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microRNAs (miRNAs) have been intensively studied as valuable biomarkers in cardiometabolic disease. Typically, miRNAs are detected in plasma or serum, but the use of samples collected in heparinized tubes is problematic for miRNA studies using quantitative PCR (qPCR). Heparin and its derivatives interfere with qPCR-based analysis, leading to a substantial reduction or even complete loss of detectable miRNA levels. Given that red blood cells (RBCs) express abundant miRNAs, whose expression is altered in cardiometabolic disease, RBCs could serve as an attractive alternative in biomarker studies. Here, we aim to explore the stability of miRNAs in RBCs collected from whole blood with different anticoagulants and thereby the potential of RBCs as alternative materials for miRNA biomarker studies. miRNA profiling was performed in human RBCs via RNA sequencing, followed by qPCR validation of selected miRNAs in RBCs and plasma in both heparinized and EDTA tubes. RNA sequencing revealed abundant miRNA presence in RBCs isolated from blood collected in EDTA tubes. miR-210-3p, miR-21-5p, miR-16-5p, and miR-451a were detected at comparable levels in RBCs isolated from both heparinized and EDTA tubes but not in plasma from heparinized tubes. Of note, miR-210-3p levels were consistently lower in RBCs from individuals with type 2 diabetes compared with healthy controls, regardless of anticoagulant type, supporting their potential as biomarker materials. In conclusion, RBCs offer a promising alternative for miRNA biomarker studies, overcoming heparin-related challenges. NEW & NOTEWORTHY microRNAs are valuable biomarkers in cardiometabolic disease, but heparinized tubes hinder their detection because of qPCR interference. RBCs, which express abundant microRNAs like miR-210-3p, may serve as an alternative. microRNAs, including miR-210-3p, are consistently detectable in RBCs at comparable levels between heparinized and EDTA tubes. miR-210-3p levels in RBCs are similarly reduced in heparinized tubes of patients with type 2 diabetes. Thus, RBCs offer a promising solution for miRNA biomarker studies, overcoming heparin-related challenges.

Background and Purpose: MicroRNA (miR)-210 function in endothelial cells and its role in diabetes-associated endothelial dysfunction are not fully understood. We aimed to characterize the miR-210 function in endothelial cells and study its therapeutic potential in diabetes., Experimental Approach: Two different diabetic mouse models (db/db and Western diet-induced), miR-210 knockout and transgenic mice, isolated vessels and human endothelial cells were used., Key Results: miR-210 levels were lower in aortas isolated from db/db than in control mice. Endothelium-dependent relaxation (EDR) was impaired in aortas from miR-210 knockout mice, and this was restored by inhibiting miR-210 downstream protein tyrosine phosphatase 1B (PTP1B), mitochondrial glycerol-3-phosphate dehydrogenase 2 (GPD2), and mitochondrial oxidative stress. Inhibition of these pathways also improved EDR in both diabetic mouse models. High glucose reduced miR-210 levels in endothelial cells and impaired EDR in mouse aortas, effects that were reversed by overexpressing miR-210. However, plasma miR-210 levels were not affected in individuals with type 2 diabetes (T2D) following improved glycaemic status. Of note, genetic overexpression using miR-210 transgenic mice and pharmacological overexpression using miR-210 mimic in vivo ameliorated endothelial dysfunction in both diabetic mouse models by decreasing PTP1B, GPD2 and oxidative stress. Genetic overexpression of miR-210 altered the aortic transcriptome, decreasing genes in pathways involved in oxidative stress. miR-210 mimic restored decreased nitric oxide production by high glucose in endothelial cells., Conclusion and Implications: This study unravels the mechanisms by which down-regulated miR-210 by high glucose induces endothelial dysfunction in T2D and demonstrates that miR-210 serves as a novel therapeutic target., (© 2024 The Author(s). British Journal of Pharmacology published by John Wiley & Sons Ltd on behalf of British Pharmacological Society.)

The mechanisms underlying endothelial dysfunction in Type 1 and Type 2 diabetes (T1DM and T2DM) are unresolved. The red blood cells (RBCs) with increased arginase activity induce endothelial dysfunction in T2DM, but the implications of RBCs and the role of arginase inhibition in T1DM are unexplored. We aimed to investigate the differences in endothelial function in patients with T1DM and T2DM, with focus on RBCs and arginase. Thirteen patients with T1DM and twenty-six patients with T2DM, matched for HbA1c and sex were included. In vivo endothelium-dependent and -independent vasodilation (EDV and EIDV) were assessed by venous occlusion plethysmography before and after administration of an arginase inhibitor. RBCs were co-incubated with rat aortic segments for 18h followed by evaluation of endothelium-dependent (EDR) and -independent relaxation (EIDR) in isolated organ chambers. In vivo EDV, but not EIDV, was significantly impaired in patients with T2DM compared with patients with T1DM. Arginase inhibition resulted in improved EDV only in T2DM. RBCs from patients with T2DM induced impaired EDR but not EIDR in isolated aortic segments, whereas RBCs from patients with T1DM did not affect EDR nor EIDR. The present study demonstrates markedly impaired EDV in patients with T2DM in comparison with T1DM. In addition, it highlights the divergent roles of RBCs and arginase in mediating endothelial dysfunction in T1DM and T2DM. While endothelial dysfunction is mediated via RBCs and arginase in T2DM, these phenomena are not prominent in T1DM thereby indicating distinct differences in underlying mechanisms., (© 2024 The Author(s).)

Background: The comparative effectiveness of glucagon-like peptide-1 (GLP-1) agonists, dipeptidyl peptidase-4 (DPP-4) inhibitors, and sulfonylureas on the risk of dementia in older individuals with type 2 diabetes mellitus (T2DM) is unknown., Methods: We conducted a sequential trial emulation from 1st January 2010 to 30th June 2020 using data from Swedish national registers. Swedish residents who were aged 65 or older, had type 2 diabetes (T2DM), and initiated GLP-1 agonists, DPP-4 inhibitors, or sulfonylureas were followed for up to 10 years to assess the risk of dementia. Participants who had dementia, used the three drug classes, or had contraindications were excluded from enrollment. The characteristics between arms were balanced through the application of propensity scores estimated from predefined covariates. Intention-to-treat effects were analysed with all enrolled participants, while the per-protocol effects were analysed with participants who adhered to the assigned treatment., Findings: The pooled trial included 88,381 participants who received prescriptions for GLP-1 agonists (n = 12,351), DPP-4 inhibitors (n = 43,850), or sulfonylureas (n = 32,216) at baseline and were followed for an average of 4.3 years. A total of 4607 dementia cases developed during follow-up: 278 for the GLP-1 agonist initiators (incidence rate: 6.7 per 1000 person years), 1849 for DPP-4 inhibitor initiators (IR: 11.8), and 2480 for sulfonylurea initiators (IR: 13.7). In an intention-to-treat analysis, GLP-1 agonist initiation was associated with a reduced risk of dementia compared to sulfonylureas (hazard ratio: 0.69, 95% CI: 0.60-0.79, p < 0.0001) and DPP-4 inhibitors (HR: 0.77, 95% CI: 0.68-0.88, p < 0.0001), after adjusting for age, enrollment year, sex, socioeconomic factors, health conditions, and past medication uses. These findings were consistent in several sensitivity analyses, including a per-protocol analysis (HR for sulfonylureas: 0.41, 95% CI: 0.32-0.53, p < 0.0001; HR for DPP-4 inhibitors: 0.38, 95% CI: 0.30-0.49, p < 0.0001)., Interpretation: Our research suggested that GLP-1 agonists were associated with a lower risk of dementia compared to sulfonylureas and DPP-4 inhibitors in older individuals with T2DM. Further clinical trials are needed to validate these findings., Funding: Swedish Research Council, Karolinska Institutet, the National Institute on Aging, the National Institutes of Health, and Riksbankens Jubileumsfond., Competing Interests: All authors have provided signed conflict of interest forms and declared no competing interests., (© 2024 The Author(s).)

Objectives: Polycystic ovary syndrome (PCOS) and thyroid disorders have both been linked to adverse pregnancy and neonatal outcomes. Even small variations in thyroid function within the normal range may influence fetal growth. Our aim was to investigate whether maternal thyroid function is associated with newborn anthropometrics in PCOS and explore the potential modifying effect of metformin., Methods: Post-hoc analyses of two RCTs in which pregnant women with PCOS were randomized to metformin or placebo, from first trimester to delivery. Maternal serum levels of thyroid stimulating hormone (TSH) and free thyroxine (fT4) were measured at gestational weeks (gw) 5-12, 19, 32 and 36 in 309 singleton pregnancies. The mean z-scores of birthweight, birth length, and head circumference were estimated in the offspring. Associations of maternal thyroid parameters with offspring anthropometrics and the outcomes large for gestational age (LGA) and small for gestational age (SGA) were studied using linear and logistic regression models, with adjustment for body mass index (BMI) when relevant., Results: Maternal fT4 at baseline was negatively associated with birth length (b= -0.09, p=0.048). Furthermore, ΔfT4 during pregnancy correlated positively to z-score of both birth weight and length (b=0.10, p=0.017 and b=0.10, p=0.047 respectively), independently of treatment group. TSH at baseline and gw19 was inversely associated with LGA (OR 0.47, p=0.012 and OR 0.58, p=0.042), while ΔTSH was positively associated with LGA (OR 1.99, p=0.023). There were inverse associations between TSH at baseline and SGA (OR 0.32, p=0.005) and between ΔfT4 and SGA (OR 0.59, p=0.005) in the metformin group only. There were no associations between maternal thyroid function and head circumference of the newborns., Conclusion: In women with PCOS, a higher maternal fT4 in early pregnancy and a greater decrease in fT4 during pregnancy was associated with a lower offspring birthweight and shorter birth length. Higher TSH by mid-gestation and smaller increase in TSH during pregnancy was associated with less risk of LGA. Subclinical variations in maternal thyroid function might play a role for birth anthropometrics of PCOS offspring., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Trouva, Alvarsson, Calissendorff, Åsvold, Ujvari, Hirschberg and Vanky.)

Reduced nitric oxide (NO) bioactivity in red blood cells (RBCs) is critical for augmented myocardial ischemia-reperfusion injury in type 2 diabetes. This study identified the nature of "NO bioactivity" by stimulating the intracellular NO receptor soluble guanylyl cyclase (sGC) in RBCs. sGC stimulation in RBCs from patients with type 2 diabetes increased export of cyclic guanosine monophosphate from RBCs and activated cardiac protein kinase G, thereby attenuating ischemia-reperfusion injury. These results provide novel insight into RBC signaling by identifying cyclic guanosine monophosphate from RBC as a mediator of protection against cardiac ischemia-reperfusion injury induced by sGC stimulation in RBCs., Competing Interests: This study was supported by the Swedish Heart and Lung Foundation (20190266 and 20220210 to Dr Pernow, 20190341 and 20200326 to Dr Zhou), the Swedish Research Council (2020-01372 to Dr Pernow), the Diabetes Research Wellness Foundation (720-1519-16 and 363-PG to Dr Pernow), the Stockholm County Council (20190031 and FoUI-972326 to Dr Pernow), and the European Association for the Study of Diabetes EASD/Sanofi European Diabetes Research Programme in Macrovascular Complications (to Dr Pernow). Dr Collado is supported by a Novo Nordisk postdoctoral fellowship run in partnership with Karolinska Institutet. Dr Milne is an employee of Cyclerion Therapeutics. Dr Lundberg is coinventor of patents related to the therapeutic use of inorganic nitrate. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose., (© 2023 The Authors.)

Objective: Polycystic ovary syndrome (PCOS) and hypothyroidism are related conditions, and both are associated with adverse pregnancy outcomes. Knowledge is lacking about the complex interaction between thyroid status and PCOS during pregnancy. We investigated the thyroid status and its association with pregnancy complications in PCOS, and in relation to metformin treatment., Design: Post-hoc analyses of two randomized, double-blind, placebo-controlled trials., Methods: 288 pregnant women with PCOS were randomized to treatment with metformin or placebo from first trimester to delivery. We measured serum levels of thyroid stimulating hormone (TSH) and free thyroxine (fT4) at gestational week (gw) 5-12, 19, 32 and 36 and related to metformin treatment and pregnancy complications. Thyroid peroxidase antibodies (TPO-ab) were analyzed at inclusion and at gw 36., Results: The overall prevalence of subclinical and overt hypothyroidism was 1.5% and 0%, respectively. The TSH level was not affected by metformin, whereas fT4 was significantly higher in the metformin group with less decrease throughout pregnancy compared to placebo, p<0.001. A lower decrease in fT4 during pregnancy correlated to less weight gain (r= -0.17, p=0.020) and tended to be associated with reduced odds ratio for gestational diabetes (OR 0.85 per 1 pmol/L, 95% CI 0.71;1.02)., Conclusions: In women with PCOS, metformin treatment during pregnancy was associated with less decrease in fT4 compared to placebo, while it did not affect TSH. A smaller decrease in fT4 correlated to less weight gain and tended to be associated with a lower risk of gestational diabetes., Clinical Trial Registration: ClinicalTrials.gov, identifier NCT00159536 (The PregMet study); identifier NCT03259919 (The pilot study)., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Trouva, Alvarsson, Calissendorff, Åsvold, Vanky and Hirschberg.)

Red blood cells (RBC) act as mediators of vascular injury in type 2 diabetes mellitus (T2DM). miR-210 plays a protective role in cardiovascular homeostasis and is decreased in whole blood of T2DM mice. We hypothesized that downregulation of RBC miR-210 induces endothelial dysfunction in T2DM. RBC were coincubated with arteries and endothelial cells ex vivo and transfused in vivo to identify the role of miR-210 and its target protein tyrosine phosphatase 1B (PTP1B) in endothelial dysfunction. RBC from patients with T2DM and diabetic rodents induced endothelial dysfunction ex vivo and in vivo. miR-210 levels were lower in human RBC from patients with T2DM (T2DM RBC) than in RBC from healthy subjects. Transfection of miR-210 in human T2DM RBC rescued endothelial function, whereas miR-210 inhibition in healthy subjects RBC or RBC from miR-210 knockout mice impaired endothelial function. Human T2DM RBC decreased miR-210 expression in endothelial cells. miR-210 expression in carotid artery plaques was lower in T2DM patients than in patients without diabetes. Endothelial dysfunction induced by downregulated RBC miR-210 involved PTP1B and reactive oxygen species. miR-210 mimic attenuated endothelial dysfunction induced by RBC via downregulating vascular PTP1B and oxidative stress in diabetic mice in vivo. These data reveal that the downregulation of RBC miR-210 is a novel mechanism driving the development of endothelial dysfunction in T2DM., (© 2022 by the American Diabetes Association.)

Background: The effectiveness of glucose-lowering drugs (GLDs) is unknown among patients with dementia., Objective: To analyze all-cause mortality among users of six GLDs in dementia and dementia-free subjects, respectively., Methods: This was a longitudinal open-cohort registry-based study using data from the Swedish Dementia Registry, Total Population Register, and four supplemental registers providing data on dementia status, drug usage, confounders, and mortality. The cohort comprised 132,402 subjects with diabetes at baseline, of which 11,401 (8.6%) had dementia and 121,001 (91.4%) were dementia-free. Subsequently, comparable dementia - dementia-free pairs were sampled. Then, as-treated and intention-to-treat exposures to metformin, insulin, sulfonylurea, dipeptidyl-peptidase-4 inhibitors, glucagon-like peptide-1 analogues (GLP-1a), and sodium-glucose cotransporter-2 inhibitors (SGLT-2i) were analyzed in the parallel dementia and dementia-free cohorts. Confounding was addressed using inverse-probability weighting and propensity-score matching, and flexible parametric survival models were used to produce hazard ratios (HR) and 95% confidence intervals (CI) of the association between GLDs and all-cause mortality., Results: In the as-treated models, increased mortality was observed among insulin users with dementia (HR 1.34 [95%CI 1.24-1.45]) as well as in dementia-free subjects (1.54 [1.10-1.55]). Conversely, sulfonylurea was associated with higher mortality only in dementia subjects (1.19 [1.01-1.42]). GLP-1a (0.44 [0.25-0.78]) and SGLT-2i users with dementia (0.43 [0.23-0.80]) experienced lower mortality compared to non-users., Conclusion: Insulin and sulfonylurea carried higher mortality risk among dementia patients, while GLP-1a and SGLT-2i were associated with lower risk. GLD-associated mortality varied between dementia and comparable dementia-free subjects. Further studies are needed to optimize GLD use in dementia patients.

Background: The effect of antidiabetic medication on cognitive function is unclear. We analyzed the association between five antidiabetic drugs and change in Mini-Mental State Examination (MMSE) scores in patients with diabetes and dementia., Methods: Using the Swedish Dementia Registry and four supplementary Swedish registers/databases, we identified 1873 patients (4732 observations) with diagnosis of type 2 diabetes (diabetes) and Alzheimer's disease or mixed-pathology dementia who were followed up at least once after dementia diagnosis. Use of metformin, insulin, sulfonylurea, thiazolidinediones (TZD), and dipeptidyl-peptidase-4 inhibitors (DPP-4i) was identified at baseline. Prevalent-user, incident-user, and drug-drug cohorts were sampled, and propensity-score matching was used to analyze comparable subjects. Beta coefficients with 95% confidence intervals (CI) from the random intercept and slope linear mixed-effects models determined the association between the use of antidiabetic medications and decline in MMSE score points between the follow-ups. Inverse-probability weighting was used to account for patient dropout., Results: Compared to non-users, prevalent users of metformin (beta 0.89, 95% CI 0.44; 1.33) and DPP-4i (0.72, 0.06; 1.37) experienced a slower cognitive decline with time. Secondly, compared to DPP-4i, the use of insulin (-1.00, -1.95; -0.04) and sulfonylureas (-1.19; -2.33; -0.04) was associated with larger point-wise decrements in MMSE with annual intervals., Conclusions: In this large cohort of patients with diabetes and dementia, the use of metformin and DPP-4i was associated with a slower decline in MMSE scores. Further examination of the cognitive effects of metformin and incretin-based medications is warranted., (© 2021. The Author(s).)

Aims: To observe and report population demography, comorbidities, risk factor levels and risk factor treatment in a sample of individuals treated for type 2 diabetes in primary care in Norway, Sweden and Denmark., Methods: Retrospective observational cohort using extraction of data from electronic medical records linked with national health care registries., Results: Sixty primary care clinics participated with annual cross-sectional data (2003 to 2015). In 2015 the sample consisted of 31,632 individuals. Mean age (64.5-66.8 years) and proportion of women (43-45%) were similar. The prevalence of cardiovascular disease in 2015 was 40.7%, 41.6% and 38.0% for Norway, Sweden and Denmark, respectively and 84% to 89% of patients were receiving a pharmacological anti-diabetic treatment. More Danish patients reached targets for HbA 1c and LDL cholesterol, while more patients in Sweden and Denmark met the blood pressure target of <130/80 mmHg as compared to Norway., Conclusions: In three comparable public primary health care systems we found a high prevalence of cardiovascular disease and differences in risk factor treatment and attainment of risk factor goals. With recent guideline changes there is potential for further prevention of diabetes complications in primary care in the future., (Copyright © 2020 The Authors. Published by Elsevier Ltd.. All rights reserved.)

It is well established that altered purinergic signaling contributes to vascular dysfunction in type 2 diabetes (T2D). Red blood cells (RBCs) serve as an important pool for circulating ATP and the release of ATP from RBCs in response to physiological stimuli is impaired in T2D. We recently demonstrated that RBCs from patients with T2D (T2D RBC) serve as key mediators of endothelial dysfunction. However, it remains unknown whether altered vascular purinergic signaling is involved in the endothelial dysfunction induced by dysfunctional RBCs in T2D. Here, we evaluated acetylcholine-induced endothelium-dependent relaxation (EDR) of isolated rat aortas after 18 h ex vivo co-incubation with human RBCs, and aortas of healthy recipient rats 4 h after in vivo transfusion with RBCs from T2D Goto-Kakizaki (GK) rats. Purinergic receptor (PR) antagonists were applied in isolated aortas to study the involvement of PRs. EDR was impaired in aortas incubated with T2D RBC but not with RBCs from healthy subjects ex vivo, and in aortas of healthy rats after transfusion with GK RBCs in vivo . The impairment in EDR by T2D RBC was attenuated by non-selective P1R and P2R antagonism, and specific A1R, P2X 7 R but not P2Y 6 R antagonism. Transfusion with GK RBCs in vivo impaired EDR in aortas of recipient rats, an effect that was attenuated by A1R, P2X 7 R but not P2Y 6 R antagonism. In conclusion, RBCs induce endothelial dysfunction in T2D via vascular A1R and P2X 7 R but not P2Y 6 R. Targeting vascular purinergic singling may serve as a potential therapy to prevent endothelial dysfunction induced by RBCs in T2D., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2020 Mahdi, Tratsiakovich, Tengbom, Jiao, Garib, Alvarsson, Yang, Pernow and Zhou.)

Objective: To investigate the association of the cardiovascular risk factor lipoprotein (Lp)(a) and vascular complications in patients with type 1 diabetes., Research Design and Methods: Patients with type 1 diabetes receiving regular care were recruited in this observational cross-sectional study and divided into four groups according to their Lp(a) levels in nmol/L (very low <10, low 10-30, intermediate 30-120, high >120). Prevalence of vascular complications was compared between the groups. In addition, the association between metabolic control, measured as HbA 1c , and Lp(a) was studied., Results: The patients ( n = 1,860) had a median age of 48 years, diabetes duration of 25 years, and HbA 1c of 7.8% (61 mmol/mol). The median Lp(a) was 19 (interquartile range 10-71) nmol/L. No significant differences between men and women were observed, but Lp(a) levels increased with increasing age. Patients in the high Lp(a) group had higher prevalence of complications than patients in the very low Lp(a) group. The age- and smoking-status-adjusted relative risk ratio of having any macrovascular disease was 1.51 (95% CI 1.01-2.28, P = 0.048); coronary heart disease, 1.70 (95% CI 0.97-3.00, P = 0.063); albuminuria, 1.68 (95% CI 1.12-2.50, P = 0.01); and calcified aortic valve disease, 2.03 (95% CI 1.03-4.03; P = 0.042). Patients with good metabolic control, HbA 1c <6.9% (<52 mmol/mol), had significantly lower Lp(a) levels than patients with poorer metabolic control, HbA 1c >6.9% (>52 mmol/mol)., Conclusions: Lp(a) is a significant risk factor for macrovascular disease, albuminuria, and calcified aortic valve disease in patients with type 1 diabetes. Poor metabolic control in patients with type 1 diabetes is associated with increased Lp(a) levels., (© 2020 by the American Diabetes Association.)

We recently showed that red blood cells (RBCs) from patients with type 2 diabetes mellitus (T2DM-RBCs) induce endothelial dysfunction through a mechanism involving arginase I and reactive oxygen species. Peroxynitrite is known to activate arginase in endothelial cells. Whether peroxynitrite regulates arginase activity in RBCs, and whether it is involved in the cross-talk between RBCs and the vasculature in T2DM, is unclear and elusive. The present study was designed to test the hypothesis that endothelial dysfunction induced by T2DM-RBCs is driven by peroxynitrite and upregulation of arginase. RBCs were isolated from patients with T2DM and healthy age matched controls. RBCs were co-incubated with aortae isolated from wild type rats for 18 h in the absence and presence of peroxynitrite scavenger FeTTPS. Evaluation of endothelial function in organ chambers by cumulative addition of acetylcholine as well as measurement of RBC and vessel arginase activity was performed. In another set of experiments, RBCs isolated from healthy subjects (Healthy RBCs) were incubated with the peroxynitrite donor SIN-1 with subsequent evaluation of endothelial function and arginase activity. T2DM-RBCs, but not Healthy RBCs, induced impairment in endothelial function, which was fully reversed by scavenging of RBC but not vascular peroxynitrite with FeTPPS. Arginase activity was up-regulated by the peroxynitrite donor SIN-1 in Healthy RBCs, an effect that was inhibited by FeTTPS. Healthy RBCs co-incubated with aortae in the presence of SIN-1 caused impairment of endothelial function, which was inhibited by FeTTPS or the arginase inhibitor ABH. T2DM-RBCs induced up-regulation of vascular arginase, an effect that was fully inhibited by FeTTPS. Collectively, our data indicate that RBCs impair endothelial function in T2DM via an effect that is driven by a peroxynitrite-mediated increase in arginase activity. This mechanism may be targeted in patients with T2DM for improvement in endothelial function.

Objective: Cholinesterase inhibitors (ChEIs) and memantine are the only approved pharmacological treatments for Alzheimer's disease (AD). Recent literature suggests reductions in cardiovascular burden and risk of stroke in ChEI users. However, the clinical effectiveness of these drugs in patients with diabetes mellitus (DM) and dementia has not been evaluated., Research Design and Methods: We conducted a registry-based open-cohort study of 22 660 patients diagnosed with AD and mixed-pathology dementia registered in the Swedish Dementia Registry until December 2015. Information on drug use, comorbidity and mortality was extracted using the linkage with the National Patient Registry, the Prescribed Drug Registry and the Cause of Death Registry. In total, 3176 (14%) patients with DM and 19 484 patients without DM were identified. Propensity-score matching, Cox-regression and competing-risk regression models were applied to produce HRs with 95% CIs for differences in all-cause, cardiovascular and diabetes-related mortality rates in ChEI users and non-users., Results: After matching the ChEI use in patients with DM was associated with 24% all-cause mortality reduction (HR 0.76 (95% CI 0.67 to 0.86)), compared with 20% reduction (0.80 (0.75 to 0.84)) in non-DM users. Donepezil and galantamine use were associated with a reduced mortality in both patients with DM (0.84 (0.74 to 0.96); 0.80 (0.66 to 0.97)) and patients without DM (0.85 (0.80 to 0.90); 0.93 (0.86 to 0.99)). Donepezil was further associated with reduction in cardiovascular mortality, however only in patients without DM (0.84 (0.75 to 0.94)). Rivastigmine lowered mortality only in the whole-cohort analysis and in patients without DM (0.82 (0.75 to 0.89)). Moreover, ChEI use was associated with 48% reduction in diabetes-related mortality (HR 0.52 (0.32 to 0.87)) in the whole-cohort analysis. Last, low and high doses were associated with similar benefit., Conclusions: We found reductions in mortality in patients with DM and AD or mixed-pathology dementia treated with ChEIs, specifically donepezil and galantamine were associated with largest benefit. Future studies should evaluate whether ChEIs help maintain self-management of diabetes in patients with dementia., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2020. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Background: Care individualization dominates in clinical guidelines for cognitively impaired patients with diabetes; however, few studies examined such adaptations., Objective: Describe long-term pharmacological changes in diabetes treatment in subjects with and without dementia., Methods: We performed a registry-based cohort study on 133,318 Swedish subjects (12,284 [9.2%] with dementia) with type 2 or other/unspecified diabetes. Dementia status originated from the Swedish Dementia Registry, while the National Patient Register, Prescribed Drug Register, and Cause of Death Register provided data on diabetes, comorbidities, drug dispensation, and mortality. Drug dispensation interval comprised years between 2005 and 2018 and the dispensation was assessed relative to index date (dementia diagnosis) in full cohort and propensity-score (PS) matched cohorts. Annual changes of drug dispensation were analyzed by linear regression, while Cox and competing-risk regression were used to determine the probability of drug dispensation after index date in naïve subjects. Studied medications included insulin, metformin, sulfonylureas, thiazolidinediones, dipeptidyl-peptidase-4 inhibitors (DPP-4i), glucagon-like peptide-1 agonists (GLP-1a), and sodium-glucose cotransporter-2 inhibitors (SGLT-2i)., Results: Dementia patients had higher probability of insulin dispensation (hazard ratio 1.21 [95% CI 1.11-1.31] and lower probability of DPP-4i (0.72 [0.66-0.79]), GLP-1a (0.51 [0.41-0.63]), and SGLT-2i dispensation (0.44 [0.36-0.54]) after index date. PS-matched analyses showed increased annual insulin dispensation (β difference 0.97%) and lower increase in DPP-4i (-0.58%), GLP-1a (-0.13%), and SGLT-2i (-0.21%) dispensation in dementia patients compared to dementia-free controls., Conclusion: Dementia patients had lower probability of receiving newer antidiabetic drugs, with simultaneous higher insulin dispensation compared to dementia-free subjects.

Red blood cells (RBCs) from patients with type 2 diabetes mellitus (T2DM) induce endothelial dysfunction and impair cardiac function following ischemia via increase in RBC arginase and oxidative stress. Here, we aimed to elucidate whether the effect of RBC-mediated cardiac impairment following ischemia and endothelial dysfunction in T2DM is dependent on glycemic control. Patients with T2DM at poor glycemic control (T2DM PGC) and at improvement in glycemic control (T2DM IGC) and healthy subjects were recruited. Isolated RBCs from subjects were incubated with aortic rings from healthy wild-type rats with subsequent evaluation of endothelium-dependent relaxation (EDR) using wire myograph. Moreover, RBCs were administered to isolated wild-type rat hearts with subsequent evaluation of left ventricular developed pressure (LVDP) during reperfusion using Langendorff setup. In separate experiments, RBCs were preincubated with an arginase inhibitor before perfusion. Blood glucose and glycated hemoglobin were 33 and 26%, respectively, lower in T2DM IGC compared with those in T2DM PGC. RBCs from T2DM PGC and T2DM IGC impaired EDR to a similar magnitude compared with RBCs from healthy subjects. LVDP was significantly impaired in hearts given RBCs from T2DM PGC as compared with those from healthy subjects. The impairment of LVDP induced by T2DM PGC was attenuated by RBCs from T2DM IGC. Arginase inhibition improved LVDP to a similar extent between T2DM PGC and IGC groups. These observations indicate that glycemic control abrogate the impairment in postischemic recovery but not endothelial dysfunction induced by RBCs from T2DM. Moreover, inhibition of RBC arginase improves cardiac function irrespective of glycemic control.

Aims: TECOS was a randomized, double-blind, placebo-controlled trial assessing the impact of sitagliptin vs. placebo on cardiovascular outcomes when added to usual care in patients with type 2 diabetes. We report the use of concomitant diabetes medications and the risk for progression to insulin during follow-up., Materials and Methods: TECOS enrolled 14 671 participants with HbA1c 6.5%-8.0% on monotherapy with metformin, pioglitazone, sulfonylurea (SU), or dual therapy with two oral agents or insulin with or without metformin. Subsequent diabetes management was by the participant's usual care physician. Time to initiation of insulin and risk of hypoglycaemia were estimated using Cox proportional hazards models., Results: The most common glucose-lowering regimens at baseline were metformin monotherapy (30.2%), SU monotherapy (8.5%), metformin/SU therapy (35.1%), and insulin with or without metformin (13.9% and 8.6%, respectively). Over a median 3.0 years' follow-up, diabetes therapy was intensified in 25.2% of participants (sitagliptin 22.0%, placebo 28.3%). Medications most commonly added were SU (8.3%) or insulin (8.8%). Insulin initiation in the usual care setting occurred at mean (standard deviation) HbA1c of 8.5 (1.5)%. Sitagliptin did not impact rates of severe hypoglycaemia, but delayed progression to insulin when added to metformin or metformin/SU regimens., Conclusion: Consistent with the trial's pragmatic design, TECOS participants underwent typical progression of diabetes medications. Sitagliptin was associated with lower HbA1c, without increased risk for severe hypoglycaemia and was associated with delayed progression to insulin when added to metformin with or without SU.

Background: Arginase is implicated in the pathogenesis behind endothelial dysfunction in type 2 diabetes mellitus (T2DM) by its inhibition of nitric oxide formation. Strict glycaemic control is not sufficient to improve endothelial function or cardiovascular outcomes in patients with T2DM, thus other treatment strategies are needed. We hypothesized that arginase inhibition improves endothelial function beyond glucose-lowering therapy following glucose optimization in patients with poorly controlled T2DM., Methods and Results: Endothelial function was evaluated in 16 patients with poorly controlled T2DM (visit 1) and 16 age-matched controls using venous occlusion plethysmography. T2DM patients were re-evaluated (visit 2) after intensive glucose-lowering regimen. Endothelium-dependent (EDV) and -independent (EIDV) vasodilatations were evaluated before and after 120 min intra-arterial infusion of the arginase inhibitor N(ω)-hydroxy-nor-L-arginine (nor-NOHA). HbA1c was reduced from 87 ± 17 (visit 1) to 65 ± 11 mmol mol -1 (visit 2, P < 0.001). Basal EDV, but not EIDV, was significantly lower in patients with T2DM than in healthy subjects (P < 0.05). EDV and EIDV were unaffected by glucose-lowering regimen in patients with T2DM. Arginase inhibition enhanced EDV in T2DM patients both at visit 1 and visit 2 (P < 0.01). There was no difference in improvement in EDV between the two occasions. EIDV was unaltered by nor-NOHA in T2DM at visit 1, but was slightly improved at visit 2., Conclusions: Arginase inhibition improves endothelial function in patients with poorly controlled T2DM, which is maintained following glucose optimization. Thus, arginase inhibition is a promising therapeutic target beyond glucose lowering for improving endothelial function in T2DM patients., (© 2018 The Association for the Publication of the Journal of Internal Medicine.)

Background: Cardiovascular complications are major clinical problems in type 2 diabetes mellitus (T2DM). The authors previously demonstrated a crucial role of red blood cells (RBCs) in control of cardiac function through arginase-dependent regulation of nitric oxide export from RBCs. There is alteration of RBC function, as well as an increase in arginase activity, in T2DM., Objectives: The authors hypothesized that RBCs from patients with T2DM induce endothelial dysfunction by up-regulation of arginase., Methods: RBCs were isolated from patients with T2DM and age-matched healthy subjects and were incubated with rat aortas or human internal mammary arteries from nondiabetic patients for vascular reactivity and biochemical studies., Results: Arginase activity and arginase I protein expression were elevated in RBCs from patients with T2DM (T2DM RBCs) through an effect induced by reactive oxygen species (ROS). Co-incubation of arterial segments with T2DM RBCs, but not RBCs from age-matched healthy subjects, significantly impaired endothelial function but not smooth muscle cell function in both healthy rat aortas and human internal mammary arteries. Endothelial dysfunction induced by T2DM RBCs was prevented by inhibition of arginase and ROS both at the RBC and vascular levels. T2DM RBCs induced increased vascular arginase I expression and activity through an ROS-dependent mechanism., Conclusions: This study demonstrates a novel mechanism behind endothelial dysfunction in T2DM that is induced by RBC arginase I and ROS. Targeting arginase I in RBCs may serve as a novel therapeutic tool for the treatment of endothelial dysfunction in T2DM., (Copyright © 2018 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)

This study tested the hypothesis that red blood cell (RBC) arginase represents a potential therapeutic target in ischemia-reperfusion in type 2 diabetes. Post-ischemic cardiac recovery was impaired in hearts from db/db mice compared with wild-type hearts. RBCs from mice and patients with type 2 diabetes attenuated post-ischemic cardiac recovery of nondiabetic hearts. This impaired cardiac recovery was reversed by inhibition of RBCs arginase or nitric oxide synthase. The results suggest that RBCs from type 2 diabetics impair cardiac tolerance to ischemia-reperfusion via a pathway involving arginase activity and nitric oxide synthase-dependent oxidative stress.

Objective: To evaluate chronic kidney disease (CKD) and cardiovascular outcomes in TECOS (Clinical trial reg. no. NCT00790205, clinicaltrials.gov) participants with type 2 diabetes and cardiovascular disease treated with sitagliptin, a dipeptidyl peptidase 4 inhibitor, according to baseline estimated glomerular filtration rate (eGFR)., Research Design and Methods: We used data from 14,671 TECOS participants assigned in a double-blind design to receive sitagliptin or placebo added to existing therapy, while aiming for glycemic equipoise between groups. Cardiovascular and CKD outcomes were evaluated over a median period of 3 years, with participants categorized at baseline into eGFR stages 1, 2, 3a, and 3b (≥90, 60-89, 45-59, or 30-44 mL/min/1.73 m 2 , respectively)., Results: Participants with eGFR stage 3b were older, were more often female, and had a longer duration of diabetes. Four-point major adverse cardiovascular event rates increased with lower baseline eGFR (3.52, 3.55, 5.74, and 7.34 events/100 patient-years for stages 1-3b, respectively). Corresponding adjusted hazard ratios for stages 2, 3a, and 3b versus stage 1 were 0.93 (95% CI 0.82-1.06), 1.28 (1.10-1.49), and 1.39 (1.13-1.72), respectively. Sitagliptin therapy was not associated with cardiovascular outcomes for any eGFR stage (interaction P values were all >0.44). Kidney function declined at the same rate in both treatment groups, with a marginally lower but constant eGFR difference (-1.3 mL/min/1.73 m 2 ) in those participants who were assigned to sitagliptin. Treatment differences in these eGFR values remained after adjustment for region, baseline eGFR, baseline HbA 1c , time of assessment, and within-study HbA 1c levels., Conclusions: Impaired kidney function is associated with worse cardiovascular outcomes. Sitagliptin has no clinically significant impact on cardiovascular or CKD outcomes, irrespective of baseline eGFR., (© 2016 by the American Diabetes Association.)

Purpose: Insulin sensitivity changes in response to exercise training demonstrate a large variation. Vascular endothelial growth factor A could promote increased insulin sensitivity through angiogenesis. We investigated associations between changes in expression of key genes and insulin sensitivity, aerobic capacity and glycaemic control following exercise training in diabetes mellitus type 2., Methods: Subjects with diabetes mellitus type 2 underwent 12 weeks of structured exercise. Euglycaemic clamp, exercise test and HbA1c were performed. Muscle biopsies were obtained for mRNA expression., Results: A total of 16 subjects completed the study. Change in vascular endothelial growth factor A expression was positively associated with an increase in insulin sensitivity (p = 0.004) and with a decrease in HbA1c (p = 0.034). Vascular endothelial growth factor A receptor-1 expression showed similar associations., Conclusion: The variation in physical adaptation to exercise training in diabetes mellitus type 2 was associated with changes in expression of vascular endothelial growth factor A in muscle. This difference in induced gene expression could contribute to the variation in exercise training effects on insulin sensitivity. Measures of capillary blood flow need to be assessed in future studies., (© The Author(s) 2016.)

Objective: There has been conflicting evidence regarding the potential role of vitamin D in glucose homeostasis. This study was designed to investigate the effect of high-dose vitamin D3 treatment on β-cell function, insulin sensitivity, and glucose tolerance in subjects with prediabetes or diet-treated type 2 diabetes., Research Design and Methods: Subjects (n = 44) were randomized to 30,000 IU vitamin D3 once weekly or placebo for 8 weeks. Hyperglycemic clamp assessed first-phase (0-12 min) and second-phase (12-120 min) insulin response, insulin sensitivity, and disposition index (DI). An oral glucose tolerance test assessed glucose tolerance and glycosylated hemoglobin assessed glycemic control., Results: A total of 21 (vitamin D) and 22 (placebo) subjects completed the study, respectively. Season-adjusted 25-OH-vitamin D [25(OH)D] levels were doubled in the active treated group (43-82 nmol/L). No effect of vitamin D treatment, compared with placebo, was seen on first-phase or second-phase insulin secretion. There were no group differences in insulin sensitivity, DI, or any measures of glycemic control. No hypercalcemia or other adverse effects of vitamin D treatment were seen compared with placebo. Subgroup analyses of those with the lowest basal and greatest increase in 25(OH)D levels did not change these results., Conclusions: This study gives no support for any substantial effect of high-dose vitamin D treatment for 8 weeks in prediabetes or diet-treated type 2 diabetes on β-cell function, insulin sensitivity, or glycemic control., (© 2016 by the American Diabetes Association. 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.)

Importance: Elevated cortisol levels and dysregulated insulin-like growth factor binding protein-1 (IGFBP-1; a marker of hepatic insulin sensitivity) are both related to insulin resistance and glucose abnormalities. It is unknown whether improvement in these parameters is related to improved glucose metabolism during treatment with sitagliptin., Objective: To determine whether improved insulin sensitivity and beta-cell function during treatment with sitagliptin is related to lower cortisol levels and/or improved regulation of IGFBP-1 in patients with recent acute coronary syndrome (ACS) and newly discovered glucose abnormalities., Design: Samples were taken from The BEta-cell function in Glucose abnormalities and Acute Myocardial Infarction (BEGAMI) trial, a double-blinded, placebo-controlled randomized clinical trial on the efficacy and safety of sitagliptin for patients with ACS and newly discovered glucose abnormalities., Setting: Cardiology departments (cardiac ICU and outpatient clinic) in two hospitals in Stockholm, Sweden., Participants: Subjects hospitalized (or recently hospitalized) for ACS, in whom an oral glucose tolerance test revealed previously unknown glucose abnormalities., Interventions: Subjects were randomized to sitagliptin 100mg once daily (n=34) or placebo (n=37) for twelve weeks. Oral glucose tolerance test (OGTT) and randomization occurred after stabilization median 7 days after ACS., Main Outcomes and Measures: Fasting serum cortisol and IGFBP-1 were analyzed before OGTT, around 8a.m., and after at 10a.m. The latter time point was chosen as the spread in cortisol levels around is small then, allowing improved chances to detect differences between groups., Results: Glucose tolerance and insulin sensitivity improved in both groups, while HbA1c and indices of β-cell function improved only in the sitagliptin group as reported previously. Both groups displayed decreased cortisol levels around 10a.m. (from 338±21 to 278±14 nmol/L, p=0.038, in the sitagliptin group; from 343±17 to 302±15 nmol/L, p=0.017, in the placebo group), and improved correlation between fasting log-IGFBP-1 and insulin., Conclusions and Relevance: These findings suggest that a stress-related elevation in cortisol may have negative impact on glucose tolerance in patients with recent ACS. However, improved glycemic control with sitagliptin does not appear to be related to changes in cortisol levels or hepatic insulin sensitivity as assessed by IGFBP-1., (Copyright © 2015 Elsevier Ltd. All rights reserved.)

Background: Diabetes is currently the most common cause of kidney disease among patients receiving renal replacement therapy. Pedagogical interventions to promote self-management and secondary prevention have been shown to be effective in delaying disease progression., Objectives and Design: A non-randomised, quasi-experimental design ('uncontrolled before and after') to evaluate the effects of a group-based, multidisciplinary and multidimensional support programme in patients with diabetic kidney disease. The programme comprised 1) Disease-related knowledge, 2) Skills training and increased self-care agency 3) A motivational approach, with group discussions, participant questions and narratives, setting and follow-up of individual health goals., Participants: Fifty-eight patients with diabetic kidney disease., Outcome Measures: Glycated haemoglobin (HbA1c), urine albumin/creatinine ratio, blood pressure, body mass index, waist, physical activity and participant experiences from the programme., Results: The evaluation indicated positive effects on HbA1c, albuminuria and physical activity at follow-up after four months. The proportion of patients achieving blood pressure targets increased. The participants reported improved understanding of their health condition and treatment regime., Conclusion: The multidimensional support programme, addressing health-promoting factors and self-management in small patient groups, has a potential to effectively reduce HbA1c and may have some beneficial effects which contribute to health promotion in patients with diabetic kidney disease. This mode of a multidimensional support programme should continue to develop, with longer term follow-up and further evaluations with appropriate research designs., (© 2015 European Dialysis and Transplant Nurses Association/European Renal Care Association.)

Objective: Dysfunction of the hypothalamus-pituitary-adrenal (HPA) axis has been implicated in type 2 diabetes (T2D). The aim of this study was to investigate the impact of T2D and gender on the HPA axis., Methods: Synthetic ACTH (1 μg) was administered to 21 subjects with T2D (age 62 (54-70) years, 11 men/ten women, HbA1c 49±2 mmol/mol, treated with diet or oral antidiabetic drugs) and 38 controls (age 58 (41-67) years, 20 men/18 women). Fasting basal B-glucose, serum cortisol, insulin, IGF1 and IGFBP1 concentrations were measured, and sampling for all but IGF1 was repeated 30, 60, and 90 min after ACTH injection. Patients took 0.25 mg dexamethasone at 2200-2300 h and returned the next morning for the measurement of serum cortisol concentration., Design: Cross-sectional study., Results: Patients with T2D had similar fasting serum cortisol, IGF1 and IGFBP1 concentrations; however, serum cortisol concentration after administration of dexamethasone did not differ between the groups. Healthy women exhibited higher peak cortisol levels compared with healthy men (675±26 vs 582±21 nmol/l, P=0.014), while the peak levels were equally high in men and women with T2D, resulting in a higher peak level in men with T2D compared with healthy men (691±42 vs 582±21 nmol/l, P=0.024). Serum cortisol concentration after administration of dexamethasone did not differ between the groups, nor did IGF1 and IGFBP1., Novelty of the Findings: Some studies have previously indicated disturbed regulation of the hypothalamus-pituitary-adrenal (HPA) axis in subjects with type 2 diabetes (T2D); however, much remains unknown in this area. To the best of our knowledge, this is the first study to show that the gender difference in the adrenal response to ACTH (with greater reactivity in women) is abolished in T2D. While the clinical implications cannot be determined by this paper, it is known that gender differences exist in the pathogenesis and complications of T2D. Thus, our findings suggest that further research into gender differences in the HPA axis is warranted., Conclusions: Gender differences in adrenal response to ACTH were abolished in T2D. Men with T2D had a higher peak cortisol compared with controls. Further studies are needed to elucidate the clinical implications., (© 2015 The authors.)

Background: Women with type 2 diabetes (T2D) are less likely to reach the goals for hemoglobin A1c compared with men, and have higher all-cause mortality. The risk of cardiovascular disease is elevated among both men and women with T2D, however, the risk has declined among men over recent years while it remains stationary in women. Reasons for these sex differences remain unclear, and guidelines for diabetes treatment do not differentiate between sexes. Possible causes for varying outcome include differences in physiology, treatment response, and psychological factors. This review briefly outlines sex differences in hormonal pathophysiology, and thereafter summarizes the literature to date on sex differences in disease course and outcome., Methods: Systematic searches were performed on PubMed using "sex", "gender", and various glucose-lowering therapies as keywords. Earlier reviews are summarized and results from individual studies are reported. Reference lists from studies were used to augment the search., Results: There is an increased risk of missing the diagnosis of T2D when screening women with only fasting plasma glucose instead of with an oral glucose tolerance test. The impact of various risk factors for complications may differ by sex. Efficacy and side effects of some glucose-lowering drugs differ between men and women. Men with T2D appear to suffer more microvascular complications, while women have higher morbidity and mortality in cardiovascular disease and also fare worse psychologically., Conclusion: Few studies to date have focused on sex differences in T2D. Several questions demand further study, such as whether risk factors and treatment guidelines should be sex-specific. There is a need for clinical trials designed specifically to evaluate sex differences in efficacy and outcome of the available treatments.

Excess cortisol and GH induce insulin resistance, a central feature of type 2 diabetes (T2D). To study whether the insulin sensitizer pioglitazone affects basal cortisol levels and the GH-IGF-I axis in patients with T2D. Forty-eight patients with T2D (men/women = 28:20, age 61 ± 1 years, BMI 31 ± 0.6 kg/m(2)) were treated for 26 weeks with pioglitazone 30-45 mg daily in addition to their preexisting therapy. Insulin, proinsulin, HbA(1c), IGF-I, IGFBP-1, and basal cortisol were analyzed before and after treatment. Pioglitazone decreased proinsulin/insulin ratio and HbA(1c) decreased (HbA(1c) from 7.8 ± 0.2 to 6.6 ± 0.2% in men and from 7.6 ± 0.2 to 6.1 ± 0.2% in women, p < 0.001 in both). There was a redistribution of fat but no change in waist circumference. IGF-I and adiponectin increased (p ≤ 0.001) in both genders. IGFBP-1 increased but significantly only for the whole group (p = 0.033). Triglycerides decreased significantly in women only (p = 0.015). Before treatment, women had lower basal cortisol (p = 0.045). Basal cortisol increased in women (from 390 ± 26 to 484 ± 32 nmol/L, p = 0.020) but not in men and did not differ between genders at week 26. ΔIGFBP-1 correlated with Δcortisol (r = 0.458; p = 0.049) and Δadiponectin (r = 0.600; p = 0.005) in women only. In addition to the known effect of improving insulin sensitivity, pioglitazone increased IGF-I regardless of gender and in women also increased basal cortisol. Increased IGF-I may contribute to improved insulin sensitivity after treatment. There seems to be gender differences in treatment responses to pioglitazone on lipid metabolism and basal cortisol, perhaps correcting different mechanisms of insulin resistance between genders.

Background. Hypercortisolism and type 2 diabetes (T2D) share clinical characteristics. We examined pioglitazone's effects on the GH-IGF-I and HPA axes in men with varying glucose intolerance. Methods. 10 men with T2D and 10 with IGT received pioglitazone 30-45 mg for 12 weeks. OGTT with microdialysis in subcutaneous adipose tissue and 1 μg ACTH-stimulation test were performed before and after. Glucose, insulin, IGF-I, IGFBP1, and interstitial measurements were analyzed during the OGTT. Insulin sensitivity was estimated using HOMA-IR. Results. HOMA-IR improved in both groups. IGF-I was initially lower in T2D subjects (P = 0.004) and increased during treatment (-1.4 ± 0.5 to -0.5 ± 0.4 SD; P = 0.007); no change was seen in IGT (0.4 ± 39 SD before and during treatment). Fasting glycerol decreased in T2D (P = 0.038), indicating reduced lipolysis. Fasting cortisol decreased in T2D (400 ± 30 to 312 ± 25 nmol/L; P = 0.041) but increased in IGT (402 ± 21 to 461 ± 35 nmol/L; P = 0.044). Peak cortisol was lower in T2D during treatment (599 ± 32 to 511 ± 43, versus 643 ± 0.3 to 713 ± 37 nmol/L in IGT; P = 0.007). Conclusions. Pioglitazone improved adipose tissue and liver insulin sensitivity in both groups. This may explain increased IGF-I in T2D. Pioglitazone affected cortisol levels in both groups but differently, suggesting different mechanisms for improving insulin sensitivity between T2D and IGT.

Background: Lower extremity amputations are costly and debilitating complications in patients with diabetes mellitus (DM). Our aim was to investigate changes in the amputation rate in patients with DM at the Karolinska University Hospital in Solna (KS) following the introduction of consensus guidelines for treatment and prevention of diabetic foot complications, and to identify risk groups of lower extremity amputations that should be targeted for preventive treatment., Methods: 150 diabetic and 191 nondiabetic patients were amputated at KS between 2000 and 2006; of these 102 diabetic and 99 nondiabetic patients belonged to the catchment area of KS. 21 diabetic patients who belonged to KS catchment area were amputated at Danderyd University Hospital. All patients' case reports were searched for diagnoses of diabetes, vascular disorders, kidney disorders, and ulcer infections of the foot., Results: There was a 60% reduction in the rate of amputations performed above the ankle in patients with DM during the study period. Patients with DM who underwent amputations were more commonly affected by foot infections and kidney disorders compared to the nondiabetic control group. Women with DM were 10 years older than the men when amputated, whereas men with DM underwent more multiple amputations and had more foot infections compared to the women. 88% of all diabetes-related amputations were preceded by foot ulcers. Only 30% of the patients had been referred to the multidisciplinary foot team prior to the decision of amputation., Conclusions: These findings indicate a reduced rate of major amputations in diabetic patients, which suggests an implementation of the consensus guidelines of foot care. We also propose further reduced amputation rates if patients with an increased risk of future amputation (i.e. male sex, kidney disease) are identified and offered preventive treatment early.

Background: Early insulin treatment is considered more beneficial than anti-diabetic medication with sulphonylureas, because the latter may exert negative effects on beta-cell function, while the former may help preserve it. In a previous study, we found that C-peptide response was increased in the insulin-treated group, whereas it was decreased in the glibenclamide group. However, it was not certain whether the advantage remained in the longer term., Aim: In this study, we tested whether early insulin treatment is more beneficial than glibenclamide against a 6-year follow-up perspective., Methods: We designed a randomized clinical trial in subjects with newly diagnosed type 2 diabetes. Glucagon stimulatory tests, measuring C-peptide and islet amyloid polypeptide (IAPP), were performed after 2, and 3, days of temporary insulin and glibenclamide withdrawal., Results: 18 subjects initially randomized to glibenclamide, and 16 randomized to two daily injections of insulin, participated in end-of-study investigations. C-peptide response to glucagon deteriorated (p < 0.01 vs. baseline) in initially glibenclamide-treated patients (n = 18), but not in insulin-treated patients (p < 0.05 for difference between groups, after 2 days of treatment withdrawal). The IAPP response to glucagon declined in the glibenclamide group (p < 0.001), but not in insulin-treated subjects (p = 0.05 for difference between groups)., Conclusions: Early insulin treatment preserves beta-cell secretory function better than glibenclamide even in a 6-year perspective.

Aims: To examine factors in middle-aged Swedish men and women predicting the conversion from a state of abnormal glucose regulation to normal glucose tolerance (NGT) after 8-10 years., Methods: At baseline 3128 men and 4821 women, aged 35-56 years, without previously diagnosed diabetes underwent an oral glucose tolerance test and completed a questionnaire. At follow-up, 2383 men and 3329 women were re-examined. The study group consisted of 156 men and 124 women with impaired fasting glucose (IFG), impaired glucose tolerance (IGT), or both at baseline., Results: The rate of reversal to NGT from IFG or IGT was similar regardless of gender. In participants having IFG or IGT, reversal to NGT was predicted by low fasting and 2-h insulin, homeostasis model assessment of insulin resistance and of pancreatic beta cell function, body mass index and waist circumference without differences between gender and baseline glucose tolerance group. Low 2-h glucose, however, predicted reversal to NGT in men with IFG at baseline, but not in men with IGT at baseline, or in women with either IFG or IGT at baseline. Men reverting to NGT had higher coffee consumption and women had higher baseline leisure-time physical activity. In multiple logistic regression, including all participants, low fasting and 2-h glucose remained independent predictors of reverting to NGT., Conclusions: Factors predicting reversal to NGT were measures correlated with low insulin resistance, but also lower insulin secretion, perhaps indicating a lower pancreatic beta cell workload in those who reverted. In men, but not in women, low 2-h glucose was of predictive value.

Aim: To compare effects of early insulin vs. glibenclamide treatment on beta-cell function, metabolic control and quality of life (QL) in recently diagnosed patients with type 2 diabetes., Methods: Forty-nine patients with type 2 diabetes diagnosed 0-2 years before inclusion were randomized to two daily injections of premixed 30% soluble and 70% NPH insulin or glibenclamide at six diabetic clinics in Sweden. C-peptide-glucagon tests were performed yearly after 3 days of withdrawal of treatment., Results: Thirty-four patients completed 4 years of study. Daily dose of insulin was increased from 20.4 +/- 1.8 U at year 1 to 26.1 +/- 2.9 U at year 4 (p = 0.005). Glibenclamide dosage increased from 2.7 +/- 0.4 mg at year 1 to 4.5 +/- 0.8 mg at year 4 (p = 0.02). Weight increased more in insulin than in glibenclamide treated (+4.4 +/- 0.8 vs. +0.3 +/- 1.0 kg, p < 0.005). Following short-term withdrawal of treatment, the C-peptide responses to glucagon were significantly higher in the insulin vs. glibenclamide group at years 1 (p < 0.01) and 2 (p < 0.02). HbA1c improved identical during the first year but thereafter deteriorated in the glibenclamide group (p < 0.005 for difference at year 4). Ratios of proinsulin to insulin were higher during treatment in glibenclamide- vs. insulin-treated patients after year 2. QL after 4 years as measured by the MOS 36-item Short-Form Health Survey (SF-36) form was not significantly altered., Conclusions: In a 4-year perspective, beta-cell function deteriorated in both groups. However, deterioration occurred faster in the glibenclamide group, indicating that alleviating demands on secretion by insulin treatment is beneficial.

It is generally accepted that a poor glycaemic control increases the risk for development of vascular complications in diabetic patients. This advocates for early introduction of insulin treatment in patients with type 2 diabetes exhibiting a secondary failure to oral treatment. This strategy is facilitated by introduction of long-acting insulin glargine and biphasic insulin aspart 70/30. The introduction of Glucagon-like peptide-1 (GLP-1) mimetics and dipeptidyl peptidase 4 (DPP-4) inhibitors in treatment of type 2 diabetes will however, to a large extent, influence therapeutic policy. Thus we suggest that DPP-4 inhibitors or long-acting GLP-1 mimetics will be used as either first-line therapy or as an early addition to metformin. The already generated results in animal and clinical studies suggest that these two classes of antidiabetic drugs may in addition to improving glycaemic control protect islet beta-cell mass and thereby postpone development of a secondary failure. When patients treated with metformin, sulfonylurea (SU), tiazolidinediones or a combination of these drugs fail, the GLP-1 mimectics may be preferred to insulin treatment. First, the risk of hypoglycaemia is less if not combined with SU. Secondly, the body weight is usually decreased while insulin treatment increases weight. Patients not responding to GLP-1 mimetics or experiencing significant side effects will be treated with insulin. Irrespective of the policy used for the drug treatment of type 2 diabetes, exercise and proper diet will remain important for optimization of metabolic control.

Objective: Insulin is often postponed for years because initiation is time-consuming. We sought to compare initiation of insulin individually and in groups with respect to change in A1C and several other parameters in type 2 diabetic patients., Research Design and Methods: A randomized (1:1), multicenter, two-arm, parallel design study with a recruiting period of up to 14 weeks and a 24-week treatment period. Either in groups of 4-8 or individually, using the same personnel and education program, 121 insulin-naive type 2 diabetic patients with an A1C of 7.0-12.0% were randomized to initiate bedtime insulin glargine. The patients visited the treatment center before and at the time of insulin initiation and at 6, 12, and 24 weeks. Patients self-adjusted the insulin dose to achieve a fasting plasma glucose 4.0-5.5 mmol/l., Results: At 24 weeks, mean +/- SE A1C had decreased from 8.7 +/- 0.2 to 6.9 +/- 0.1% in those treated individually and from 8.8 +/- 0.2 to 6.8 +/- 0.1% in those in groups (not significant [NS]). Insulin doses averaged 62 +/- 5 IU and 56 +/- 5 IU at 24 weeks (NS), respectively. The frequency of hypoglycemia was similar. The total time (visits and phone calls) spent in initiating insulin in the patients in groups (2.2 +/- 0.1 h) was 48% less than in those treated individually (4.2 +/- 0.2 h). Diabetes treatment satisfaction improved significantly in both sets of patients., Conclusions: Similar glycemic control and treatment satisfaction can be achieved by initiating insulin in groups and individually. Starting insulin in groups takes one-half as much time as individual initiation.