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Peroxisome proliferator-activated receptor (PPAR) alpha, a transcription factor of the nuclear receptor superfamily, regulates fatty acid oxidation. We evaluated the association of single nucleotide polymorphisms (SNPs) of the PPAR-alpha gene (PPARA) with the conversion from impaired glucose tolerance to type 2 diabetes in 767 subjects of the STOP-NIDDM trial in order to investigate the effect of acarbose in comparison with placebo on the prevention of diabetes. In the placebo group, the G (162V) allele of rs1800206 increased the risk for diabetes by 1.9-fold (95% CI 1.05-3.58) and was associated with elevated levels of plasma glucose and insulin. The effect of this allele on the risk of diabetes in the placebo group was enhanced by the simultaneous presence of the risk alleles of the PPAR-gamma2, PPAR-gamma coactivator 1alpha, and hepatic nuclear factor 4alpha genes (odds ratios 2.2, 2.5, and 3.4, respectively). In the acarbose group, subjects carrying the minor G allele of rs4253776 and the CC genotype of rs4253778 of PPARA had a 1.7- and 2.7-fold increased risk for diabetes. Our data indicate that SNPs of PPARA increase the risk of type 2 diabetes alone and in combination with the SNPs of other genes acting closely with PPAR-alpha. [ABSTRACT FROM AUTHOR]

AIMS: To develop a risk-score model, based on available clinical data to assess absolute risk of type 2 diabetes among people with impaired glucose tolerance (IGT). METHODS: Data from the study to prevent non-insulin dependent diabetes mellitus (STOP-NIDDM) investigating acarbose treatment in individuals with IGT were used to develop multivariable Cox proportional hazards model for the time to onset of diabetes. The final model equation was externally validated using data from the Finnish Cardiovascular Risk Factor (FINRISK) population. RESULTS: The risk-score model included the variables acarbose treatment, gender, serum triglyceride level, waist circumference, fasting plasma glucose, height, history of cardiovascular disease (CVD) and hypertension. The final model yielded an area under the receiver-operating-characteristic curve (AUC(ROC)) of 0.64 when applied to people with IGT in the STOP-NIDDM, and 0.84 and 0.90 when applied to FINRISK population with IGT alone and IGT and normal glucose tolerance combined, respectively; AUC(ROC) is a measure of the discriminatory power of the model (1, perfect discrimination). CONCLUSIONS: The STOP-NIDDM risk-score is a simple and validated tool that can identify high-risk individuals with IGT who would benefit most from type 2 diabetes or CVD prevention strategies, such as lifestyle management or early acarbose treatment. [ABSTRACT FROM AUTHOR]

Glomerular endothelial cell (GEC) dysfunction occurs in diabetic kidney disease (DKD) and generally precedes albuminuria. We recently reported that hedgehog interacting protein (Hhip), highly expressed in GECs, contributes to DKD development in diabetic mice. Here, we hypothesized that urinary Hhip (uHhip) could identify early DKD; we tested uHhip in mice and humans with diabetes (DM). In both type 1 (Akita) and type 2 (db/db) DM mice, uHhip is elevated prior to the development of albuminuria, while non-DM controls excrete minimal amount of uHhip. In 87 type 2 DM patients and 39 healthy controls, the uHhip/creatinine (Cr) ratio provides a significant discrimination between non-DM and DM groups; 0 [0-69.5] in non-DM, 9.9 [1.7-39.5] in normoalbuminuric DM, 167.7 [95.7-558.7] in microalbuminuric DM, and 207.9 [0-957.2] in macroalbuminuric DM (median [IQR] ng/mmol, P < 0.0001). The log-uHhip/Cr is positively correlated with urine albumin/Cr ratio (UACR) (spearman correlation coefficient 0.47, P < 0.0001). The log-uHhip/Cr is also associated with eGFR, pulse pressure, and urinary cytokines (IL-1β, IL-6, IL-8, and TGFβ1) independent of UACR. By immunostaining, Hhip is localized in glomeruli and tubules, and is increased in human DM kidneys compared with non-DM kidneys. TGFβ1 shares the similar staining pattern as Hhip in human DM kidneys. Thus, uHhip appears to be a novel indicator of diabetic GEC injury and is elevated in early DKD before the development of microalbuminuria in mice and humans. Clinical value for detecting early DKD warrants further investigation., (Copyright © 2019 Elsevier Inc. All rights reserved.)

We conducted a comprehensive in vivo study evaluating the influence of type 2 diabetes (T2D) on major cytochrome P450 (CYP450) activities. These activities were assessed in 38 T2D and 35 non-T2D subjects after a single oral administration of a cocktail of probe drugs: 100 mg caffeine (CYP1A2), 100 mg bupropion (CYP2B6), 250 mg tolbutamide (CYP2C9), 20 mg omeprazole (CYP2C19), 30 mg dextromethorphan (CYP2D6), 2 mg midazolam (CYP3As), and 250 mg chlorzoxazone (alone; CYP2E1). Mean metabolic activity for CYP2C19, CYP2B6, and CYP3A was decreased in subjects with T2D by about 46%, 45%, and 38% (P < 0.01), respectively. CYP1A2 and CYP2C9 activities seemed slightly increased in subjects with diabetes, and no difference was observed for CYP2D6 or CYP2E1 activities. Several covariables, such as inflammatory markers (interleukin (IL)-1ß, IL-6, gamma interferon, and tumor necrosis factor alpha), genotypes, and diabetes-related and demographic-related factors were considered in our analyses. Our results indicate that low chronic inflammatory status associated with T2D modulates CYP450 activities in an isoform-specific manner., (© 2019 The Authors Clinical Pharmacology & Therapeutics © 2019 American Society for Clinical Pharmacology and Therapeutics.)

The relevance of endogenous 4β-hydroxycholesterol (4β-OHC) plasma concentrations or of the 4β-OHC/total cholesterol concentration ratio (4β-OHC ratio) as surrogate markers of cytochrome P450 3A (CYP3A) activity was evaluated in individuals with (n = 38) or without (n = 35) type 2 diabetes (T2D). Midazolam was used as a comparator to validate exploratory measures of phenotypic CYP3A activity. Metabolic ratios of orally administered midazolam in nondiabetic and diabetic populations correlated significantly with 4β-OHC (r s  = 0.64 and 0.48; P ≤ 0.003) and 4β-OHC ratio (r s  = 0.69 and 0.46; P ≤ 0.003), respectively. Activity of CYP3A was lower in the T2D population compared with nondiabetic subjects; this decrease was reflected in 4β-OHC concentrations (24.33 vs. 12.58 ng/mL; P < 0.0001) and 4β-OHC ratio (0.13 vs. 0.09 (× 10 4 ); P < 0.0002). These results suggest that 4β-OHC should be considered as a valid, convenient, and easy to use endogenous biomarker of CYP3A activity in patients., (© 2019 The Authors Clinical Pharmacology & Therapeutics © 2019 American Society for Clinical Pharmacology and Therapeutics.)

We investigated whether renal hedgehog interacting protein (Hhip) expression contributes to the progression of diabetic nephropathy (DN) and studied its related mechanism(s) in vivo and in vitro. Here, we show that Hhip expression is highly elevated in glomerular endothelial cells of adult type 1 diabetic (T1D) Akita and T2D db/db mouse kidneys as compared to non-diabetic control littermates. Hyperglycemia enhances reactive oxygen species (ROS) generation via NADPH oxidase 4 (Nox4) activation and stimulates renal Hhip gene expression, and that elevated renal Hhip gene expression subsequently activates the TGFβ1- Smad2/3 cascade and promotes endothelial to mesenchymal transition associated with endothelial cell fibrosis/apoptosis in vivo and in vitro. Furthermore, kidneys of low-dose streptozotocin-induced diabetic heterozygous Hhip deficient (Hhip +/- ) mice displayed a normal albumin/creatinine ratio with fewer features of DN (glomerulosclerosis/fibrosis and podocyte apoptosis/loss) and less evidence of renal compensation (glomerular hypertrophy and hyperfiltration) as compared to diabetic wild type controls (Hhip +/+ ). Thus, our studies demonstrated that renal Hhip expression is associated with nephropathy development in diabetes and that hyperglycemia-induced renal Hhip expression may mediate glomerular endothelial fibrosis and apoptosis in diabetes, a novel finding.

Introduction: Diabetes affects more than 9% of the adult population worldwide. Patients with type 2 diabetes mellitus (T2DM) show variable responses to some drugs which may be due, in part, to variability in the functional activity of drug-metabolising enzymes including cytochromes P450 (CYP450s). CYP450 is a superfamily of enzymes responsible for xenobiotic metabolism. Knowledge must be gained on the impact of T2DM and related inflammatory processes on drug metabolism and its consequences on drug response. The aim of this study is to characterise the activity of CYP1A2, CYP2B6, CYP2C9, CYP2C19, CYP2D6, CYP2E1 and CYP3A4/5 in T2DM versus non-T2DM subjects following the administration of a cocktail of probe drug substrates., Methods and Analysis: This single-centre clinical study proposes the first detailed characterisation of T2DM impacts on major CYP450 drug-metabolising enzyme activities. We intend to recruit 42 patients with controlled T2DM (A1C≤7%), 42 patients with uncontrolled T2DM (A1C>7%) and 42 non-diabetic control subjects. The primary objective is to determine and compare major CYP450 activities in patients with T2DM versus non-diabetic subjects by dosing in plasma and urine probe drug substrates and metabolites following the oral administration of a drug cocktail: caffeine (CYP1A2), bupropion (CYP2B6), tolbutamide (CYP2C9), omeprazole (CYP2C19), dextromethorphan (CYP2D6), chlorzoxazone (CYP2E1) and midazolam (CYP3A4/5). Secondary objectives will evaluate the influence of variables such as glycaemia, insulinaemia, genetic polymorphisms and inflammation. The value of an endogenous biomarker of CYP3A activity is also evaluated. The first patient was recruited in May 2015 and patients will be enrolled up to completion of study groups., Ethics and Dissemination: Approval was obtained from the ethic review board of the CHUM research centre (Montreal, Canada)., Trial Registration Number: NCT02291666., Competing Interests: Competing interests: None declared., (© Article author(s) (or their employer(s) unless otherwise stated in the text of the article) 2018. All rights reserved. No commercial use is permitted unless otherwise expressly granted.)

Background: The effect of the α-glucosidase inhibitor acarbose on cardiovascular outcomes in patients with coronary heart disease and impaired glucose tolerance is unknown. We aimed to assess whether acarbose could reduce the frequency of cardiovascular events in Chinese patients with established coronary heart disease and impaired glucose tolerance, and whether the incidence of type 2 diabetes could be reduced., Methods: The Acarbose Cardiovascular Evaluation (ACE) trial was a randomised, double-blind, placebo-controlled, phase 4 trial, with patients recruited from 176 hospital outpatient clinics in China. Chinese patients with coronary heart disease and impaired glucose tolerance were randomly assigned (1:1), in blocks by site, by a centralised computer system to receive oral acarbose (50 mg three times a day) or matched placebo, which was added to standardised cardiovascular secondary prevention therapy. All study staff and patients were masked to treatment group allocation. The primary outcome was a five-point composite of cardiovascular death, non-fatal myocardial infarction, non-fatal stroke, hospital admission for unstable angina, and hospital admission for heart failure, analysed in the intention-to-treat population (all participants randomly assigned to treatment who provided written informed consent). The secondary outcomes were a three-point composite outcome (cardiovascular death, non-fatal myocardial infarction, and non-fatal stroke), death from any cause, cardiovascular death, fatal or non-fatal myocardial infarction, fatal or non-fatal stroke, hospital admission for unstable angina, hospital admission for heart failure, development of diabetes, and development of impaired renal function. The safety population comprised all patients who received at least one dose of study medication. This trial is registered with ClinicalTrials.gov, number NCT00829660, and the International Standard Randomised Controlled Trial Number registry, number ISRCTN91899513., Findings: Between March 20, 2009, and Oct 23, 2015, 6522 patients were randomly assigned and included in the intention-to-treat population, 3272 assigned to acarbose and 3250 to placebo. Patients were followed up for a median of 5·0 years (IQR 3·4-6·0) in both groups. The primary five-point composite outcome occurred in 470 (14%; 3·33 per 100 person-years) of 3272 acarbose group participants and in 479 (15%; 3·41 per 100 person-years) of 3250 placebo group participants (hazard ratio 0·98; 95% CI 0·86-1·11, p=0·73). No significant differences were seen between treatment groups for the secondary three-point composite outcome, death from any cause, cardiovascular death, fatal or non-fatal myocardial infarction, fatal or non-fatal stroke, hospital admission for unstable angina, hospital admission for heart failure, or impaired renal function. Diabetes developed less frequently in the acarbose group (436 [13%] of 3272; 3·17 per 100 person-years) compared with the placebo group (513 [16%] of 3250; 3·84 per 100 person-years; rate ratio 0·82, 95% CI 0·71-0·94, p=0·005). Gastrointestinal disorders were the most common adverse event associated with drug discontinuation or dose changes (215 [7%] of 3263 patients in the acarbose group vs 150 [5%] of 3241 in the placebo group [p=0·0007]; safety population). Numbers of non-cardiovascular deaths (71 [2%] of 3272 vs 56 [2%] of 3250, p=0·19) and cancer deaths (ten [<1%] of 3272 vs 12 [<1%] of 3250, p=0·08) did not differ between groups., Interpretation: In Chinese patients with coronary heart disease and impaired glucose tolerance, acarbose did not reduce the risk of major adverse cardiovascular events, but did reduce the incidence of diabetes., Funding: Bayer AG., (Copyright © 2017 Elsevier Ltd. All rights reserved.)

Objectives: To determine the long-term effects of changing the amount or source of dietary carbohydrate on quality of life (QOL), symptoms and dietary satisfaction in people with type 2 diabetes., Methods: Subjects with diabetes treated by diet alone (n=162) were randomly assigned to high-carbohydrate/high-glycemic-index (HGI) diets; high-carbohydrate/low-glycemic-index (LGI) diets; or lower-carbohydrate/high-monounsaturated-fat (LC) diets for 1 year. We measured QOL at baseline and at study's end, and we measured symptoms and dietary satisfaction quarterly., Results: The HGI, LGI and LC diets contained, respectively, 47±1, 52±1 and 40±1% energy carbohydrate; 30±1, 27±1 and 40±1% fat with GI 64±0.4, 55±0.4 and 59±0.4. Significantly more participants reported increased flatulence on LGI than on LC and HGI diets at 3 months (41%, 19%, 14%; p<0.05), but not at 12 months (29%, 17%, 17%; ns). Abdominal distension was more severe (46% vs. 14%, 19%; p<0.05), and headache less severe (8% vs. 22%, 23%; p<0.05) on LGI than on both other diets. Increased appetite was more severe on LC (33%) than on HGI diets (14%, p<0.05). Joint/limb pains were less severe on LGI (16%) than HGI (28%) diets. LC elicited more severe gloomy thoughts (23%) than LGI (4%; p<0.05) but greater dietary-satisfaction (70%; p<0.05) than LGI (40%) and HGI (48%) diets. For all diets, glycated hemoglobin (A1C) levels increased less in those who gained less weight, had less increased appetite and were more satisfied with the enjoyment obtained from eating., Conclusions: Each diet elicited increased severity of 1 or more symptoms than the other diets. Although overall dietary satisfaction was greater on the 40% carbohydrate diet than on the 50% carbohydrate diet, the LGI diet was no less satisfying than the HGI diet. Changes in appetite and dietary satisfaction may influence body weight and glycemic control, or vice-versa., (Copyright © 2016 Canadian Diabetes Association. Published by Elsevier Inc. All rights reserved.)

Aims/hypothesis: The aim of this study was to assess whether the dual-hormone (insulin and glucagon) artificial pancreas reduces hypoglycaemia compared with the single-hormone (insulin alone) artificial pancreas during two types of exercise., Methods: An open-label randomised crossover study comparing both systems in 17 adults with type 1 diabetes (age, 37.2 ± 13.6 years; HbA 1c, 8.0 ± 1.0% [63.9 ± 10.2 mmol/mol]) during two exercise types on an ergocycle and matched for energy expenditure: continuous (60% [Formula: see text] for 60 min) and interval (2 min alternating periods at 85% and 50% [Formula: see text] for 40 min, with two 10 min periods at 45% [Formula: see text] at the start and end of the session). Blocked randomisation (size of four) with a 1:1:1:1 allocation ratio was computer generated. The artificial pancreas was applied from 15:30 hours until 19:30 hours; exercise was started at 18:00 hours and announced 20 min earlier to the systems. The study was conducted at the Institut de recherches cliniques de Montréal., Results: During single-hormone control compared with dual-hormone control, exercise-induced hypoglycaemia (plasma glucose <3.3 mmol/l with symptoms or <3.0 mmol/l regardless of symptoms) was observed in four (23.5%) vs two (11.8%) interventions (p = 0.5) for continuous exercise and in six (40%) vs one (6.25%) intervention (p = 0.07) for interval exercise. For the pooled analysis (single vs dual hormone), the median (interquartile range) percentage time spent at glucose levels below 4.0 mmol/l was 11% (0.0-46.7%) vs 0% (0-0%; p = 0.0001) and at glucose levels between 4.0 and 10.0 mmol/l was 71.4% (53.2-100%) vs 100% (100-100%; p = 0.003). Higher doses of glucagon were needed during continuous (0.126 ± 0.057 mg) than during interval exercise (0.093 ± 0.068 mg) (p = 0.03), with no reported side-effects in all interventions., Conclusions/interpretation: The dual-hormone artificial pancreas outperformed the single-hormone artificial pancreas in regulating glucose levels during announced exercise in adults with type 1 diabetes., Trial Registration: ClinicalTrials.gov NCT01930110 FUNDING: : Société Francophone du Diabète and Diabète Québec.

Objective: The study's aim was to test prospective associations between information, motivation, and behavioral skills (IMB model) and self-care behaviors (diet, exercise, and blood glucose testing) among patients with type 2 diabetes., Methods: 295 participants were surveyed one (T1), six (T2), and 12 (T3) months after a diabetes course. Cross-lagged panel analyses were performed to test unidirectional and bidirectional relationships between IMB model variables and self-care behaviors., Results: Blood-glucose testing at T1 was positively related to information at T2, which in turn was positively related to blood-glucose testing at T3. Controlled motivation at T1 was positively related to exercise at T2. Autonomous motivation at T2 was positively associated with exercise at T3. There was a positive bidirectional relationship across time between behavioral skills and general diet., Conclusion: Patterns of prospective associations between IMB model variables and diabetes self-care depend on the self-care behavior considered. This model offers an interesting framework for examining how diabetes self-care behaviors evolve., Practice Implications: Diabetes education programs should provide information about current health status and promote experiential learning to help patients realize the impact of their behaviors on glycemic control; should foster autonomous motivation for long-term change; and should build on patients' strengths and skills., (Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.)

Background: Despite technological advances, the accuracy of continuous glucose monitoring (CGM) systems may not always be satisfactory with rapidly changing glucose levels, as is notable during exercise. We compare the performance of two current and widely used CGM systems, Dexcom G4 Platinum (Dexcom) and Medtronic Paradigm Veo Enlite system (Enlite), during both rest and exercise in adults with type 1 diabetes (T1D)., Research Design and Methods: Paired sensor and plasma glucose (PG) values (total of 431 data pairs for Dexcom and 425 for Enlite) were collected from 17 adults (37.3 ± 13.6 years) with T1D. To evaluate and compare the accuracy of sensor readings, criteria involving sensor bias (sensor minus PG levels), absolute relative difference (ARD), and percentage of readings meeting International Organization for Standardization (ISO) criteria were considered., Results: Both Dexcom and Enlite performed equally well during the rest period, with respective mean/median biases of -0.12/-0.02 mmol/L versus -0.18/-0.40 (P = 0.78, P = 0.66) mmol/L and ARDs of 13.77/13.34% versus 12.38/11.95% (P = 0.53, P = 0.70). During exercise, sensor bias means/medians were -0.40/-0.21 mmol versus -0.26/-0.24 mmol/L (P = 0.67, P = 0.62) and ARDs were 22.53/15.13% versus 20.44/14.11% (P = 0.58, P = 0.68) for Dexcom and Enlite, respectively. Both sensors demonstrated significantly lower performance during exercise; median ARD comparison at rest versus exercise for both Dexcom and Enlite showed a P = 0.02. More data pairs met the ISO criteria for Dexcom and Enlite at rest, 73.6% and 76.9% compared with exercise 48.2% and 53.9%., Conclusion: Dexcom and Enlite demonstrated comparable overall performances during rest and physical activity. However, a lower accuracy was observed during exercise for both sensors, necessitating a fine-tuning of their performance with physical activity.

Purpose: Rosuvastatin disposition is modulated by the expression and activity of several membrane transporters including BCRP (ABCG2). The objective of our study was to investigate the effects of pantoprazole, a previously proposed BCRP inhibitor, on the disposition of rosuvastatin., Methods: The impact of pantoprazole (40 mg ID for 2 days) on rosuvastatin pharmacokinetics was evaluated in healthy volunteers (n = 16) who received a single oral dose of rosuvastatin (10 mg) either alone or with pantoprazole. Rosuvastatin, N-desmethylrosuvastatin, and rosuvastatin lactone levels were quantified in plasma while rosuvastatin and N-desmethylrosuvastatin excretion were measured in urine., Results: Ratios and 90 % standard confidence interval of geometric means for C max (1.03 [0.91-1.16]), AUC0-∞ (1.03 [0.89-1.19]) and renal clearance (0.96 [0.85-1.09]) were all within the pre-specified range of 0.8-1.25, indicating a lack of drug-drug interaction between pantoprazole and rosuvastatin., Conclusions: Concomitant administration of pantoprazole with rosuvastatin did not affect rosuvastatin plasma concentrations. The use of pantoprazole as a BCRP inhibitor should be revisited when characterizing BCRP-mediated transport in humans.

Objective: The purpose of this study is to examine the contribution of health behaviors (self-management and coping), quality of care, and individual characteristics (depressive symptoms, self-efficacy, illness representations) as mediators in the relationship between socioeconomic status (SES) and glycemic control., Methods: A sample of 295 adult patients with type 2 diabetes was recruited at the end of a diabetes education course. Glycemic control was evaluated through glycosylated hemoglobin (HbA1c). Living in poverty and education level were used as indicators of SES., Results: Bootstrapping analysis showed that the significant effects of poverty and education level on HbA1c were mediated by avoidance coping and depressive symptoms. The representation that diabetes is unpredictable significantly mediated the relationship between living in poverty and HbA1c, while healthy diet mediated the relationship between education level and HbA1c., Conclusions: To improve glycemic control among patients with low SES, professionals should regularly screen for depression, offering treatment when needed, and pay attention to patients' illness representations and coping strategies for handling stress related to their chronic disease. They should also support patients in improving their self-management skills for a healthy diet.

Aim: To better understand the associations between changes in self-management behaviours and glycaemic control., Methods: We conducted a prospective observational study of 295 adult patients with Type 2 diabetes evaluated at baseline, 6 and 12 months. Four self-management behaviours were evaluated using the Summary of Diabetes Self-Care Activities instrument, which assesses healthy diet, physical activity, medication taking and self-monitoring of blood glucose. Using hierarchical linear regression models, we tested whether changes in self-management behaviours were associated with short-term (6-month) or long-term (12-month) changes in glycaemic control, after controlling for demographic and clinical characteristics., Results: Improved diet was associated with a decrease in HbA1c level, both at 6 and 12 months. Improved medication taking was associated with short-term improvement in glycaemic control, while increased self-monitoring of blood glucose frequency was associated with a 12-month improvement in HbA1c . Completely stopping exercise after being physically active at baseline was associated with a rise in HbA1c level at 6-month follow-up. Interaction analysis indicated that a healthy diet benefitted all participant subgroups, but that medication taking was associated with glycaemic control only for participants living in poverty and more strongly for those with lower educational levels. Finally, a higher self-monitoring of blood glucose frequency was associated with better glycaemic control only in insulin-treated participants., Conclusions: Even after adjusting for potential confounders (including baseline HbA1c ), increased frequency of healthy diet, medication taking and self-monitoring of blood glucose were associated with improved HbA1c levels. These self-management behaviours should be regularly monitored to identify patients at risk of deterioration in glycaemic control. Barriers to optimum self-management should be removed, particularly among socio-economically disadvantaged populations., (© 2015 The Authors. Diabetic Medicine © 2015 Diabetes UK.)

Objective: This study determined the effects of insulin versus liraglutide therapy on liver fat in patients with type 2 diabetes inadequately controlled with oral agents therapy, including metformin., Research Design and Methods: Thirty-five patients with type 2 diabetes inadequately controlled on metformin monotherapy or in combination with other oral antidiabetic medications were randomized to receive insulin glargine or liraglutide therapy for 12 weeks. The liver proton density fat fraction (PDFF) was measured by MRS. The mean liver PDFF, the total liver volume, and the total liver fat index were measured by MRI. The Student t test, the Fisher exact test, and repeated-measures ANOVA were used for statistical analysis., Results: Insulin treatment was associated with a significant improvement in glycated hemoglobin (7.9% to 7.2% [62.5 to 55.2 mmol/mol], P = 0.005), a trend toward a decrease in MRS-PDFF (12.6% to 9.9%, P = 0.06), and a significant decrease in liver mean MRI-PDFF (13.8% to 10.6%, P = 0.005), liver volume (2,010.6 to 1,858.7 mL, P = 0.01), and the total liver fat index (304.4 vs. 209.3 % ⋅ mL, P = 0.01). Liraglutide treatment was also associated with a significant improvement in glycated hemoglobin (7.6% to 6.7% [59.8 to 50.2 mmol/mol], P < 0.001) but did not change MRS-PDFF (P = 0.80), liver mean MRI-PDFF (P = 0.15), liver volume (P = 0.30), or the total liver fat index (P = 0.39)., Conclusions: The administration of insulin glargine therapy reduced the liver fat burden in patients with type 2 diabetes. However, the improvements in the liver fat fraction and glycemia control were not significantly different from those in the liraglutide group., (© 2015 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.)

Oxytocin (OT) is involved in the regulation of energy metabolism and in the activation of cardioprotective mechanisms. We evaluated whether chronic treatment with OT could prevent the metabolic and cardiac abnormalities associated with diabetes and obesity using the db/db mice model. Four-week-old male db/db mice and their lean nondiabetic littermates (db/+) serving as controls were treated with OT (125 ng/kg · h) or saline vehicle for a period of 12 weeks. Compared with db/+ mice, the saline-treated db/db mice developed obesity, hyperglycemia, and hyperinsulinemia. These mice also exhibited a deficient cardiac OT/natriuretic system and developed systolic and diastolic dysfunction resulting from cardiomyocyte hypertrophy, fibrosis, and apoptosis. These abnormalities were associated with increased reactive oxygen species (ROS) production, inflammation, and suppressed 5'-adenosine monophosphate kinase signaling pathway. The db/db mice displayed reduced serum levels of adiponectin and adipsin and elevated resistin. OT treatment increased circulating OT levels, significantly reduced serum resistin, body fat accumulation (19%; P<.001), fasting blood glucose levels by (23%; P<.001), and improved glucose tolerance and insulin sensitivity. OT also normalized cardiac OT receptors, atrial natriuretic peptide, and brain natriuretic peptide, expressions and prevented systolic and diastolic dysfunction as well as cardiomyocyte hypertrophy, fibrosis, and apoptosis. Furthermore, OT reduced cardiac oxidative stress and inflammation and normalized the 5'-adenosine monophosphate-activated protein kinase signaling pathway. The complete normalization of cardiac structure and function by OT treatment in db/db mice contrasted with only partial improvement of hyperglycemia and hyperinsulinemia. These results indicate that chronic treatment with OT partially improves glucose and fat metabolism and reverses abnormal cardiac structural remodeling, preventing cardiac dysfunction in db/db mice.

In hypertensive rodents, retinoic acid (RA) prevents adverse cardiac remodelling and improves myocardial infarction outcome, but its role in obesity-related changes of cardiac tissue are unclear. We hypothesized that all-trans RA (ATRA) treatment will improve the cardioprotective oxytocin-natriuretic peptides (OT-NP) system, preventing apoptosis and collagen accumulation in hearts of ob/ob mice, a mouse model of obesity and insulin resistance. Female 9-week-old B6.V-Lep/J ob/ob mice (n = 16) were divided into 2 groups: 1 group (n = 8) treated with 100 μg of ATRA dissolved in 100 μL of corn oil (vehicle) delivered daily (∼2 μg·g body weight(-1)·day(-1)) by stomach intubation for 16 days, and 1 group (n = 8) that received the vehicle alone. A group of nonobese littermate mice (n = 9) served as controls. Ob/ob mice exhibited obesity, hyperglycaemia, and downregulation of the cardiac OT-NP system, including the mRNA for the transcription factor GATA4, OT receptor and brain NP, and the protein expression for endothelial nitric oxide synthase. Hearts from ob/ob mice also demonstrated increased apoptosis and collagen accumulation. ATRA treatment induced weight loss and decreased adipocytes diameter in the visceral fat, thus reducing visceral obesity, which is associated with a high risk for cardiovascular disease. RA treatment was associated with a reduction in hyperglycemia and a normalization of the OT-NP system's expression in the hearts of ob/ob mice. Furthermore, ATRA treatment prevented apoptosis and collagen accumulation in hearts of ob/ob mice. The present study indicates that ATRA treatment was effective in restoring the cardioprotective OT-NP system and in preventing abnormal cardiac remodelling in the ob/ob mice.

Patients with cardiovascular disease and impaired glucose tolerance are at increased risk of cardiovascular events and type 2 diabetes mellitus (T2DM). Lifestyle modification or pharmacological intervention can delay progression to T2DM, but there is no clear evidence that they reduce cardiovascular risk in this population. Acarbose, an α-glucosidase inhibitor that lowers postprandial blood glucose, has been shown to reduce T2DM risk by 25%, and possibly cardiovascular risk in impaired glucose tolerance subjects without cardiovascular disease., (Copyright © 2014 Mosby, Inc. All rights reserved.)

Objective: Health administrative data are frequently used for diabetes surveillance, but validation studies are limited, and undiagnosed diabetes has not been considered in previous studies. We compared the test properties of an administrative definition with self-reported diabetes and estimated prevalence of undiagnosed diabetes by measuring glucose levels in mailed-in capillary blood samples., Research Design and Methods: A stratified random sample of 6,247 individuals (Quebec province) was surveyed by telephone and asked to mail in fasting blood samples on filter paper to a central laboratory. An administrative definition was applied (two physician claims or one hospitalization for diabetes within a 2-year period) and compared with self-reported diabetes alone and with self-reported diabetes or elevated blood glucose level (≥7 mmol/L). Population-level prevalence was estimated with the use of the administrative definition corrected for its sensitivity and specificity., Results: Compared with self-reported diabetes, sensitivity and specificity were 84.3% (95% CI 79.3-88.5%) and 97.9% (97.4-98.4%), respectively. Compared with diabetes by self-report and/or glucose testing, sensitivity was lower at 58.2% (52.2-64.6%), whereas specificity was similar at 98.7% (98.0-99.3%). Adjusted for sampling weights, population-level prevalence of physician-diagnosed diabetes was 7.2% (6.3-8.0%). Prevalence of total diabetes (physician-diagnosed and undiagnosed) was 13.4% (11.7-15.0%), indicating that ∼40% of diabetes cases are undiagnosed., Conclusions: A substantial proportion of diabetes cases are missed by surveillance methods that use health administrative databases. This finding is concerning because individuals with undiagnosed diabetes are likely to have a delay in treatment and, thus, a higher risk for diabetes-related complications.

Background and Aims: Nutrition recommendations for type 2 diabetes (T2DM) are partly guided by the postprandial responses elicited by diets varying in carbohydrate (CHO). We aimed to explore whether long-term changes in postprandial responses on low-glycemic-index (GI) or low-CHO diets were due to acute or chronic effects in T2DM., Methods and Results: Subjects with diet-alone-treated T2DM were randomly assigned to high-CHO/high-GI (H), high-CHO/low-GI (L), or low-CHO/high-monounsaturated-fat (M) diets for 12-months. At week-0 (Baseline) postprandial responses after H-meals (55% CHO, GI = 61) were measured from 0800 h to 1600 h. After 12 mo subjects were randomly assigned to H-meals or study diet meals (L, 57% CHO, GI = 50; M, 44% CHO, GI = 61). This yielded 5 groups: H diet with H-meals (HH, n = 34); L diet with H- (LH, n = 17) or L-meals (LL, n = 16); and M diet with H- (MH, n = 18) or M meals (MM, n = 19). Postprandial glucose fluctuations were lower in LL than all other groups (p < 0.001). Changes in postprandial-triglycerides differed among groups (p < 0.001). After 12 mo in HH and MM both fasting- and postprandial-triglycerides were similar to Baseline while in MH postprandial-triglycerides were significantly higher than at Baseline (p = 0.028). In LH, triglycerides were consistently (0.18-0.34 mmol/L) higher than Baseline throughout the day, while in LL the difference from Baseline varied across the day from 0.04 to 0.36 mmol/L (p < 0.001)., Conclusion: Low-GI and low-CHO diets have both acute and chronic effects on postprandial glucose and triglycerides in T2DM subjects. Thus, the composition of the acute test-meal and the habitual diet should be considered when interpreting the nutritional implications of different postprandial responses., (Copyright © 2012 Elsevier B.V. All rights reserved.)

Introduction: The efficacy and safety of taspoglutide, a long-acting human glucagon-like peptide-1 analog, were compared with sitagliptin or placebo, as adjunct to metformin, in patients with inadequately controlled type 2 diabetes., Methods: In this randomized, double-blind, double-dummy, parallel-group trial, patients were randomized to taspoglutide 10 mg once weekly (QW), 20 mg QW, 100 mg sitagliptin once daily (QD), or placebo for 24 weeks, followed by 28-week short-term and 104-week long-term extension periods. The primary endpoint was change in glycosylated hemoglobin (HbA(1c)) after 24 weeks., Results: In this study, 666 patients (baseline HbA(1c), 7.96% [SD, 0.87]; fasting plasma glucose, 9.61 mmol/L [2.56]; body weight, 92.4 kg [19.3]) were randomized to taspoglutide 10 mg QW (n = 190), 20 mg QW (n = 198), 100 mg sitagliptin QD (n = 185), or placebo (n = 93) for 24 weeks. After 24 weeks, least squares mean (SE) HbA(1c) reductions were greater with taspoglutide 10 mg (-1.23% [0.06]) and 20 mg (-1.30% [0.06]) versus sitagliptin (-0.89% [0.06]) or placebo (-0.10% [0.08]). Mean treatment differences with taspoglutide 10 mg and 20 mg were -0.34 (95% confidence intervals [CI]: -0.49, -0.19) and -0.41 (-0.56, -0.26) versus sitagliptin; and -1.13 (-1.31, -0.95) and -1.20 (-1.38, -1.02) versus placebo. Weight loss was greater with taspoglutide 10 mg (-1.8 kg [0.3]) and 20 mg (-2.6 kg [0.3]) than sitagliptin (-0.9 kg [0.3]) or placebo (-0.5 kg [0.4]). Effects on HbA(1c) and weight loss continued through 52 weeks of treatment. No cases of severe hypoglycemia occurred with any active treatment. Gastrointestinal adverse events, and allergic and injection-site reactions were higher in the taspoglutide groups, causing higher discontinuation rates. Anti-taspoglutide antibodies were confirmed in 46% of patients., Conclusion: Taspoglutide demonstrated better efficacy on glycemic control and weight loss than sitagliptin, but a high incidence of adverse events led to high discontinuation rates. The safety profile of taspoglutide in this trial was similar to other trials in the clinical program, and led to the discontinuation of dosing.

Aim: Simple estimates of insulin secretion feasible for large epidemiological studies have been proposed in adults, but have been little evaluated in young people. For this reason, this study examined the correlation between OGTT-derived and fasting-based indices of insulin secretion against the acute insulin response to glucose (AIRg) in children., Methods: Twenty subjects (nine boys and 11 girls; mean [SD] age: 9 [2] years) were studied. Their mean (SD) BMI Z score was 1.5 (0.8). All participants had normal fasting and 2-h post-load glucose. Each subject underwent an insulin-modified minimal model frequently sampled intravenous glucose tolerance test (FSIVGTT) as the reference method, and a 3-h OGTT. AIRg was computed from the FSIVGTT. A total of ten indices were calculated using OGTT data, while HOMA%beta (original formula) and HOMA2%beta (computer-based) were computed from fasting samples. Correlations were established using Spearman's rank correlations., Results: Of the ten indices derived from the OGTT, those most closely correlated with the AIRg (using FSIVGTT) included the insulinogenic index(t30)(min) (r = 0.80), insulin/glucose ratio(t30)(min) (r = 0.71) and ratio of the area under the curve for insulin to glucose(t0-30)(min) (r = 0.74). Both the HOMA%beta and HOMA2%beta correlated modestly with AIRg (r = 0.62 and r=0.65, respectively)., Conclusion: Our results suggest that OGTT-derived measures of insulin secretion provide adequate estimates of first-phase insulin secretion in youth. HOMA2%beta and HOMA%beta represent acceptable compromises, although HOMA2%beta may be preferable in younger individuals, as it allows for a wider spectrum of insulin and glucose values that are physiological in this age group., (Copyright © 2012 Elsevier Masson SAS. All rights reserved.)

The concentration of carnitine in plasma is generally increased with exercise training, suggesting that either carnitine biosynthesis is stimulated or renal reabsorption of carnitine is enhanced, or both. Carnitine, an essential cofactor in the oxidation of fatty acids, is released into the plasma following hydroxylation by γ-butyrobetaine hydroxylase (BBH), the final enzyme in the biosynthetic pathway found primarily in the liver. The organic cation transporter (OCTN2), the carnitine transporter found in kidney, is important in the distribution of carnitine by facilitating its renal reabsorption from urine. In this study, we tested the hypothesis that exercise training increases gene and protein expression of BBH and OCTN2, resulting in enhanced plasma carnitine levels. Male Wistar rats were subjected to 2 daily exercise sessions of treadmill running, 5 days per week, for a 10-week period. The concentration of total carnitine in plasma was significantly increased in trained rats compared with sedentary rats. In trained rats, mRNA and protein expression of BBH were increased in liver, whereas only BBH mRNA expression was increased in kidney. Liver of trained rats demonstrated increased mRNA and protein expression of OCTN2 compared with sedentary rats. In kidney of trained rats, however, only an increase in mRNA expression of OCTN2 was observed. Our results suggest that the improved plasma carnitine status in the trained rat is associated with increased carnitine biosynthesis in liver and kidney. The observation that OCTN2 expression was increased in kidney suggests a potential role of the kidney in the reabsorption of carnitine from the urine.

Aims/hypothesis: The Diabetes Reduction Assessment with Ramipril and Rosiglitazone Medication (DREAM) trial reported that 3 years of therapy with rosiglitazone reduced the primary outcome of diabetes or death by 60%. Here we investigated whether an effect on diabetes prevention persists more than 1.5 years after therapy has been discontinued., Methods: The DREAM On passive follow-up study was conducted at 49 of the 191 DREAM sites. Consenting participants were invited to have a repeat OGTT 1-2 years after active therapy ended. A diagnosis of diabetes at that time was based on either a fasting or 2 h plasma glucose level of ≥7.0 mmol/l or ≥11.1 mmol/l, respectively, or a confirmed diagnosis by a non-study physician. Regression to normoglycaemia was defined as a fasting and 2 h plasma glucose level of <6.1 mmol/l and <7.8 mmol/l, respectively., Results: After a median of 1.6 years after the end of the trial and 4.3 years after randomisation, rosiglitazone participants had a 39% lower incidence of the primary outcome (hazard ratio [HR] 0.61, 95% CI 0.53-0.70; p < 0.0001) and 17% more regression to normoglycaemia (95% CI 1.01-1.34; p = 0.034). When the analysis was restricted to the passive follow-up period, a similar incidence of both the primary outcome and regression was observed in people from both treatment groups (HR 1.00, 95% CI 0.81-1.24 and HR 1.14, 95% CI 0.97-1.32, respectively). Similar effects were noted when new diabetes was analysed separately from death. Ramipril did not have any significant long-term effect., Conclusions/interpretation: Time-limited exposure to rosiglitazone reduces the longer term incidence of diabetes by delaying but not reversing the underlying disease process.

Aim: The objective of the study was to examine the correlation between three methods of measuring insulin sensitivity (IS) - namely, the frequently sampled intravenous glucose tolerance test (FSIVGTT), indices derived from the oral glucose tolerance test (OGTT) and fasting indices (HOMA-IR, QUICKI, fasting insulin [INS(0)]) - and the gold-standard method, the hyperinsulinaemic-euglycaemic clamp (HEC) test, in children., Methods: A total of 20 children [nine boys and 11 girls; mean (SD) age: 9 (2) years] were studied. Their mean (SD) BMI Z score was 1.5 (0.8). All participants had normal glucose metabolism. Each child underwent a 3-h HEC (40 mU/m(2)/min of insulin), an insulin-modified minimal-model FSIVGTT and a 3-h OGTT. The clamp-derived IS was calculated, using DeFronzo's metabolized glucose index and Bergman's IS index. Correlations were established using Spearman's rank correlations., Results: The two clamp-derived measures were highly correlated (r=0.85), and the IS measured from the FSIVGTT was well correlated with both clamp measures [r=0.69, 0.74]. Of the nine indices derived from the OGTT, the three with the highest correlation with clamp results were the ISI Matsuda [r=0.63, 0.68], SI(is)OGTT [r=0.53, 0.65] and log sum insulin [r=-0.64, -0.75]. Fasting indices of IS had similar correlations to clamp results: HOMA-IR [r=-0.55, -0.56]; QUICKI [r=0.55, 0.57]; and INS(0) [r=-0.59, -0.63]., Conclusion: While fasting-based indices of IS are a suitable option for large cohorts, OGTT-derived indices may represent a useful compromise for obtaining both clinical (glucose tolerance) and physiological (insulin sensitivity) information, making them particularly useful for large-scale physiological and epidemiological studies., (Copyright © 2010 Elsevier Masson SAS. All rights reserved.)

Background: Cystic fibrosis (CF) patients present a high incidence of glucose tolerance abnormalities. Altered insulin secretion combined with recommended high-fat intake could be associated with dysregulation of glucose and lipid metabolism. We examined postprandial glucose and lipid profiles during an oral glucose tolerance test (OGTT) and following a standardized high-fat test meal (TM)., Methods: Sixteen CF patients with normal glucose tolerance (NGT) or CF-related diabetes (CFRD) and 16 controls underwent a 4 h OGTT and a TM. We then measured plasma glucose, insulin, free fatty acid (FFA) and triglyceride (TG) concentrations., Results: CF patients presented higher glucose excursion compared to controls after the OGTT and TM. However, in CF patients, this excursion was significantly reduced in both amplitude and length after the TM. The TM provoked a comparable increase in TG levels in both groups whereas they remained stable during the OGTT. FFAs were suppressed similarly in both groups after both challenges., Conclusion: CF is associated with abnormal glucose excursion in the presence of relatively normal lipid excursion. The rapid normalization of glucose values after a mixed meal should be further explored and, if confirmed, might have significant implications for CFRD diagnostic.

The STOP-NIDDM trial was an international, double-blind, placebo-controlled randomised study in people with impaired glucose tolerance (IGT). They were treated with an alpha-glucosidase inhibitor, acarbose, to prevent diabetes; the overall number needed to treat (NNT) was 11. In a secondary analysis, we considered the impact of single traits and overall metabolic syndrome (MetS) respectively on risk of diabetes and NNT respectively. In all, there were 1,368 patients. They were followed up for 3.3 years, and the prevalence of MetS was 61%. Multivariate analysis revealed treatment group 2-hour (post-challenge) plasma glucose, glycosylated haemoglobin (HbA1C), triglycerides and leukocyte count as independent predictors. The annual incidence of diabetes in the placebo group with MetS was 18.7% vs. 11.2% in patients without MetS; the corresponding figures in the acarbose group were 13.5% and 9.4%, respectively. The NNT in patients was 5.8 in patients with MetS and 16.5 in those without MetS. In conclusion, most single traits and overall MetS label a very high-risk group in people with IGT. People with MetS reach a NNT to prevent development of new diabetes with acarbose of 5.8.

Aim: Cystic fibrosis-related diabetes (CFRD) prevalence has increased dramatically with the improved life expectancy of patients with cystic fibrosis (CF). Glycated haemoglobin (HbA(1c)) is an important tool for monitoring blood glucose control but, unlike in type 1 and type 2 diabetes, a correlation between HbA(1c), fructosamine and mean plasma glucose has not been clearly established in CF. This study aimed to examine the relationship between mean plasma glucose and HbA(1c) or fructosamine in stable patients with CFRD., Methods: Fifteen type 1 diabetes and 13 CFRD patients (HbA(1c)<9.0%; no anaemia), matched for age and body mass index (BMI), provided 72 capillary blood glucose profiles taken 3days/month for three months. At the end of this time, HbA(1c) and fructosamine were measured. Mean plasma glucose was estimated using the Diabetes Control and Complications Trial (DCCT) conversion formula, and linear regressions carried out to establish its relationship with HbA(1c) and fructosamine., Results: In type 1 diabetes patients, mean plasma glucose correlated significantly with HbA(1c) (r=0.68; P=0.005). In CFRD patients, no correlation was found between mean plasma glucose and HbA(1c) (r=0.24; P=0.460). Also, no association was found between mean plasma glucose, representing the month before blood sampling, and fructosamine in either group., Conclusion: Unlike in type 1 diabetes, HbA(1c) did not correlate with mean plasma glucose in CFRD subjects. Thus, having a normal HbA(1c) may not be sufficient to indicate a low risk of diabetes complications in CFRD. Further studies are required to explain such a discrepancy.

Aims/hypothesis: We recently found that oral glucose tolerance over 1 year in type 2 diabetic patients declined to a significantly lesser degree on a low-glycaemic-index than on a reduced-carbohydrate diet. Here, we examined whether that finding was associated with an improvement in disposition index, an index of beta cell function defined as the product of insulin sensitivity and insulin secretion. Since this is a report of secondary analysis on a previously published trial, the results should be considered as hypothesis-generating., Methods: Type 2 diabetic patients treated by diet alone (n = 162) were randomised by computer to high-carbohydrate/high-glycaemic index (High-GI, n = 52), high-carbohydrate/low-glycaemic index (Low-GI, n = 56) or low-carbohydrate/high-monounsaturated-fat (Low-CHO, n = 54) diets for 1 year in a multi-centre, parallel-design clinical trial conducted at University teaching hospitals. At baseline and at 3, 6 and 12 months participants underwent 75 g OGTTs; 27 participants dropped out or were excluded. Indices of insulin sensitivity, insulin secretion and disposition index, derived from the OGTT, were compared among diets. Those assessing the outcomes were blinded to group assignment., Results: Neither muscle insulin sensitivity index nor insulinogenic index differed significantly among diets. However, a significant time x diet interaction existed for disposition index (muscle insulin sensitivity index x insulinogenic index) (p = 0.036). After 3 months, disposition index tended to be higher on Low-CHO than on Low-GI diets, namely by 0.07 h(-1) (95% CI -0.04, 0.18). However, by 12 months this reversed and disposition index became higher on Low-GI than on Low-CHO, namely by 0.12 h(-1) (0.01, 0.23; p < 0.05, baseline disposition index 0.23 h(-1)). There were no important adverse effects associated with the treatments., Conclusions/interpretation: These results suggest that, in patients with type 2 diabetes on diet alone, a Low-GI diet for 1 year increases disposition index, an index of beta cell function, compared with a Low-CHO diet.

1. Levels of insulin-signalling molecules are altered in streptozotocin (STZ)-induced diabetes, a model of Type 1 diabetes. However, the tissue-specific regulation of these changes and the effect of insulin supplementation on signalling molecule protein levels have not been well characterized. 2. In the present study, we evaluated the level of proximal insulin-signalling intermediates in the heart and in red and white gastrocnemius muscles of 2 week diabetic rats and diabetic rats supplemented with insulin. 3. Diabetes augmented levels of the insulin receptor and the p85 regulatory subunit of phosphatidylinositol 3-kinase in the red gastrocnemius, but not in the white gastrocnemius or the heart. Furthermore, diabetes reduced insulin receptor substrate-1 levels in both the red and white gastrocnemius, but not in the heart. Examination of the levels and basal activities of distal insulin-signalling intermediates (protein kinase B (PKB)/Akt, extracellular signal-regulated kinase (ERK) 1/2, p38 mitogen-activated protein kinase (MAPK)) also failed to reveal a specific pattern in these changes. Thus, diabetes reduced basal ERK1/2 and PKB/Akt phosphorylation in the heart and white gastrocnemius, respectively, whereas it augmented basal p38 MAPK activity in the red gastrocnemius. Insulin supplementation normalized the levels and activities of some but not all proteins. 4. In conclusion, the results of the present study demonstrate that adaptation to STZ-induced diabetes varies among skeletal muscle fibre types and the heart, emphasizing the complex tissue-specific responses to diabetes.

Objective: To measure with ultrasound the increased erythrocyte aggregation (EA) kinetics and adhesion energy between erythrocytes in patients with type 2 diabetes and poor metabolic control., Research Design and Methods: Blood samples were analyzed in a Couette rheometer at 32 MHz following shear rate reductions from 500 s(-1) to residual shears of 0 (stasis), 1, 2, 10, 50, 100, and 200 s(-1). The increase in EA was determined with the integrated backscatter coefficient as a function of time and shear rate., Results: The time required to form aggregates was shorter in diabetic patients at shear rates below 200 s(-1) (P < 0.01). Erythrocytes formed larger aggregates in diabetic patients than in control subjects (P < 0.05 at 2 to 100 s(-1))., Conclusions: Ultrasound can potentially noninvasively demonstrate, in vivo and in situ, the impact of local abnormal EA on arteriovenous flow disorders in diabetes.

Background: The optimal source and amount of dietary carbohydrate for managing type 2 diabetes (T2DM) are unknown., Objective: We aimed to compare the effects of altering the glycemic index or the amount of carbohydrate on glycated hemoglobin (HbA1c), plasma glucose, lipids, and C-reactive protein (CRP) in T2DM patients., Design: Subjects with T2DM managed by diet alone (n=162) were randomly assigned to receive high-carbohydrate, high-glycemic-index (high-GI), high-carbohydrate, low-glycemic-index (low-GI), or low-carbohydrate, high-monounsaturated-fat (low-CHO) diets for 1 y., Results: The high-GI, low-GI, and low-CHO diets contained, respectively, 47%, 52%, and 39% of energy as carbohydrate and 31%, 27%, and 40% of energy as fat; they had GIs of 63, 55, and 59, respectively. Body weight and HbA1c did not differ significantly between diets. Fasting glucose was higher (P=0.041), but 2-h postload glucose was lower (P=0.010) after 12 mo of the low-GI diet. With the low-GI diet, overall mean triacylglycerol was 12% higher and HDL cholesterol 4% lower than with the low-CHO diet (P<0.05), but the difference in the ratio of total to HDL cholesterol disappeared by 6 mo (time x diet interaction, P=0.044). Overall mean CRP with the low-GI diet, 1.95 mg/L, was 30% less than that with the high-GI diet, 2.75 mg/L (P=0.0078); the concentration with the low-CHO diet, 2.35 mg/L, was intermediate., Conclusions: In subjects with T2DM managed by diet alone with optimal glycemic control, long-term HbA1c was not affected by altering the GI or the amount of dietary carbohydrate. Differences in total:HDL cholesterol among diets had disappeared by 6 mo. However, because of sustained reductions in postprandial glucose and CRP, a low-GI diet may be preferred for the dietary management of T2DM.

The growing prevalence of Type 2 diabetes with its high morbidity and excess mortality is imposing a heavy burden on healthcare systems. Because of the magnitude of the problem, obviating diabetes has been a long-standing dream. In the last decade, a number of intervention strategies have been shown to be effective for the prevention of diabetes in high-risk populations with prediabetes. Seven studies have now confirmed that lifestyle modifications, including weight-reducing diets and exercise programs, are very effective in precluding or delaying Type 2 diabetes in high-risk populations with impaired glucose tolerance (IGT). Two major trials are the Diabetes Prevention Study (n = 522) from Finland and the Diabetes Prevention Program (n = 3234) from the US. Both studies have shown that intensive lifestyle intervention could reduce the progression of IGT to diabetes by 58%. Furthermore, four currently-available drugs have been established as being effective in preventing diabetes in subjects with prediabetes. The Diabetes Prevention Program revealed that metformin 850 mg b.i.d. reduced the risk of diabetes by 31%. The STOP-NIDDM (Study To Prevent Non-Insulin-Dependent Diabetes Mellitus) trial (n = 1429) showed that acarbose 100 mg t.i.d. with meals decreased the incidence of diabetes by 36% when the diagnosis was based on 2 oral glucose tolerance tests. The XENDOS (Xenical in the Prevention of Diabetes in Obese Subjects) study examined the use of orlistat, an antiobesity drug, as an adjunct to an intensive lifestyle modification program in obese non-diabetic subjects. Orlistat treatment resulted in a 37% decline in the development of diabetes. More recently, the DREAM (Diabetes Reduction Assessment with Ramipril and Rosiglitazone Medication) study (n = 5269) demonstrated that rosiglitazone at 8 mg once/day in subjects with prediabetes (IGT and/or impaired fasting glucose) was effective in reducing the risk of diabetes by 60%. It can be concluded that Type 2 diabetes can be prevented or delayed through lifestyle modifications and/or pharmacologic interventions. This is a fact.