Severe hypoglycemia and hypoglycemia awareness are associated with preclinical atherosclerosis in patients with type 1 diabetes without an estimated high cardiovascular risk.

AIMS: To explore the relationship between severe hypoglycemia (SH) and hypoglycemia awareness with preclinical atherosclerosis in type 1 diabetes (T1D). MATERIALS AND METHODS: Cross-sectional study in patients with T1D without cardiovascular disease (CVD), and with ≥1 of the following: ≥40 years, diabetic kidney disease, or ≥10 years of T1D duration with another risk factor. CVD risk was estimated with the Steno T1 Risk Engine (Steno-Risk). Carotid plaque was evaluated using standardised ultrasonography protocol. Logistic regression models adjusted for CVD risk factors were constructed to test the independent associations with SH or hypoglycemia awareness assessed by the Clarke questionnaire (Clarke). The inclusion of SH and Clarke in Steno-Risk was further evaluated. RESULTS: We included 634 patients (52.4% men, age 48.3 ± 10.8 years, T1D duration 27.4 ± 11.1 years, 39.9% harbouring plaque). A stepped increase in the presence of plaque according to Steno-Risk was observed (13.5%, 37.7%, and 68.7%, for low, moderate, and high risk, respectively; p < 0.001). SH history (OR 4.4 [1.3-14.6]) and Clarke score (OR 1.7 [1.2-2.2]) were associated with plaque in low-risk patients (n = 192). Clarke score was also associated with plaque burden in low-moderate-risk participants (n = 436; ≥2 plaques: OR 1.2 [1.0-1.5], p = 0.031; ≥3 plaques: OR 1.4 [1.1-2.0], p = 0.025). The inclusion of SH and Clarke scores in Steno-Risk significantly improved the identification of low-risk individuals with atherosclerosis (area under the curve: 0.658 vs. 0.576; p = 0.036). CONCLUSIONS: In patients with T1D without an estimated high CVD risk, SH and hypoglycemia awareness assessment score were independently associated with preclinical atherosclerosis and improved identification of patients who would benefit from an intensive approach.

Adherence to an energy-restricted Mediterranean diet is associated with the presence and burden of carotid atherosclerosis in people with type 1 diabetes.

AIMS: People with type 1 diabetes (T1D) have an increased risk of cardiovascular disease (CVD). The Mediterranean diet is associated with reduced CVD; however, the evidence in T1D is scarce. We aimed to analyse the relationships between adherence to the energy-restricted Mediterranean diet (erMEDd) and carotid atherosclerosis. MATERIALS AND METHODS: We included children with T1D without CVD, with ≥1 of the following: age ≥40 years, diabetic kidney disease, or ≥10 years of disease duration with another risk factor. Plaque presence (intima-media thickness ≥1.5 mm) was determined by ultrasonography. The PREDIMED-Plus 17-item questionnaire (PP-17) was used to assess adherence to the erMEDd. RESULTS: Four hundred one individuals were included (48% males, age 48.3 ± 11 years, diabetes duration 26.8 ± 11.4 years). Those harbouring plaques (42%) showed lower adherence to the erMEDd (PP-17: 8.9 ± 2.3 of a maximum of 17 vs. 9.8 ± 2.5, p < 0.001). Greater adherence to the erMEDd was correlated with an overall better metabolic profile. After adjusting for multiple confounders, adherence to the erMEDd was independently associated with carotid atherosclerosis (OR 0.86 [0.77-0.95] for plaque presence and OR 0.85 [0.75-0.97] for ≥2 plaques). The consumption of fruit and nuts and preference of white over red meat was higher in individuals without atherosclerosis (p < 0.05). Fruit and nut consumption was associated with lower plaque prevalence in the fully adjusted models (OR 0.38 [0.19-0.73] and 0.51 [0.29-0.93]). CONCLUSIONS: Greater adherence to the erMEDd is associated with less carotid atherosclerosis in children with T1D at high risk of CVD. Strategies to improve and implement healthy dietary patterns in this population should be encouraged.

Neutrophil-to-lymphocyte ratio is independently associated with carotid atherosclerosis burden in individuals with type 1 diabetes.

BACKGROUND AND AIMS: Recent studies have identified a relationship between innate versus. Adaptative immunity and cardiovascular disease (CVD) in the general population, but information on type 1 diabetes (T1D) is lacking. We aimed to study the relationship between inflammatory biomarkers and preclinical atherosclerosis in this population. METHODS AND RESULTS: Cross-sectional study in T1D individuals without CVD and with ≥1 of the following: ≥40 years, diabetic kidney disease, or ≥10 years of diabetes duration with classical CVD risk factors. Carotid plaques were evaluated by ultrasonography. C-reactive protein, total leukocyte count, neutrophil-to-lymphocyte ratio (NLR), platelet-to-lymphocyte ratio and systemic immune-inflammation index were assessed as inflammatory markers. Multivariate-adjusted models including age, sex, and other CVD risk factors were constructed to test their independent associations with atherosclerosis burden. We included 602 subjects (52.8% men, 48.7 ± 10.2 years old and 27.0 ± 10.5 years of diabetes duration). Carotid plaques were found in 41.2% of the individuals (12.8%, ≥3 plaques). The number of carotid plaques (none, 1-2, ≥3 plaques), was directly associated with the leukocyte count (6570 [5445-8050], 6640 [5450-8470] and 7310 [5715-8935] per mm3, respectively; p for trend = 0.021) and the NLR (1.63 [1.28-2.13], 1.78 [1.38-2.25] and 2.14 [1.58-2.92], respectively; p for trend <0.001), but only the NLR remained directly associated in fully-adjusted models (presence of plaques; OR 1.285 [1.040-1.587]; ≥3 plaques, OR 1.377 [1.036-1.829]). CONCLUSIONS: The NLR was independently and directly associated with carotid plaque burden in T1D individuals. Our data support the role of innate versus. Adaptative immunity in atherosclerosis also among the T1D population.

Advanced lipoprotein profile identifies atherosclerosis better than conventional lipids in type 1 diabetes at high cardiovascular risk.

BACKGROUND AND AIMS: People with type 1 diabetes (T1D) present lipoprotein disturbances that could contribute to their increased cardiovascular disease (CVD) risk. We evaluated the relationship between lipoprotein alterations and atherosclerosis in patients with T1D. METHODS AND RESULTS: Cross-sectional study in subjects with T1D, without previous CVD, but high-risk (≥40 years, nephropathy, or ≥10 years of evolution of diabetes with another risk factor). The presence of plaque (intima-media thickness ≥1.5 mm) in the different carotid segments was determined by ultrasound. The advanced lipoprotein profile was analysed by magnetic resonance imaging (1H NMR). We included 189 patients (42% women, 47.8 ± 10.7 years, duration of diabetes 27.3 ± 10.1 years, HbA1c 7.5% [7-8]). Those with carotid plaques (35%) were older, with longer diabetes duration, had a higher prevalence of hypertension, and showed lower and smaller LDL particles (LDL-P) and HDL particles (HDL-P), but higher VLDL particles (VLDL-P). Some LDL, HDL and VLDL-related parameters were associated with atherosclerosis in sex, age and statin use adjusted models (p < 0.05), but after adjusting for multiple confounders, including conventional lipid parameters, only HDL-P (OR 0.440 [0.204-0.951]; p = 0.037), medium HDL-P (OR 0.754 [0.590-0.963]; p = 0.024), HDL-P cholesterol content (OR 0.692 [0.495-0.968]; p = 0.032), 1H NMR LDL-P number/conventional LDL-cholesterol (OR 1.144 [1.026-1.275]; p = 0.015), and 1H NMR non-HDL particle number/conventional non-HDL-cholesterol ratios (OR 1.178 [1.019-1.361], p = 0.026) remained associated with atherosclerosis. CONCLUSIONS: In adults with T1D at high-risk, variables related to HDL, LDL and total atherogenic particle number are independently associated with preclinical atherosclerosis. Advanced lipoprotein profiling could be used to identify those at the highest risk of CVD.

Addition of intermittently scanned continuous glucose monitoring to standard care in a cohort of pregnant women with type 1 diabetes: effect on glycaemic control and pregnancy outcomes.

AIMS/HYPOTHESIS: The aim of this study was to assess whether the addition of intermittently scanned continuous glucose monitoring (isCGM) to standard care (self-monitoring of blood glucose [SMBG] alone) improves glycaemic control and pregnancy outcomes in women with type 1 diabetes and multiple daily injections. METHODS: This was a multicentre observational cohort study of 300 pregnant women with type 1 diabetes in Spain, including 168 women using SMBG (standard care) and 132 women using isCGM in addition to standard care. In addition to HbA1c, the time in range (TIR), time below range (TBR) and time above range (TAR) with regard to the pregnancy glucose target range (3.5-7.8 mmol/l) were also evaluated in women using isCGM. Logistic regression models were performed for adverse pregnancy outcomes adjusted for baseline maternal characteristics and centre. RESULTS: The isCGM group had a lower median HbA1c in the second trimester than the SMBG group (41.0 [IQR 35.5-46.4] vs 43.2 [IQR 37.7-47.5] mmol/mol, 5.9% [IQR 5.4-6.4%] vs 6.1% [IQR 5.6-6.5%]; p=0.034), with no differences between the groups in the other trimesters (SMBG vs isCGM: first trimester 47.5 [IQR 42.1-54.1] vs 45.9 [IQR 39.9-51.9] mmol/mol, 6.5% [IQR 6.0-7.1%] vs 6.4% [IQR 5.8-6.9%]; third trimester 43.2 [IQR 39.9-47.5] vs 43.2 [IQR 39.9-47.5] mmol/mol, 6.1% [IQR 5.8-6.5%] vs 6.1% [IQR 5.7-6.5%]). The whole cohort showed a slight increase in HbA1c from the second to the third trimester, with a significantly higher rise in the isCGM group than in the SMBG group (median difference 2.2 vs 1.1 mmol/mol [0.2% vs 0.1%]; p=0.033). Regarding neonatal outcomes, newborns of women using isCGM were more likely to have neonatal hypoglycaemia than newborns of non-sensor users (27.4% vs 19.1%; ORadjusted 2.20 [95% CI 1.14, 4.30]), whereas there were no differences between the groups in large-for-gestational-age (LGA) infants (40.6% vs 45.1%; ORadjusted 0.73 [95% CI 0.42, 1.25]), Caesarean section (57.6% vs 48.8%; ORadjusted 1.33 [95% CI 0.78, 2.27]) or prematurity (27.3% vs 24.8%; ORadjusted 1.05 [95% CI 0.55, 1.99]) in the adjusted models. A sensitivity analysis in pregnancies without LGA infants or prematurity also showed that the use of isCGM was associated with a higher risk of neonatal hypoglycaemia (non-LGA: ORadjusted 2.63 [95% CI 1.01, 6.91]; non-prematurity: ORadjusted 2.52 [95% CI 1.12, 5.67]). For isCGM users, the risk of delivering an LGA infant was associated with TIR, TAR and TBR in the second trimester in the logistic regression analysis. CONCLUSIONS/INTERPRETATION: isCGM use provided an initial improvement in glycaemic control that was not sustained. Furthermore, offspring of isCGM users were more likely to have neonatal hypoglycaemia, with similar rates of macrosomia and prematurity to those of women receiving standard care.

Nuclear magnetic resonance lipoproteins are associated with carotid atherosclerosis in type 1 diabetes and pre-eclampsia.

AIMS: Persistence of lipoprotein abnormalities in type 1 diabetes (T1D) and/or pre-eclampsia could be associated with cardiovascular disease (CVD). We assessed differences in the advanced lipoprotein profiles according to the presence of both conditions and their differential association with atherosclerosis. MATERIAL AND METHODS: We recruited 112 women without CVD and last pregnancy ≥5 years previously, divided into four groups (n = 28 per group): (a) T1D and previous pre-eclampsia; (b) T1D without pre-eclampsia; (c) pre-eclampsia without T1D; and (d) controls (without T1D/pre-eclampsia). Groups were matched by several risk factors, and diabetes duration and retinopathy in T1D. Carotid intima-media thickness (IMT) and the presence of plaque (IMT ≥1.5 mm) were assessed by ultrasonography. The lipoprotein profile was evaluated by nuclear magnetic resonance (NMR) spectroscopy. RESULTS: The participants were 44.9 ± 7.8 years old. Carotid plaque presence was 20.5%, with a higher prevalence in T1D and/or pre-eclampsia vs controls (P < .05). High-density lipoprotein (HDL)-related variables differed among groups, mainly driven by an increase in T1D (P < .05), whereas triglyceride-related variables were increased in pre-eclampsia [medium very low-density lipoprotein (VLDL) particles and triglyceride enrichment in HDL and low-density lipoprotein (LDL)]. Overall, in multivariate-adjusted models, LDL-related variables were the most strongly associated with atherosclerosis (P < .05). In age- and statin-adjusted models, previous pre-eclampsia showed an independent association with triglyceride-related variables (plaque: medium-VLDL-particles, OR 1.550 [1.013-2.374]; HDL-cholesterol/HDL-triglycerides ratio, OR 0.411 [0.175-0.967]). Regarding T1D, HDL-parameters were also differentially associated (maximum-IMT: HDL-cholesterol/HDL-particles ratio, ß = -.258, P = .036). CONCLUSIONS: NMR lipoproteins were differentially and independently associated with atherosclerosis in T1D/pre-eclampsia. Further studies are needed to ascertain the role of NMR parameters as CVD biomarkers in this high-risk population.

Biomarkers of fatty acid intake are independently associated with preclinical atherosclerosis in individuals with type 1 diabetes.

PURPOSE: Information on the association between diet and cardiovascular disease (CVD) in type 1 diabetes (T1D) is scarce. We assessed the association between biomarkers of fatty acid (FA) intake and the presence of carotid plaques (a surrogate marker of future CVD events) in this high-risk population. METHODS: Cross-sectional study in 167 consecutive T1D patients without CVD and with at least one of the following: ≥ 40 years, diabetic nephropathy, or ≥ 10 years of T1D duration with another CVD risk factor. The FA profile of erythrocyte membranes was determined by gas chromatography, and the number of carotid plaques (intima-media thickness ≥ 1.5 mm) was assessed by ultrasonography. Regression models were constructed adjusting for classical (age, gender, blood pressure, smoking habit, LDL-cholesterol, body mass index and statins) and T1D-specific risk factors (diabetes duration, HbA1c and chronic complications). RESULTS: A total of 58.7% were men (mean age 48.3 ± 10.3 years, T1D duration 27.2 ± 10.1 years). Sixty-one patients (36.5%) showed carotid plaque. Linoleic acid decreased and all-C18:1trans increased with the number of carotid plaques (none, 1-2, ≥ 3 plaques; p for trend < 0.05). In multivariate regression models, linoleic acid remained inversely associated with the presence of plaque [1% increase of total FAs; OR 0.71 (0.53-0.95), p = 0.021] and ≥ 2 plaques [OR 0.70 (0.51-0.98), p = 0.039]; whereas, all-C18:1trans was positively associated with ≥ 3 plaques (0.1% increase of total FAs; OR 1.51 [1.05-2.16], p = 0.026). CONCLUSIONS: Erythrocyte FA composition, as a biomarker of FA intake, was independently associated with preclinical atherosclerosis in T1DM. Our data support the potential role of an unfavorable pattern of fat intake and CVD risk in this population.

Novel glycoproteins identify preclinical atherosclerosis among women with previous preeclampsia regardless of type 1 diabetes status.

BACKGROUND AND AIMS: Information regarding inflammation and cardiovascular disease (CVD) risk in type 1 diabetes (T1D) or preeclampsia (PE) is scarce. We assessed differences in inflammation markers according to the presence of both conditions and their association with atherosclerosis. METHODS AND RESULTS: We recruited 112 women without CVD and last pregnancy ≥5 years previously (n = 28 per group): a)T1D and PE; b)T1D without PE; c)PE without T1D; and d)Controls (without T1D or PE). Groups were matched by several CVD risk factors, and diabetes duration and retinopathy in T1D. Carotid intima-media thickness (IMT) and plaque presence (IMT ≥1.5 mm) were assessed by ultrasonography. Inflammatory markers included classical variables (leucocytes and high-sensitivity C-reactive protein [hsCRP]) and glycoproteins by nuclear magnetic resonance (1H-NMR) spectroscopy (GlycA, GlycB, GlycF and the height/width [H/W] ratios of GlycA and GlycB). The age of the participants was 44.9 ± 7.8 years, and 20.5% harbored plaque. There were no differences in inflammatory markers among the four study groups. Overall, in multivariate-adjusted models, all 1H-NMR-glycoproteins (except GlycB) were positively associated with IMT measures (IMT of bulb and maximum-IMT of any carotid segment; p < 0.05). After dividing the sample according to PE status, previous findings remained largely unchanged. Furthermore, GlycF was independently associated with carotid plaque only in PE group (OR 5.08 [1.03-25.01] per 0.1 log-increments, p = 0.046). Neither leucocytes nor hsCRP were related to atherosclerosis. Regarding T1D status, non-uniform results were observed. CONCLUSIONS: High 1H-NMR-glycoprotein concentrations have a negative impact on carotid atherosclerosis among women with preeclampsia, regardless of T1D status.

Quantification of glycoproteins by nuclear magnetic resonance associated with preclinical carotid atherosclerosis in patients with type 1 diabetes.

BACKGROUND AND AIMS: Glycoproteins play a key role in inflammatory and cardiometabolic processes. Their implication in atherosclerosis in type 1 diabetes (T1D) is unknown. We assessed the relationships between classic inflammatory markers, glycoproteins measured by nuclear magnetic resonance (1H-NMR), and preclinical atherosclerosis in these patients. METHODS AND RESULTS: We selected patients with T1D, without cardiovascular disease (CVD), with: age ≥40 years, nephropathy (micro/macroalbuminuria), or ≥10 years of evolution with another risk factor. The presence of plaque (intima-media thickness >1.5 mm) was determined by ultrasonography. Concentrations of high-sensitive C-reactive protein (hsCRP), circulating leukocytes (classical inflammation markers) and 1H-NMR-glycoproteins (GlycA, GlycB, GlycF, and the height/width [H/W] ratios of GlycA and GlycB) were determined. We included 189 patients (58% male, age 47.0 [40.7-55.2] years). Thirty-five percent presented plaques (22%, ≥2 plaques). There was no association between hsCRP or leukocytes and atherosclerosis. However, in age- and sex-adjusted models, GlycA, GlycF, and the H/W ratios of GlycA and GlycB gradually increased with the number of plaques (0, 1, ≥2 plaques) only in patients without statins (p < 0.05), with no association in patients receiving this drug (p for interaction <0.05; in ≥2 plaques). Finally, in models adjusted for other classical and T1D-specific risk factors, GlycA and GlycB H/W ratios remained associated with carotid plaque (OR 1.39 [1.12-1.90] and OR 6.89 [1.85-25.62], respectively). CONCLUSION: In T1D individuals without lipid-lowering treatment, 1H-NMR-glycoproteins were independently associated with the presence and amount of carotid atherosclerosis, unlike other classical inflammatory markers. Further studies are needed to ascertain their utility as CVD biomarkers.

Insulin resistance is associated with preclinical carotid atherosclerosis in patients with type 1 diabetes.

AIM: Although insulin resistance (IR) is a growing trait among type 1 diabetes (T1D) population, its relationship with atherosclerosis has been scarcely studied. We assessed the association between IR indexes and carotid atherosclerosis in T1D, a population at high cardiovascular disease (CVD) risk. MATERIALS AND METHODS: We evaluated 191 participants with T1D and no prior CVD with at least one of the following criteria: ≥40 years old; diabetic nephropathy; or T1D duration ≥10 years harbouring ≥1 additional CVD risk factor. IR was assessed with the metabolic syndrome (MetS) harmonized definition proposed in 2009 and the estimated glucose disposal rate (eGDR), a T1D-specific IR surrogate marker (lower values indicating higher IR). Standardized carotid ultrasonography was performed, recording intima-media thickness (IMT), plaque presence and maximum height of plaque. Comparisons between patients according to their MetS status as well as concerning eGDR values were performed. RESULTS: The participants' median age was 47.4 (41.1-53.3) years and diabetes duration 25.7 (21.6-32.5) years. Plaque prevalence was higher in patients with greater IR (49.1%, 29.1% and 20%, P = .001, for any plaque according to decreasing eGDR tertiles). Conversely, no statistically significant higher plaque prevalence was found in participants with MetS. In multivariate analyses (adjusted for general- and T1D-specific risk factors, and statin treatment), MetS was associated with neither IMT nor plaque. On the contrary, eGDR was independently related to ≥2 plaques (P = .018) and maximum plaque height (P < .01). CONCLUSIONS: In T1D, IR assessed through eGDR but not by MetS definition was independently associated with plaque burden, a predictor of CVD.

Impaired awareness of hypoglycaemia: A new risk factor for adverse pregnancy outcomes in type 1 diabetes.

AIM: The aim of this study is to evaluate the impact of impaired awareness of hypoglycaemia (IAH) on metabolic control and pregnancy outcomes in women with type 1 diabetes. MATERIAL AND METHODS: This was a single-centre prospective cohort study of singleton pregnant women with type 1 diabetes. IAH was assessed at the first antenatal visit using Clarke's test (score ≥ 3). Data on metabolic control, hypoglycaemic events, and the lipid profile were collected from prior to pregnancy and in each trimester of gestation. Pregnancy outcomes were also recorded. RESULTS: A total of 77 patients with type 1 diabetes were included; 24 (31.2%) were classified as having IAH. Compared with the normal awareness of hypoglycaemia (NAH) group, the IAH group did not show differences in HbA1c , weight gain, insulin doses, or severe and nonsevere hypoglycaemia events throughout pregnancy. IAH was associated with higher triglyceride concentrations in the second trimester (IAH: 154.8 ± 61.1 mg/dL, NAH: 128.6 ± 31.2 mg/dL, P = .034) and an increased risk of neonatal respiratory distress (odds ratio [OR] 11.24; 95% CI, 1.01-124.9, P = .041) in adjusted models. Increased risk of pre-eclampsia was related to higher second trimester triglyceride concentrations (OR 1.028; 95% CI, 1.004-1.053, P = .023) adjusted for confounders. CONCLUSIONS: The IAH was associated with increased risk of neonatal respiratory distress and pre-eclampsia, despite showing no differences in metabolic control. Hypoglycaemia awareness in the first antenatal visit should be assessed to identify the subgroup of pregnant women with increased risk of complications.

Evaluation of microvascular changes in the perifoveal vascular network using optical coherence tomography angiography (OCTA) in type I diabetes mellitus: a large scale prospective trial.

BACKGROUND: Diabetic retinopathy (DR) is the leading cause of blindness in type 1 Diabetes Mellitus (DM) patients, as a consequence of impaired blood flow in the retina. Optical coherence tomography angiography (OCTA) is a newly developed, non-invasive, retinal imaging technique that permits adequate delineation of the perifoveal vascular network. It allows the detection of paramacular areas of capillary non perfusion and/or enlargement of the foveal avascular zone (FAZ), representing an excellent tool for assessment of DR. The relationship of these microvascular changes with systemic factors such as metabolic control or duration of the disease still needs to be elucidated. METHODS: Prospective, consecutive, large-scale OCTA study. A complete ocular examination including a comprehensive series of OCTA images of different scan sizes captured with 2 OCT devices (Cirrus HD-OCT, Carl Zeiss Meditec, Dublin, CA, USA, and Triton Deep Range Imaging OCT, Topcon Corp, Topcon, Japan) will be obtained as part of the yearly routine follow up visits in type 1 DM patients seen in the Diabetes Unit of the Endocrinology department which give written informed consent to participate in the project. The aim of this study is to investigate the relationship between OCTA-derived parameters and systemic factors, as metabolic control (Hb1Ac, lipid profile, cholesterol, etc), and other relevant clinical factors as demographics or duration of the disease. DISCUSSION: This study is directed to investigate the relationship between the status of the perifoveal vascular network and systemic markers of the disease, and in particular to study whether these changes reflect those occurring elsewhere in the body affected by diabetic microvascular disease, as the kidneys or the brain. If these relationships were demonstrated, early detection of these microvascular changes by OCTA could lead to modifications in the pharmacological management of type 1 diabetic patients, as a way to reduce the risk of future complications in both the eye and other organs. TRIAL REGISTRATION: ClinicalTrials.gov, trial number NCT03422965.

Detailed description of a prepregnancy care program and its impact on maternal glucose control, weight gain, and dropouts.

BACKGROUND: The aim of this study was to analyze the clinical and metabolic changes observed during a prepregnancy care (PPC) program. METHODS: We performed a retrospective, observational, cohort study of 104 women with type 1 diabetes initiating a PPC program from 2011 to 2014. The outcomes measured were changes in HbA1c levels, weight and hypoglycemic events during PPC. Risk factors associated with severe hypoglycemia events, achieving the HbA1c target and dropouts were evaluated. RESULTS: HbA1c decreased from 7.2 ± 0.8% (55.3 ± 8.8 mmol/mol) to 6.7 ± 0.9% (49.8 ± 10.3 mmol/mol) (P < .001) within a median of 14.2 months (interquartile interval 5.4-23.2); 71.2% obtained HbA1c  < 7% (53 mmol/mol). HbA1c at the end of PPC was associated with baseline HbA1c (ß = .318, P = .001) and the number of previous pregnancies (ß = .224, P = .038), PPC was accompanied by 1.4 ± 4.0 kg weight gain (P = .003) without changes in severe hypoglycemic events. The risk factors for severe hypoglycemia were severe hypoglycemic events during the 2 years before (odds ratio [OR] 11.99, confidence interval 95% 1.89-75.95) and PPC duration (OR 1.09, 1.03-1.16). A total of 33 patients (31.7%) dropped out from PPC during follow-up, with dropout being associated with age (OR 1.17, 1.04-1.36) and PPC duration (OR 1.06, 1.02-1.11). CONCLUSIONS: Our PPC program was associated with an improvement in glycemic control without a significant increase in severe hypoglycemic events, although with some weight gain. A considerable number of patients dropped out during follow-up, this being related to older age and a longer duration of the program. This information could be of help to design new and more effective PPC approaches. Copyright © 2016 John Wiley & Sons, Ltd.

Hypovitaminosis D in type 2 diabetes: relation with features of the metabolic syndrome and glycemic control.

AIM: To assess the association of hypovitaminosis D with clinical and biochemical characteristics of type 2 diabetic patients and to determine the effect of glycemic control optimization on 25-hydroxyvitamin D (25(OH)D) concentrations. METHODS: Cross-sectional study of 63 patients with type 2 diabetes (mean age 60 ± 9.8 years, 69.8% men). Twenty of the 63 patients were also studied before and after glycemic control optimization. RESULTS: Mean 25(OH)D concentrations were 63.64 ± 25.51 nmol/L and 74.6% of patients had hypovitaminosis D. Compared with patients with vitamin D sufficiency, patients with hypovitaminosis D had higher prevalence of overweight or obesity (72.3% versus 37.5%; p = 0.012) and higher VLDL cholesterol (VLDL-c) (0.71 (0.24-3.59) versus 0.45 (0.13-1.6) mmol/L; p = 0.011) and C-reactive protein (3.28 (0.36-17.69) versus 1.87 (0.18-17.47) mg/L; p = 0.033) concentrations. The composition of HDL particles also differed in both groups, with higher relative content of triglycerides and lower of cholesterol in patients with hypovitaminosis D. After adjustment for age, seasonality and BMI, differences remained significant for VLDL-c and triglyceride content of HDL. No differences were found regarding other diabetes characteristics. Improvement of glycemic control (HbA1c 9.4 (7.6-14.8) versus 7.3 (6.2-8.7)%; p = 0.000) was accompanied by a decrease in 25(OH)D concentrations (72.7 ± 33.3 to 59.0 ± 21.0 nmol/L; p = 0.035). Correlation analysis revealed that changes in 25(OH)D concentrations were negatively associated to changes in HbA1c (r - 0.482; p = 0.032). CONCLUSION: Hypovitaminosis D is associated with features of the metabolic syndrome in type 2 diabetes and improvement of glycemic control decreases 25(OH)D concentrations.

Inflammatory biomarkers in type 2 diabetic patients: effect of glycemic control and impact of LDL subfraction phenotype.

BACKGROUND: Type 2 diabetes mellitus (T2D) is associated with higher cardiovascular risk partly related to an increase in inflammatory parameters. The aim of this study was to determine the association of inflammatory biomarkers with low-density lipoprotein (LDL) subfraction phenotype and glycemic control in subjects with T2D and poor glycemic control. METHODS: A cross-sectional study was performed comparing 122 subjects with T2D (59 ± 11 years old, body mass index 30.2 ± 5.6 kg/m2) with 54 control subjects. Patients with T2D were classified according to their LDL subfraction phenotype and inflammatory biomarkers (C-reactive protein, Interleukin-6, Interleukin-8, Transforming growth factor ß1, Monocyte chemotactic protein 1, Leptin, Adiponectin) were evaluated according to the degree of glycemic control, LDL phenotype and other clinical characteristics. Forty-two subjects with T2D were studied before and after 3 months of improving glycemic control by different strategies. RESULTS: Patients with T2D had higher C-reactive protein (CRP) and monocyte chemotactic protein-1 (MCP1) levels and lower adiponectin concentration, compared to controls. T2D subjects with body mass index ≥ 30 kg/m2 had higher CRP levels (5.2 ± 4.8 mg/l vs 3.7 ± 4.3 mg/l; p < 0.05). The presence of LDL phenotype B was related to higher levels of transforming growth factor-ß1 (TGF-ß1) (53.92 ± 52.82 ng/l vs 31.35 ± 33.74 ng/l; p < 0.05) and lower levels of adiponectin (3663 ± 3044 ng/l vs 2723 ± 1776 ng/l; p < 0.05). The reduction of HbA1c from 9.5 ± 1.8% at baseline to 7.4 ± 0.8% was associated with a significant reduction of TGF-ß1 (41.86 ± 32.84 ng/l vs 26.64 ± 26.91 ng/l; p = 0.02). CONCLUSIONS: Subjects with T2D, especially those with LDL phenotype B and obesity, have higher levels of inflammatory biomarkers. Improvement of glycemic control reduces TGF-ß1 levels, which may contribute partly to its renoprotective role.

Impact of Preeclampsia and Parity on Sex-based Discrepancies in Subclinical Carotid Atherosclerosis in Type 1 Diabetes.

CONTEXT: The excess risk of fatal and nonfatal cardiovascular events is roughly twice as high in women than in men with type 1 diabetes. OBJECTIVE: To evaluate the impact of preeclampsia and parity on sex-based discrepancies in preclinical atherosclerosis and on the diagnostic performance of a cardiovascular risk scale. DESIGN: Cross-sectional study. SETTING: Single tertiary hospital. PATIENTS: A total of 728 people with type 1 diabetes (48.5% women) without cardiovascular disease and age ≥40 years, nephropathy, and/or ≥10 years of diabetes duration with another risk factor. INTERVENTION: Standardized carotid ultrasonography. MAIN OUTCOME MEASURES: Carotid plaque determined by ultrasonography and cardiovascular risk estimated according to the Steno T1 Risk Engine (Steno-Risk). RESULTS: Nulliparous women and parous women without previous preeclampsia had a lower risk for carotid plaque than men (adjusted odds ratio: .48, 95% confidence interval [.28-.82]; adjusted odds ratio: .51 [.33-.79], respectively), without differences in the preeclampsia group. The prevalence of carotid plaque increased as the estimated cardiovascular risk increased in all subgroups except for preeclampsia group. The area under the curve of the Steno-Risk for identifying ≥2 carotid plaques was lower in the preeclampsia group (men: .7886; nulliparous women: .9026; women without preeclampsia: .8230; preeclampsia group: .7841; P between groups = .042). Neither the addition of parity nor preeclampsia in the Steno-Risk led to a statistically significant increase in the area under the curve. CONCLUSION: The risk for carotid plaque in women compared with men decreased as exposure to obstetric factors diminished. However, the addition of these factors did not improve the prediction of the Steno-Risk.

Impact of an Advanced Hybrid Closed-Loop System on Glycemic Control Throughout the Menstrual Cycle in Women with Type 1 Diabetes Prone to Hypoglycemia.

This study aimed to evaluate the impact of advanced hybrid closed loop (AHCL) on glycemic control throughout the menstrual cycle (MC) in women with type 1 diabetes. We included 39 pairs of spontaneous MCs from 13 participants, before and after switching from sensor-augmented pump to AHCL. Baseline time below range <70 mg/dL (TBR <70) was significantly higher during the midfollicular phase than during late luteal phase (5.7% ± 5.0% vs. 4.1% ± 3.0%), but similar time in range 70-180 mg/dL (TIR) was observed throughout the MC. After switching to AHCL, a reduction in TBR <70 and an increase in TIR were observed in all phases. Phase-dependent changes in insulin infusion were detected and pre-existing differences in TBR <70 were eradicated (3.5% ± 3.2% vs. 3.0% ± 3.0%). However, TIR became significantly higher during the early follicular phase than during the late luteal phase (79.1% ± 9.3% vs. 74.5% ± 10.0%). In conclusion, AHCL improved glycemic control throughout the MC, but performance differed according to phase.

Dose-Dependent association of cumulative tobacco consumption with the presence of carotid atherosclerosis in individuals with type 1 diabetes.

AIMS: Evaluate the association between cumulative tobacco consumption (CTC; packs-year) and atherosclerosis in type 1 diabetes (T1D), and study whether the inclusion of CTC in the Steno T1 Risk Engine (ST1RE) equation improves the identification of plaques. METHODS: Cross-sectional study in T1D patients without cardiovascular disease (CVD), with ≥ 1 of the following: ≥40 years-old, diabetic kidney disease, and/or T1D duration ≥ 10 years + cardiovascular risk factors.Preclinical atherosclerosis was evaluated by carotid ultrasonography. RESULTS: N = 584 patients were included (46.1 % women, age 48.7 ± 10.5 years, T1D duration 27.3 ± 10.8 years, 26.2 % active smokers). The overall plaque prevalence was 40.9 %. In models adjusted for age, sex, lipids, blood pressure, kidney function, statin use, microvascular complications and HbA1c, CTC was dose-dependently associated with the number of plaques (none, 1-2, ≥3) overall and in both active and former smokers (p < 0.001). This association remained after adjusting for ST1RE (OR 1.11 [1.02-1.19]). Although the inclusion of CTC in the ST1RE did not improve plaque identification overall (p = 0.180), it did so when analyzing active smokers separately (AUC 0.738 vs. 0.768; p < 0.01). CONCLUSIONS: In T1D patients, CTC is dose-dependently associated with atherosclerosis. Further prospective studies are needed to determine if CTC could identify T1D individuals more prone to accelerated atherosclerosis.

Impact of the LDL subfraction phenotype on Lp-PLA2 distribution, LDL modification and HDL composition in type 2 diabetes.

BACKGROUND: Qualitative alterations of lipoproteins underlie the high incidence of atherosclerosis in diabetes. The objective of this study was to assess the impact of low-density lipoprotein (LDL) subfraction phenotype on the qualitative characteristics of LDL and high-density lipoprotein (HDL) in patients with type 2 diabetes. METHODS: One hundred twenty two patients with type 2 diabetes in poor glycemic control and 54 healthy subjects were included in the study. Patients were classified according to their LDL subfraction phenotype. Seventy-seven patients presented phenotype A whereas 45 had phenotype B. All control subjects showed phenotype A. Several forms of modified LDL, HDL composition and the activity and distribution of lipoprotein-associated phospholipase A2 (Lp-PLA2) were analyzed. RESULTS: Oxidized LDL, glycated LDL and electronegative LDL were increased in both groups of patients compared with the control group. Patients with phenotype B had increased oxidized LDL and glycated LDL concentration than patients with phenotype A. HDL composition was abnormal in patients with diabetes, being these abnormalities more marked in patients with phenotype B. Total Lp-PLA2 activity was higher in phenotype B than in phenotype A or in control subjects. The distribution of Lp-PLA2 between HDL and apoB-containing lipoproteins differed in patients with phenotype A and phenotype B, with higher activity associated to apoB-containing lipoproteins in the latter. CONCLUSIONS: The presence of LDL subfraction phenotype B is associated with increased oxidized LDL, glycated LDL and Lp-PLA2 activity associated to apoB-containing lipoproteins, as well as with abnormal HDL composition.