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Background: Insulin bolus calculators assist people with Type 1 diabetes (T1D) to calculate the amount of insulin required for meals to achieve optimal glucose levels but lack adaptability and personalization. We have proposed enhancing bolus calculators by the means of case-based reasoning (CBR), an established problem-solving methodology, by individualizing and optimizing insulin therapy for various meal situations. CBR learns from experiences of past similar meals, which are described in cases through a set of parameters (eg, time of meal, alcohol, exercise). This work discusses the selection, representation and effect of case parameters used for a CBR-based Advanced Bolus Calculator for Diabetes (ABC4D)., Methods: We analyzed the usage and effect of selected parameters during a pilot study (n = 10), where participants used ABC4D for 6 weeks. Retrospectively, we evaluated the effect of glucose rate of change before the meal on the glycemic excursion. Feedback from study participants about the choice of parameters was obtained through a nonvalidated questionnaire., Results: Exercise and alcohol were the most frequently used parameters, which was congruent with the feedback from study participants, who found these parameters most useful. Furthermore, cases including either exercise or alcohol as parameter showed a trend in reduction of insulin at the end of the study. A significant difference ( P < .01) was found in glycemic outcomes for meals where glucose rate of change was rising compared to stable rate of change., Conclusions: Results from the 6-week study indicate the potential benefit of including parameters exercise, alcohol and glucose-rate of change for insulin dosing decision support.

Objective: To report the impact of continuous glucose monitoring (CGM) on glycemic variability (GV) indices, factors predictive of change, and to correlate variability with conventional markers of glycemia., Methods: Data from the JDRF study of CGM in participants with type 1 diabetes were used. Participants were randomized to CGM or self-monitored blood glucose (SMBG). GV indices at baseline, at 26 weeks in both groups, and at 52 weeks in the control group were analyzed. The associations of demographic and clinical factors with change in GV indices from baseline to 26 weeks were evaluated., Results: Baseline data were available for 448 subjects. GV indices were all outside normative ranges (P < 0.001). Intercorrelation between GV indices was common and, apart from coefficient of variation (CV), low blood glucose index (LBGI), and percentage of glycemic risk assessment diabetes equation score attributable to hypoglycemia (%GRADE hypoglycemia ), all indices correlate positively with HbA1c. There was strong correlation between time spent in hypoglycemia, and CV, LBGI, and %GRADE hypoglycemia , but not with HbA1c. A significant reduction in all GV indices, except lability index and mean absolute glucose change per unit time (MAG), was demonstrated in the intervention group at 26 weeks compared with the control group. Baseline factors predicting a change in GV with CGM include baseline HbA1c, baseline GV, frequency of daily SMBG, and insulin pump use., Conclusions: CGM reduces most GV indices compared with SMBG in people with type 1 diabetes. The strong correlation between time spent in hypoglycemia and CV, LBGI, and %GRADE hypoglycemia highlights the value of these metrics in assessing hypoglycemia as an adjunct to HbA1c in the overall assessment of glycemia.

Objective: To undertake a comprehensive evaluation of apolipoprotein risk markers for cardiovascular disease (CVD) according to gender, age and menopausal status., Design: Cross-sectional analysis of independent associations of gender, age and menopause with serum apolipoproteins., Participants: Apparently healthy Caucasian premenopausal (n = 109) and postmenopausal (n = 252) women not taking oral contraceptives or hormone replacement, and Caucasian men (n = 307)., Measurements: Serum apolipoprotein (apo) B, A-I and A-II concentrations were measured, plus serum total cholesterol, low-density and high-density lipoprotein cholesterol (LDL-C and HDL-C, respectively), triglycerides, cholesterol in HDL subfractions and the apoB/apoA-I, LDL-C/apoB, HDL-C/apoA-I and HDL-C/apoA-II ratios. Analyses were undertaken with and without standardization for confounding characteristics and in 5-year age ranges., Results: Overall, apoB concentrations were highest in men but in women rose with age and menopause to converge, in the age range of 50-55 years, with concentrations in men. The LDL-C/apoB ratio was generally higher in women than in men. ApoA-I concentrations were highest in postmenopausal women and lowest in men (standardized median (IQR) 144 (130, 158) vs 119 (108, 132) g/l, respectively, P < 0·001). ApoA-II concentrations were also highest in postmenopausal women but were lowest in premenopausal women (40·3 (37·5, 44·5) vs 32·9 (30·5, 35·7) g/l, respectively, P < 0·001). Nevertheless, postmenopausal women had HDL-C/apoA-I and HDL-C/apoA-II ratios approaching the lowest ratios, which were seen in men., Conclusions: Consistent with adverse effects on CVD risk, male gender, ageing in women and menopause were associated with increased apoB concentrations, and menopause and male gender were associated with a decreased cholesterol content of HDL particles., (© 2016 John Wiley & Sons Ltd.)

Background: The objective was to study the ability of the 30-min plasma glucose (30-min PG) during an oral glucose tolerance test to predict the future risk of type 2 diabetes among Asian Indians with impaired glucose tolerance., Methods: For the present analyses, we utilized data from 753 participants from two diabetes primary prevention studies, having complete data at the end of the study periods, including 236 from Indian Diabetes Prevention Programme-1 and 517 from the 2013 study. Baseline 30-min PG values were divided into tertiles: T1 < 9.1 mmol/L (<163.0 mg/dL); T2 9.2-10.4 mmol/L (164.0-187.0 mg/dL) and T3 ≥ 10.4 mmol/L (≥188 mg/dL). The predictive values of tertiles of 30-min PG for incident diabetes were assessed using Cox regression analyses RESULTS: At the end of the studies, 230 (30.5%) participants developed diabetes. Participants with higher levels of 30-min PG were more likely to have increased fasting, 2-h PG and HbA 1c levels, increased prevalence of impaired fasting glucose and decreased beta cell function. The progression rate of diabetes increased with increasing tertiles of 30-min PG. Cox's regression analysis showed that 30-min PG was an independent predictor of incident diabetes after adjustment for an array of covariates [Hazard Ratio (HR):1.44 (1.01-2.06)] CONCLUSIONS: This prospective analysis demonstrates, for the first time, an independent association between an elevated 30-min PG level and incident diabetes among Asian Indians with impaired glucose tolerance. Predictive utility of glycemic thresholds at various time points other than the traditional fasting and 2-h PG values should therefore merit further consideration. Copyright © 2016 John Wiley & Sons, Ltd., (Copyright © 2016 John Wiley & Sons, Ltd.)

Objective: Overweight and obese individuals may be metabolically healthy, but attention needs to be given to long-term persistence of this trait and any associated variation in cardiovascular risk., Design: Cross-sectional and longitudinal variation in metabolic health and associated cardiovascular mortality were analysed in 1099 white European-origin normal-weight and overweight or obese males followed for 20years., Methods: Definitions of metabolic health were based on LDL and HDL cholesterol, triglycerides, blood pressure, fasting glucose and cardiovascular risk. Insulin resistance (e.g. HOMA-IR) and sub-clinical inflammation (ESR and white blood cell count) were explored. Cardiovascular mortality risks and persistence of metabolic health status were evaluated., Results: There were 87 cardiovascular deaths. Insulin resistance was increased in metabolically healthy overweight or obese participants (median HOMA-IR 2.63, 95% CI: 1.79-3.65, P<0.001) relative to normal-weight participants (median HOMA-IR 1.67, 95% CI: 1.08-2.67, P<0.001) as was sub-clinical inflammation but metabolically healthy overweight or obese individuals were not at increased risk of cardiovascular mortality compared with the metabolically healthy normal-weight individuals (hazard ratio 1.13, 95% CI: 0.34-3.72, P=0.8). The proportions of initially metabolically healthy overweight or obese who remained metabolically healthy for visits 2, 3 and 4 were 54, 48 and 39% respectively, and for initially normal-weight individuals, 68, 51 and 41%. A lower proportion of metabolically healthy overweight or obese individuals remained metabolically healthy at visit 2 compared with normal-weight individuals (P=0.007), but proportions converged thereafter., Conclusions: Despite being insulin resistant and having greater sub-clinical inflammation, and despite instability in metabolic health status, metabolically healthy overweight or obese individuals were at no greater risk of cardiovascular mortality than their normal-weight equivalents., (© 2016 European Society of Endocrinology.)

Epithelial barrier function and innate immunity are fundamental to the pathogenesis of inflammatory and infectious disease. Along with plasma membranes, epithelial cells are the primary cellular determinant of epithelial barrier function. The mechanism by which polarized epithelia form a permeability barrier is of fundamental importance to the prevention of many infectious and inflammatory diseases. Moreover, epithelial cells express Toll-like receptors (TLRs) which upon recognition of conserved microbial factors such as lipopolysaccharide (LPS) induce epithelial responses including epithelial cell proliferation, secretion of secretory IgA into the lumen and production mucins and antimicrobial peptides, thereby promoting intestinal barrier function. Understanding gut barrier integrity and regulation of permeability is crucial to increase our understanding of the pathogenesis of intestinal disease. A variety of tests have been developed to assess this barrier, including assessing intestinal epithelial cell proliferation or death, intestinal tight junction status and the consequence of intestinal barrier integrity loss such as increased intestinal permeability and susceptibility to bacterial infection. Using a mouse model, this chapter describes some of the methods to assess the functional integrity of this epithelial barrier and the part played by a TLR signalling pathway.

Aims: We describe a two-step screening approach using non-invasive risk assessment and glycated hemoglobin (HbA1c) to identify participants for a diabetes prevention trial., Methods: A total of 6030 non-diabetic persons of 35-55 years were screened using risk assessment for diabetes. Those with three or more risk factors were screened using point of care HbA1c test. For this study, participants in HbA1c categories of 6.0% (42.1 mmol/mol)-6.4% (46.4 mmol/mol) were selected and their characteristics were analyzed., Results: Among 6030 persons, 2835 (47%) had three or more risk factors for diabetes. Among those screened with HbA1c, 43.2% (1225) had HbA1c values of <6.0% (42.1 mmol/mol), 46.8% (1327) had HbA1c values between 6.0% (42.1 mmol/mol) and ≤ 6.4% (46.4 mmol/mol) and 10% (283) had undiagnosed diabetes with ≥6.5% (47.5 mmol/mol). Positive family history was present in 53.2%, 81.7% were obese and 14.8% were overweight., Conclusions: Opportunistic screening using a two-step approach: diabetes risk profile and HbA1c measurement detected a large percentage of individuals with prediabetes. Prediabetic persons recruited to the trial had higher percentage of obesity and presence of positive family history than those who had lower HbA1c values. Outcomes from this trial will enable comparisons with the previous prevention studies that used blood glucose levels as the screening criteria., (Copyright © 2015. Published by Elsevier Ireland Ltd.)

Background: The Bio-inspired Artificial Pancreas (BiAP) is a closed-loop insulin delivery system based on a mathematical model of beta-cell physiology and implemented in a microchip within a low-powered handheld device. We aimed to evaluate the safety and efficacy of the BiAP over 24 hours, followed by a substudy assessing the safety of the algorithm without and with partial meal announcement. Changes in lactate and 3-hydroxybutyrate concentrations were investigated for the first time during closed-loop., Methods: This is a prospective randomized controlled open-label crossover study. Participants were randomly assigned to attend either a 24-hour closed-loop visit connected to the BiAP system or a 24-hour open-loop visit (standard insulin pump therapy). The primary outcome was percentage time spent in target range (3.9-10 mmol/l) measured by sensor glucose. Secondary outcomes included percentage time in hypoglycemia (<3.9 mmol/l) and hyperglycemia (>10 mmol/l). Participants were invited to attend for an additional visit to assess the BiAP without and with partial meal announcements., Results: A total of 12 adults with type 1 diabetes completed the study (58% female, mean [SD] age 45 [10] years, BMI 25 [4] kg/m(2), duration of diabetes 22 [12] years and HbA1c 7.4 [0.7]% [58 (8) mmol/mol]). The median (IQR) percentage time in target did not differ between closed-loop and open-loop (71% vs 66.9%, P = .9). Closed-loop reduced time spent in hypoglycemia from 17.9% to 3.0% (P < .01), but increased time was spent in hyperglycemia (10% vs 28.9%, P = .01). The percentage time in target was higher when all meals were announced during closed-loop compared to no or partial meal announcement (65.7% [53.6-80.5] vs 45.5% [38.2-68.3], P = .12)., Conclusions: The BiAP is safe and achieved equivalent time in target as measured by sensor glucose, with improvement in hypoglycemia, when compared to standard pump therapy., (© 2015 Diabetes Technology Society.)

Background: There is evidence suggesting that glycemic variability reduces quality of life (QoL) in people with type 2 diabetes, but this association has not been explored in type 1 diabetes. We aimed to assess whether glycemic variability has an impact on QoL in adults with established type 1 diabetes using multiple daily injections (MDI) of insulin or continuous subcutaneous insulin infusion (CSII)., Methods: Participants wore a blinded continuous glucose monitor for up to 5 days and completed the diabetes quality of life (DQOL) questionnaire. Glycemic variability measures were calculated using the EasyGV version 9.0 software. A correlation analysis was performed to assess whether there was a relationship between glycemic variability and measures of QoL., Results: In all, 57 participants with type 1 diabetes (51% male, 65% on CSII, 35% on MDI, mean [SD] age 41 [13] years, duration of diabetes 21 [12] years, HbA1c 63 [12] mmol/mol [7.9% (1.1)], body mass index 25.2 [4.0] kg/m(2)) were included in the analysis. No significant associations between glycemic variability and DQOL total or subscale scores were demonstrated. The glycemic variability was significantly higher for MDI participants compared to CSII participants (P < .05 for all glycemic variability measures), but no significant difference in QoL between the 2 treatment modality groups was observed., Conclusions: Treatment with CSII is associated with lower glycemic variability compared to MDI. Despite this, and contrary to findings in type 2 diabetes, this study did not find an association between glycemic variability and QoL in adults with relatively well-controlled type 1 diabetes, irrespective of whether they are on MDI or CSII., (© 2015 Diabetes Technology Society.)

Aims: The aims of this study were: (1) to assess the association of adiponectin, leptin and interleukin-6 (IL-6) with incidence of type 2 diabetes (T2DM) in Asian Indian men with impaired glucose tolerance (IGT) and (2) to evaluate the additional contribution of these with the well-established glycaemic marker HbA1c., Methods: This is an ancillary analyses of a nested case-control study derived from a prospective, prevention trial in India. All the participants had IGT at baseline. For this subanalysis a total of 147 (T2DM: 71; nondiabetic: 76) participants were selected based on the final glycemic outcomes. Association of these selected adipokines with T2DM were assessed using logistic regression analyses. Clinical usefulness of adding adipokine markers with HbA1c on prediction of T2DM was assessed using the area under the curve (AUC) of the receiver operating characteristics., Results: Baseline levels of adiponectin were lower and the levels of IL-6 were higher in T2DM cases when compared with non-diabetic cases (P<0.05). Levels of leptin were similar in both groups. In fully adjusted models, adiponectin (odds ratio (OR): 0.55 [95%CI: 0.33-0.91]; P=0.019) and IL-6 (OR: 2.27 [95%CI: 1.40-3.691]; P=0.001) were associated with diabetes. Addition of adiponectin to HbA1c improved the AUC (ΔAUC: 0.0619; P=0.0251), whereas addition of IL-6 did not improve the predictive power of HbA1c alone., Conclusions: Adiponectin and IL-6 are independently associated with incident diabetes. However, they are unlikely to serve as simple tools to predict future risk of diabetes but may have a role in understanding the pathogenesis., (Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.)

Aims: In this analysis, we sought to examine the prospective association of the disposition index (DIo) derived from oral glucose tolerance test with incident diabetes in Asian Indian men with impaired glucose tolerance (IGT)., Methods: These post hoc analyses used data from a 2-year prospective study in primary prevention of diabetes using lifestyle intervention among 517 men with IGT. All the participants received standard lifestyle advice at baseline. The surrogate insulin sensitivity and insulin secretion measures were tested for their hyperbolic relationship. Predictive associations of various surrogate measures with incident diabetes were determined using receiver operating characteristic curves., Results: The combination of total area under the curve of insulin-to-glucose ratio (AUCinsulin/glucose) and Matsuda's insulin sensitivity index was the best equation to depict DIo [β: -0.954 (95 % CI -1.015 to -0.893)] compared to other measures tested in this cohort. There was an inverse association between change in DIo at the final follow-up and development of incident diabetes. Among the surrogate insulin measures studied, DIo [AUC (0.717 (95 % CI 0.675-0.756))] as a composite measure was superior than other surrogate indices., Conclusions: Among the surrogate indices studied, DIo was the best measure associated with incident diabetes.

The association of retinol binding protein-4 (RBP4) with incident type 2 diabetes (T2DM) in Asian Indian middle-aged men with impaired glucose tolerance (IGT) was studied. This was an ancillary analysis of a subsample from a cohort of participants with IGT in a 2 year prospective diabetes prevention program in India. For this analysis, 71 incident T2DM and 76 non-diabetic cases (non-progressors) based on the final glycemic outcome were selected. Baseline serum RBP4 was measured using competitive enzyme immunoassay. Correlations of RBP4 with relevant anthropometric and biochemical variables and also its association with diabetes were assessed using appropriate statistical analyses. Participants who developed T2DM had higher levels of serum RBP4 (21.3 [IQR: 17.7-24.9] µg/mL) compared with non-progressors (17.3 [IQR: 13.1-21.0] µg/mL; P = 0.001). Levels of RBP4 were lower than in Caucasians. Stepwise linear regression analysis showed that body mass index (BMI), systolic blood pressure, triglycerides, and HbA1c had independent associations with RBP4 levels. Multiple logistic regression analyses showed that RBP4 was independently associated with incident diabetes (odds ratio [OR] [95%confidence interval (CI)]: 1.69 [1.18-2.41]; P = 0.004). Adjustment for study group, age, BMI, waist circumference, 2 H plasma glucose, triglycerides, gamma glutamyl transferase, and insulin resistance weakened the significance of its association (OR [95%CI]: 1.65 [1.03-2.66]; P = 0.038).The results of this preliminary analyses showed that baseline serum RBP4 levels were independently associated with incident diabetes in Asian Indian men with IGT. It may be used as an additional predictor of future diabetes., (© 2015 International Union of Biochemistry and Molecular Biology.)

Objective: To distinguish the effects of menopause, gender and age on serum lipid risk markers for vascular disease, including high-density lipoprotein cholesterol (HDL-C) subfractions 2 and 3 (HDL2-C and HDL3-C)., Methods: We undertook a cross-sectional database analysis of apparently healthy Caucasian pre- and postmenopausal women and men (n=515, 518 and 800, respectively) not taking drugs affecting lipid metabolism (including contraceptive or post-menopausal steroids). Measurements of serum total cholesterol (TC), low-density lipoprotein (LDL-C), triglycerides (TG), HDL-C, HDL2-C, HDL3-C and non-HDL-C concentrations and the TC/HDL-C concentration ratio were considered., Results: Men had lower TC than postmenopausal women (p<0.001) and similar LDL-C. Compared with premenopausal women, postmenopausal women had a more atherogenic lipid profile with lower HDL2-C (median 0.67 vs 0.60 mmol/L, p<0.001) but no difference in HDL3-C (0.96 vs 0.96 mmol/L, p=0.8). Compared with either pre or postmenopausal women, men had a more atherogenic profile with lower HDL2-C (0.36 mmol/L) and HDL3-C (0.91 mmol/L, all p<0.001). With standardization for confounding variables, including standardization to age of menopause (50 years), differences apparent in the non-standardized comparisons were generally sustained, although HDL3-C levels were lower at menopause, HDL2-C ceased to differ and LDL-C was lower in postmenopausal women than men., Conclusions: Male gender is associated with a more atherogenic profile than female gender, with appreciably lower levels of the HDL2-C subfraction. Among women, menopause is associated with a more atherogenic lipid profile, but has less effect than male gender., (Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.)

Macrophages activated by the TLR4 agonist LPS undergo dramatic changes in their metabolic activity. We here show that LPS induces expression of the key metabolic regulator Pyruvate Kinase M2 (PKM2). Activation of PKM2 using two well-characterized small molecules, DASA-58 and TEPP-46, inhibited LPS-induced Hif-1α and IL-1β, as well as the expression of a range of other Hif-1α-dependent genes. Activation of PKM2 attenuated an LPS-induced proinflammatory M1 macrophage phenotype while promoting traits typical of an M2 macrophage. We show that LPS-induced PKM2 enters into a complex with Hif-1α, which can directly bind to the IL-1β promoter, an event that is inhibited by activation of PKM2. Both compounds inhibited LPS-induced glycolytic reprogramming and succinate production. Finally, activation of PKM2 by TEPP-46 in vivo inhibited LPS and Salmonella typhimurium-induced IL-1β production, while boosting production of IL-10. PKM2 is therefore a critical determinant of macrophage activation by LPS, promoting the inflammatory response., (Copyright © 2015 Elsevier Inc. All rights reserved.)

Aim: To determine prospectively the association of baseline hypertriglyceridaemic waist phenotype with incident diabetes in Asian-Indian men with impaired glucose tolerance., Methods: In a randomized 2-year diabetes prevention trial in 517 men with impaired glucose tolerance, 123 (23.8%) developed diabetes. Baseline anthropometric, metabolic and clinical variables were estimated. Associations of hypertriglyceridaemic waist phenotype (waist circumference ≥ 90cm and a serum triglyceride level of ≥ 1.7 mmol/l) with insulin resistance and incident diabetes were assessed using multiple linear regression and Cox's proportional hazard models, respectively., Results: Men with an isolated enlarged waistline and hypertriglyceridaemic waist phenotype had significantly higher BMI and percentage of total body fat compared with the group with normal waistline and triglyceride levels and the group with isolated hypertriglyceridaemia. The men with hypertriglyceridaemic waist phenotype had higher insulin resistance (mean ± sd homeostasis model assessment of insulin resistance value: 3.6 ± 1.5) compared with those in the isolated enlarged waistline, the isolated hypertriglyceridaemia or the normal waistline and triglyceride level groups (3.1 ± 1.4, 2.7 ± 1.0 and 2.5 ± 1.1, respectively, all P < 0.05 compared with hypertriglyceridaemic waist phenotype). Multiple linear regression analyses showed that hypertriglyceridaemic waist phenotype was significantly associated with insulin resistance after adjusting for age, BMI, family history, percentage of total body fat, smoking, alcohol intake, 2-h plasma glucose and HDL cholesterol level. Hypertriglyceridaemic waist phenotype was independently associated with incident diabetes after adjusting for the above confounders and gamma-glutamyl transferase (hazard ratio 1.49, 95% CI 1.01-2.21; P = 0.047). The association of hypertriglyceridaemic waist phenotype with incident diabetes was abolished when insulin resistance was introduced into the model (hazard ratio 1.39, 95% CI 0.092-2.10; P=0.12)., Conclusions: Hypertriglyceridaemic waist phenotype is a simple clinical proxy measurement for insulin resistance and is strongly associated with incident diabetes in Asian-Indian men with impaired glucose tolerance., (© 2014 The Authors. Diabetic Medicine © 2014 Diabetes UK.)

The relative risk for cardiovascular disease (CVD) events and mortality in diabetic women (in comparison with non-diabetic women) is believed to be greater than that in diabetic men. However, the absolute risk for CVD mortality and morbidity does not appear to be higher in women. In general, there is heterogeneity between studies, and whether there is any definite difference in the CVD risk between sexes at any level of glycaemia is not known. The same arguments also apply when comparing the CVD risk factors, such as lipid profiles and systemic inflammation indices, which seem to be worse in women than in men with diabetes mellitus (DM). The same questions emerge at any given glycaemic state: are women at worse risk and do they have a worse risk factor profile than men? These issues have yet to be resolved. Similar, though less extensive, data have been reported for prediabetes. Furthermore, women with DM are suboptimally treated compared with men regarding lipid and blood pressure targets. Large prospective studies representative of the general population are therefore needed to define the differences between sexes regarding CVD events and mortality at a given glucose level and after adjusting for any other confounders., (© 2014 European Society of Endocrinology.)

Aims: To assess the beneficial effects of the components of lifestyle intervention in reducing incidence of diabetes in Asian Indian men with impaired glucose tolerance (IGT) in India., Methods: This analysis was based on a 2 year prospective, randomized controlled primary prevention trial in a cohort of Asian Indian men with IGT (n=537) (Clinical Trial No: NCT00819455). Intervention and control groups were given standard care advice at baseline. Additionally, the intervention group received frequent, mobile phone based text message reminders on healthy lifestyle principles. Dietary intake and physical activity habits were recorded by validated questionnaires. The lifestyle goals were: reductions in consumption of carbohydrates, oil, portion size and body mass index of at least 1 unit (1 kg/m(2)) from baseline and maintenance of good physical activity. The association between diabetes and lifestyle goals achieved was assessed using multiple logistic regression analyses. Changes in insulin sensitivity (Matsuda's insulin sensitivity index) and oral disposition index during the follow-up were assessed., Results: At the end of the study, 123 (23.8%) participants developed diabetes. The mean lifestyle score was higher in the intervention group compared with control (2.59 ± 1.13 vs. 2.28 ± 1.17; P=0.002). Among the 5 lifestyle variables, significant improvements in the 3 dietary goal were seen with intervention. Concomitant improvement in insulin sensitivity and oral disposition index was noted. Higher lifestyle score was associated with lower risk of developing diabetes (odds ratio: 0.54 [95% CI: 0.44-0.70]; P<0.0001)., Conclusions: Beneficial effects of intervention were associated with increased compliance to lifestyle goals. The plausible mechanism is through improvement in insulin sensitivity and beta cell preservation., (Copyright © 2014 Elsevier Ireland Ltd. All rights reserved.)

Objective: To study the associations of baseline gamma-glutamyltransferase (GGT) and alanine transaminase (ALT) with incident diabetes among Asian Indian men with impaired glucose tolerance (IGT)., Methods: In a 2 year prospective, randomised, controlled primary prevention study of diabetes, among 537 IGT men aged 35-55 years, 123 incident diabetes (DM) cases occurred. Anthropometric {body mass index (BMI), waist circumference (WC)}, and laboratory measurements (fasting, 30 min and 2 hr plasma glucose (2 hr PG), HbA1c and plasma insulin, lipid profile, ALT, GGT) were estimated at baseline (Clinical Trial Identification No: NCT00819455). Predictive associations of baseline GGT and ALT values during the study were assessed using appropriate statistical methods., Results: Baseline GGT but not ALT was significantly higher in incident diabetes cases. Mean (95% CI) GGT decreased in subjects who reverted to normal glucose tolerance (NGT), whereas it increased in subjects who deteriorated to diabetes (NGT:-3.5 (-6.4 to -0.6); IGT:0.3 (-3.0 to 2.4); DM:8.3 (3.6 to 13.0) UL(-1); P < 0.0001). The risk of DM significantly increased with increasing baseline GGT after adjusting for confounders such as BMI, alcohol drinking, 2 hr PG and insulin resistance (2.02[1.35-3.02]; P = 0.001). Receiver operating characteristic curve showed that the model comprising of baseline fasting plasma glucose (FPG) and GGT (area-under-curve(AUC)[95% CI]: 0.668 [0.613-0.722]; P < 0.0001) was equally sensitive in identifying subjects with risk of diabetes as compared to 2 hr PG (AUC [95% CI]: 0.670 [0.614-0.725]; P < 0.0001) and HbA1c (AUC [95% CI]: 0.677 [0.619-0.734]; P < 0.0001) alone., Conclusions: GGT was an independent predictor of incident diabetes. Combination of GGT and FPG offers a simple and sensitive tool to identify subjects at high risk of developing diabetes.

Objective: Objectives of this ancillary analysis of a prospective, prevention study among Asian Indians with impaired glucose tolerance (IGT) were a) to quantify the reduction in incident diabetes at 24 months in participants who achieved normal glucose tolerance (NGT) at 6 months (NGT-6 m) compared with the other participants, b) the factors influencing the reversal to NGT at the end of the study at 24 months (NGT-24 m), and c) to assess changes in cardiometabolic risk factors in different categories of dysglycemia at 24 months., Research Design and Methods: Data from a 2-year primary prevention trial were used. Effect of reversion to NGT-6 m on incidence of type 2 diabetes mellitus (T2DM) was analyzed using the Cox proportional hazards model. Predictive variables for reversal to NGT were identified using multiple logistic regression analysis. Changes in cardiometabolic risk factors were estimated according to the final glycemic status using fixed-effect, mixed-linear regression modeling., Results: The risk of T2DM in 2 years was lower by 75% in NGT-6 m group (hazard ratio 0.25 [95% CI 0.12-0.52]). Predictive variables for reversal to NGT-24 m were good baseline β-cell function (odds ratio [OR] 2.79 [95% CI 2.30-3.40]) and its further improvement (OR 5.70 [95% CI 4.58-7.08]), and NGT-6 m (OR 2.10 [95% CI 1.14-3.83]). BMI decreased in those who reverted to NGT. Deterioration to T2DM was associated with an increase in the levels of cardiometabolic risk factors., Conclusions: Early reversion to NGT by lifestyle intervention in prediabetic men was associated with a significant reduction in subsequent incidence of diabetes. Good baseline β-cell function and its further improvement and NGT-6 m were associated with reversion to NGT-24 months. Reversion to NGT was associated with modest improvements, whereas conversion to T2DM was associated with significant worsening of the cardiometabolic risk profile., (© 2014 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.)

Toll-like receptors (TLRs) play a central role in the recognition and response to microbial pathogens and in the maintenance and function of the epithelial barrier integrity in the gut. The protein MyD88 adaptor-like (Mal/TIRAP) serves as a bridge between TLR2/TLR4- and MyD88-mediated signaling to orchestrate downstream inflammatory responses. Whereas MyD88 has an essential function in the maintenance of intestinal homeostasis, a role for Mal in this context is less well described. Colitis was induced in wild-type (WT) and Mal-deficient (Mal(-/-)) mice by administration of dextran sodium sulfate (DSS). Colitis-associated cancer was induced by DSS and azoxymethane (AOM) treatment. Chimeric mice were generated by total body gamma irradiation followed by transplantation of bone marrow cells. In the DSS model of colon epithelial injury, Mal(-/-) mice developed increased inflammation and severity of colitis relative to WT mice. Mal(-/-) mice demonstrated the presence of inflammatory cell infiltrates, increased crypt proliferation, and presence of neoformations. Furthermore, in the AOM/DSS model, Mal(-/-) mice had greater incidence of tumors. Mal(-/-) and WT bone marrow chimeras demonstrated that nonhematopoietic cell expression of Mal had an important protective role in the control of intestinal inflammation and inflammation-associated cancer. Mal is essential for the maintenance of intestinal homeostasis and expression of Mal in nonhematopoietic cells prevents chronic intestinal inflammation that may predispose to colon neoplasia.

Objective: To study the magnitude of undetected diabetes, impaired glucose tolerance (IGT) and clustering of cardiometabolic risk factors among male industrial workers., Methods: Measurements of 2h post glucose blood glucose (2h PG), blood pressure, body mass index (BMI) and waist circumference (WC) were done in 8741 non-diabetic men of 35-55 years. Presence of family history of diabetes (FH) was noted. Risk associations with diabetes and IGT were studied using multiple logistic regression analysis. Clustering of overweight/obesity, abdominal obesity, hypertension was noted., Results: Prevalence of undetected diabetes (14.9%) and IGT (31.4%) were high. FH, age, hypertension and BMI showed strong associations with diabetes and IGT. More than 40% had clustering of risk factors., Conclusion: High prevalence of undetected diabetes, IGT and clustering of cardiometabolic risk factors among young industrial workers mandates that regular screening for metabolic disorders should be undertaken to prevent development of severe morbidity in the productive years of life.

Background: Type 2 diabetes can often be prevented by lifestyle modification; however, successful lifestyle intervention programmes are labour intensive. Mobile phone messaging is an inexpensive alternative way to deliver educational and motivational advice about lifestyle modification. We aimed to assess whether mobile phone messaging that encouraged lifestyle change could reduce incident type 2 diabetes in Indian Asian men with impaired glucose tolerance., Methods: We did a prospective, parallel-group, randomised controlled trial between Aug 10, 2009, and Nov 30, 2012, at ten sites in southeast India. Working Indian men (aged 35-55 years) with impaired glucose tolerance were randomly assigned (1:1) with a computer-generated randomisation sequence to a mobile phone messaging intervention or standard care (control group). Participants in the intervention group received frequent mobile phone messages compared with controls who received standard lifestyle modification advice at baseline only. Field staff and participants were, by necessity, not masked to study group assignment, but allocation was concealed from laboratory personnel as well as principal and co-investigators. The primary outcome was incidence of type 2 diabetes, analysed by intention to treat. This trial is registered with ClinicalTrials.gov, number NCT00819455., Results: We assessed 8741 participants for eligibility. 537 patients were randomly assigned to either the mobile phone messaging intervention (n=271) or standard care (n=266). The cumulative incidence of type 2 diabetes was lower in those who received mobile phone messages than in controls: 50 (18%) participants in the intervention group developed type 2 diabetes compared with 73 (27%) in the control group (hazard ratio 0·64, 95% CI 0·45-0·92; p=0·015). The number needed to treat to prevent one case of type 2 diabetes was 11 (95% CI 6-55). One patient in the control group died suddenly at the end of the first year. We recorded no other serious adverse events., Interpretation: Mobile phone messaging is an effective and acceptable method to deliver advice and support towards lifestyle modification to prevent type 2 diabetes in men at high risk., Funding: The UK India Education and Research Initiative, the World Diabetes Foundation., (Copyright © 2013 Elsevier Ltd. All rights reserved.)

Aims/hypothesis: We have previously reported a high prevalence of non-alcoholic fatty liver disease (NAFLD) among women with previous gestational diabetes mellitus (pGDM). We wanted to confirm that intrahepatocellular lipid (IHCL) is associated with pGDM independently of adiposity and determine: (1) if VLDL metabolism is dysregulated; and (2) the extent to which NAFLD and IHCL account for the dysmetabolic phenotype in pGDM., Methods: We analysed data from a cohort of 234 women (114 with pGDM) and identified effects of pGDM on lipid and glucoregulation that were independent of ultrasound-diagnosed NAFLD. We then measured IHCL by MR spectroscopy in a representative subgroup (n = 36) and conducted detailed metabolic studies (IVGTT, VLDL apolipoprotein B [apoB] kinetics and palmitate turnover) and measurement of regional body fat by MRI to demonstrate effects of IHCL that were independent of a history of pGDM., Results: pGDM was associated with increased IHCL (p = 0.04) after adjustment for adiposity. Independently of IHCL, pGDM was associated with a lower IVGTT disposition index (p = 0.02) and acute insulin response to glucose (pGDM+/NAFLD-, 50% lower; pGDM+/NAFLD+, 36% lower; effect of pGDM, p = 0.03), increased VLDL apoB pool size (pGDM+/NAFLD-, 3.1-fold higher; pGDM+/NAFLD+, 1.2-fold higher; effect of pGDM, p = 0.02) and, at borderline significance (p = 0.05), increased rate of VLDL apoB synthesis., Conclusions/interpretation: pGDM is associated with increased IHCL independently of adiposity. The increased liver fat contributes to the phenotype, but pGDM status is independently associated with diminished insulin secretion and (shown for the first time) augmented VLDL metabolism. IHCL with pGDM may compound a dysmetabolic phenotype.

Accumulating evidence continues to underpin the role of the innate immune system in pathologies associated with neuroinflammation. Innate immunity is regulated by pattern recognition receptors that detect pathogens, and in the case of Gram-positive bacteria, binding of bacterial lipopeptides to toll-like receptor (TLR)2 is emerging as an important mechanism controlling glial cell activation. In the present study, we employed the use of the synthetic bacterial lipoprotein and a selective TLR2 agonist, Pam3CSK4, to induce inflammatory signaling in microglia and astrocytes. The adaptor proteins, downstream of kinase (Dok)1 and Dok2, are known to have a role in negatively regulating the Ras-ERK signaling cascade, with downstream consequences on pro-inflammatory cytokine expression. Data presented herein demonstrate that TLR2 enhanced the tyrosine phosphorylation of Dok1 and Dok2 in astrocytes and microglia, and that knockdown of these adaptors using small interfering RNA robustly elevated TLR2-induced ERK activation. Importantly, TLR2-induced NF-κB activation, and IL-6 production was exacerbated in astrocytes transfected with Dok1 and Dok2 siRNA, indicating that both Dok proteins negatively regulate TLR2-induced inflammatory signaling in astrocytes. In contrast, Dok1 knockdown attenuated TLR2-induced NF-κB activation and IL-6 production in microglia, while Dok2 siRNA failed to affect TLR2-induced NF-κB activity and subsequent cytokine expression in this cell type. Overall, this indicates that Dok1 and Dok2 are novel adaptors for TLR2 in glial cells and importantly indicates that Dok1 and Dok2 differentially regulate TLR2-induced pro-inflammatory signaling in astrocytes and microglia., (Copyright © 2013 Elsevier Inc. All rights reserved.)

Most stroke survivors exhibit a partial recovery from their deficits. This presumably occurs because of remapping of lost capabilities to functionally related brain areas. Functional brain imaging studies suggest that remapping in the contralateral uninjured cortex might represent a transient stage of compensatory plasticity. Some postmortem studies have also shown that cortical lesions, including stroke, can trigger dendritic plasticity in the contralateral hemisphere, but the data are controversial. We used longitudinal in vivo two-photon microscopy in the contralateral homotopic cortex to record changes in dendritic spines of layer 5 pyramidal neurons in green fluorescent protein mice. We could not detect de novo growth of dendrites or changes in the density or turnover of spines for up to 4 weeks after stroke. We also used intrinsic optical signal imaging to investigate whether the forepaw (FP) sensory representation is remapped to the spared homotopic cortex after stroke. Stimulation of the contralateral FP reliably produced strong intrinsic signals in the spared hemisphere, but we could never detect a signal with ipsilateral FP stimulation after stroke. This lack of contralateral plasticity at the level of apical dendrites of layer 5 pyramidal neurons and FP sensory maps suggests that the contralesional cortex may not contribute to functional recovery after stroke and that, at least in mice, the peri-infarct cortex plays the dominant role in postischemic plasticity.

Background: Lipid desaturase enzymes mediate the metabolism of fatty acids to long chain polyunsaturated fatty acids and their activities are related to metabolic risk factors for Type 2 diabetes (T2DM) and coronary heart disease (CHD). There are marked ethnic differences in risks of CHD and T2DM but little is known about ethnic differences in desaturase activities., Methods: Samples from a study of CVD risk in women with previous gestational diabetes were analysed for percentage fatty acids in plasma free fatty acid, triglyceride, cholesterol ester and phospholipid pools for 89 white European, 53 African Caribbean and 56 Asian Indian women. The fatty acid desaturase activities, stearoyl-CoA desaturase (SCD, calculated separately for C16 and C18 fatty acids), delta 6 desaturase (D6D) and delta 5 desaturase (D5D) were estimated from precursor-to-product ratios and their relationships with adiposity, blood pressure, cholesterol, triglycerides, HDL cholesterol and insulin sensitivity explored. Ethnic differences in desaturase activities independent of ethnic variation in risk factor correlates of desaturase activities were then identified., Results: There was significant ethnic variation in age, BMI, waist circumference, blood pressure, serum triglycerides and HDL cholesterol concentrations and insulin resistance. Desaturase activities showed significant correlations, independent of ethnicity, with BMI, waist circumference, triglycerides and HDL cholesterol. Independent of ethnic variation in BMI, waist circumference, triglycerides and HDL cholesterol, SCD-16 activity, calculated from each of the four lipid pools measured, was 18-35 percent higher in white Europeans than in African Caribbeans or Asian Indians (all p < 0.001). Similar, though less consistent differences were apparent for SCD-18 activity. Also independently of risk factor variation, but specifically when calculated from the cholesterol ester and phospholipid, pools, D6D activity was significantly lower in Asian Indians, and D5D activity higher in African Caribbeans., Conclusions: Significant ethnic differences exist in desaturase activities, independently of ethnic variation in other risk factors. These characteristics did not accord with higher risk of T2DM among African Caribbeans and Asian Indians nor with lower risk of CHD among African Caribbeans but did accord with the higher risk of CHD in Asian Indians.

Background: Choice of adiposity measure may be important in the evaluation of relationships between adiposity and risk markers for cardiovascular disease and diabetes., Aim: We explored the strengths of risk marker associations with BMI, a simple measure of adiposity, and with measures provided by skinfold thicknesses and dual energy X-ray absorptiometry (DXA)., Subjects and Methods: We evaluated in three subgroups of white males (n = 156-349), participating in a health screening program, the strengths of relationship between measures of total and regional adiposity and risk markers relating to blood pressure, lipids and lipoproteins, insulin sensitivity, and subclinical inflammation., Results: Independent of age, smoking, alcohol intake, and exercise, the strongest correlations with adiposity measures were seen with serum triglyceride concentrations and indices of insulin sensitivity, with strengths of association showing little difference between BMI and skinfold and DXA measures of total and percent body fat (R = 0.20-0.46, P < 0.01). Significant but weaker associations with adiposity were seen for serum HDL cholesterol and only relatively inconsistent associations with adiposity for total and LDL cholesterol and indices of subclinical inflammation., Conclusions: BMI can account for variation in risk markers in white males as well as more sophisticated measures derived from skinfold thickness measurements or DXA scanning.

Context: Insulin is pivotal in regulating hepatic lipid synthesis, metabolism, and export., Objective: We tested the hypothesis that intrahepatic insulin exposure is an important determinant of intrahepatocellular lipid (IHCL), taking into account regional adiposity and both glucoregulatory and antilipolytic insulin sensitivity., Research Design and Methods: We compared 21 European males with known nonalcoholic fatty liver disease (NAFLD) with 19 healthy male controls. Insulin sensitivity, secretion, and percentage hepatic extraction were derived from iv glucose tolerance test (IVGTT) glucose, insulin, and C-peptide concentrations. Intrahepatic insulin exposure was calculated as percentage hepatic insulin extraction multiplied by basal or IVGTT insulin secretion. IHCL was quantified by proton magnetic resonance spectroscopy. Total and regional adipose tissue was measured using whole body magnetic resonance imaging., Results: Percentage hepatic extraction of newly secreted insulin differed between cases with NAFLD and controls at borderline significance (median, 76 vs. 83%; P = 0.07). Cases had higher intrahepatic insulin exposure than controls, both in the basal (34 vs. 18 pmol; P = 0.0002) and glucose-stimulated states (58 vs. 24 pmol; P = 0.01). IHCL was significantly related to both basal (r(s) = 0.62; P < 0.0001) and IVGTT intrahepatic insulin exposure (r(s) = 0.47; P = 0.002). As predictors of IHCL, both basal and IVGTT intrahepatic insulin exposure were dependent on the waist-to-hip ratio and homeostasis model assessment insulin resistance, but not on magnetic resonance imaging fat measures or IVGTT insulin sensitivity., Conclusions: Men with NAFLD have higher intrahepatic insulin exposure than controls. This correlates with IHCL, but the principal determinants of IHCL were fat distribution and hepatic rather than peripheral insulin resistance.

Introduction: Control algorithms for closed-loop insulin delivery in type 1 diabetes have been mainly based on control engineering or artificial intelligence techniques. These, however, are not based on the physiology of the pancreas but seek to implement engineering solutions to biology. Developments in mathematical models of the β-cell physiology of the pancreas have described the glucose-induced insulin release from pancreatic β cells at a molecular level. This has facilitated development of a new class of bio-inspired glucose control algorithms that replicate the functionality of the biological pancreas. However, technologies for sensing glucose levels and delivering insulin use the subcutaneous route, which is nonphysiological and introduces some challenges. In this article, a novel glucose controller is presented as part of a bio-inspired artificial pancreas., Methods: A mathematical model of β-cell physiology was used as the core of the proposed controller. In order to deal with delays and lack of accuracy introduced by the subcutaneous route, insulin feedback and a gain scheduling strategy were employed. A United States Food and Drug Administration-accepted type 1 diabetes mellitus virtual population was used to validate the presented controller., Results: Premeal and postmeal mean ± standard deviation blood glucose levels for the adult and adolescent populations were well within the target range set for the controller [(70, 180) mg/dl], with a percent time in range of 92.8 ± 7.3% for the adults and 83.5 ± 14% for the adolescents., Conclusions: This article shows for the first time very good glucose control in a virtual population with type 1 diabetes mellitus using a controller based on a subcellular β-cell model., (© 2012 Diabetes Technology Society.)

Insulin resistance-related risk factor clustering (the insulin resistance syndrome or IRS) may be a cardiovascular disease (CVD) risk factor, but a convincing demonstration of this requires a rigorously derived reference measure and a systematic evaluation of measures and indices that derive from that measure. Using established IRS characteristics, factor analysis in 832 white men, generally healthy at baseline, generated a priori an IRS reference measure. An IRS diagnostic was chosen by evaluating CVD mortality risk in percentiles of the reference measure. An IRS clinical index was derived by (1) identification of readily measured, independent predictors of the IRS reference measure by multiple linear regression; (2) assignment to each predictor of a cut point optimal for discrimination of participants diagnosed with IRS; and (3) selection of a combination of the dichotomized predictors that further optimized IRS discrimination. The reference IRS diagnostic was defined by the top 16.7% of the IRS reference measure and predicted CVD mortality in Cox proportional hazards modeling (hazard ratio, 2.7; 95% confidence interval, 1.5-5.2; P = .002). An optimized IRS index was defined by triglycerides of at least 1.6 mmol/L and uric acid of at least 400 μmol/L plus any one of fasting plasma glucose of at least 5.4 mmol/L, diastolic blood pressure of at least 90 mm Hg, or body mass index of at least 27.0 kg/m(2) and predicted CVD mortality (hazard ratio, 2.14 [1.08-4.24]; P = .02). Prediction was independent of hypertension, hypercholesterolemia, and smoking. Conventionally derived glucoregulatory insulin resistance and metabolic syndrome were not predictive. The IRS is an independent risk factor for CVD mortality; and an effective, clinically usable index can be derived from readily measured variables., (Copyright © 2011 Elsevier Inc. All rights reserved.)

Background: Previous studies have identified sub-clinical inflammation as a potential factor in the pathogenesis of cancer and cardiovascular disease (CVD) but the possibility that simple, readily measured indices of sub-clinical inflammation might predict both CVD and cancer has not been tested in the context of a single, prospective analysis., Aim: To evaluate simply measured indices of inflammation as long-term predictors of death from either cancer or CVD., Design: Prospective open cohort study., Methods: A total of 1192 white males received measurements of a range of risk markers including the inflammation indices white blood cell count (WBC), erythrocyte sedimentation rate (ESR) and serum globulin concentrations. Inflammation marker clustering was quantified as a factor-analysis-derived inflammation score and survival time to death from any cancer or CVD was modeled on baseline measures using the Cox proportional hazards model., Results: A total of 1010 participants met inclusion criteria, of whom 94 died of cancer and 67 of CVD. Mean follow-up times among cases and survivors ranged from 18.2-21.9 years. Independently of established risk factors [age, body mass index (BMI), smoking, alcohol and exercise], WBC, ESR and globulin levels were all individually predictive of both cancer (hazard ratio 1.43, P = 0.002; 1.27, P = 0.02; 1.26, P = 0.02, respectively) and CVD mortality (1.29, P = 0.06; 1.43, P = 0.007; 1.50, P = 0.001). The inflammation score predicted both cancer mortality (1.35, P = 0.003) and CVD mortality (1.46, P = 0.002). Risks associated with high inflammation score were equivalent to and independent of smoking cigarettes for cancer or, for CVD, having a serum cholesterol concentration ≥6.2 mmol/l., Conclusions: Simple indices of inflammation predict death from cancer or CVD two decades later as strongly as smoking predicts cancer or cholesterol predicts CVD. Their measurement could contribute to evaluation of both cancer and CVD risk.

Aims/hypothesis: Non-alcoholic fatty liver disease (NAFLD) is common in type 2 diabetes but it is unknown whether NAFLD is prevalent in European women at risk of type 2 diabetes. We studied the prevalence of, and risk factors for, NAFLD in European women with previous gestational diabetes (GDM) at high risk of type 2 diabetes., Methods: A total of 110 women with previous GDM and 113 without previous GDM, with non-diabetic glucose tolerance were recruited retrospectively from antenatal databases. Participants underwent liver ultrasound scan examination, anthropometry and blood sampling for liver function tests and to determine levels of fasting lipids, NEFA and insulin and glucose concentrations in order to derive insulin sensitivity and insulin secretion indices (HOMA%S and HOMA%B, respectively)., Results: There was no significant difference in BMI in women with previous GDM compared with those without previous GDM (28.9 ± 0.6 vs. 27.9 ± 0.6 kg/m(2), respectively; p = 0.12). Women with previous GDM had higher fasting and 2 h glucose concentrations following a 75 g OGTT ([mean ± SEM] fasting glucose 5.3 ± 0.1 vs. 5.1 ± 0.1 mmol/l, p = 0.02; 2 h glucose 6.8 ± 0.2 vs. 5.8 ± 0.3 mmol/l, p = 0.02), dyslipidaemia (LDL-cholesterol 3.3 ± 0.1 vs. 2.8 ± 0.1 mmol/l; HDL-cholesterol [median {interquartile range}] 1.3 [1.2-1.6] vs. 1.8 [1.5-1.9] mmol/l; triacylglycerol 1.3 [0.9-1.6] vs. 1.0 [0.7-1.7] mmol/l, all p ≤ 0.03), higher insulin secretion and lower insulin sensitivity. NAFLD prevalence was greater in women with previous GDM compared with those without previous GDM: 38% (95% CI 28-47%) vs. 17% (95% CI 10-24%), p = 0.001. In multiple logistic regression analysis, lower insulin sensitivity and raised serum alanine transaminase concentrations were associated with NAFLD., Conclusions/interpretation: NAFLD is prevalent in European women with previous GDM. Impaired insulin sensitivity and increased liver transaminase activity are closely associated with NAFLD in these women.

Objective: Increasing plasma glucose levels are associated with increasing risk of vascular disease. We tested the hypothesis that there is a glycaemia-mediated impairment of reverse cholesterol transport (RCT). We studied the influence of plasma glucose on expression and function of a key mediator in RCT, the ATP binding cassette transporter-A1 (ABCA1) and expression of its regulators, liver X receptor-α (LXRα) and peroxisome proliferator-activated receptor-γ (PPARγ)., Methods and Results: Leukocyte ABCA1, LXRα and PPARγ expression was measured by polymerase chain reaction in 63 men with varying degrees of glucose homeostasis. ABCA1 protein concentrations were measured in leukocytes. In a sub-group of 25 men, ABCA1 function was quantified as apolipoprotein-A1-mediated cholesterol efflux from 2-3 week cultured skin fibroblasts. Leukocyte ABCA1 expression correlated negatively with circulating HbA1c and glucose (rho = -0.41, p<0.001; rho = -0.34, p = 0.006 respectively) and was reduced in Type 2 diabetes (T2DM) (p = 0.03). Leukocyte ABCA1 protein was lower in T2DM (p = 0.03) and positively associated with plasma HDL cholesterol (HDL-C) (rho = 0.34, p = 0.02). Apolipoprotein-A1-mediated cholesterol efflux correlated negatively with fasting glucose (rho = -0.50, p = 0.01) and positively with HDL-C (rho = 0.41, p = 0.02). It was reduced in T2DM compared with controls (p = 0.04). These relationships were independent of LXRα and PPARγ expression., Conclusions: ABCA1 expression and protein concentrations in leukocytes, as well as function in cultured skin fibroblasts, are reduced in T2DM. ABCA1 protein concentration and function are associated with HDL-C levels. These findings indicate a glycaemia-related, persistent disruption of a key component of RCT.

Changes in dendritic spine turnover are a major mechanism of experience-dependent plasticity in the adult neocortex. Dendritic spine plasticity may also contribute to functional recovery after stroke, but in that setting its expression may be complicated by alterations in local tissue perfusion, especially around the infarct. Using adult Thy-1 GFP-M mice, we simultaneously recorded long-term spine dynamics in apical dendrites from layer 5 pyramidal cells and blood flow from surrounding capillaries with in vivo two-photon microscopy in peri-infarct cortex before and after unilateral middle cerebral artery occlusion. Blood flow in peri-infarct cortex decreased significantly immediately after stroke and improved gradually over time, in a distance-dependent manner from the epicenter of the infarct. However, local tissue perfusion was never fully restored even after a 3 month recovery period. On average, surviving layer 5 pyramidal neurons experienced a ∼20% decrease in spine density acutely after stroke but eventually recovered. The dynamics of this improvement were different depending on the degree of tissue perfusion acutely after arterial occlusion. Cells in ischemic areas closer to the infarct returned to normal spine density levels slowly by retaining spines, while cells in more remote regions with preserved blood flow recovered faster by adding more spines, eventually surpassing baseline spine density by 15%. Our data suggest that maintaining tissue perfusion in the area surrounding the infarct could hasten or augment synaptic plasticity and functional recovery after stroke.

Objectives: Risk of cancer is increased in conditions associated with insulin resistance, but this could be secondary to subclinical inflammation. We evaluated whether insulinemia, indices of insulin resistance or a validated insulin resistance-related biomarker cluster, could predict cancer mortality independently of subclinical inflammation., Methods: Fasting insulin and glucose concentrations and insulin-related metabolic variables were recorded in 1,016 white males, of whom 718 also had an oral glucose tolerance test (OGTT). Baseline measurements included the following: fasting insulin and the derived insulin resistance index, HOMA-IR; OGTT insulin and the derived insulin resistance index, Matsuda-IS; the factor score for a validated insulin resistance-related biomarker cluster; white blood cell count; erythrocyte sedimentation rate; and serum albumin and globulin concentrations., Results: There were 105 deaths from cancer during the 21.5-year mean follow-up. Insulin concentrations and insulin resistance were not predictive. Insulin resistance-related biomarker clustering predicted cancer mortality (hazard ratio 1.65, 95% CI 1.26-2.17, p < 0.001). Subclinical inflammation markers were also predictive, but the insulin resistance-related biomarker cluster predicted cancer mortality independently of these and was particularly associated with death from colorectal cancer., Conclusions: Despite insulin concentrations or derived indices of insulin resistance failing to predict cancer mortality, insulin resistance-related biomarker clustering was highly predictive and predicted independently of simple measures of subclinical inflammation.

Aim: The increasing prevalence of fatty liver disease requires routine assessment methods. Proton magnetic resonance spectroscopy ((1)H MRS) is increasingly used for steatosis measurement, but due to cost, is unlikely to become a widely-used screening tool. Ultrasound is cheaper and more widely available, although subject to observer variability. Our aim was to determine the sensitivity and specificity of ultrasound against (1)H MRS, using MRS as a gold standard, for the detection and quantification of hepatic fat content., Methods: Fifty adults participated (43 men, seven women) in this study. Hepatic steatosis was assessed by ultrasound and (1)H MRS. Images were graded by two independent radiologists to classify severity and distribution of liver fat., Results: Ultrasound detected liver fat infiltration in 82% of cases measurable by (1)H MRS, while liver fat was detectable in 44% of cases graded absent by ultrasound. Ultrasound grading was subjective, with the radiologists in agreement in 53% of cases (kappa = 0.39, P = 0.002). Considerable overlap in intrahepatocellular lipid content was observed between different grades: absent (0.0-1.58%), mild (2.2-16.2%), moderate (4.9-26.7%) and severe (8.1-76.8%) steatosis. Ultrasound could not detect liver fat levels below 2% as measured by (1)H MRS Conclusion: Ultrasound is less sensitive than (1)H MRS in detecting very low levels of liver fat content, but is sensitive to fatty infiltration greater than 2%. There is a tendency of higher ultrasound grades to correlate with higher degrees of fatty infiltration, although some overlap exists. Our findings are still consistent with ultrasound being useful as a low cost screening tool.

Objectives: To analyze whether a decreased sensitivity to adrenaline in women with earlier gestational diabetes (GDM) explains the impairment in the thermogenic response to food (=post-prandial thermogenesis (PPT)) that is observed in these women at future risk of obesity and type II diabetes., Subjects/methods: Ten normal-weight women with previous GDM and 10 controls matched for body weight, all with normal glucose tolerance, had insulin sensitivity, PPT and the thermogenic response to an adrenaline infusion measured., Results: Insulin sensitivity was similar in the previous GDM compared with control groups: (mean+/-s.e.m.) 29.1+/-3.2 vs 30.9+/-1.6 mg/l/min. The early (0-30 min) PPT response was diminished and delayed in women with previous GDM compared with controls: (10+/-2 vs 15+/-1 kJ, P=0.04); time constant for PPT (median (interquartile range)) (57 (47-79) vs 29 (25-49) min, P=0.01). The overall PPT response and the thermogenic response to adrenaline were not significantly different between the groups. The 30 min and 2 h PPT response correlated positively and significantly with the increment in energy expenditure as a result of the adrenaline infusion (rho=+0.65; P=0.04 and rho=+0.71; P=0.02, respectively) in women with previous GDM only. There was no correlation between adrenaline and insulin sensitivity., Conclusions: There is no evidence of diminished adrenaline sensitivity but a positive relationship exists between PPT and sensitivity to adrenaline in women with previous GDM. The mechanism is not mediated through insulin resistance. This relationship may predispose these normal-weight at-risk women to future weight gain.

Background: There is recent evidence suggesting that rosiglitazone increases death from cardiovascular causes. We investigated the direct effect of this drug on atheroma using 3D carotid cardiovascular magnetic resonance., Results: A randomized, placebo-controlled, double-blind study was performed to evaluate the effect of rosiglitazone treatment on carotid atherosclerosis in subjects with type 2 diabetes and coexisting vascular disease or hypertension. The primary endpoint of the study was the change from baseline to 52 weeks of carotid arterial wall volume, reflecting plaque burden, as measured by carotid cardiovascular magnetic resonance. Rosiglitazone or placebo was allocated to 28 and 29 patients respectively. Patients were managed to have equivalent glycemic control over the study period, but in fact the rosiglitazone group lowered their HbA1c by 0.88% relative to placebo (P < 0.001). Most patients received a statin or fibrate as lipid control medication (rosiglitazone 78%, controls 83%). Data are presented as mean +/- SD. At baseline, the carotid arterial wall volume in the placebo group was 1146 +/- 550 mm3 and in the rosiglitazone group was 1354 +/- 532 mm3. After 52 weeks, the respective volumes were 1134 +/- 523 mm3 and 1348 +/- 531 mm3. These changes (-12.1 mm3 and -5.7 mm3 in the placebo and rosiglitazone groups, respectively) were not statistically significant between groups (P = 0.57)., Conclusion: Treatment with rosiglitazone over 1 year had no effect on progression of carotid atheroma in patients with type 2 diabetes mellitus compared to placebo.

Glucose monitoring technology has been used in the management of diabetes for three decades. Traditional devices use enzymatic methods to measure glucose concentration and provide point sample information. More recently continuous glucose monitoring devices have become available providing more detailed data on glucose excursions. In future applications the continuous glucose sensor may become a critical component of the closed loop insulin delivery system and, as such, must be selective, rapid, predictable and acceptable for continuous patient use. Many potential sensing modalities are being pursued including optical and transdermal techniques. This review aims to summarize existing technology, the methods for assessing glucose sensing devices and provide an overview of emergent sensing modalities.

Clustering of risk factors for coronary heart disease and diabetes is well established, particularly in relation to insulin resistance. To determine whether evaluation of risk factor clustering will contribute to risk assessment, it is first necessary to discriminate co-association between risk factors from correlation. We undertook this in a large homogenous group, using a sophisticated measure of insulin sensitivity and a broad range of risk factors. Cross-sectional analysis of an occupational cohort using regression and factor analyses was performed. Subjects were 472 apparently healthy white men. The main outcome measures were insulin sensitivity, S(I), by minimal model analysis of the intravenous glucose tolerance test plus liver function and hematologic variables, including the inflammation indices, leukocyte count, and erythrocyte sedimentation rate. The S(I) correlated independently with serum gamma-glutamyl transferase (GGT), aspartate transaminase, and alkaline phosphatase activities; blood pressure; leukocyte count; and erythrocyte sedimentation rate (P < .01). On factor analysis, the factor that explained the greatest proportion of the variance (56.7%) included, in decreasing order of factor loading, triglycerides, S(I) (negative), body mass index, high-density lipoprotein cholesterol (negative), insulin, uric acid, and GGT activity (loadings >0.40). Mean arterial pressure was not a feature (loading 0.29), neither were indices of subclinical inflammation. In apparently healthy men, blood pressure and indices of subclinical inflammation do not cluster with other insulin resistance-related risk factors, despite correlating with insulin sensitivity. In contrast, both GGT activity and uric acid concentrations correlated with insulin sensitivity and co-associated with insulin resistance-related risk factors and are therefore components of a true risk factor cluster.

The pro- and antiatherogenic roles of apolipoproteins B and A-I, respectively, are well-established although the importance of apolipoprotein A-II remains unclear. There is extensive evidence for the involvement of plasma lipoproteins in haemostatic function. However, in-vivo studies of relationships between haemostatic variables and apolipoprotein concentrations are very limited. Plasma fibrinogen, factors VIIc and Xc (FVIIc and FXc, respectively), apolipoproteins (apo) A-I, A-II and B, triglycerides, total, low-density and high-density lipoprotein (HDL) cholesterol, and cholesterol in HDL subfractions 2 and 3 were measured in 186 apparently healthy Caucasian men (aged 26-78 years; body mass index 19.9-37.8 kg/m(2)). Associations between haemostatic, apolipoprotein, lipid and lipoprotein variables were explored in uni- and multivariable analyses. Fibrinogen did not correlate with any of the lipid-related variables. FVIIc and FXc were significant positive univariate correlates of total cholesterol (correlation coefficients 0.26, p<0.001 and 0.19, p<0.05, respectively) triglycerides (0.37, p<0.001 and 0.36, p<0.001), and apoB (0.21, p<0.01 and 0.17, p<0.05) and apoA-II (0.19, p<0.05 and 0.29, p<0.001). HDL(2) subfraction cholesterol correlated negatively with FVIIc and FXc (-0.20, p<0.01 and -0.22, p<0.01, respectively). In multivariable analysis, only the associations of FVIIc and FXc with total cholesterol, triglycerides and apoA-II remained statistically significant. In conclusion, total cholesterol and triglycerides were the major independent lipid correlates of FVIIc and FXc. The independent and positive associations of apoA-II with FVIIc and FXc suggest a prothrombotic involvement for this apolipoprotein.

Hepatic steatosis affects 20% to 30% of the general adult population in the western world. Currently, the technique of choice for determining hepatic fat deposition and the stage of fibrosis is liver biopsy. However, it is an invasive procedure and its use is limited, particularly in children. It may also be subject to sampling error. Non-invasive techniques such as ultrasound, computerised tomography (CT), magnetic resonance imaging (MRI) and proton magnetic resonance spectroscopy ((1)H MRS) can detect hepatic steatosis, but currently cannot distinguish between simple steatosis and steatohepatitis, or stage the degree of fibrosis accurately. Ultrasound is widely used to detect hepatic steatosis, but its sensitivity is reduced in the morbidly obese and also in those with small amounts of fatty infiltration. It has been used to grade hepatic fat content, but this is subjective. CT can detect hepatic steatosis, but exposes subjects to ionising radiation, thus limiting its use in longitudinal studies and in children. Recently, magnetic resonance (MR) techniques using chemical shift imaging have provided a quantitative assessment of the degree of hepatic fatty infiltration, which correlates well with liver biopsy results in the same patients. Similarly, in vivo (1)H MRS is a fast, safe, non-invasive method for the quantification of intrahepatocellular lipid (IHCL) levels. Both techniques will be useful tools in future longitudinal clinical studies, either in examining the natural history of conditions causing hepatic steatosis (e.g. non-alcoholic fatty liver disease), or in testing new treatments for these conditions.

Objective: To determine the clinical effect of dietary supplementation with low-dose omega-3-polyunsaturated fatty acids on disease activity and endothelial function in patients with systemic lupus erythematosus., Methods: A 24-week randomised double-blind placebo-controlled parallel trial of the effect of 3 g of omega-3-polyunsaturated fatty acids on 60 patients with systemic lupus erythematosus was performed. Serial measurements of disease activity using the revised Systemic Lupus Activity Measure (SLAM-R) and British Isles Lupus Assessment Group index of disease activity for systemic lupus erythematosus (BILAG), endothelial function using flow-mediated dilation (FMD) of the brachial artery, oxidative stress using platelet 8-isoprostanes and analysis of platelet membrane fatty acids were taken at baseline, 12 and 24 weeks., Results: In the fish oil group there was a significant improvement at 24 weeks in SLAM-R (from 9.4 (SD 3.0) to 6.3 (2.5), p<0.001); in BILAG (from 13.6 (6.0) to 6.7 (3.8), p<0.001); in FMD (from 3.0% (-0.5 to 8.2) to 8.9% (1.3 to 16.9), p<0.001) and in platelet 8-isoprostanes (from 177 pg/mg protein (23-387) to 90 pg/mg protein (32-182), p = 0.007)., Conclusions: Low-dose dietary supplementation with omega-3 fish oils in systemic lupus erythematosus not only has a therapeutic effect on disease activity but also improves endothelial function and reduces oxidative stress and may therefore confer cardiovascular benefits.

Separation of lipoproteins by traditional sequential salt density floatation is a prolonged process ( approximately 72 h) with variable recovery, whereas iodixanol-based, self-generating density gradients provide a rapid ( approximately 4 h) alternative. A novel, three-layered iodixanol gradient was evaluated for its ability to separate lipoprotein fractions in 63 subjects with varying degrees of dyslipidemia. Lipoprotein cholesterol, triglycerides, and apolipoproteins were measured in 21 successive iodixanol density fractions. Iodixanol fractionation was compared with sequential floatation ultracentrifugation. Iodixanol gradient formation showed a coefficient of variation of 0.29% and total lipid recovery from the gradient of 95.4% for cholesterol and 84.7% for triglyceride. Recoveries for VLDL-, LDL-, and HDL-cholesterol, triglycerides, and apolipoproteins were approximately 10% higher with iodixanol compared with sequential floatation. The iodixanol gradient effectively discriminated classic lipoproteins and their subfractions, and there was evidence for improved resolution of lipoproteins with the iodixanol gradient. LDL particles subfractionated by the gradient showed good correlation between density and particle size with small, dense LDL (<25.5 nm) separated in fractions with density >1.028 g/dl. The new iodixanol density gradient enabled rapid separation with improved resolution and recovery of all lipoproteins and their subfractions, providing important information with regard to LDL phenotype from a single centrifugation step with minimal in-vitro modification of lipoproteins.

Introduction: The purpose of this study was to examine the normal pituitary gland in male subjects with ultrashort echo time (TE) pulse sequences, describe its appearance and measure its signal intensity before and after contrast enhancement., Methods: Eleven male volunteers (mean age 57.1 years; range 36-81 years) were examined with a fat-suppressed ultrashort TE (=0.08 ms) pulse sequence. The studies were repeated after the administration of intravenous gadodiamide. The MR scans were examined for gland morphology and signal intensity before and after enhancement. Endocrinological evaluation included baseline pituitary function tests and a glucagon stimulatory test to assess pituitary cortisol and growth hormone reserve., Results: High signal intensity was observed in the anterior pituitary relative to the brain in nine of the 11 subjects. These regions involved the whole of the anterior pituitary in three subjects, were localised to one side in two examples and were seen inferiorly in three subjects. Signal intensities relative to the brain increased with age, with a peak around the sixth or seventh decade and decreasing thereafter. Overall, the pituitary function tests were considered to be within normal limits and did not correlate with pituitary gland signal intensity., Conclusion: The anterior pituitary shows increased signal intensity in normal subjects when examined with T(1)-weighted ultrashort TE pulse sequences. The cause of this increased intensity is unknown, but fibrosis and iron deposition are possible candidates. The variation in signal intensity with age followed the temporal pattern of iron content observed at post mortem. No relationship with endocrine status was observed.

Aims: To determine whether rate of change and variability in risk factors provides insight into the development of impaired fasting glucose (IFG), impaired glucose tolerance (IGT) or Type 2 diabetes (DM)., Methods: In a nested case-control study, repeated risk factor measurements (mean number 4.3, duration 11.4 years) culminated in 59 men developing IFG (n = 37), IGT (n = 14) and/or DM (n = 11). For each case, two control subjects were matched for age and equivalence of follow-up. Rates of change and variability in diabetes risk factors prior to diagnosis were quantified by regression analysis. Changes between penultimate and diagnostic visits were also analysed., Results: The age-related rise in body mass index (BMI) was attenuated prior to IFG compared with control subjects (+0.102 vs. +0.772 kg/m2/decade, P = 0.02). There was also some evidence for this prior to IGT and DM (IGT: -1.530 vs. +0.158 kg/m2/decade, P = 0.09; DM: -1.146 vs. +0.332 kg/m2/decade, non-significant). Prior to onset, IGT cases were distinguished by higher inflammatory marker levels, a decline in insulinogenic index and greater variability in oral glucose tolerance test (OGTT) insulin, and DM cases by lower insulin sensitivity and higher liver enzyme activities. Fasting and OGTT glucose levels changed little during the mean 8.9 years prior to onset of IFG, IGT or DM. The transition to IGT or DM was accompanied by a fall in insulin sensitivity., Conclusions: Except for BMI, change or variability in risk factor levels appears relatively unimportant in the development of clinically elevated glucose levels. Deterioration in glucose levels to IGT or DM occurs as a rapid, incremental increase accompanied by a decline in insulin sensitivity.

Context: By definition, levels of metabolic risk factors predict atherosclerotic vascular disease, but the effects of long-term adverse change and instability remain underresearched., Objective: Our objective was to quantify long-term rates of change and instability in risk factors and relate these measures to clinical atherosclerotic vascular disease outcomes., Design and Setting: We conducted a prospective cohort study with unmatched and age- and follow-up-matched control analyses at a teaching hospital day ward., Participants: Participants included 465 predominantly healthy white males in an occupational cohort who had undergone repeated metabolic risk factor measurements (mean observation period 11.6 yr, range 2-28 yr), 62 of whom developed clinical atherosclerotic vascular disease., Main Outcome Measures: Rate of change and instability in metabolic risk factor levels were quantified in each individual by linear regression with time and evaluated as predictors of atherosclerotic vascular disease and coronary and cerebrovascular disease separately., Results: As expected, baseline and/or mean follow-up measures of established risk factors relating to blood pressure, lipid metabolism, and subclinical inflammation were significant predictors. Predictors independent of baseline and mean follow-up levels, confirmed in matched and unmatched analyses, were 1) for atherosclerotic vascular disease, instability in weight (cases vs. controls: 2.9 vs. +2.5%); 2) for coronary heart disease, instability in body mass index (3.0 vs. +2.3%), a decline (-0.041 vs. -0.011 per decade) and instability (19.1 vs. 14.6%) in the high-density lipoprotein/non-high-density lipoprotein cholesterol ratio, declining erythrocyte sedimentation rate, and increasing uric acid; and 3) for cerebrovascular disease, a decline in insulin sensitivity (-0.394 vs. 0.324 per decade)., Conclusions: Within an individual, long-term change in metabolic risk factors, as well as their absolute levels, can be important in atherosclerotic vascular disease.