Diabetic Macrovascular Disease Research Articles

Proteome profiling in the aorta and kidney of type 1 diabetic rats.

Diabetes is associated with a number of metabolic and cardiovascular risk factors that contribute to a high rate of microvascular and macrovascular complications. The risk factors and mechanisms that contribute to the development of micro- and macrovascular disease in diabetes are not fully explained. In this study, we employed mass spectrometric analysis using tandem LC-MS/MS to generate a proteomic profile of protein abundance and post-translational modifications (PTM) in the aorta and kidney of diabetic rats. In addition, systems biology analyses were employed to identify key protein markers that can provide insights into molecular pathways and processes that are differentially regulated in the aorta and kidney of type 1 diabetic rats. Our results indicated that 188 (111 downregulated and 77 upregulated) proteins were significantly identified in the aorta of diabetic rats compared to normal controls. A total of 223 (109 downregulated and 114 upregulated) proteins were significantly identified in the kidney of diabetic rats compared to normal controls. When the protein profiles from the kidney and aorta of diabetic and control rats were analyzed by principal component analysis, a distinct separation of the groups was observed. In addition, diabetes resulted in a significant increase in PTM (oxidation, phosphorylation, and acetylation) of proteins in the kidney and aorta and this effect was partially reversed by insulin treatment. Ingenuity pathway analysis performed on the list of differentially expressed proteins depicted mitochondrial dysfunction, oxidative phosphorylation and acute phase response signaling to be among the altered canonical pathways by diabetes in both tissues. The findings of the present study provide a global proteomics view of markers that highlight the mechanisms and putative processes that modulate renal and vascular injury in diabetes.

Association between microfibrillar-associated protein 4 (MFAP4) and micro- and macrovascular complications in long-term type 1 diabetes mellitus.

To evaluate microfibrillar-associated protein 4 (MFAP4) as a marker of micro- and macrovascular complications in patients with type 1 diabetes. This cross-sectional study included 203 persons with a long duration of type 1 diabetes from a population-based cohort ascertained in the former Funen County, Denmark. Detection of plasma-MFAP4 (pMFAP4) was performed by the AlphaLISA Technique. Diabetic retinopathy (DR) was graded in accordance with the Early Treatment Diabetic Retinopathy Study adaptation of the modified Airlie House classification. A monofilament test was used to test for neuropathy, and nephropathy was evaluated in a single spot urine sample. Data describing macrovascular disease were obtained from the Danish National Patient Register. Median age and duration of diabetes were 58.7 and 43years, respectively, and 61% were males. High levels of pMFAP4 were found in participants of old age, in women and in non-smokers (p<0.05). In a multiple logistic regression model, patients with high levels of pMFAP4 were more likely to have diabetic neuropathy (OR 2.47 for quartile 4 versus quartile 1, 95% CI 1.01-6.03). No association was found between pMFAP4 and proliferative diabetic retinopathy, nephropathy or macrovascular disease. No association between pMFAP4 and macrovascular vascular complications was found. However, high levels of pMFAP4 correlated independently with diabetic neuropathy. Further studies on the predictive value of increased circulating MFAP4 in diabetic neuropathy are warranted.

The connection of diabetic dyslipidemia and erectile dysfunction

Background Diabetes is an established risk factor for sexual dysfunction in men; a threefold increased risk of erectile dysfunction (ED) was documented in diabetic compared with non-diabetic men. Diabetic vasculopathy concerns macroangiopathy, microangiopathy and endothelial dysfunction. Macrovascular disease in diabetes corresponds to the atherosclerotic damage in the blood vessels, which limits blood flow to the penis. Aim Value the connection of dyslipidemia and erectile dysfunction in men patients who are ill with diabetes. Materials and methods In the research, 180 patients at the age of 33–67 with type 2 diabetes mellitus were participated. According to the duration of diabetes, the patients were divided into three groups and revealed the erectile dysfunction. The lipid metabolism was revealed and HbA1c was determined in all the patients. Results The patients who are ill with diabetes within 1–5 years ( n =41, 22,78%), the erectile dysfunction is met in 34.15% of patients (in this group n =14), those who are ill with diabetes within 5–10 years, the erectile dysfunction is met in 57.53% (in this group n =43), who are ill with diabetes within 10 years and more the erectile dysfunction is met in 69.7% of patients ( n =46). The result of lipid metabolism value showed that hypercholesterolemia was met in 42.22% ( n =76) of the patients, hypertriglyceridemia was met in 21.11% ( n =38), combined disorder was met in 24.44% ( n =44). Thus, 87.77% of the examined patients have lipid metabolism disorder. The result of the research showed that erectile dysfunction was usual in case of dyslipidemia. It should be noted that 60.52% of the patients ( n =23) who had isolated hypertriglyceridemia had erectile dysfunction, 63.16% of the patients ( n =48) who had hypercholesterolemia had erectile dysfunction and 72.73% ( n =32) of the patients with combined disorder had erectile dysfunction. Conclusion Surely, the erectile dysfunction in diabetes mellitus has a multifactorial nature such as duration of diabetes, level of compensation, complications especially neuropathy availability and harmful habits. According to our findings, we have a lot of patients with erectile dysfunction and hypertriglyceridemia. The findings remind us once more that medical practitioners have to pay attention especially to lipid metabolism condition, triglyceridemia level in diabetic patients. So, dyslipidemia is the reason of increasing cardiovascular risks and decreasing quality of life.

A causal relationship between uric acid and diabetic macrovascular disease in Chinese type 2 diabetes patients: A Mendelian randomization analysis.

As the association between uric acid and macrovascular disease has been heavily debated, we aimed to confirm whether there is a causal relationship between uric acid and diabetic macrovascular disease through Mendelian randomization analysis. In 3207 type 2 diabetes patients, seventeen SNPs (single nucleotide polymorphisms) related to uric acid were genotyped. A weighted GRS (genetic risk score) was calculated using selected SNPs and the strength of their effects on uric acid levels. Diabetic macrovascular disease was diagnosed through vascular ultrasound, magnetic resonance imaging or other clinical evidence. Associations of diabetic macrovascular disease with uric acid and weighted GRS were evaluated separately. In total participants and among females, the prevalence of diabetic macrovascular disease was significantly higher in hyperuricemic group than in normouricemic group, and uric acid was associated with diabetic macrovascular disease (OR=1.068, p=0.0349; OR=1.122, p=0.0158). The prevalence of diabetic macrovascular disease increased with the weighted GRS in a J-shaped manner for the females. The weighted GRS was positively correlated with uric acid in total population, male patients and female patients (β=0.203, p<0.0001; β=0.255, p<0.0001; β=0.142, p<0.0001, respectively). The weighted GRS was significantly associated with diabetic macrovascular disease in female patients (OR=1.184, p=0.0039). Among females, the observed association between weighted GRS and diabetic macrovascular disease was greater than predicted. Using the uric acid-related weighted GRS as an instrumental variable for Mendelian randomization analysis, our study provided an evidence for causal relationship between uric acid and diabetic macrovascular disease in Chinese females with type 2 diabetes mellitus.

The effect and action mechanism of resveratrol on the vascular endothelial cell by high glucose treatment

To investigate the effect and action mechanism of resveratrol on the vascular endothelial cell by high glucose treatment. Primarily cultured human umbilical vein endothelial cells (HUVECs) were pretreated by resveratrol (0.2μmol/L) and holding for 6h, and then cultured in Dulbecco Modified Eagle Medium (DMEM) within 0.45mmol/L of palmimte acid and 32.8mmol/L of glucose, which is holding for 12h. The cells were collected to analyze the expression of E-selected element. Supernatant of cultured cells, induced by 100nmol/L insulin for 30min, was used to analyze the nitric oxide content. Compared with normal control cells, the secretion of nitric oxide is stimulated by insulin decrease, however, the expression of E-selected element increased in HUVEC. Resveratrol treatment increased the secretion of nitric oxide stimulated by insulin and decreased the expression of E-selected element and partly counteracts the impairment of high glucose and palmitate acid on the function of endothelial cells. Resveratrol can improve and protect the function of high glucose and fatty acid cultured endothelial cell, and therefore may be a promising medicine in the prevention or therapy of diabetic macrovascular diseases.

Insulin therapy in insulin resistance: Could it be part of a lethal pathway?

Insulin therapy in insulin resistance: Could it be part of a lethal pathway?

Effect of single nucleotide polymorphism in thrombin-activatable fibrinolysis inhibitor on the risk of diabetic macrovascular disease.

Hypofibrinolysis is commonly found in patients with diabetes mellitus and is associated with the increased risk for many diabetic complications. An important inhibitor of fibrinolysis, thrombin-activatable fibrinolysis inhibitor (TAFI), participates in hypofibrinolysis in diabetes mellitus and may be involved in diabetic macrovascular disease. The present study was designed to determine whether TAFI polymorphisms (505G/A and 1040C/T) and TAFI levels are correlated with the development of type 2 diabetes mellitus (T2DM) and macrovascular diseases (MVDs). A total of 249 clinical samples were collected, including 102 healthy individuals (H group), 44 T2DM patients without MVD (T group) and 103 T2DM patients with MVD (M group). The 505G/A polymorphism was equally represented in the three groups. In contrast, analysis of the 1040C/T polymorphism revealed a statistically lower percentage of the T allele in the M group than in the H group (P = 0.014). This difference was due to decreased T/T homozygotes in the M groups compared with the H group (P = 0.029). The antigen TAFI level was 31.72 ± 13.64% in the H group, 62.56 ± 18.77% in the T group (P < 0.05, compared with the H group) and 63.70 ± 15.76% in the M group (P < 0.05, compared with the H group). As high plasma TAFI level is associated with the increasing risk of T2DM, it may thus serve as a potential marker for the diagnosis of T2DM.

Glycemic control with empagliflozin, a novel selective SGLT2 inhibitor, ameliorates cardiovascular injury and cognitive dysfunction in obese and type 2 diabetic mice.

BackgroundThere has been uncertainty regarding the benefit of glycemic control with antidiabetic agents in prevention of diabetic macrovascular disease. Further development of novel antidiabetic agents is essential for overcoming the burden of diabetic macrovascular disease. The renal sodium glucose co-transporter 2 (SGLT2) inhibitor is a novel antihyperglycemic agent for treatment of type 2 diabetes. This work was performed to determine whether empagliflozin, a novel SGLT2 inhibitor, can ameliorate cardiovascular injury and cognitive decline in db/db mouse, a model of obesity and type 2 diabetes.Methods(1) Short-term experiment: The first experiment was performed to examine the effect of 7 days of empagliflozin treatment on urinary glucose excretion and urinary electrolyte excretion in db/db mice. (2) Long-term experiment: The second experiment was undertaken to examine the effect of 10 weeks of empagliflozin treatment on cardiovascular injury, vascular dysfunction, cognitive decline, and renal injury in db/db mice.Results(1) Short-term experiment: Empagliflozin administration significantly increased urinary glucose excretion, urine volume, and urinary sodium excretion in db/db mice on day 1, but did not increase these parameters from day 2. However, blood glucose levels in db/db mice were continuously decreased by empagliflozin throughout 7 days of the treatment. (2) Long-term experiment: Empagliflozin treatment caused sustained decrease in blood glucose in db/db mice throughout 10 weeks of the treatment and significantly slowed the progression of type 2 diabetes. Empagliflozin significantly ameliorated cardiac interstitial fibrosis, pericoronary arterial fibrosis, coronary arterial thickening, cardiac macrophage infiltration, and the impairment of vascular dilating function in db/db mice, and these beneficial effects of empagliflozin were associated with attenuation of oxidative stress in cardiovascular tissue of db/db mice. Furthermore, empagliflozin significantly prevented the impairment of cognitive function in db/db mice, which was associated with the attenuation of cerebral oxidative stress and the increase in cerebral brain-derived neurotrophic factor. Empagliflozin ameliorated albuminuria, and glomerular injury in db/db mice.ConclusionsGlycemic control with empagliflozin significantly ameliorated cardiovascular injury and remodeling, vascular dysfunction, and cognitive decline in obese and type 2 diabetic mice. Thus, empagliflozin seems to be potentially a promising therapeutic agent for diabetic macrovascular disease and cognitive decline.

Diabetic Macrovascular Disease

Diabetic macrovascular disease, a significant contributor to the morbidity and mortality of individuals, is an occult problem which is frequently only identified after the occurrence of an ischemic event. Evaluating arterial pulsations of the foot using a hand held Doppler can suggest the presence or absence of peripheral vascular disease, therefore allowing more specific studies to be performed and appropriate interventions taken.

Modified low density lipoprotein and lipoprotein-containing circulating immune complexes as diagnostic and prognostic biomarkers of atherosclerosis and type 1 diabetes macrovascular disease.

In atherosclerosis; blood low-density lipoproteins (LDL) are subjected to multiple enzymatic and non-enzymatic modifications that increase their atherogenicity and induce immunogenicity. Modified LDL are capable of inducing vascular inflammation through activation of innate immunity; thus, contributing to the progression of atherogenesis. The immunogenicity of modified LDL results in induction of self-antibodies specific to a certain type of modified LDL. The antibodies react with modified LDL forming circulating immune complexes. Circulating immune complexes exhibit prominent immunomodulatory properties that influence atherosclerotic inflammation. Compared to freely circulating modified LDL; modified LDL associated with the immune complexes have a more robust atherogenic and proinflammatory potential. Various lipid components of the immune complexes may serve not only as diagnostic but also as essential predictive markers of cardiovascular events in atherosclerosis. Accumulating evidence indicates that LDL-containing immune complexes can also serve as biomarker for macrovascular disease in type 1 diabetes.

Quinapril treatment abolishes diabetes-associated atherosclerosis in RAGE/apolipoprotein E double knockout mice

Objective/RationaleBoth the renin-angiotensin system (RAS) and the receptor for advanced glycation end products (RAGE) potentiate diabetes-associated atherosclerosis (DAA). We assessed the effectiveness of concomitant RAS and RAGE inhibition on DAA. MethodsDiabetic (5 × 55 mg/kg streptozotocin daily) and non-diabetic male RAGE/apolipoprotein E double knockout (RAGE/apoE DKO) mice were treated with quinapril (30 mg/kg/day) for 20 weeks. At the end of the study aortic plaques were assessed. ResultsDiabetic RAGE/apoE DKO showed significantly less plaque area than diabetic apoE KO mice. Plaque deposition was almost abolished in quinapril treated diabetic RAGE/apoE DKOs, with significant attenuation of vascular collagen deposition, nitrotyrosine staining, and reduced macrophage infiltration. Expression of the advanced glycation end product receptor 3 (galectin 3) was also significantly reduced. ConclusionConcomitant inhibition of RAS and RAGE signalling almost completely inhibited the development of experimental DAA. A dual therapeutic approach may be a superior strategy for the treatment of diabetic macrovascular disease..

Diabetes complications in congenic leptin receptor deficient BBDR.cg‐lepr.cp rats (1072.6)

Diabetes is a chronic disease that is associated with devastating complications. Here, we characterize micro‐ and macrovascular changes in a novel congenic BBDR.cg‐lepr.cp rat line, generated by introgression of the Koletsky leptin receptor mutation onto BioBreeding Diabetes Resistant rats. Interestingly, two subgroups of male BBDR.cg‐lepr.cp rats could be distinguished based on their blood glucose (BG), one severely diabetic (D) and one with moderately (M) elevated BG. Both groups were obese and showed significant enlargement of liver, heart and kidneys when compared to control littermates. Serum insulin, leptin, triglycerides and cholesterol were increased in all BBDR.cg‐lepr.cp rats when compared to controls, but with significant differences between groups; triglycerides and cholesterol were higher in D rats, leptin and insulin were higher in M rats. Albumin/creatinine ratio was dramatically increased and histological examination of kidneys revealed dilated and filled tubuli and loss of glomerular podocin expression, this was more pronounced in D rats when compared to M rats. All BBDR.cg‐lepr.cp rats had significantly higher systolic blood pressure, but surprisingly only M rats had increased aortic mRNA expression of endothelial activation and inflammatory markers. Collectively, our results point to different underlying factors for micro‐ and macrovascular disease in diabetes.Grant Funding Source: Supported by VR 2011‐3900; the SUMMIT consortium (IMI‐2008/115006), Påhlsson and Diabetes Found.

AGEs, rather than hyperglycemia, are responsible for microvascular complications in diabetes: A “glycoxidation-centric” point of view

AimsAdvanced glycation end products (AGE) excess is one of the most important mechanisms involved in the pathophysiology of chronic diabetic complications. This review first summarizes the role of these compounds in microvascular pathogenesis, particularly in the light of recently proposed biochemical mechanisms for diabetic retinopathy, nephropathy and neuropathy. Then we focus on the relationship between AGE and metabolic memory, trying to clarify the former's role in the missing link between micro- and macrovascular complications. Data synthesisAn excessive AGE formation has been demonstrated in the newly disclosed biochemical pathways involved in the microvascular pathobiology of type 2 diabetes, confirming the central role of AGE in the progression of diabetic neuropathy, retinopathy and nephropathy. As shown by recent studies, AGE seem to be not "actors", but "directors" of processes conducting to these complications, for at least two main reasons: first, AGE have several intra- and extracellular targets, so they can be seen as a "bridge" between intracellular and extracellular damage; secondly, whatever the level of hyperglycemia, AGE-related intracellular glycation of the mitochondrial respiratory chain proteins has been found to produce more reactive oxygen species, triggering a vicious cycle that amplifies AGE formation. This may help to explain the clinical link between micro- and macrovascular disease in diabetes, contributing to clarify the mechanisms behind metabolic memory. ConclusionsThe pathophysiological cascades triggered by AGE have a dominant, hyperglycemia-independent role in the onset of the microvascular complications of diabetes. An effective approach to prevention and treatment must therefore focus not only on early glycemic control, but also on reducing factors related to oxidative stress, and the dietary intake of exogenous AGE in particular.

Increased PD-1 on CD4+CD28− T cell and soluble PD-1 ligand-1 in patients with T2DM: Association with atherosclerotic macrovascular diseases

ObjectiveTo study the role of the programmed death-1 (PD-1)/programmed death-1 ligand 1 (PD-L1) coinhibitory pathway in regulating CD4+CD28− T cells, and to explore the association of soluble PD-L1 (sPD-L1) in the development of T2DM with atherosclerotic macrovascular diseases. MethodsThe percentage of CD4+CD28− T lymphocyte subsets from peripheral blood mononuclear cells (PBMCs) and the expression of PD-1/PD-L1 on lymphocytes were analyzed by immunostaining and flow cytometry, respectively. The serum levels of sPD-L1 and IFN-γ were determined by ELISA system. T cell proliferation was determined by cocultivation and WST-8 incorporation. ResultsIn 125 T2DM patients and 48 healthy donors, CD4+CD28− T cells from patients with T2DM expressed higher PD-1 than that of the cells from healthy individuals, and the proliferation response of CD4+CD28− T cells could be enhanced by advanced glycation end products (AGEs). The levels of sPD-L1 in patients were also much higher than those of healthy donors, and the increase was displayed in an exacerbation-dependent manner in the T2DM with atherosclerotic macrovascular patients especially with acute coronary syndrome (ACS). The production of sPD-L1 was significantly positively correlated with the level of IFN-γ and could enhance T cell proliferation. ConclusionBoth the upregulation of PD-1 and the increase of sPD-L1 were closely associated with the severity of diabetic atherosclerotic macrovascular diseases. sPD-L1 may contribute to the continuous T cell activation and development of diabetic macrovascular diseases.

Current therapeutic interventions in the glycation pathway: evidence from clinical studies

The increased formation of advanced glycation endproducts (AGEs) constitutes a potential mechanism of hyperglycaemia-induced micro- and macrovascular disease in diabetes. In vitro and animal experiments have shown that various interventions can inhibit formation and/or actions of AGEs, in particular the specific AGE inhibitor aminoguanidine and the AGEs crosslink breaker alagebrium, and the B vitamins pyridoxamine and thiamine, and the latter's synthetic derivative, benfotiamine. The potential clinical value of these interventions, however, remains to be established. The present review provides, from the clinical point of view, an overview of current evidence on interventions in the glycation pathway relating to (i) the clinical benefits of specific AGE inhibitors and AGE breakers and (ii) the potential AGE-inhibiting effects of therapies developed for purposes unrelated to the glycation pathway. We found that safety and/or efficacy in clinical studies with the specific AGE inhibitor, aminoguanidine and the AGE breaker, alagebrium, appeared to be a concern. The clinical evidence on the potential AGE-inhibiting effects of B vitamins is still limited. Finally, current evidence for AGE inhibition by therapies developed for purposes unrelated to glycation is limited due to a large heterogeneity in study designs and/or measurement techniques, which have often been sub-optimal. We conclude that, clinical evidence on interventions to inhibit formation and/or action of AGEs is currently weak and unconvincing.

IMMUNOASSAY OF MODIFIED FORMS OF HUMAN LOW DENSITY LIPOPROTEIN IN ISOLATED CIRCULATING IMMUNE COMPLEXES

Modified lipoproteins are able to induce inflammatory reactions through innate immunity pathways and are immunogenic, leading to an autoimmune response that results in the formation of proinflammatory immune complexes. The measurement of circulating oxidized lipoproteins and corresponding antibodies has, therefore, been proposed as an approach to assess the risk for complications in patients with diabetes and for the risk of cardiovascular disease in the general population. However, the majority of modified low density lipoprotein (LDL) in the peripheral circulation exists in the form of immune complexes, and this is a significant obstacle for the measurement of modified LDL and the corresponding antibodies. In this manuscript, we describe in detail the methodology developed by our group for isolation and fractionation of circulating immune complexes (IC), allowing the accurate assay of different LDL modifications. This approach has resulted in several studies showing that the levels of modified LDL are risk factors with a stronger association to diabetic retinopathy, nephropathy, and macrovascular disease. Ongoing research is focused on evaluating the predictive power of modified LDL levels for the development or progression of atherosclerotic cardiovascular disease in other patient populations and on the simplification of the assay to make it more applicable to diagnostic laboratories.

Community-based Nutritional Management for Secondary Prevention of Diabetic Macrovascular Diseases

Community health projects focusing on secondary prevention of diabetic macrovascular diseases have become increasingly common. In Daegu, Korea, a metropolitan hypertension diabetes management project has been developed in which community primary physicians refer clinic patients to education centers or clinical education teams for target education on lifestyle modification through technology-based information networks. Call centers provide information on lifestyle management and encourage continuous treatment through periodic calls and SMS. Integrative education is presented by doctors, dietitians, exercise specialists, and nurses. This project was developed in response to an educational need study of patients and educators. Patients participating in the program showed significant improvement in both self-efficiency and in clinical outcomes. (J Korean Diabetes 2013;14:36-41)

Does severe hypoglycaemia influence microvascular complications in Type 1 diabetes? An analysis of the Diabetes Control and Complications Trial database

Severe hypoglycaemia may have a role in aggravating micro- and macrovascular disease in diabetes. Data from the Diabetes Control and Complication Trial have been reanalysed to ascertain whether the frequency of severe hypoglycaemia exerted an influence on the development and progression of retinopathy or nephropathy in people with Type 1 diabetes. Using binary longitudinal multiple logistic regression, HbA(1c) at study baseline, mean HbA(1c) throughout the study and the number of severe hypoglycaemic episodes during the trial were compared to examine the risk of development/progression of retinopathy and nephropathy. Average HbA(1c) during the study and/or HbA(1c) at baseline were independently predictive of retinopathy and nephropathy both in the intensively and the conventionally treated patients (all P ≤ 0.001). However, the number of hypoglycaemic episodes did not add to HbA(1c) in predicting retinopathy [odds ratio (95% CI) 0.99 (0.96-1.01), P = 0.51 in intensively treated patients, 0.94 (0.89-1.00), P = 0.05, conventional] or nephropathy [odds ratio (95% CI) 0.98 (0.95-1.01), P = 0.48 intensive, 1.03 (0.98-1.10), P = 0.17 conventional]. The frequency of exposure to severe hypoglycaemia did not predict a different risk of developing retinopathy or nephropathy in either treatment group of the Diabetes Control and Complications Trial at any given HbA(1c) .

Type 2 diabetes mellitus is associated with an imbalance in circulating endothelial and smooth muscle progenitor cell numbers

Aims/hypothesisIndividuals with type 2 diabetes mellitus have increased rates of macrovascular disease (MVD). Endothelial progenitor cells (EPCs), circulating angiogenic cells (CACs) and smooth muscle progenitor cells (SMPCs) are suggested to play a role in the pathogenesis of MVD. The relationship between vasoregenerative EPCs or CACs and damaging SMPCs and the development of accelerated MVD in diabetes is still unknown. We tried to elucidate whether EPC, CAC and SMPC numbers and differentiation capacities in vitro differ in patients with and without diabetes or MVD.MethodsPeripheral blood was obtained from insdividuals with and without diabetes and MVD (coronary or peripheral artery disease). EPC and SMPC numbers were determined with flow cytometry. Furthermore, CAC and SMPC numbers were quantified after in vitro culture. Their in vitro differentiation capacity was investigated with real-time RT-PCR and quantitative immunofluorescence.ResultsIn diabetic patients both EPC and CAC levels were reduced (1.3-fold [p < 0.05] and 1.5-fold [p < 0.05], respectively). CAC outgrowth from diabetic patients with MVD was reduced 1.5-fold compared with diabetic patients without MVD (p < 0.05). SMPC levels were similar between diabetic patients and healthy controls. The CAC/SMPC ratio of in vitro cultured progenitor cells was reduced 2.3-fold in samples from diabetic patients (p < 0.001). The differentiation capacity of CACs and SMPCs in vitro remained similar independently of diabetes or MVD.Conclusions/interpretationThe ratio between EPCs or CACs and SMPCs is disturbed in type 2 diabetes in favour of SMPCs. This may translate into reduced vascular repair capacity, thereby promoting MVD in type 2 diabetes.Electronic supplementary materialThe online version of this article (doi:10.1007/s00125-012-2590-5) contains peer-reviewed but unedited supplementary material, which is available to authorised users.

Macrovascular Disease in Diabetes: Is the Mouse a Suitable Model?

To elucidate the pathogenesis of macrovascular disease in diabetes, animal models are widely used. Diabetic mice are of particular interest because they can be crossed to knockout mice lacking specific genes that are under consideration to contribute to diabetic vascular complications. However, the mouse is relative resistant to develop atherosclerosis. Therefore, we review some commonly used mouse models and discuss their advantages and disadvantages.