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Neutrophil elastase contributes to the pathological vascular permeability characteristic of diabetic retinopathy

期刊: DIABETOLOGIA, 2019; 62 (12)

Aims/hypothesis Levels of neutrophil elastase, a serine protease secreted by neutrophils, are elevated in diabetes. The purpose of this study was to determine whether neutrophil elastase (NE) contributes to the diabetes-induced increase in retinal vascular permeability in mice with streptozotocin-induced diabetes, and, if so, to investigate the potential role of IL-17 in this process. Methods In vivo, diabetes was induced in neutrophil elastase-deficient (Elane(-/-)), Il-17a(-/-) and wild-type mice. After 8 months of diabetes, Elane(-/-) mice and wild-type age-matched control mice were injected with FITC-BSA. Fluorescence microscopy was used to assess leakage of FITC-BSA from the retinal vasculature into the neural retina. The level of NE in Il-17a(-/-) diabetic retina and sera were determined by ELISA. In vitro, the effect of NE on the permeability and viability of human retinal endothelial cells and the expression of junction proteins and adhesion molecules were studied. Results Eight months of diabetes resulted in increased retinal vascular permeability and levels of NE in retina and plasma of wild-type animals. All of these abnormalities were significantly inhibited in mice lacking the elastase. The diabetes-induced increase in NE was inhibited in mice lacking IL-17. In vitro, NE increased retinal endothelial cell permeability, which was partially inhibited by a myeloid differentiation primary response 88 (MyD88) inhibitor, NF-kappa B inhibitor, and protease-activated receptor (PAR)2 inhibitor. NE degraded vascular endothelial-cadherin (VE-cadherin) in a concentration-dependent manner. Conclusions/interpretation IL-17 regulates NE expression in diabetes. NE contributes to vascular leakage in diabetic retinopathy, partially through activation of MyD88, NF-kappa B and PAR2 and degradation of VE-cadherin.

JIF:7.11

Adenine nucleotide-mediated regulation of hepatic PTP1B activity in mouse models of type 2 diabetes

期刊: DIABETOLOGIA, 2019; 62 (11)

Aims/hypothesis Plasma 5 '-AMP (pAMP) is elevated in mouse models of type 2 diabetes. However, the metabolic regulatory role of adenine nucleotides in type 2 diabetes remains unclear. Methods Adenine nucleotides and their metabolites in plasma and liver were examined by HPLC. H-1 NMR-based metabolomics analysis was performed to explore the changes of metabolites in mouse models of type 2 diabetes. Na+/K+ ATPase and Na+/H+ exchanger activity were measured in response to adenine nucleotide metabolites. Human recombinant protein tyrosine phosphatase 1B (PTP1B) was used for enzyme kinetic assays. Protein binding assays were performed with microscale thermophoresis. The intracellular pH of hepatocyte AML12 cell lines was measured using the BCECF-AM method. We also analysed pAMP levels in participants with type 2 diabetes. Results Elevation of pAMP was a universal phenomenon in all mouse models of type 2 diabetes including db/db vs lean mice (13.9 +/- 2.3 mu mol/l vs 3.7 +/- 0.9 mu mol/l; p < 0.01), ob/ob vs lean mice (9.1 +/- 2.0 mu mol/l vs 3.9 +/- 1.2 mu mol/l; p < 0.01) and high-fat diet/streptozotocin-induced vs wild-type mice (6.6 +/- 1.5 mu mol/l vs 4.1 +/- 0.9 mu mol/l; p < 0.05); this elevation was required for the occurrence of hyperglycaemia in obese mice. H-1 NMR-based metabolomics study following HPLC analysis revealed that the metabolite profile in wild-type mice treated with 5 '-AMP was similar to that in db/db diabetic mice, especially the accumulation of a large quantity of ATP and its metabolites. The glucose-lowering drug metformin reduced the severity of hyperglycaemia both in 5 '-AMP-induced wild-type mice and db/db mice. Metformin decreased the accumulation of liver ATP but not its metabolites in these hyperglycaemic mice. ATP and metformin reciprocally change cellular pH homeostasis in liver, causing opposite shifts in liver activity of PTP1B, a key negative regulator of insulin signalling. Furthermore, pAMP levels were also elevated in individuals with type 2 diabetes (45.2 +/- 22.7 nmol/l vs 3.1 +/- 1.9 nmol/l; p < 0.01). Conclusions/interpretation These results reveal an emerging role for adenine nucleotide in the regulation of hyperglycaemia and provide a potential therapeutic target in obesity and type 2 diabetes.

JIF:7.11

Association between glucose variation and lower extremity amputation incidence in individuals with type 2 diabetes: a nationwide retrospective cohort study

期刊: DIABETOLOGIA, 0; ()

Aims/hypothesis Elevated glucose level is one of the risk factors for lower extremity amputation (LEA), but whether glycaemic variability confers independent risks of LEA remains to be elucidated. This study aimed to investigate the association between visit-to-visit glycaemic variability and minor and major LEA risks during 8 years of follow-up in type 2 diabetic individuals aged 50 years and older. Methods This retrospective cohort study included 27,574 ethnic Chinese type 2 diabetic individuals aged >= 50 years from the National Diabetes Care Management Program in Taiwan. Glycaemic variability measures were presented as the CVs of fasting plasma glucose (FPG-CV) and of HbA(1c) (A(1c)-CV). The effect of glycaemic variability on the incidence of LEA events was analysed using Cox proportional hazards models. Results After a median follow-up of 8.9 years, 541 incident cases of LEA with a crude incidence density rate of 2.4 per 1000 person-years were observed. After multivariate adjustment, FPG-CV and A(1c)-CV were found to be significantly associated with minor LEA, with corresponding HRs of 1.53 (95% CI 1.15, 2.04) and 1.34 (95% CI 1.02, 1.77) for the third tertiles of FPG-CV and A(1c)-CV, respectively. In addition, these associations were stronger amongst older adults with longer diabetes duration (>= 3 years) than amongst those with shorter duration (<3 years) (p(interaction) < 0.01). Conclusions/interpretation Our study suggests that visit-to-visit variations in HbA(1c) and FPG are important predictors of minor LEA amongst older adults with type 2 diabetes, particularly for those with more than 3 years of diabetes duration.

Prospective associations of circulating adipocyte fatty acid-binding protein levels with risks of renal outcomes and mortality in type 2 diabetes

期刊: DIABETOLOGIA, 2019; 62 (1)

Aims/hypothesisElevated circulating adipocyte fatty acid-binding protein (AFABP) levels have been found to correlate with diabetic nephropathy staging in cross-sectional studies. However, it remains unclear whether these higher serum levels reflect a role of AFABP in the development of diabetic kidney disease (DKD), or simply result from its impaired renal clearance in DKD. Here we investigated prospectively the prognostic importance of serum AFABP level in the development of adverse renal outcomes in a large clinic-based cohort of participants with type 2 diabetes.MethodsBaseline serum AFABP levels were measured in 5454 Chinese participants from the Hong Kong West Diabetes Registry. The association between circulating AFABP levels and incident adverse renal outcomesdefined as a composite endpoint of a sustained 40% decline in eGFR, end-stage renal disease requiring renal replacement therapy or kidney transplantation, or renal deathswas evaluated using multivariable Cox regression analysis.ResultsOver a median follow-up of 5years, 754 of the 5454 participants developed incident adverse renal outcomes. Elevated circulating AFABP levels were independently associated with incident adverse renal outcomes (HR 1.43, 95% CI 1.31, 1.57, p<0.001) after adjustments for conventional risk factors for DKD progression. Importantly, the prognostic role of serum AFABP was independent of the baseline albuminuria status or eGFR levels of the study participants.Conclusions/interpretationCirculating AFABP levels were predictive of incident adverse renal outcomes, even in participants with relatively well-preserved kidney function at baseline, suggesting its potential to be a useful marker for early risk stratification in DKD.

JIF:7.11

Growth differentiation factor 15 is positively associated with incidence of diabetes mellitus: the Malmo Diet and Cancer-Cardiovascular Cohort

期刊: DIABETOLOGIA, 2019; 62 (1)

Aims/hypothesisGrowth differentiation factor 15 (GDF-15) is an anti-inflammatory cytokine of the transforming growth factor- superfamily. Circulating levels of GDF-15 are associated with hyperglycaemia among people with obesity or diabetes, but longitudinal evidence on the association between GDF-15 levels and diabetes risk is scarce. Our aim was to explore whether circulating levels of GDF-15 at baseline are positively associated with future diabetes incidence in a middle-aged urban population.MethodsBetween 1991 and 1994, baseline fasting plasma GDF-15 levels were measured in 4360 individuals without diabetes (mean age 57.45.96years, 38.6% men) who were participants in the Malmo Diet and Cancer-Cardiovascular Cohort. After a follow-up of 19.05.16years (mean +/- SD), Cox proportional hazards regression analysis was used for the study of the relationship between baseline GDF-15 and incident diabetes, with adjustment for established confounders. A sensitivity analysis included further adjustment for levels of C-reactive protein (CRP).Results During the follow-up period, 621 individuals developed diabetes. The multivariate-adjusted HR for diabetes incidence was 1.43 (95% CI 1.11, 1.83; p for trend = 0.007) for the fourth compared with the first quartile of GDF-15, and was 1.17 (95% CI 1.07, 1.28; p<0.001) per SD increase of GDF-15. If participants were grouped according to baseline fasting glucose, the association between GDF-15 and diabetes risk was only evident in the group without impaired fasting glucose (n=3973). The association tended to be less significant with increasing age: multivariate-adjusted HRs for diabetes per SD increase of GDF-15 were 1.24 (95% CI 1.08, 1.42), 1.19 (95% CI 1.00, 1.41) and 1.04 (95% CI 0.89, 1.23) for participants aged 55, 56-60 (>55 and 60) and >60years, respectively. With adjustment for levels of CRP, the HR per SD increase of GDF-15 (1.21, 95% CI 1.09, 1.35) was significant (p=0.015), but the HR for the fourth compared with the first quartile of GDF-15 was not significant (HR 1.30; 95% CI 1.01, 1.67; p for trend = 0.061).Conclusions/interpretation GDF-15 may be useful for identification of people with a risk of incident diabetes, especially if those people are 60years old.

JIF:7.11

Trajectories of childhood BMI and adult diabetes: the Bogalusa Heart Study

期刊: DIABETOLOGIA, 2019; 62 (1)

Aims/hypothesisThe aim of this study was to characterise longitudinal profiles of BMI from childhood and to examine the impact of level-independent childhood BMI trajectories on adult type 2 diabetes.MethodsThe longitudinal cohort consisted of 2449 adults (1613 white and 836 black) who had their BMI measured between four and 15 times from childhood (4-19years) to adulthood (20-51years) and fasting glucose measured in adulthood. Model-estimated levels and linear slopes of BMI at childhood age points were calculated in 1-year intervals using growth-curve parameters and their first derivatives, respectively.ResultsBMI from childhood to adulthood fit cubic growth curves; linear and non-linear curve parameters differed significantly between race-sex groups. BMI showed race and sex differences from 15years onwards. Individuals with hyperglycaemia had higher long-term BMI levels than those who were normoglycaemic in race-sex groups. Linear and non-linear slope parameters of BMI differed consistently and significantly between adult hyperglycaemia groups. The OR of childhood BMI levels for ages 4-19years was 1.45-1.83 (p<0.001 for all) for adult hyperglycaemia after adjustment for confounders. Level-adjusted linear slopes of BMI at ages 10-19years showed significantly positive associations with adult hyperglycaemia (OR 1.17-1.50, p<0.01 for all). The associations of childhood BMI linear slopes with adult hyperglycaemia were not significant during the age period 5-9years. The trends in these associations were consistent across race-sex groups.Conclusions/interpretationThese observations indicate that childhood BMI trajectories have a significant impact on adult diabetes, independent of BMI levels. The adolescence age period is a crucial window for the development of diabetes in later life, which has implications for early-life prevention.Data availabilityAll data and materials are publicly available at the National Heart, Lung, and Blood Institute (NHLBI) Biologic Specimen and Data Repository and can be accessed at https://biolincc.nhlbi.nih.gov/studies/bhs.

JIF:7.11

Heterozygous deletion of Seipin in islet beta cells of male mice has an impact on insulin synthesis and secretion through reduced PPAR gamma expression

期刊: DIABETOLOGIA, 0; ()

Aims/hypothesis Berardinelli-Seip congenital lipodystrophy type 2 (BSCL2) is an autosomal recessive disorder characterised by lipodystrophy and insulin resistance. BSCL2 is caused by loss-of-function mutations in the Seipin gene (also known as Bscl2). Deletion of this gene in mice induces insulin resistance, glucose intolerance and a loss of adipose tissue. This study evaluated the effects of genetic deletion of Seipin on islet beta cell function. Methods We examined seipin expression in islet cells and measured glucose profiles, insulin synthesis, glucose-stimulated insulin secretion (GSIS), islet expression of peroxisome proliferator-activated receptor gamma (PPAR gamma), levels of Pdx-1, Nkx6.1, Glut2 (also known as Slc2a2) and proinsulin mRNA, nuclear translocation of pancreatic duodenal homeobox 1 (PDX-1), islet numbers, and beta cell mass and proliferation in male and female Seipin-knockout homozygous (Seipin(-/-)) and heterozygous (Seipin(+/-)) mice. Results Male and female Seipin(-/-) mice displayed glucose intolerance, insulin resistance, hyperinsulinaemia and a lack of adipose tissue. By contrast, male but not female Seipin(+/-) mice showed glucose intolerance without adipose tissue loss or insulin resistance. Seipin was highly expressed in islet beta cells in wild-type mice. Expression of islet PPAR gamma was reduced in male Seipin(-/-) and Seipin(+/-) mice but not in female Seipin(-/-) or Seipin(+/-) mice. Treatment of male Seipin(+/-) mice with rosiglitazone corrected the glucose intolerance. Male Seipin(+/-) mice displayed a decrease in islet insulin concentration and GSIS with low expression of Pdx-1, Nkx6.1, Glut2 and proinsulin, and a decline in PDX-1 nuclear translocation; these changes were rescued by rosiglitazone administration. Male Seipin(-/-) mice showed obvious, but rosiglitazone-sensitive, increases in islet insulin concentration, islet number and beta cell mass and proliferation, with a notable decline in GSIS. Ovariectomised female Seipin(+/-) mice displayed glucose intolerance and deficits in insulin synthesis and secretion, with a decline in islet PPAR gamma level; these deleterious effects were reversed by administration of oestradiol or rosiglitazone. Conclusions/interpretation Heterozygous deletion of Seipin in islet beta cells impacts on insulin synthesis and secretion through reduced PPAR gamma expression. This leads to glucose intolerance and is relieved by oestradiol, which rescues PPAR gamma expression.

Prostaglandin E-2/EP2 receptor signalling pathway promotes diabetic retinopathy in a rat model of diabetes

期刊: DIABETOLOGIA, 2019; 62 (2)

Aims/hypothesisDiabetic retinopathy is a common microvascular complication of diabetes mellitus and is initiated by inflammation and apoptosis-associated retinal endothelial cell damage. Prostaglandin E-2 (PGE(2)) has emerged as a critical regulator of these biological processes. We hypothesised that modulating PGE(2) and its E-prostanoid receptor (EP2R) would prevent diabetes mellitus-induced inflammation and microvascular dysfunction.MethodsIn a streptozotocin (STZ)-induced rat model of diabetes, rats received intravitreal injection of PGE(2), butaprost (a PGE(2)/EP2R agonist) or AH6809 (an EP2R antagonist). Retinal histology, optical coherence tomography, ultrastructure of the retinal vascular and biochemical markers were assessed.ResultsIntravitreal injection of PGE(2) and butaprost significantly accelerated retinal vascular leakage, leucostasis and endothelial cell apoptosis in STZ-induced diabetic rats. This response was ameliorated in diabetic rats pre-treated with AH6809. In addition, pre-treatment of human retinal microvascular endothelial cells with AH6809 attenuated PGE(2)- and butaprost-induced activation of caspase 1, activation of the complex containing nucleotide-binding domain and leucine rich repeat containing family, pyrin domain containing 3 (NLRP3) and apoptosis-associated speck-like protein containing a C-terminal caspase-activation and recruitment domain (ASC), and activation of the EP2R-coupled cAMP/protein kinase A/cAMP response element-binding protein signalling pathway.Conclusions/interpretationThe PGE(2)/EP2R signalling pathway is involved in STZ-induced diabetic retinopathy and could be considered as a potential target for diabetic retinopathy prevention and treatment.

JIF:7.11

Loss of X-box binding protein 1 in Muller cells augments retinal inflammation in a mouse model of diabetes

期刊: DIABETOLOGIA, 2019; 62 (3)

inf Aims/hypothesisMuller glia (MG) are major sources of retinal cytokines, and their activation is closely linked to retinal inflammation and vascular leakage in diabetic retinopathy. Previously, we demonstrated that X-box binding protein 1 (XBP1), a transcription factor activated by endoplasmic reticulum (ER) stress in diabetic retinopathy, is involved in regulation of inflammation in retinal endothelial cells. Now, we have explored the role of XBP1 and ER stress in the regulation of MG-derived proinflammatory factors, and their influence on vascular permeability in diabetic retinopathy.MethodsMG-specific conditional Xbp1 knockout (Xbp1(Muller-/-)) mice were generated by crossing Xbp1 flox/flox mice with Muller-Cre transgenic mice. Diabetes was modelled by induction with streptozotocin, and retinal vascular permeability was measured with FITC-conjugated dextran 2months after induction. Primary Muller cells were isolated from Xbp1(Muller-/-) and Xbp1(Muller+/+) mice and exposed to hypoxia and high levels of glucose. Levels of ER-stress andlammatory factors were examined by real-time PCR, western blotting or immunohistochemistry.ResultsXbp1(Muller-/-) mice exhibited normal retinal development and retinal function and expressed similar levels of ER-stress and inflammatory genes to Xbp1(Muller+/+) littermates. In diabetes-inducing conditions, compared with Xbp1(Muller+/+) mice, Xbp1(Muller-/-) mice had higher mRNA levels of retinal Vegf (also known as Vegfa) and Tnf- (also known as Tnf) and ER-stress marker genes Grp78 (also known as Hspa5), Atf4, Chop (also known as Ddit3) and Atf6 and higher protein levels of vascular endothelial growth factor (VEGF), TNF-, phospho-c-Jun N-terminal kinase (JNK), 78kDa glucose-regulated protein (GRP78), phospho-eukaryotic translation initiation factor (eIF)2 and activating transcription factor (ATF)6. Retinal vascular permeability was significantly higher in diabetic Xbp1(Muller-/-) mice than in diabetic Xbp1(Muller+/+) mice (p<0.01). Results obtained in vitro with primary Muller cells isolated from Xbp1(Muller-/-) mice confirmed higher expression levels of inflammatory and ER-stress markers (but not GRP78) than in cells from Xbp1(Muller+/+) mice. Moreover, XBP1-deficient Muller cells were more susceptible to high-glucose- or hypoxia-induced ER stress and inflammation than cells from Xbp1(Muller+/+) mice. Inhibition of ER stress with chemical chaperones suppressed hypoxia-induced VEGF and TNF- production in XBP1-deficient Muller cells.Conclusions/interpretationOur results have revealed an important role of XBP1 and ER stress in MG-driven retinal inflammation, and suggest that targeting ER stress may represent a promising approach for the prevention and treatment of diabetic retinopathy.

JIF:7.11

Tetraspanin 7 autoantibodies predict progressive decline of beta cell function in individuals with LADA

期刊: DIABETOLOGIA, 2019; 62 (3)

Aims/hypothesisThe aim of this work was to investigate whether tetraspanin 7 autoantibodies (TSPAN7A) are valuable in predicting poor beta cell function in individuals with latent autoimmune diabetes in adults (LADA).MethodsThe cross-sectional study involved participants with LADA (n=173), type 1 diabetes (n=158), type 2 diabetes (n=204) and healthy control participants (n=170). The longitudinal study involved 53 participants with LADA, with a 3-year follow-up. In both cohorts, TSPAN7A in the sera were measured by a luciferase immunoprecipitation system assay, and physical and clinical characteristics were recorded.ResultsThe prevalence of TSPAN7A in LADA, type 1 diabetes, type 2 diabetes and healthy control participants was 21.4% (37/173), 26% (41/158), 0.5% (1/204) and 1.2% (2/170), respectively. Importantly, measurement of TSPAN7A significantly increased the number of individuals with LADA found to be positive for multiple antibodies (32.4% vs 22%; p<0.001). Further logistic regression analysis demonstrated that positivity for TSPAN7A (OR 2.87, p=0.034), disease duration (OR 1.83, p=0.019) and GAD antibody titre (OR 2.67, p=0.009) were risk factors for beta cell function in LADA, while BMI (OR 0.34, p=0.001) was a protective factor. In the prospective study in individuals with LADA, the median annual decrease in rates of fasting C-peptide and 2h postprandial C-peptide in individuals who were positive for TSPAN7A was significantly higher when compared with the decrease in those who were negative for TSPAN7A (34.6% vs 7.9%, p=0.043 and 33.2% vs 11%, p=0.041, respectively).Conclusions/interpretationTSPAN7A are valid islet autoantibodies for use in East Asian populations with autoimmune diabetes and can discriminate individuals with LADA who have lower beta cell function after disease progression.

JIF:7.11

Carvedilol prevents counterregulatory failure and impaired hypoglycaemia awareness in non-diabetic recurrently hypoglycaemic rats

期刊: DIABETOLOGIA, 2019; 62 (4)

Aims/hypothesisThis study evaluates whether the non-selective -blocker, carvedilol, can be used to prevent counterregulatory failure and the development of impaired awareness of hypoglycaemia (IAH) in recurrently hypoglycaemic rats.MethodsSprague Dawley rats were implanted with vascular catheters and intracranial guide cannulas targeting the ventromedial hypothalamus (VMH). These animals underwent either three bouts of insulin-induced hypoglycaemia or received three saline injections (control group) over 3days. A subgroup of recurrently hypoglycaemic animals was treated with carvedilol. The next day, the animals underwent a hypoglycaemic clamp with microdialysis without carvedilol treatment to evaluate changes in central lactate and hormone levels. To assess whether carvedilol prevented IAH, we treated rats that had received repeated 2-deoxyglucose (2DG) injections to impair their awareness of hypoglycaemia with carvedilol and measured food intake in response to insulin-induced hypoglycaemia as a surrogate marker for hypoglycaemia awareness.ResultsCompared with the control group, recurrently hypoglycaemic rats had a similar to 1.7-fold increase in VMH lactate and this was associated with a 75% reduction in the sympathoadrenal response to hypoglycaemia. Treatment with carvedilol restored VMH lactate levels and improved the adrenaline (epinephrine) responses. In 2DG-treated rats compared with control animals receiving saline, food intake was reduced in response to hypoglycaemia and increased with carvedilol treatment.Conclusions/interpretationWe conclude that carvedilol may be a useful therapy to prevent counterregulatory failure and improve IAH.

JIF:7.11

The PNPLA3 rs738409 C > G variant interacts with changes in body weight over time to aggravate liver steatosis, but reduces the risk of incident type 2 diabetes

期刊: DIABETOLOGIA, 2019; 62 (4)

Aims/hypothesisThe rs738409 C>G variant of the patatin-like phospholipase domain containing 3 gene (PNPLA3) increases the risk of non-alcoholic fatty liver disease (NAFLD) with no predisposition for insulin resistance. In this study, we aimed to investigate the influence of PNPLA3 polymorphisms on liver fat content (LFC) and glucose metabolic variables, and the associations between these, during the natural course of body weight changes in a Chinese adult cohort.MethodsThe LFC, measured using a quantitative ultrasound method, was prospectively monitored in 2189 middle-aged and elderly adults from the Shanghai Changfeng Study, together with changes in body weight and metabolic variables. General linear models were used to detect interactive effects between the PNPLA3 rs738409 genotype and 4year changes in body weight on liver steatosis and glucose metabolism.ResultsThe PNPLA3 homozygous GG genotype dissociated the changes in the LFC and OGTT 2h post-load blood glucose (PBG) in relation to 4year changes in body weight. PNPLA3 GG genotype carriers showed greater increases in the LFC and serum alanine aminotransferase (ALT) but lower PBG elevation and incident diabetes than PNPLA3 wild-type (CC) genotype carriers exhibiting the same degree of body weight increase. The interactions between the PNPLA3 genotype and changes in body weight on the LFC (false discovery rate [FDR]-adjusted p(interaction)=0.044) and ALT (FDR-adjusted p(interaction)=0.044) were significant. Subgroup analyses showed that the effect of the PNPLA3 GG genotype on changes in the LFC and PBG was only observed in metabolically unhealthy participants with insulin resistance or abdominal obesity.Conclusions/interpretationThe PNPLA3 GG genotype interacted with changes in body weight to aggravate liver steatosis but reduced the risk of incident type 2 diabetes in metabolically unhealthy participants.

JIF:7.11

Selective deletion of endothelial cell calpain in mice reduces diabetic cardiomyopathy by improving angiogenesis

期刊: DIABETOLOGIA, 2019; 62 (5)

Aims/hypothesis The role of non-cardiomyocytes in diabetic cardiomyopathy has not been fully addressed. This study investigated whether endothelial cell calpain plays a role in myocardial endothelial injury and microvascular rarefaction in diabetes, thereby contributing to diabetic cardiomyopathy. Methods Endothelial cell-specific Capns1-knockout (KO) mice were generated. Conditions mimicking prediabetes and type 1 and type 2 diabetes were induced in these KO mice and their wild-type littermates. Myocardial function and coronary flow reserve were assessed by echocardiography. Histological analyses were performed to determine capillary density, cardiomyocyte size and fibrosis in the heart. Isolated aortas were assayed for neovascularisation. Cultured cardiac microvascular endothelial cells were stimulated with high palmitate. Angiogenesis and apoptosis were analysed. Results Endothelial cell-specific deletion of Capns1 disrupted calpain 1 and calpain 2 in endothelial cells, reduced cardiac fibrosis and hypertrophy, and alleviated myocardial dysfunction in mouse models of diabetes without significantly affecting systemic metabolic variables. These protective effects of calpain disruption in endothelial cells were associated with an increase in myocardial capillary density (wild-type vs Capns1-KO 3646.14 +/- 423.51 vs 4708.7 +/- 417.93 capillary number/high-power field in prediabetes, 2999.36 +/- 854.77 vs 4579.22 +/- 672.56 capillary number/high-power field in type 2 diabetes and 2364.87 +/- 249.57 vs 3014.63 +/- 215.46 capillary number/high-power field in type 1 diabetes) and coronary flow reserve. Ex vivo analysis of neovascularisation revealed more endothelial cell sprouts from aortic rings of prediabetic and diabetic Capns1-KO mice compared with their wild-type littermates. In cultured cardiac microvascular endothelial cells, inhibition of calpain improved angiogenesis and prevented apoptosis under metabolic stress. Mechanistically, deletion of Capns1 elevated the protein levels of beta-catenin in endothelial cells of Capns1-KO mice and constitutive activity of calpain 2 suppressed beta-catenin protein expression in cultured endothelial cells. Upregulation of beta-catenin promoted angiogenesis and inhibited apoptosis whereas knockdown of beta-catenin offset the protective effects of calpain inhibition in endothelial cells under metabolic stress. Conclusions/interpretation These results delineate a primary role of calpain in inducing cardiac endothelial cell injury and impairing neovascularisation via suppression of beta-catenin, thereby promoting diabetic cardiomyopathy, and indicate that calpain is a promising therapeutic target to prevent diabetic cardiac complications.

JIF:7.11

Lean mass, grip strength and risk of type 2 diabetes: a bi-directional Mendelian randomisation study

期刊: DIABETOLOGIA, 2019; 62 (5)

Aims/hypothesis Muscle mass and strength may protect against type 2 diabetes as a sink for glucose disposal. In randomised controlled trials, resistance training improves glucose metabolism in people with the metabolic syndrome. Whether increasing muscle mass and strength protects against diabetes in the general population is unknown. We assessed the effect of markers of muscle mass and strength on diabetes and glycaemic traits using bi-directional Mendelian randomisation. Methods Inverse variance weighting estimates were obtained by applying genetic variants that predict male lean mass, female lean mass and grip strength, obtained from the UK Biobank GWAS, to the largest available case-control study of diabetes (DIAbetes Genetics Replication And Meta-analysis [DIAGRAM]; n=74,124 cases and 824,006 controls) and to a study of glycaemic traits (Meta-Analyses of Glucose and Insulin-related traits Consortium [MAGIC]). Conversely, we also applied genetic variants that predict diabetes, HbA(1c), fasting glucose, fasting insulin and HOMA-B to UK Biobank summary statistics for genetic association with lean mass and grip strength. As sensitivity analyses we used weighted median, Mendelian randomisation (MR)-Egger and Mendelian Randomization Pleiotropy RESidual Sum and Outlier (MR-PRESSO) and removed pleiotropic SNPs. Results Grip strength was not significantly associated with diabetes using inverse variance weighting (OR 0.72 per SD increase in grip strength, 95% CI 0.51, 1.01, p=0.06) and including pleiotropic SNPs but was significantly associated with diabetes using MR-PRESSO (OR 0.77, 95% CI 0.62, 0.95, p=0.02) after removing pleiotropic SNPs. Female lean mass was significantly associated with diabetes (OR 0.91, 95% CI 0.84, 0.99, p=0.02) while male lean mass was not significant but directionally similar (OR 0.94, 95% CI 0.88, 1.01, p=0.09). Conversely, diabetes was inversely and significantly associated with male lean mass (beta-0.02 SD change in lean mass, 95% CI -0.04, -0.00, p=0.04) and grip strength (beta-0.01, 95% CI -0.02, -0.00, p=0.01). Conclusions/interpretation Increased muscle mass and strength may be related to lower diabetes risk. Diabetes may also be associated with grip strength and lean mass. Muscle strength could warrant further investigation as a possible target of intervention for diabetes prevention.

JIF:7.11

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