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Key Points Cardiovascular disease is the leading cause of mortality among individuals with diabetes mellitus—over 50% of patients die from a cardiovascular event High LDL cholesterol levels, elevated blood pressure and smoking are major risk factors for cardiovascular disease in diabetes mellitus; low HDL cholesterol levels, insulin resistance, hyperglycaemia and inflammation also predict adverse cardiovascular events Tissue-specific insulin resistance, such as in adipose tissue, the liver and the endothelium, and cell-type-specific insulin resistance, for example in macrophages, contribute to cardiovascular complications in diabetes mellitus Hyperglycaemia exerts harmful effects on the endothelium, vascular smooth muscle cells and macrophages, and can cause thrombosis and fibrinolysis, which lead to formation of artherosclerotic plaques In hyperglycaemia and insulin resistance, overproduction of reactive oxygen species and advance glycation end products further increases low-grade inflammation, which contributes to an elevated risk of cardiovascular disease This Review outlines the cell and tissue-specific mechanisms that lead to cardiovascular events in patients with type 1 and type 2 diabetes mellitus. The authors discuss how these complications relate to classic cardiovascular risk factors and highlight a common mechanism that might link coronary artery disease to both forms of diabetes mellitus. The prevalence of diabetes mellitus will likely increase globally from 371 million individuals in 2013 to 552 million individuals in 2030. This epidemic is mainly attributable to type 2 diabetes mellitus (T2DM), which represents about 90–95% of all cases. Cardiovascular disease is the leading cause of mortality among individuals with diabetes mellitus, and >50% of patients will die from a cardiovascular event—especially coronary artery disease, but also stroke and peripheral vascular disease. Classic risk factors such as elevated levels of LDL cholesterol and blood pressure, as well as smoking, are risk factors for adverse cardiovascular events in patients with type 1 diabetes mellitus (T1DM) and T2DM to a similar degree as they are in healthy individuals. Patients with T1DM develop insulin resistance in the months after diabetes mellitus diagnosis, and patients with T2DM typically develop insulin resistance before hyperglycaemia occurs. Insulin resistance and hyperglycaemia, in turn, further increase the risk of adverse cardiovascular events. This Review discusses the mechanisms by which T1DM and T2DM can lead to cardiovascular disease and how these relate to the risk factors for coronary artery disease.

Background The gut microbiome is a complex and metabolically active community that directly influences host phenotypes. In this study, we profile gut microbiota using 16S rRNA gene sequencing in 531 well-phenotyped Finnish men from the Metabolic Syndrome In Men (METSIM) study. Results We investigate gut microbiota relationships with a variety of factors that have an impact on the development of metabolic and cardiovascular traits. We identify novel associations between gut microbiota and fasting serum levels of a number of metabolites, including fatty acids, amino acids, lipids, and glucose. In particular, we detect associations with fasting plasma trimethylamine N-oxide (TMAO) levels, a gut microbiota-dependent metabolite associated with coronary artery disease and stroke. We further investigate the gut microbiota composition and microbiota–metabolite relationships in subjects with different body mass index and individuals with normal or altered oral glucose tolerance. Finally, we perform microbiota co-occurrence network analysis, which shows that certain metabolites strongly correlate with microbial community structure and that some of these correlations are specific for the pre-diabetic state. Conclusions Our study identifies novel relationships between the composition of the gut microbiota and circulating metabolites and provides a resource for future studies to understand host–gut microbiota relationships.

Loci identified in genome-wide association studies (GWAS) can include multiple distinct association signals. We sought to identify the molecular basis of multiple association signals for adiponectin, a hormone involved in glucose regulation secreted almost exclusively from adipose tissue, identified in the Metabolic Syndrome in Men (METSIM) study. With GWAS data for 9,262 men, four loci were significantly associated with adiponectin: ADIPOQ, CDH13, IRS1, and PBRM1. We performed stepwise conditional analyses to identify distinct association signals, a subset of which are also nearly independent (lead variant pairwise r2<0.01). Two loci exhibited allelic heterogeneity, ADIPOQ and CDH13. Of seven association signals at the ADIPOQ locus, two signals colocalized with adipose tissue expression quantitative trait loci (eQTLs) for three transcripts: trait-increasing alleles at one signal were associated with increased ADIPOQ and LINC02043, while trait-increasing alleles at the other signal were associated with decreased ADIPOQ-AS1. In reporter assays, adiponectin-increasing alleles at two signals showed corresponding directions of effect on transcriptional activity. Putative mechanisms for the seven ADIPOQ signals include a missense variant (ADIPOQ G90S), a splice variant, a promoter variant, and four enhancer variants. Of two association signals at the CDH13 locus, the first signal consisted of promoter variants, including the lead adipose tissue eQTL variant for CDH13, while a second signal included a distal intron 1 enhancer variant that showed ~2-fold allelic differences in transcriptional reporter activity. Fine-mapping and experimental validation demonstrated that multiple, distinct association signals at these loci can influence multiple transcripts through multiple molecular mechanisms.

Aims/hypothesis Our aim was to investigate the fasting proportions of fatty acids and estimated desaturase and elongase activities in three different lipid fractions in plasma, phospholipids (PLs), cholesteryl esters (CEs) and triacylglycerols (TGs), as predictors for the worsening of glycaemia (area under the glucose curve in an OGTT [glucose AUC]) and incident type 2 diabetes in a 5.9 year follow-up of the Metabolic Syndrome in Men population-based cohort. Methods Fatty acid proportions were measured in plasma PL, CE and TG fractions in 1,364 Finnish men aged 45–68 years at baseline. The prospective follow-up study included only men who were non-diabetic at baseline and had data available at follow-up ( n  = 1,302). A total of 71 participants developed new type 2 diabetes during follow-up. Results After adjusting for confounding factors, total saturated fatty acids, palmitoleic acid (16:1 n -7), dihomo-γ-linolenic acid (20:3 n -6) and estimated stearoyl-CoA desaturase 1 and Δ 6 -desaturase (D6D) enzyme activities significantly predicted the worsening of glycaemia whereas total polyunsaturated fatty acid, linoleic acid (18:2 n -6) and elongase activity predicted a decrease in the glucose AUC. Estimated D6D activity and dihomo-γ-linolenic acid (20:3 n -6) were associated with an increased risk of incident type 2 diabetes. Results were consistent across the three different lipid fractions. However, fatty acid proportions in the PL and CE fractions were stronger predictors for glycaemia and incident type 2 diabetes compared with fatty acid proportions in the TG fraction. Conclusions/interpretation Selected fatty acid proportions of plasma lipid fractions and their ratios, which reflect desaturase and elongase enzyme activities, may be good biomarkers for the worsening of glycaemia and incident type 2 diabetes.

Changes in Insulin Sensitivity and Insulin Release in Relation to Glycemia and Glucose Tolerance in 6,414 Finnish Men Alena Stančáková 1 , Martin Javorský 1 , Teemu Kuulasmaa 1 , Steven M. Haffner 2 , Johanna Kuusisto 1 and Markku Laakso 1 1 Department of Medicine, University of Kuopio and Kuopio University Hospital, Kuopio, Finland; and 2 Department of Medicine, University of Texas Health Science Center at San Antonio, San Antonio, Texas. Corresponding author: Markku Laakso, markku.laakso{at}kuh.fi . A.S. and M.J. contributed equally to the work. Abstract OBJECTIVE We evaluated insulin sensitivity and insulin secretion across the entire range of fasting (FPG) and 2-h plasma glucose (PG), and we investigated the differences in insulin sensitivity and insulin release in different glucose tolerance categories. RESEARCH DESIGN AND METHODS A total of 6,414 Finnish men (aged 57 ± 7 years, BMI 27.0 ± 3.9 kg/m 2 ) from our ongoing population-based METSIM (Metabolic Syndrome in Men) study were included. Of these subjects, 2,168 had normal glucose tolerance, 2,859 isolated impaired fasting glucose (IFG), 217 isolated impaired glucose tolerance (IGT), 701 a combination of IFG and IGT, and 469 newly diagnosed type 2 diabetes. RESULTS The Matsuda index of insulin sensitivity decreased substantially within the normal range of FPG (−17%) and 2-h PG (−37%) and was approximately −65 and −53% in the diabetic range of FPG and 2-h PG, respectively, compared with the reference range (FPG and 2-h PG <5.0 mmol/l). Early-phase insulin release declined by only approximately −5% within the normal range of FPG and 2-h PG but decreased significantly in the diabetic range of FPG (by 32–70%) and 2-h PG (by 33–51%). Changes in insulin sensitivity and insulin secretion in relation to hyperglycemia were independent of obesity. The predominant feature of isolated IGT was impaired peripheral insulin sensitivity. Isolated IFG was characterized by impaired early and total insulin release. CONCLUSIONS Peripheral insulin sensitivity was already decreased substantially at low PG levels within the normoglycemic range, whereas impairment in insulin secretion was observed mainly in the diabetic range of FPG and 2-h PG. Obesity did not affect changes in insulin sensitivity or insulin secretion in relation to hyperglycemia. Footnotes The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked “advertisement” in accordance with 18 U.S.C. Section 1734 solely to indicate this fact. Received November 18, 2008. Accepted February 9, 2009. Readers may use this article as long as the work is properly cited, the use is educational and not for profit, and the work is not altered. See http://creativecommons.org/licenses/by-nc-nd/3.0/ for details. © 2009 by the American Diabetes Association.

Human cerebral organoids, derived from induced pluripotent stem cells, offer a unique in vitro research window to the development of the cerebral cortex. However, a key player in the developing brain, the microglia, do not natively emerge in cerebral organoids. Here we show that erythromyeloid progenitors (EMPs), differentiated from induced pluripotent stem cells, migrate to cerebral organoids, and mature into microglia-like cells and interact with synaptic material. Patch-clamp electrophysiological recordings show that the microglia-like population supported the emergence of more mature and diversified neuronal phenotypes displaying repetitive firing of action potentials, low-threshold spikes and synaptic activity, while multielectrode array recordings revealed spontaneous bursting activity and increased power of gamma-band oscillations upon pharmacological challenge with NMDA. To conclude, microglia-like cells within the organoids promote neuronal and network maturation and recapitulate some aspects of microglia-neuron co-development in vivo, indicating that cerebral organoids could be a useful biorealistic human in vitro platform for studying microglia-neuron interactions.

Both hypertrophic cardiomyopathy (HCM) and hypertensive heart disease (HHD) are characterized by left ventricular hypertrophy. Distinguishing HCM from HHD is a common clinical problem, particularly in subjects with moderate left ventricular maximal wall thickness (LVMWT) < 18 mm. Previously, we showed that cardiac magnetic resonance (CMR)-derived septal convexity (SC) into the left ventricle is increased in subjects with HCM-causing mutations with and without LVH. Our objective now was to determine whether CMR-derived SC differentiates HCM from HHD. We measured the maximal distance between the LV septal endocardial border and a line connecting the proximal and distal septal mid-wall points in 4-chamber images, in subjects with hypertension and LVH ( n  = 29), in subjects with HCM ( n  = 49), and in healthy controls ( n  = 20). Here, we show significantly increased SC in subjects with HCM compared to subjects with HHD both in non-indexed and in BSA-indexed measurements. Cutoff SC values of 7.9 mm and 3.7 mm/m2 in all HCM patients and SC values of 7.9 mm and 3.8 mm/m2 in HCM patients with LVMWT < 18 mm differentiated between HCM and HHD with good sensitivity and excellent specificity: SC cutoff value of 7.9 mm had a sensitivity of 77% and a specificity of 90% in all HCM patients, and 67% and 90% in HCM patients with LVMWT < 18 mm, respectively. Our study shows that measuring CMR-derived septal convexity is straightforward and enhances diagnostic performance, providing a novel technique to distinguish between HCM caused by sarcomere mutations and hypertension-induced LVH.

Hyperproinsulinemia is an indicator of β-cell dysfunction, and fasting proinsulin levels are elevated in patients with hyperglycemia. It is not known whether proinsulin levels after a glucose load are better predictors of hyperglycemia and type 2 diabetes than fasting proinsulin. Participants were 9,396 Finnish men (mean±SD, age 57.3±7.1 years, BMI 27.0±4.0 kg/m2) of the population-based METabolic Syndrome In Men Study who were non-diabetic at the recruitment, and who participated in a 6-year follow-up study. Proinsulin and insulin levels were measured in the fasting state and 30 and 120 min after an oral glucose load. Area under the curve (AUC) and proinsulin to insulin ratios were calculated. Fasting proinsulin, proinsulin at 30 min and proinsulin AUC during the first 30 min of an oral glucose tolerance test significantly predicted both the worsening of hyperglycemia and type 2 diabetes after adjustment for confounding factors. Further adjustment for insulin sensitivity (Matsuda index) or insulin secretion (Disposition index) weakened these associations. Insulin sensitivity had a major impact on these associations. Our results suggest that proinsulin in the fasting state and after an oral glucose load similarly predict the worsening of hyperglycemia and conversion to type 2 diabetes.

ObjectiveTo investigate the role of inflammation in the phenotypic expression of myocardial fibrosis in hypertrophic cardiomyopathy (HCM).DesignClinical study.SettingKuopio University Hospital and University of Eastern Finland, Kuopio, Finland.SubjectsTwenty-four patients with a single HCM-causing mutation D175N in the α-tropomyosin gene and 17 control subjects.Main outcome measuresEndomyocardial biopsy samples taken from the patients with HCM were compared with matched myocardial autopsy specimens. Levels of high-sensitivity C-reactive protein (hsCRP) and proinflammatory cytokines were measured in patients and controls. Myocardial late gadolinium enhancement (LGE) in cardiac MRI (CMRI) was detected.ResultsEndomyocardial samples in patients with HCM showed variable myocyte hypertrophy and size heterogeneity, myofibre disarray, fibrosis, inflammatory cell infiltration and nuclear factor kappa B (NF-κB) activation. Levels of hsCRP and interleukins (IL-1β, IL-1RA, IL-6, IL-10) were significantly higher in patients with HCM than in control subjects. In patients with HCM, there was a significant association between the degree of myocardial inflammatory cell infiltration, fibrosis in histopathological samples and myocardial LGE in CMRI. Levels of hsCRP were significantly associated with histopathological myocardial fibrosis. hsCRP, tumour necrosis factor α and IL-1RA levels had significant correlations with LGE in CMRI.ConclusionsA variable myocardial and systemic inflammatory response was demonstrated in patients with HCM attributable to an identified sarcometric mutation. Inflammatory response was associated with myocardial fibrosis, suggesting that myocardial fibrosis in HCM is an active process modified by an inflammatory response.

Correspondence to Professor Johanna Kuusisto, Department of Medicine and Clinical Research, Kuopio University Hospital and University of Eastern Finland, Kuopio, Finland; johanna.kuusisto@kuh.fi Preface Two family stories A 9-year-old apparently healthy girl died suddenly after a running test at school. Intriguingly, trials on first-generation gene-specific treatments of HCM are currently in phase II.2 Mavacamten, which decreases contractility by inducing allosteric inhibition of cardiac myosin ATPase, has shown very promising preliminary results for the treatment of obstructive HCM caused by MYH7 mutations.2 Genetic testing does not always help clinical work. [...]with an increasing use of the next generation sequencing, rare variants of unknown significance (VUS) are often identified, and uncertainty of the pathogenicity of the variants may complicate clinical decision making. [...]with current genetic testing, the cause of the disease remains unknown in about 25% of patients with a family history of HCM, and if there is no family history this percentage is even higher.2 Current concept of the genetic basis of HCM: Founder mutations, most often in MYBPC3, may account for a considerable proportion of cases with HCM in populations with a history of genetic isolation or bottleneck.3 4 In the FinHCM study, we sequenced 59 cardiomyopathy-associated genes in 382 unrelated Finnish patients with HCM, and found 24 pathogenic or likely pathogenic mutations in six genes in 38.2% of patients.3 Four founder or frequent mutations, Gln1061Ter in MYBPC3, p.Arg1053Gln in MYH7, p.Asp175Asn in TPM1 and p.Val606Met in MYH7, accounted for 28.0% of cases but were absent or very rare in non-Finnish Europeans in the gnomAD database.3 Mutations in MYL2, PRKAG2 and GLA were found in one or two patients.3 What about the rest?