney failure, and overall quality of life in individuals with diabetes. Clinical risk factors and glycemic management alone cannot predict the development of vascular problems; multiple genetic investigations have revealed a clear hereditary component to both diabetes and its related complications. In the twenty-first century, technological advancements (genome-wide association studies, next-generation sequencing, and exome-sequencing) have led to the identification of genetic variants associated with diabetes, however, these variants can only explain a small proportion of the total heritability of the condition. In this review, we address some of the likely explanations for this "missing heritability", for diabetes such as the significance of uncommon variants, gene-environment interactions, and epigenetics. Current discoveries clinical value, management of diabetes, and future research directions are also discussed.     

The role of protein kinase C activation in diabetic nephropathy

Diabetic nephropathy is the leading cause of end-stage renal disease worldwide and an independent risk factor for all-cause and cardiovascular mortalities in diabetic patients. New insights into the molecular mechanisms that underlie the development and progression of microvascular complications of diabetes including nephropathy are emerging rapidly from experimental and clinical studies. Chronic hyperglycemia is a major initiator of diabetic microvascular complications. Activation of diacylglycerol (DAG)-protein kinase C (PKC) pathway, enhanced polyol pathway, increased oxidative stress, and overproduction of advanced glycation end products have all been proposed as potential cellular mechanisms by which hyperglycemia induces diabetic vascular complications. The DAG-PKC pathway contributes to vascular function in many ways such as the regulation of endothelial permeability, vasoconstriction, extracellular matrix synthesis/turnover, cell growth, angiogenesis, cytokine activation, and leukocyte adhesion. We will briefly review the current knowledge base regarding the pathogenic role for the activation of DAG-PKC pathway in diabetic nephropathy and other microvascular complications of diabetes. The results from animal studies and key clinical studies investigating specific effects of the PKC isoforms on the renal and other vascular tissues to induce diabetic complications are also reviewed.     

Hypertension and diabetes

Hypertension is often associated clinically with diabetes either as part of the insulin resistance syndrome or as a manifestation of renal disease. Elevated systemic blood pressure accelerates the progression of both microvascular and macrovascular complications in diabetes. Agents that interrupt the renin-angiotensin system confer renoprotection via a range of hemodynamic and nonhemodynamic mechanisms. Recent clinical trials confirm that these agents confer renoprotection in type 1 and type 2 diabetic patients with early or advanced renal disease. Hypertension also appears to accelerate vascular and cardiac abnormalities in diabetes, including increased atherosclerosis, arterial stiffness, left ventricular hypertrophy and diastolic dysfunction. A number of recently published and ongoing trials are exploring the role of aggressive antihypertensive treatment with a range of antihypertensive drugs in diabetic subjects at risk of or with macrovascular disease.     

Normalization of coronary microvascular reactivity and improvement in myocardial perfusion by surgical vascular endothelial growth factor therapy combined with oral supplementation of l-arginine in a porcine model of endothelial dysfunction

OBJECTIVE: Vascular endothelial growth factor acts in part through nitric oxide release, the availability of which is decreased in endothelial dysfunction associated with advanced coronary artery disease. This could explain the relatively disappointing results of vascular endothelial growth factor therapy in clinical studies compared with animal studies. We examined the influence of L-arginine supplementation to vascular endothelial growth factor therapy on myocardial microvascular reactivity and perfusion in a porcine model of endothelial dysfunction. METHODS: Twenty-four pigs were fed either a normal (NORM, n = 8) or high-cholesterol diet with (CHOL-ARG, n = 8) or without (CHOL, n = 8) L-arginine. All pigs underwent ameroid placement on the circumflex artery and then 3 weeks later received surgical vascular endothelial growth factor treatment. Four weeks after treatment, endothelial-dependent coronary microvascular responses and lateral myocardial perfusion were assessed. Endothelial cell density was determined by means of immunohistochemistry. Vascular endothelial growth factor, endothelial nitric oxide synthase, and Akt levels were determined by means of immunoblotting. RESULTS: Pigs from the CHOL group showed endothelial dysfunction in the circumflex territory, which was normalized by L-arginine supplementation. Vascular endothelial growth factor treatment was ineffective in the CHOL group (circumflex/left anterior descending coronary artery blood flow ratios: 0.95 [rest] and 0.74 [pace] before-after treatment; P < .05 compared with the NORM group). Addition of L-arginine restored the angiogenic effect of vascular endothelial growth factor (ratios: 1.13 [rest] and 1.20 [pace]; P < .05) and was associated with increased endothelial cell density, as well as vascular endothelial growth factor, endothelial nitric oxide synthase, and Akt protein levels in the ischemic territory. CONCLUSIONS: L-Arginine supplementation can restore normal endothelium-dependent vasorelaxation and angiogenic response to vascular endothelial growth factor in a swine model of chronic myocardial ischemia with hypercholesterolemia-induced endothelial dysfunction. These findings suggest a putative role for L-arginine in combination with vascular endothelial growth factor therapy for end-stage coronary artery disease.     

Diabetes and Peripheral Vascular Disease

The risk of peripheral vascular disease (PVD) is increased in diabetic patients, occurs earlier and is often more severe and diffuse. Endothelial dysfunction, vascular smooth muscle cell dysfunction, inflammation and hypercoagubil-ity are the key factors in diabetic arteriopathy. The presence of PVD, apart from its increased risk of claudication, ischemic ulcers, gangrene and possible amputation, is also a marker for generalized atherosclerosis and a strong predictor for cardiovascular ischemic events. However, despite the recognition that PVD is associated with increased ischemic event rates and death, particularly in diabetic patients, this specific manifestation of systemic atherosclerosis is largely underdiagnosed and undertreated.

In type-1 diabetes, early intensive insulin treatment reduces both microvascular (nephropathy, retinopathy and neuropathy) and macrovascular complications of diabetes (DCCT/EDIC study). In type-2 diabetes, UKPDS showed that tight glucose control reduces micro-and macrovascular complications, when therapy is started early after diagnosis and that early intervention has long lasting protective effects. However recently published trials (ADVANCE, ACCORD and VADT) pointed out that lowering glycemic targets to nearly normal glycaemia does not further reduce cardiovascular events in individuals with longstanding type 2 diabetes and that hypoglycaemia is to be avoided in individuals with ischemic heart disease. Finally, the small but important Steno-2 trial demonstrated that to significantly reduce peripheral vascular disease, ischemic events and mortality in type-2 diabetes, intensified multifactorial treatment of all modifiable risk factors is needed. Therefore, to prevent micro-and macrovascular complications, like PVD, in type-1 and type-2 diabetes, intensive therapy, targeting glycemia and all other modifiable cardiovascular risk factors, should be initiated as soon after diagnosis as possible and maintained in a safe way throughout life.     

Insulin sensitivity and complications in type 1 diabetes: New insights

Despite improvements in glucose, lipids and bloodpressure control, vascular complications remain the most important cause of morbidity and mortality in patients with type 1 diabetes. For that reason, there is a need to identify additional risk factors to utilize in clinical practice or translate to novel therapies to prevent vascular complications. Reduced insulin sensitivity is an increasingly recognized component of type 1 diabetes that has been linked with the development and progression of both micro- and macrovascular complications. Adolescents and adults with type 1 diabetes have reduced insulin sensitivity, even when compared to their non-diabetic counterparts of similar adiposity, serum triglycerides, high-density lipoprotein cholesterol, level of habitual physical activity, and in adolescents, pubertal stage. Reduced insulin sensitivity is thought to contribute both to the initiation and progression of macro- and microvascular complications in type 1 diabetes. There are currently clinical trials underway examining the benefits of improving insulin sensitivity with regards to vascular complications in type 1 diabetes. Reduced insulin sensitivity is an increasingly recognized component of type 1 diabetes, is implicated in the pathogenesis of vascular complications and is potentially an important therapeutic target to prevent vascular complications. In this review, we will focus on the pathophysiologic contribution of insulin sensitivity to vascular complications and summarize related ongoing clinical trials.     

Angiogenesis — a New Goal in Peripheral Artery Occlusive Disease Therapy

The vasculature is mostly quiescent in the normal adult, with the exception of the growth of new blood vessels during the female reproductive cycle. Recent advances in the knowledge concerning the molecular changes and the identification of genetic events in this vascular quiescence, as well as in vascular growth, has led to an increasing number of studies in which these phenomena are manipulated. Angiogenesis is the growth of new vessels from existing ones. Although new vessel formation is involved in many pathologic situations, like tumour growth, therapeutic angiogenesis has been presented as a novel method for the treatment of ischemic diseases, like peripheral arterial occlusive disease (PAOD).

In experimental studies therapeutic angiogenesis has been produced by recombinant growth-factor protein application as well as by growth factor gene therapy. Most widely studied factors belong to vascular endothelial growth factor (VEGF) or fibroblast growth factor (FGF) families. Studies have also shown that, angiogenic growth factors stimulate endothelial cell migration and accelerate endothelial repair by enhancing post-injury re-endothelization. In clinical studies angiogenic therapy has been evaluated in patients with severe vascular diseases. The results have revealed that therapy is well tolerated as well as safe and that angiogenic therapy has a clear biologic effect. However, controlled studies are still needed to answer the question whether therapeutic angiogenesis offers a real clinical benefit to patients with PAOD.     

Relationship between TaqIB cholesteryl ester transfer protein gene polymorphism and macrovascular complications in Japanese patients with type 2 diabetes

Cholesteryl ester transfer protein (CETP) is a key regulating factor of lipid metabolism, and the polymorphism of its gene may therefore be a candidate for modulating the lipid parameters, altering the susceptibility to atherosclerosis in type 2 diabetic subjects. In a group of 443 unrelated Japanese patients with type 2 diabetes, we studied the B1B2 polymorphism at the CETP locus, which is detectable with the restriction enzyme TaqI. Patients were separated into three groups according to genotype and compared based on their clinical characteristics, lipid parameters, and macrovascular complications. The B2 allele was associated in a dose-dependent fashion with higher HDL cholesterol and apolipoprotein AI levels, together with lower CETP concentrations. Furthermore, the prevalence of macrovascular complications, such as coronary heart disease, arteriosclerosis obliterans, and cerebral vascular disease, was significantly higher in subjects with the B1B1 genotype. Multiple logistic regression analysis also showed that the B1 allele of CETP genotype was associated with the incidence of these three complications independently of other risk factors. Thus, in type 2 diabetic patients, the B1B2 polymorphism of CETP gene is likely to be a strong genetic predictor of macrovascular complications.     

Angiogenesis--a new goal in peripheral artery occlusive disease therapy

The vasculature is mostly quiescent in the normal adult, with the exception of the growth of new blood vessels during the female reproductive cycle. Recent advances in the knowledge concerning the molecular changes and the identification of genetic events in this vascular quiescence, as well as in vascular growth, has led to an increasing number of studies in which these phenomena are manipulated. Angiogenesis is the growth of new vessels from existing ones. Although new vessel formation is involved in many pathologic situations, like tumour growth, therapeutic angiogenesis has been presented as a novel method for the treatment of ischemic diseases, like peripheral arterial occlusive disease (PAOD). In experimental studies therapeutic angiogenesis has been produced by recombinant growth-factor protein application as well as by growth factor gene therapy. Most widely studied factors belong to vascular endothelial growth factor (VEGF) or fibroblast growth factor (FGF) families. Studies have also shown that, angiogenic growth factors stimulate endothelial cell migration and accelerate endothelial repair by enhancing post-injury re-endothelization. In clinical studies angiogenic therapy has been evaluated in patients with severe vascular diseases. The results have revealed that therapy is well tolerated as well as safe and that angiogenic therapy has a clear biologic effect. However, controlled studies are still needed to answer the question whether therapeutic angiogenesis offers a real clinical benefit to patients with PAOD.     

Peri-operative management of patients with diabetes mellitus

Patients with diabetes mellitus are routinely encountered in anaesthetic practice. Peri-operative maintenance of good glycaemic control to avoid metabolic decompensation and its sequelae is considered to be the ideal, as they have a worse surgical outcome. In addition to routine anaesthetic assessment, patients with diabetes should be assessed pre-operatively for macrovascular complications (ischaemic heart disease, peripheral vascular disease, cerebrovascular disease) and microvascular complications (nephropathy, neuropathy, retinopathy) of diabetes, along with a review of overall glycaemic control. For elective surgery, patients with poor metabolic control should receive intensive glucose management. For major operations, patients will require an intravenous insulin infusion for which several regimens are currently used in clinical practice. The two most popular methods are: (1) the ‘sliding scale’ and (2) the GIK (glucose–insulin–potassium) infusion. Both methods have advantages and disadvantages, but for more complex surgery the ‘sliding scale’ method is more flexible. Minor surgery should not require the use of intravenous insulin infusions since these patients may be managed by adjustments in their usual dose of insulin or oral hypoglycaemic agents. In specific operative procedures, e.g. cardiothoracic surgery, major hyperglycaemic excursions have been shown to occur highlighting the need for stringent blood glucose monitoring.     

Captopril suppresses post-transplantation angiogenic activity in rat allograft coronary vessels.

BACKGROUND: The development of transplant coronary artery disease is associated with neovascularization in the thickened neointima. We previously reported that captopril inhibits neointimal proliferation in a rat allograft model. We postulated that angiogenic inducers are upregulated post-transplantation and captopril ameliorates transplant coronary artery disease by suppressing the angiogenic activity of coronaries. METHODS: Animals received no treatment or captopril (50 mg/kg/day). Allograft hearts were analyzed at post-transplantation Days 0, 14, and 21 and angiogenic inducer, plasma platelet-activating factor, determined. The conditioned media from coronaries and myocardium were tested for vascular endothelial growth factor, thrombospondin-1 and angiogenic activity using an endothelial migration assay and rat corneal neovascularization assay. RESULTS: The captopril-treated group had reduced plasma platelet-activating factor and coronary media revealed earlier upregulation of thrombospondin-1 secretion, diminished vascular endothelial growth factor and no angiogenic activity. At Day 0, the coronary and myocardial conditioned medium had inhibitory activity due to thrombospondin-1, and circulating levels of platelet-activating factor were negligible. By 21 days post-transplantation, plasma platelet-activating factor was elevated and the conditioned medium from untreated coronaries had significantly higher angiogenic activity due to increased vascular endothelial growth factor whereas the myocardium remained non-angiogenic. CONCLUSIONS: After transplantation, coronary vessels switch to an angiogenic phenotype and vascular endothelial growth factor contributes to the high angiogenic activity, possibly exacerbated by high circulating levels of platelet-activating factor. The ability of captopril to modulate angiogenic mediators and maintain the allograft coronary to its normal anti-angiogenic phenotype may be one mechanism by which it suppresses transplant coronary artery disease.     

The kallikrein-kinin system in diabetic retinopathy: lessons for the kidney

Diabetic retinopathy and diabetic nephropathy are common microvascular complications of diabetes. The kallikrein-kinin system (KKS) has been implicated in the development of both conditions, and, in particular, bradykinin and its receptors have been shown to exert angiogenic and proinflammatory actions. Several of the key processes that underlie the development of diabetic retinopathy, such as increased vascular permeability, edema, neovascularization, and inflammatory changes, have been associated with the KKS, and recent work has shown that components of the KKS, including plasma kallikrein, factor XIIa, and high-molecular-weight kininogen, are present in the vitreous of people with diabetic retinopathy. The role of the KKS in the development of diabetic nephropathy is controversial, with both adverse and protective effects of bradykinin and its receptors reported. The review examines the role of the KKS in pathways central to the development of diabetic retinopathy and compares this with reported actions of this system in diabetic nephropathy. The possibility of therapeutic intervention targeting bradykinin and its receptors as treatment for diabetic microvascular conditions is considered.     

Vascular growth factors and angiogenesis in cardiac surgery

Therapeutic angiogenesis, in the form of growth factor protein administration or gene therapy, has emerged as a new method of treatment for patients with severe, inoperable coronary artery disease. Improved myocardial perfusion and function after administration of angiogenic growth factors has been demonstrated in animal models of chronic myocardial ischemia. Recently, preliminary clinical trials using growth factor proteins or genes encoding these angiogenic factors have demonstrated clinical and other objective evidence of relevant angiogenesis. A recent study reported beneficial long-term effects of therapeutic angiogenesis using fibroblast growth factor (FGF)-2 protein in terms of freedom from angina and perfusion on single-photon emission computed tomographic imaging. Thus, therapeutic angiogenesis has the potential to extend treatment options to patients who are not optimal candidates for conventional methods of myocardial revascularization. However, endogenous antiangiogenic influences, intrinsic lack of response of patients with severe endothelial dysfunction, and other limitations will need to be overcome before angiogenesis becomes a standard therapy for the treatment of patients with severe coronary disease.     

Amelioration of microvascular myocardial ischemia by gene transfer of vascular endothelial growth factor in rabbits

OBJECTIVES: Restoration of coronary blood flow by angiogenesis may offer a new approach to intractable ischemic heart disease. In the present study, we investigated the angiogenic effects of gene transfer of vascular endothelial growth factor 165 on microvascular myocardial ischemia. METHODS: A rabbit model of microvascular myocardial ischemia was created by plugging coronary microvessels with microspheres (15 microm in diameter, 2.8 x 10(5)/kg, n = 29). Gene transfer was performed by semi-selective intracoronary injection of recombinant adenovirus expressing vascular endothelial growth factor 165 forty minutes after microsphere injection (n = 9). RESULTS: Microsphere injection reduced myocardial perfusion (78% +/- 9% of baseline tissue flow) and diminished myocardial contraction (61% +/- 12% of the baseline ejection fraction) and cardiac performance (elevated left ventricular end-diastolic pressure and decreased systemic flow) in the acute phase. At 17 +/- 3 days, gene transfer of vascular endothelial growth factor 165 had had the following effects: (1) promoted coronary angiogenesis as evidenced by myocardial flow above the baseline (121% +/- 24%), (2) increased vascular density revealed by synchrotron radiation microangiography and histologic analysis, (3) ameliorated the degree of myocardial ischemia as evidenced by myocardial lactate content and the extent of histologic necrosis, and (4) restored heart function as evidenced by increased ejection fraction (95% +/- 10%), reduced left ventricular end-diastolic pressure, and restored body weight. CONCLUSIONS: In vivo vascular endothelial growth factor 165 gene transfer promoted angiogenesis and was an effective approach to treating microvascular myocardial ischemia.     

Therapeutic angiogenesis in peripheral arterial disease: can biotechnology produce an effective collateral circulation?

The physiological processes of angiogenesis, vasculogenesis and arteriogenesis contribute to the growth of collateral vessels in response to obstructive arterial disease causing lower limb or myocardial ischaemia, but in clinical practice the endogenous angiogenic response is often suboptimal or impaired, e.g. by factors such as ageing, diabetes or drug therapies. Therapeutic angiogenesis is an application of biotechnology to stimulate new vessel formation via local administration of pro-angiogenic growth factors in the form of recombinant protein or gene therapy, or by implantation of endothelial progenitor cells that will synthesize multiple angiogenic cytokines. Numerous experimental and clinical studies have sought to establish 'proof of concept' for therapeutic angiogenesis in PAD and myocardial ischaemia using different treatment modalities, but the results have been inconsistent. This review summarises the mechanisms of angiogenesis and the results of recent trials evaluating the efficacy and safety of different gene therapy, recombinant protein and cellular-based treatment approaches to enhance collateral vessel formation.     

Inhibition of the cardiac angiogenic response to exogenous vascular endothelial growth factor

BACKGROUND: The angiogenic effects of vascular endothelial growth factor (VEGF) are mediated by the stimulation of endothelial nitric oxide synthase (eNOS) and nitric oxide release. Nitric oxide availability is decreased in patients with coronary disease, a possible explanation for the humble results of VEGF in clinical trials. We sought to examine the effects of exogenous VEGF in a model of endothelial dysfunction. METHODS: Miniswine fed either a regular (N = 6, group NORM) or hypercholesterolemic diet (N = 6, HICHOL) underwent ameroid placement on the circumflex artery. Three weeks later, baseline myocardial perfusion was assessed by microsphere injections, and all pigs were treated with VEGF. Four weeks later, microsphere injections were repeated and the hearts harvested. Endothelial-dependent coronary microvascular reactivity, and VEGF and eNOS expression were assessed. RESULTS: HICHOL pigs showed significant endothelial dysfunction in the ischemic territory. Post-treatment myocardial blood flow in the circumflex territory was significantly higher in the NORM compared to the HICHOL group. VEGF and eNOS levels were increased in the ischemic territory in the NORM group but decreased in the HICHOL group. CONCLUSIONS: The cardiac angiogenic response to VEGF was markedly inhibited in a hypercholesterolemia-induced porcine model of endothelial dysfunction. Coronary endothelial dysfunction could be an obstacle to the efficacy of clinical angiogenesis protocols and a putative therapeutic target.     

Angiopoietins: microvascular modulators with potential roles in glomerular pathophysiology

Angiopoietins are a recently discovered family of growth factors which act on endothelial cells via Tie receptors. They are widely expressed and have essential roles in regulating vascular growth, development, maturation and permeability. Disturbances in microvascular regulation play an important part in a number of diseases prominent in the developed world including diabetes, ischemic heart disease and cancer. It is the interplay between angiopoietins and other factors including vascular endothelial growth factor (VEGF) which determines endothelial behavior both in health and in these diseases. Angiopoietin-1 is unique in its ability to reduce endothelial permeability and it antagonises the effects of VEGF in its permeability and angiogenesis-inducing actions. The renal glomerulus constitutes a highly specialized microcirculation in which the permeability characteristics of the capillary wall allow its unique filtration function. Disturbance of this function may cause a reduction in glomerular filtration rate or proteinuria. Understanding of the regulation of the filtration barrier is incomplete but the expression of angiopoietins in the glomerulus suggests a mechanism for maintenance of the glomerular endothelium and modulation of the actions of glomerular VEGF. As has been clearly shown for VEGF, angiopoietins are likely to be involved in glomerular disease and recovery from it. Manipulation of angiopoietins has a wide range of potential therapeutic applications from inhibition of diabetic retinal neovascularisation to promotion of glomerular repair.     

SGLT2 Inhibition: A Novel Prospective Strategy in Treatment of Diabetes Mellitus

The role of the kidney in glucose homeostasis and the potential of the kidney as a therapeutic target in type 2 diabetes is little appreciated. Hyperglycemia is an important pathogenic component in the development of microvascular and macrovascular complications in type 2 diabetes mellitus. Inhibition of renal tubular glucose re-absorption that leads to glycosuria has been proposed as a new mechanism to attain normoglycemia and thus prevent and diminish these complications, thus representing an innovative therapeutic strategy for the treatment of hyperglycemia and/or obesity in patients with type 1 or type 2 diabetes by enhancing glucose and energy loss through the urine. Sodium glucose co-transporter 2 (SGLT2) has a key role in re-absorption of glucose in kidney. Competitive inhibitors of SGLT2 have been discovered and a few of them have also been advanced in clinical trials for the treatment of diabetes.