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Introduction Type 2 diabetes mellitus (T2DM) is a powerful risk factor for cardiovascular disease (CVD), conferring a greater relative risk in women than men. We sought to examine sex differences in cardiometabolic risk factors and management in the contemporary cohort represented by the Glycemia Reduction Approaches in Diabetes: A Comparative Effectiveness Study (GRADE).Research design and methods GRADE enrolled 5047 participants (1837 women, 3210 men) with T2DM on metformin monotherapy at baseline. The current report is a cross-sectional analysis of baseline data collected July 2013 to August 2017.Results Compared with men, women had a higher mean body mass index (BMI), greater prevalence of severe obesity (BMI≥40 kg/m2), higher mean LDL cholesterol, greater prevalence of low HDL cholesterol, and were less likely to receive statin treatment and achieve target LDL, with a generally greater prevalence of these risk factors in younger women. Women with hypertension were equally likely to achieve blood pressure targets as men; however, women were less likely to receive ACE inhibitors or angiotensin receptor blockers. Women were more likely to be divorced, separated or widowed, and had fewer years of education and lower incomes.Conclusions This contemporary cohort demonstrates that women with T2DM continue to have a greater burden of cardiometabolic and socioeconomic risk factors than men, particularly younger women. Attention to these persisting disparities is needed to reduce the burden of CVD in women.Trial registration number ClinicalTrials.gov (NCT01794143)

Objective: We report mortality outcomes in the Glycemia Reduction Approaches in Diabetes: A Comparative Effectiveness Study (GRADE) among people with type 2 diabetes diagnosed within 10 years and no recent history of cardiovascular events or cancer., Research Design and Methods: Overall mortality rates and major causes of death were assessed over an average of 5 years of follow-up. Cause of death was adjudicated centrally by a committee masked to treatment assignment. We examined baseline covariates and the 10-year Framingham Risk Score for associations., Results: Mortality rate was low (0.59 per 100 participant-years). Participants who died during follow-up were likely to be older, be male, have a history of hypertension, have a history of smoking, and have moderate albuminuria. The two most common underlying causes of death were "cardiovascular-cause" (a composite of underlying causes) (38.6%) and cancer (26.8%). There were no differences by treatment group., Conclusions: Among people with diabetes of relatively short duration, cause of death was varied. Attention to health risks beyond cardiovascular diseases is warranted., (© 2024 by the American Diabetes Association.)

Introduction: The purpose of this study is to examine the effect of admission glucose in patients hospitalized with COVID-19 with and without diabetes mellitus in a largely African American cohort., Design and Methods: This study included 708 adults (89% non-Hispanic Black) admitted with COVID-19 to an urban hospital between 1 March and 15 May 2020. Patients with diabetes were compared with those without and were stratified based on admission glucose of 140 and 180 mg/dL. Adjusted ORs were calculated for outcomes of mortality, intubation, intensive care unit (ICU) admission, acute kidney injury (AKI), and length of stay based on admission glucose levels., Results: Patients with diabetes with admission glucose >140 mg/dL (vs <140 g/dL) had 2.4-fold increased odds of intubation (95% CI 1.2 to 4.6) and 2.1-fold increased odds of ICU admission (95% CI 1.0 to 4.3). Patients with diabetes with admission glucose >180 mg/dL (vs <180 g/dL) had a 1.9-fold increased mortality (95% CI 1.2 to 3.1). Patients without diabetes with admission glucose >140 mg/dL had a 2.3-fold increased mortality (95% CI 1.3 to 4.3), 2.7-fold increased odds of ICU admission (95% CI 1.3 to 5.4), 1.9-fold increased odds of intubation (95% CI 1.0 to 3.7) and 2.2-fold odds of AKI (95% CI 1.1 to 3.8). Patients without diabetes with glucose >180 mg/dL had 4.4-fold increased odds of mortality (95% CI 1.9 to 10.4), 2.7-fold increased odds of intubation (95% CI 1.2 to 5.8) and 3-fold increased odds of ICU admission (95% CI 1.3 to 6.6)., Conclusion: Our results show hyperglycemia portends worse outcomes in patients with COVID-19 with and without diabetes. While our study was limited by its retrospective design, our findings suggest that patients presenting with hyperglycemia require closer observation and more aggressive therapies., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2022. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Type 2 diabetes mellitus (T2DM) is characterized by endothelial dysfunction, increased thrombogenicity, and inflammation. The soluble human F11 receptor (sF11R) and annexin A5 (ANXA5) play crucial roles in inflammatory thrombosis and atherosclerosis. We examined the relationship between circulating sF11R and ANXA5 and their impact on endothelial function. The study included 125 patients with T2DM. Plasma levels of sF11R and ANXA5 were quantified by ELISA. Microvascular function was assessed using the vascular reactivity index (VRI). Large artery stiffness was assessed by carotid-femoral pulse wave velocity (PWV). Carotid intima-media thickness (CIMT) was assessed by B-mode ultrasound imaging. The mean age of patients in the study was 59.7 ± 7.8 years, 78% had hypertension, 76% had dyslipidemia, and 12% had CKD. sF11R correlated positively with ANXA5 levels (β = 0.250, p = 0.005), and correlated inversely with VRI and total nitic oxide (NO), (β = −0.201, p = 0.024; β = −0.357, p = 0.0001, respectively). Multivariate regression analysis revealed that sF11R was independently associated with ANXA5 in the total population and in patients with HbA1c > 6.5% (β = 0.366, p = 0.007; β = 0.425, p = 0.0001, respectively). sF11R and ANXA5 were not associated with vascular outcome, suggesting that they may not be reliable markers of vascular dysfunction in diabetes. The clinical significance of sF11R/ANXA5 association in diabetes warrants further investigation in a larger population.

Background: Studies examining whether measures of cognition are related to the presence of diabetic peripheral neuropathy (DPN) and/or cardiovascular autonomic neuropathy (CAN) are lacking, as are data regarding factors potentially explaining such associations., Methods: Participants were from the Glycemia Reduction Approaches in Diabetes Study (GRADE) that examined 5047 middle-aged people with type 2 diabetes of <10 years of known duration. Verbal learning and immediate and delayed recall (memory) were assessed with the Spanish English Verbal Learning Test; frontal executive function and processing speed with the Digit Symbol Substitution Test; and ability to concentrate and organize data with word and animal fluency tests. DPN was assessed with the Michigan Neuropathy Screening Instrument and CAN by indices of heart rate variability (standard deviation of normal beat to beat variation [SDNN] and root mean square of successive differences [RMSSD])., Results: DPN was significantly inversely related to measures of immediate recall and processing speed. The percent of cognitive variation explained by DPN was small. Tests of CAN had an inconsistent or absent association with measures of cognition. Higher waist circumference and urine albumin creatinine (UACR) levels were the strongest correlates in the relationship between DPN and cognitive impairment., Conclusion: DPN, but not CAN, was cross-sectionally associated with lower performance in measures of cognition in people with type 2 diabetes of <10 years of known duration. Greater waist circumference and UACR were important variables in this association. The mechanisms underlying the cross-sectional association of DPN with cognitive impairment are unknown. Clinicaltrials.gov: NCT01794143., (Copyright © 2021. Published by Elsevier Inc.)

Introduction: The shape of the glucose curve during an oral glucose tolerance test (OGTT) reflects β-cell function in populations without diabetes but has not been as well studied in those with diabetes. A monophasic shape has been associated with higher risk of diabetes, while a biphasic pattern has been associated with lower risk. We sought to determine if phenotypic or metabolic characteristics were associated with glucose response curve shape in adults with type 2 diabetes treated with metformin alone., Research Design and Methods: This is a cross-sectional analysis of 3108 metformin-treated adults with type 2 diabetes diagnosed <10 years who underwent 2-hour 75 g OGTT at baseline as part of the Glycemia Reduction Approaches in Diabetes: A Comparative Effectiveness Study (GRADE). Insulin sensitivity (homeostasis model of insulin sensitivity, HOMA2-S) and β-cell function (early, late, and total incremental insulin and C peptide responses adjusted for HOMA2-S) were calculated. Glucose curve shape was classified as monophasic, biphasic, or continuous rise., Results: The monophasic profile was the most common (67.8% monophasic, 5.5% biphasic, 26.7% continuous rise). The monophasic subgroup was younger, more likely male and white, and had higher body mass index (BMI), while the continuous rise subgroup was more likely female and African American/black. HOMA2-S and fasting glucose did not differ among the subgroups. The biphasic subgroup had the highest early, late, and total insulin and C peptide responses (all p<0.05 vs monophasic and continuous rise). Compared with the monophasic subgroup, the continuous rise subgroup had similar early insulin (p=0.3) and C peptide (p=0.6) responses but lower late insulin (p<0.001) and total insulin (p=0.008) and C peptide (p<0.001) responses., Conclusions: Based on the large multiethnic GRADE cohort, sex, race, age, and BMI were found to be important determinants of the shape of the glucose response curve. A pattern of a continuously rising glucose at 2 hours reflected reduced β-cell function and may portend increased glycemic failure rates., Trial Registration Number: NCT01794143., Competing Interests: Competing interests: KMU reports support from Medtronic and personal fees from Novo Nordisk, outside the submitted work. NR reports grants and other support from Novo Nordisk, outside the submitted work. RMC reports grants from the National Institutes of Health during the conduct of the study, and other support from Bristol Myers Squibb and Pfizer, outside the submitted work. DJW reports grants from NIDDK which funded the trial during the conduct of the study and other support from Novo Nordisk, outside the submitted work. SEK reports grants from NIH during the conduct of the study, personal fees from Boehringer Ingelheim, personal fees from Eli Lilly and Company, and personal fees from Intarcia, Janssen, Merck, Neurimmune, Novo Nordisk, and Pfizer, outside the submitted work. KJM reports grants from the National Institutes of Health during the conduct of the study, and at the time of publication KJM is an employee of Eli Lilly and Company. Data collection, analysis, and preparation of the manuscript occurred prior to this employment and were independent of Eli Lilly and Company. NY, JIB, MAB, EVG, FI-B, JML, and PR have nothing to disclose. KMU and SEK are supported by funding from the US Department of Veterans Affairs., (© Author(s) (or their employer(s)) 2021. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Aims: Evaluate the relationship between measures of glycemia with β-cell function and insulin sensitivity in adults with early type 2 diabetes mellitus (T2DM)., Methods: This cross-sectional analysis evaluated baseline data from 3108 adults with T2DM <10 years treated with metformin alone enrolled in the Glycemia Reduction Approaches in Diabetes. A Comparative Effectiveness (GRADE) Study. Insulin and C-peptide responses and insulin sensitivity were calculated from 2-h oral glucose tolerance tests. Regression models evaluated the relationships between glycemic measures (HbA1c, fasting and 2-h glucose), measures of β-cell function and insulin sensitivity., Results: Insulin and C-peptide responses were inversely associated with insulin sensitivity. Glycemic measures were inversely associated with insulin and C-peptide responses adjusted for insulin sensitivity. HbA1c demonstrated modest associations with β-cell function (range: r - 0.22 to -0.35). Fasting and 2-h glucose were associated with early insulin and C-peptide responses (range: r - 0.37 to -0.40) as well as late insulin and total insulin and C-peptide responses (range: r - 0.50 to -0.60)., Conclusion: Glycemia is strongly associated with β-cell dysfunction in adults with early T2DM treated with metformin alone. Efforts to improve glycemia should focus on interventions aimed at improving β-cell function. This Trial is registered in Clinicaltrials.gov as NCT01794143., Competing Interests: Declaration of competing interest The writing group reports the following as relevant conflicts of interest: KMU reports support from Medtronics, personal fees from Novo Nordisk, outside the submitted work; NR reports grants and other support from Novo Nordisk, outside the submitted work; RMC reports grants from National Institutes of Health during the conduct of the study; other support from Bristol Myers Squibb and Pfizer, outside the submitted work; DJW reports grants from an NIDDK funded trial during the conduct of the study; and other support from Novo Nordisk, outside the submitted work. SEK reports grants from NIH during the conduct of the study; personal fees from Boehringer Ingelheim, Eli Lilly, Intarcia, Janssen, Merck, Novo Nordisk, and Pfizer, outside the submitted work. KJM reports grants from National Institutes of Health during the conduct of the study; and at the time of publication. KJM is an employee of Eli Lilly and Company. Data collection, analysis, and preparation of the manuscript occurred prior to this employment and were independent of Eli Lilly and Company. NY, JB, MAB, EVG, FIB, JML, and PR have nothing to disclose. KMU and SEK are supported by funding from the United States Department of Veterans Affairs., (Published by Elsevier Inc.)

Higher levels of nitrated lipoproteins (NT-HDL and NT-LDL) were found in blood and atherosclerotic plaques of patients with coronary artery disease. We aimed to examine the relationship between plasma NT-HDL and NT-LDL and diabetic vascular dysfunction. The study included 125 African-American patients with T2DM. NT-HDL and NT-LDL were quantified by ELISA. Microvascular function was assessed by vascular reactivity index (VRI). Large artery stiffness was assessed by carotid-femoral pulse wave velocity (PWV). Carotid intima-media thickness (CIMT) was assessed by B-mode ultrasound imaging. In univariate analysis, NT-HDL was associated with VRI in total population and in patients with HbA1c more than or equal to 7.0 percent (beta= -0.178, p= 0.034; beta = -0.265, p= 0.042; respectively). In contrast, NT-LDL was associated with CIMT in total population and in patients with HbA1c more than 7.0 percent (beta = -0.205, p= 0.022; beta = -0.244, p= 0.042; respectively). Multivariable-adjusted regression analysis demonstrated that NT-HDL independently predicted VRI outcome in total population and in well-controlled patients (beta = -0.282, p= 0.014; beta = -0.400, p= 0.035, respectively). These results suggest that NT-HDL could be used as marker to identify diabetic patients at risk of developing early microvascular complications.

Background: This is an exploratory pilot study of novel technology enabling people with mobility disability to walk with minimal effort, in the "sedentary range". The study's premise is that impairment of the leading physical activity of daily living, walking, is a major contributor to a dysmetabolic state driving many prevalent "civilization diseases" associated with insulin resistance., Methods: We explore within-subject changes in standard oral glucose tolerance (OGT) tests including metabotropic molecules after 22 twice-weekly, 30-minute bouts of weight-supported light-moderate physical activity in 16 non-diabetic obese, otherwise healthy, reproductive-age, volunteer women walking on an "anti-gravity" lower-body positive pressure (LBPP) treadmill., Results: Subjects had reference base-line fasting plasma glucose and triglycerides (TG) but 2-hr OGT insulin levels of 467 ± 276 pmol • liter-1 (mean± S.D.) indicating nascent insulin resistance, compared to post-study 308 ± 179 (p = 0.002). Fasting TG decreased from 0.80 ± 0.30 mmol • liter-1 to 0.71 ± 0.25 (p = 0.03). Concomitantly plasma total ghrelin decreased from 69.6 ± 41.6 pmol • liter-1 to 56.0 ± 41.3 (p = 0.008). There were no statistically significant changes in body weight or any correlations between weight change and cardiometabolic markers. However, there were robust positive correlations between changes among different classes of peptides including C-reactive protein-Interleukin 6, leptin-adiponectin, β-endorphin-oxytocin and orexin A (r 2 = 0.48-0.88)., Conclusion: We conclude that brief, low-dose physical activity, walking on an anti-gravity LBPP treadmill may improve cardiometabolic risk, exhibiting favorable changes in neuro-regulatory peptides without weight loss in people with problems walking., Competing Interests: This study was made possible through a generous unrestricted equipment loan from AlterG, Fremont, CA who free of charge delivered and installed the treadmill used in this study. We were not given the treadmill; it is a revocable LOAN free of charge. There are not patents, products in development or marketed products to declare. This free-of-charge unrestricted equipment loan does not alter our adherence to PLOS ONE Editorial policies on sharing data and materials. The lender of our equipment has had no part in the design, performance, data procurement, management or interpretation or in the writing of this manuscript, which, in fact they have not read prior to or after our submission to PLOS ONE.

Purpose of Review: Ketosis-prone diabetes or Flatbush diabetes has been widely recognized as a clinical entity since 1984. Most of the early clinical studies focused on African American or Afro-Caribbean individuals. It is now being recognized as an important clinical entity in sub-Saharan Africans, Asian and Indian populations, and Hispanic populations. Major questions remain as to its pathogenesis and whether it is a unique type of diabetes or a subset of more severe type 2 diabetes with greater loss of insulin action in target tissues. This review summarizes the main clinical and mechanistic studies to improve the understanding of ketosis-prone (Flatbush) diabetes., Recent Findings: Little data are available on the magnitude of KPD in the different susceptible populations. It is relatively common in black populations. KPD is defined as a syndrome in which diabetes commences with ketoacidosis in individuals who are GAD and anti-islet cell antibody negative and have no known precipitating causes. The patients present during middle age, are overweight or mildly obese, and in many reports are more likely to be male. After intensive initial insulin therapy, many patients become insulin independent and can be well controlled on diet alone or diet plus oral medications. The clinical course of KPD is like that of patients with type 2 diabetes rather than that of type 1 diabetes. Little differences are found in the clinical characteristics and clinical outcomes between patients presenting with KPD and those presenting with severe hyperglycemia with no ketoacidosis. The mechanisms responsible for the development of ketosis-prone diabetes as well its remission remain unknown.

TIMP-4 is the newest member of a family of secreted proteins known as the tissue inhibitors of metalloproteases that selectively inhibit matrix metalloproteases. TIMP-4 is abundantly expressed in human cardiovascular structures and has been implicated in cardiovascular disease. Furthermore, it has also been shown to be a novel target of peroxisome proliferator-activated receptor gamma in rat smooth muscle cells, suggesting a potential role in diabetes mellitus as well. However, there have been no studies that have specifically examined the utility of baseline plasma TIMP-4 levels for the prediction of long-term adverse cardiovascular outcomes. In this study, baseline plasma TIMP-4 levels were measured in 162 male patients with diabetes mellitus who were referred for coronary angiography and followed prospectively for the development of all-cause mortality and enzymatically confirmed myocardial infarction (MI) out to 5 years. After adjustment for a variety of baseline clinical, angiographic and laboratory parameters, plasma TIMP-4 levels were an independent predictor of all-cause mortality (hazard ratio 1.60, 95% CI 1.13 to 2.26; p = 0.0082) and MI (hazard ratio 1.61, 95% CI 1.19 to 2.18; p = 0.0021) at 5 years. Furthermore, in additional multivariate models that adjusted for a variety of biomarkers with established prognostic efficacy, TIMP-4 remained an independent predictor of adverse outcomes. In conclusion, elevated levels of TIMP-4 are associated with an increased risk of long-term all-cause mortality and MI in patients with diabetes mellitus referred for coronary angiography. Moreover, this association is independent of a variety of clinical, angiographic, and laboratory variables, including biomarkers with established prognostic efficacy in the prediction of adverse cardiovascular outcomes., (Copyright © 2017 Elsevier Inc. All rights reserved.)

To determine the efficacy of pioglitazone to prevent type 2 diabetes in older compared to younger adults with pre-diabetes. Six hundred two participants with impaired glucose tolerance (IGT) were randomized in double blind fashion to placebo or pioglitazone for diabetes prevention in the ACT NOW study (NEJM 364:1104-1115, 2011). Cox proportional hazard regression was used to compare time to development of diabetes over a mean of 2 years between older (≥61 years) and younger participants. We compared effects of pioglitazone versus placebo on metabolic profiles, inflammatory markers, adipokines, β cell function (disposition index), insulin sensitivity (Matsuda index), and body composition by ANOVA. Diabetes incidence was reduced by 85 % in older and 69 % in younger subjects (p = 0.41). β cell function (disposition index) increased by 35.0 % in the older and 26.7 % in younger subjects (p = 0.83). Insulin sensitivity (Matsuda index) increased by 3.07 (5.2-fold) in older and by 2.54 (3.8-fold) in younger participants (p = 0.58). Pioglitazone more effectively increased adiponectin in older versus younger subjects (22.9 ± 3.2 μg/mL [2.7-fold] vs. 12.7 ± 1.4 μg/mL [2.2-fold], respectively; p = 0.04). Younger subjects tended to have a greater increase in whole body fat mass compared to older subjects (3.6 vs. 3.1 kg; p = 0.061). Younger and older subjects had similar decreases in bone mineral density (0.018 ± 0.0071 vs. 0.0138 ± 0.021 g/cm 2 ). Younger and older pre-diabetic adults taking pioglitazone had similar reductions in conversion to diabetes and older adults had similar or greater improvements in metabolic risk factors, demonstrating that pioglitazone is useful in preventing diabetes in older adults., Competing Interests: Compliance with ethical standards Briefly, eight centers participated in this investigator-initiated study, which was approved by the Institutional Review Board at each site. Written informed consent was obtained from all participants. Conflict of interest Dr. DeFronzo reports being on advisory boards for Astra Zeneca, Novo Nordisk, Janssen, Boehringer-Ingelheim, Intarcia, speaker bureaus for Novo-Nordisk and Astra Zeneca. Dr. DeFronzo also receives research support from Boehringer-Ingelheim, Takeda, Astra Zeneca, and Janssen. Dr. Reaven reports research support from Astra Zeneca and Novo Nordisk. Dr. Henry reports serving as consultant for Alere, Intarcia, Ionis, Johnson & Johnson/Janssen, and Sanofi-Aventis and serves on the advisory boards for AstraZeneca, Boehringer Ingelheim, Elcelyx, Intarcia, Johnson & Johnson/Janssen., Novo Nordis, and Sanofi-Aventis. Dr. Henry also receives research support from Hitachi, Eli Lilly, and Viacyte. No other potential conflict of interests were reported.

Background: There are no proven strategies to prevent atrial fibrillation (AF) in patients with type 2 diabetes (T2DM). We compared standard blood pressure (BP) lowering vs. intensive BP lowering in reducing incidence of AF or P-wave indices (PWI-ECG markers of left atrial abnormality that are considered intermediate phenotypes of AF) in patients with T2DM., Methods: We analyzed data from the ACCORD BP trial-a randomized controlled nonblinded trial (2001-2009) which randomized patients with T2DM and systolic BP (SBP) 130-180mm Hg on ≤3 antihypertensive medications aged 40-79 years with cardiovascular disease (CVD) or aged 55-79 years with subclinical CVD or ≥2 CVD risk factors to standard BP lowering (SBP <140mm Hg) vs. intensive BP lowering (SBP <120mm Hg). The primary outcome was a composite of incident AF and PWI., Results: Data from 3,087 participants (mean age, 62.2 years; women, 48.2%; non-White, 39.2%) were analyzed. During a mean follow-up of 4.4 years, the primary outcome occurred in 1,063 participants (incidence rate, 84.5 per 1,000 person-years in the standard-therapy group vs. 73.9 per 1,000 person-years in the intensive-therapy group). The adjusted hazard ratios (95% confidence intervals) of intensive-therapy group for the primary outcome and for incident PWI alone were 0.87 (0.77-0.98), P = 0.02 and 0.87 (0.76-0.98), P = 0.02, respectively. The effect of intensive therapy on the incidence of AF alone did not reach statistical significance., Conclusions: In patients with T2DM, intensive BP lowering reduces the incidence of the composite outcome of AF and PWI, suggesting a potential benefit from stringent BP control in patients with T2DM. clinical trials registration Trial Number NCT00000620.

Context: In trials, thiazolidinediones (TZDs) increase fracture risk in women, but the effects of discontinuation are unknown., Objective: The objective was to investigate the effects of TZD use and discontinuation on fractures in women and men., Design: This was a longitudinal observational cohort study using data from the Action to Control Cardiovascular Risk in Diabetes (ACCORD) trial bone ancillary study. Duration of TZD use and discontinuation during ACCORD, assessed every 2-4 months at clinic visits, were modeled as time-varying covariates in proportional hazards models for occurrence of first non-spine fracture., Participants: We studied a total of 6865 participants in ACCORD BONE., Main Outcome Measures: Main outcome measures were centrally adjudicated non-spine fracture., Results: Average age was 62.4 (SD, 6.6) years; average duration of diabetes was 11.1 (SD, 7.8) years. Rosiglitazone was used by 74% and pioglitazone by 13% of participants. During a mean follow-up of 4.8 (SD, 1.5) years, 262 men and 287 women experienced at least one non-spine fracture. The fracture rate was higher in women with 1-2 years of TZD use (hazard ratio [HR] = 2.32; 95% confidence interval [CI], 1.49, 3.62) or >2 years of TZD use (HR = 2.01; 95% CI, 1.35, 2.98), compared with no use. The fracture rate was reduced in women who had discontinued TZD use for 1-2 years (HR = 0.57; 95% CI, 0.35, 0.92) or > 2 years (HR = 0.42; 95% CI, 0.24, 0.74) compared with current users. TZD use and discontinuation were not associated with non-spine fractures in men., Conclusions: TZD use was associated with increased non-spine fractures in women, but not men, with type 2 diabetes. When women discontinued TZD use, the fracture effects were attenuated.

Purpose: Optimizing glycemic control in patients with type 2 diabetes mellitus (T2DM) not controlled with ≥ 1 oral antidiabetes drugs (OADs) is challenging. Many therapeutic options exist; however, data comparing the effectiveness of different strategies are lacking for the management of patients with T2DM. Our study aim was to provide comparative data on efficacy and hypoglycemia when initiating insulin glargine (glargine) versus alternative treatment options (not including the newest antidiabetes agents, glucagon-like peptide [GLP]-1 receptor agonists, dipeptidyl peptidase [DPP]-4 inhibitors or sodium-glucose linked transporter [SGLT]-2 inhibitors) in insulin-naive patients with T2DM who remained uncontrolled with OADs., Methods: Patient-level data were pooled from 9 randomized controlled trials of ≥ 24 weeks duration with comparable patient populations. The effect of adding glargine was compared with intensification of lifestyle interventions or OADs, addition of neutral protamine Hagedorn (NPH) insulin, insulin lispro, premixed insulin, or all comparators pooled, on patient glycated hemoglobin (HbA1c) level, fasting plasma glucose level, weight, and hypoglycemia., Results: A greater proportion of patients achieved a target HbA1c level ≤ 7.0% with glargine treatment than with pooled comparators, intensification of OADs, or lifestyle interventions; there was no difference when compared with NPH, premixed, or insulin lispro use. The rate for reported hypoglycemic events was lower for glargine use than for pooled comparators or other insulins, but higher compared with intensification of lifestyle interventions or OADs. When stratified by baseline HbA1c level, efficacy/target attainment with glargine use was better than for pooled comparators across all HbA1c strata; OAD intensification, when baseline HbA1c level was ≥ 8.0%; and premixed insulin if baseline HbA1c level was < 8.0%; but similar to other insulins for all other categories. The incidence of reported hypoglycemia was less frequent with glargine use than other insulins, but more frequent than intensification of lifestyle interventions or OADs., Conclusion: When adequate glycemic control is not achieved using OADs in patients with T2DM, initiating insulin glargine is generally less likely to elicit hypoglycemia than initiating NPH, premixed, or prandial insulins, and the benefit-risk balance supports initiating insulin rather than intensification of OAD therapy when baseline HbA1c level is ≥ 8.0%.

Background: Cardiovascular risk factors (CVRFs) may complicate optimization of therapy in patients with type 2 diabetes mellitus (T2DM) inadequately controlled with oral antidiabetes drugs (OADs). We assessed the influence of patient baseline CVRFs on efficacy and rate of hypoglycemia with use of insulin glargine (glargine) added to ongoing OAD treatment compared with alternative therapeutic options; namely, intensification of lifestyle interventions or adding OADs, neutral protamine Hagedorn (NPH), lispro, or premixed insulin in patients failing OADs., Methods: Patient-level data were pooled from 9 randomized controlled trials of glargine and comparators for 24 weeks in insulin-naive patients with T2DM inadequately controlled on OADs. Efficacy (goal attainment-glycated hemoglobin (HbA1c) level ≤ 7.0% or decrease ≥ 1.0% change from baseline) and hypoglycemia rates (symptomatic, confirmed, nocturnal, or severe) were compared for patients treated with glargine (n = 1462) and pooled (n = 1476) and individual comparators, overall; and in patients with hypertension (~69%), dyslipidemia (~58%), history of cardiovascular disease (~25%), or any CVRF (~83%) at baseline., Results: The patient groups were well-balanced at baseline (HbA1c level 8.7%; diabetes duration, 8.6 years). Use of glargine was associated with greater patient goal attainment (57.7% vs 51.4% for HbA1c level ≤ 7.0%; P < 0.001), modestly larger reductions in HbA1c level (-1.68% vs -1.51%; P < 0.001), and less symptomatic hypoglycemia than occurred with pooled comparators, regardless of patient CVRFs (5.04 vs 7.01 events/patient-year of exposure, respectively; P < 0.001). Reductions in HbA1c level and hypoglycemia rates were significantly greater with glargine use than with intensification of OADs or lifestyle modifications, overall, and in patients with any CVRF. Reductions in HbA1c level were greater and hypoglycemia rates lower with use of glargine compared with premixed insulin, overall, and in patients with any CVRF. Reductions in HbA1c level were similar and hypoglycemia rates lower with use of glargine, NPH, and lispro insulin, regardless of patient CVRFs., Conclusion: The glycemic benefits of glargine use compared with alternative therapeutic options are maintained without excess hypoglycemia in patients with CVRFs.

Pheochromocytomas are catecholamine producing neuroendocrine tumors that can be adrenal or extra-adrenal in origin. The classic symptoms of pheochromocytoma are headache, palpitation, anxiety and diaphoresis and the tumor can occur at any age with equal gender distribution. In patients with an established mutation or hereditary syndrome the condition may manifest at a younger age than in those with sporadic disease. Pheochromocytoma can be associated with certain genetic syndromes such as multiple endocrine neoplasia type 2 (MEN 2), neurofibromatosis (NF) and von Hippel-Lindau (VHL) syndrome. Pheochromocytoma is diagnosed with biochemical confirmation of hormonal excess followed by anatomical localization (CT or MRI). The mainstay of definitive therapy is surgical resection. In this review, we discuss in detail about the symptomatology, diagnosis, genetic aspects and management of pheochromocytoma., (Copyright © 2014 Elsevier Ireland Ltd. All rights reserved.)

Glucagon-like peptide-1 (GLP-1) regulates carbohydrate metabolism and promotes neurogenesis. We reported an inverse correlation between adult body mass and neurogenesis in nonhuman primates. Here we examine relationships between physiological levels of the neurotrophic incretin, plasma GLP-1 (pGLP-1), and body mass index (BMI) in adolescence to adult neurogenesis and associations with a diabesity diathesis and infant stress. Morphometry, fasting pGLP-1, insulin resistance, and lipid profiles were measured in early adolescence in 10 stressed and 4 unstressed male bonnet macaques. As adults, dentate gyrus neurogenesis was assessed by doublecortin staining. High pGLP-1, low body weight, and low central adiposity, yet peripheral insulin resistance and high plasma lipids, during adolescence were associated with relatively high adult neurogenesis rates. High pGLP-1 also predicted low body weight with, paradoxically, insulin resistance and high plasma lipids. No rearing effects for neurogenesis rates were observed. We replicated an inverse relationship between BMI and neurogenesis. Adolescent pGLP-1 directly predicted adult neurogenesis. Two divergent processes relevant to human diabesity emerge-high BMI, low pGLP-1, and low neurogenesis and low BMI, high pGLP-1, high neurogenesis, insulin resistance, and lipid elevations. Diabesity markers putatively reflect high nutrient levels necessary for neurogenesis at the expense of peripheral tissues.

The increasing prevalence of diabetes especially type 2 diabetes worldwide is indisputable. Diabetics suffer increased morbidity and mortality, compared to their non-diabetic counterparts, not only because of vascular complications, but also because of an increased fracture incidence. Both types 1 and 2 diabetes and some medications used to treat it are associated with osteoporotic fractures. The responsible mechanisms remain incompletely elucidated. In this review, we evaluate the role of glycemic control in bone health, and the effect of anti-diabetic medications such as thiazolidinediones, sulfonylureas, DPP-4 inhibitors, and GLP-1 agonists. In addition, we examine the possible role of insulin and metformin as anabolic agents for bone. Lastly, we identify the current and future screening tools that help evaluate bone health in diabetics and their limitations. In this way we can offer individualized treatment, to the at-risk diabetic population., (Copyright © 2013 Elsevier Ireland Ltd. All rights reserved.)

Aims: This study examined the effects of pioglitazone on body weight and bone mineral density (BMD) prospectively in patients with impaired glucose tolerance as pioglitazone (TZD) increases body weight and body fat in diabetic patients and increases the risk of bone fractures., Methods: A total of 71 men and 163 women aged 49.3 (10.7) years [mean (s.d.)]; body mass index (BMI), 34.5 (5.9) kg/m(2) were recruited at five sites for measurements of body composition by dual energy X-ray absorptiometry at baseline and at conversion to diabetes or study end, if they had not converted., Results: Mean follow-up was 33.6 months in the pioglitazone group and 32.1 months in the placebo group. Body weight increased 4.63 ± 0.60 (m ± s.e.) kg in the pioglitazone group compared to 0.98 ± 0.62 kg in the PIO group (p < 0.0001). Body fat rose 4.89 ± 0.42 kg in the pioglitazone group compared to 1.41 ± 0.44 kg, (p < 0.0001) in placebo-treated subjects. The increase in fat was greater in legs and trunk than in the arms. BMD was higher in all regions in men and significantly so in most. PIO decreased BMD significantly in the pelvis in men and women, decreased BMD in the thoracic spine and ribs of women and the lumbar spine and legs of men. Bone mineral content also decreased significantly in arms, legs, trunk and in the total body., Conclusions: Pioglitazone increased peripheral fat more than truncal fat and decreased BMD in several regions of the body., (© 2013 John Wiley & Sons Ltd.)

Background: The incidence and prevalence of type 2 diabetes continue to grow in the United States and worldwide, along with the growing prevalence of obesity. Patients with type 2 diabetes are at greater risk for comorbid cardiovascular (CV) disease (CVD), which dramatically affects overall healthcare costs., Objectives: To review the impact of glycemic control and medication adherence on morbidity, mortality, and healthcare costs of patients with type 2 diabetes, and to highlight the need for new drug therapies to improve outcomes in this patient population., Methods: This comprehensive literature search was conducted for the period between 2000 and 2013, using MEDLINE, to identify published articles that report the associations between glycemic control, medication adherence, CV morbidity and mortality, and healthcare utilization and costs. Search terms included "type 2 diabetes," "adherence," "compliance," "nonadherence," "drug therapy," "resource use," "cost," and "cost-effectiveness.", Discussion: Despite improvements in the management of CV risk factors in patients with type 2 diabetes, outcomes remain poor. The costs associated with the management of type 2 diabetes are increasing dramatically as the prevalence of the disease increases. Medication adherence to long-term drug therapy remains poor in patients with type 2 diabetes and contributes to poor glycemic control in this patient population, increased healthcare resource utilization and increased costs, as well as increased rates of comorbid CVD and mortality. Furthermore, poor adherence to established evidence-based guidelines for type 2 diabetes, including underdiagnosis and undertreatment, contributes to poor outcomes. New approaches to the treatment of patients with type 2 diabetes currently in development have the potential to improve medication adherence and consequently glycemic control, which in turn will help to reduce associated costs and healthcare utilization., Conclusions: As the prevalence of type 2 diabetes and its associated comorbidities grows, healthcare costs will continue to increase, indicating a need for better approaches to achieve glycemic control and manage comorbid conditions. Drug therapies are needed that enhance patient adherence and persistence levels far above levels reported with currently available drugs. Improvements in adherence to treatment guidelines and greater rates of lifestyle modifications also are needed. A serious unmet need exists for greatly improved patient outcomes, more effective and more tolerable drugs, as well as marked improvements in adherence to treatment guidelines and drug therapy to positively impact healthcare costs and resource use.

Pituitary dysfunction in elderly can represent a true diagnostic and therapeutic challenge to clinicians caring for these patients. Symptoms associated with partial or total hypopituitarism, such as fatigue, lower muscle strength and decreased libido, are nonspecific and can be often attributed to normal aging. Gold standard pituitary diagnostic testing carries higher risks in elderly and is classically replaced by alternative testing. Furthermore, the benefits and safety of selective pituitary hormonal replacement, specifically sexual and growth hormone replacement, remain subject of controversy in this group of patients. Recognizing and appropriately treating hypopituitarism in elderly is crucial for the survival and well being of the older patients with this disease., (Copyright © 2012 Elsevier Ireland Ltd. All rights reserved.)

Glucagon-like peptide-1 (GLP-1) [GLP-1 (7-36)-amide] plays a fundamental role in regulating postprandial nutrient metabolism. GLP-1 acts through a G-protein-coupled receptor present on the membranes of many tissues, including myocardium and endothelium. GLP-1 is cleaved by the dipeptidyl peptidase-4 enzyme to its metabolite GLP-1 (9-36)-amide within 1-2 min of its release into the circulation. Investigations have been done in humans and in animal models to determine whether GLP-1 has effects on the myocardium. Infusions of GLP-1 increase cardiac function in ischemic and non-ischemic cardiovascular disease. In humans and animal models, constant infusions of GLP-1 decrease the size of infarction and improve myocardial function in ischemic/reperfusion injury. In cardiomyopathy and heart failure, infusions of GLP-1 improve myocardial function. These beneficial effects of GLP-1 on cardiac function are mediated by both GLP-1 receptor activation and GLP-1 receptor independent actions. Infusions of the metabolite GLP-1 (9-36)-amide improve cardiac function in experimental animals with cardiovascular disease even though the metabolite does not bind to the GLP-1 receptor. The beneficial effects of GLP-1 on the heart occur in the presence of a GLP-1 receptor antagonist and in animals devoid of GLP-1 receptors. Preliminary data in animals with available GLP-1 receptor agonists and cardiac disease suggest that exenatide has beneficial effects in porcine models of ischemic heart disease. The animal data with liraglutide are inconclusive. Clinical trials with exenatide and liraglutide show significant improvements in weight, systolic blood pressure, lipid profiles, and other cardiovascular risk factors. Whether these will decrease cardiovascular events is currently under investigation.

Chronic kidney disease has a significant worldwide prevalence affecting 7.2% of the global adult population with the number dramatically increasing in the elderly. Although the causes are various, diabetes is the most common cause of CKD in the United States and an increasing cause of the same worldwide. Therefore, we chose to focus on diabetic chronic kidney disease in this review. The pathogenesis is multifactorial involving adaptive hyperfiltration, advanced glycosylated end-product synthesis (AGES), prorenin, cytokines, nephrin expression and impaired podocyte-specific insulin signaling. Treatments focus on lifestyle interventions including control of hyperglycemia, hypertension and hyperlipidemia as well treatment of complications and preparation for renal replacement therapy. This review examines the current literature on the epidemiology, pathogenesis, complications and treatment of CKD as well as possible areas of future disease intervention., (Published by Elsevier Ireland Ltd.)

Objective: Obesity is associated with the insulin resistance metabolic syndrome, postulated to be mediated by stress-induced alterations within the hypothalamic-pituitary-adrenal (HPA) axis. In adult bonnet macaques we examined relationships between components of the metabolic syndrome, hippocampal neurometabolic asymmetry, an indicator of negative affect, and juvenile cerebrospinal fluid (csf) corticotropin-releasing factor (CRF) levels obtained after stress exposure associated with maternal food insecurity and in controls., Methods: Eleven adult male monkeys (seven with early life stress) who had undergone csf-CRF analyses as juveniles had magnetic resonance spectroscopic imaging (MRSI) of bilateral hippocampus, morphometry (body mass index, BMI; sagittal abdominal diameter, SAD) and determination of fasting plasma glucose and insulin as adults. Neurometabolite ratios included N-acetyl-aspartate as numerator (NAA; a marker of neuronal integrity) and choline (Cho; cell turnover) and creatine (Cr; reference analyte) as denominators., Results: Elevated juvenile csf-CRF levels positively predicted adult BMI and SAD and were associated with right>left shift of NAA ratio within the hippocampus. Adult visceral obesity and insulin level correlated with right>left shift in hippocampal NAA concentrations, controlling for age and denominator., Conclusion: Juvenile csf-CRF levels, a neuropeptide associated with early life stress, predict adult visceral obesity and hippocampal asymmetry supporting the hypothesis that metabolic syndrome in adults may be related to early life stress. Furthermore, this study demonstrates asymmetrical hippocampal alterations related to obesity., (Copyright © 2011 Elsevier Inc. All rights reserved.)

Within the past 2 years, the American Diabetes Association (ADA)/European Association for the Study of Diabetes (EASD) and the American Association of Clinical Endocrinologists (AACE)/American College of Endocrinology (ACE) have revised their guidelines for the diagnosis and treatment of type 2 diabetes mellitus (T2DM). Both organizations recommend a diagnostic glycated hemoglobin (HbA1c) of >6.5% (based on a new appreciation of the relationship between glycemia and complications) and fasting plasma glucose levels or an oral glucose tolerance test. Findings from major trials of glucose control in patients with T2DM and the approval of novel medications have prompted revised treatment algorithms from both organizations. While both treatment guidelines recommend starting metformin in most patients on diagnosis of T2DM, they differ in terms of the "trigger" for treatment intensification (HbA1c≥7% and >6.5%, respectively) and which agents are preferred as second-line therapies. The ADA/EASD recommends a tiered approach to treatment, starting with well-validated second-line agents, such as sulfonylureas and basal insulin for patients unable to achieve target glucose levels with metformin. The AACE/ACE recommendations are based on the patient's HbA1c level and include a broader range of first- and second-line therapies and combinations. In addition to metformin, the ACCE/ACE treatment algorithm includes dipeptidyl peptidase-4 inhibitors, glucagon-like peptide-1 agonists, thiazolidinediones, α-glucosidase inhibitors, sulfonylureas, and glinides. Both organizations advocate individualizing therapy to meet patient needs. This review highlights recent changes in the guidelines and uses a case-based format to illustrate how the current guidelines may be tailored to fit individual patient characteristics and circumstances.

The number of mechanistically novel antidiabetes agents has dramatically increased over the past few years. Dipeptidyl peptidase-4 (DPP-4) inhibitors in particular have emerged as clinically efficacious oral agents for diabetes management with a low incidence of side effects. The Galvus in Addition to Metformin versus Tzd/Metformin in Lowering HbA1c (GALIANT) trial showed that vildagliptin as an add-on therapy was noninferior to thiazolidinedione therapy with regard to reduction in hemoglobin A1c, with both drugs having a similar incidence of side effects in patients with normal and impaired renal function. DPP-4 inhibitors have a low incidence of hypoglycemia without significant weight gain and there is strong evidence that the administration of vildagliptin results in improved α- and β-cell function. New data suggest that DPP-4 inhibitors might also have a role in the setting of myocardial infarction and lipid management, and in the prevention of Type 2 diabetes.

Objective: This retrospective analysis assessed safety and tolerability of vildagliptin (Vilda) as an add-on to metformin in type 2 diabetes mellitus (T2DM) patients with normal renal function (GFR >80mL/min/1.73m(2)) and mild renal impairment (GFR: >50 to ≤80mL/min/1.73m(2))., Methods: Adverse events (AE) from this 12-week, randomized, open-label study comparing Vilda 100mg and thiazolidinediones (TZD) as an add-on therapy in patients with T2DM inadequately controlled (HbA(1c): 7-10%) on a stable dose of metformin (≥1000mg/day) were analyzed., Results: Of 2627 randomized patients, 1278 in the Vilda and 635 in the TZD groups had normal renal function; 463 in the Vilda and 230 in the TZD groups had mild renal impairment. Higher incidence of headache and rash was noted in both Vilda groups, whereas those with mild renal impairment receiving TZD experienced a higher incidence of peripheral edema and URI. Fewer patients in the Vilda group discontinued the study due to AEs compared to TZD group. Serious AEs were greater in TZD groups (normal: 2.4%; mild renal impairment: 3.0%) compared to Vilda groups (normal: 1.6%; mild renal impairment: 2.4%)., Conclusion: The safety profile of Vilda or TZD as an add-on to metformin was similar in patients with mild renal impairment and normal renal function., (Copyright © 2010 Elsevier Ireland Ltd. All rights reserved.)

Background: Hyperglycaemia is associated with increased risk of cardiovascular complications in people with type 2 diabetes. We investigated whether reduction of blood glucose concentration decreases the rate of microvascular complications in people with type 2 diabetes., Methods: ACCORD was a parallel-group, randomised trial done in 77 clinical sites in North America. People with diabetes, high HbA(1c) concentrations (>7.5%), and cardiovascular disease (or >or=2 cardiovascular risk factors) were randomly assigned by central randomisation to intensive (target haemoglobin A(1c) [HbA(1c)] of <6.0%) or standard (7.0-7.9%) glycaemic therapy. In this analysis, the prespecified composite outcomes were: dialysis or renal transplantation, high serum creatinine (>291.7 micromol/L), or retinal photocoagulation or vitrectomy (first composite outcome); or peripheral neuropathy plus the first composite outcome (second composite outcome). 13 prespecified secondary measures of kidney, eye, and peripheral nerve function were also assessed. Investigators and participants were aware of treatment group assignment. Analysis was done for all patients who were assessed for microvascular outcomes, on the basis of treatment assignment, irrespective of treatments received or compliance to therapies. ACCORD is registered with ClinicalTrials.gov, number NCT00000620., Findings: 10 251 patients were randomly assigned, 5128 to the intensive glycaemia control group and 5123 to standard group. Intensive therapy was stopped before study end because of higher mortality in that group, and patients were transitioned to standard therapy. At transition, the first composite outcome was recorded in 443 of 5107 patients in the intensive group versus 444 of 5108 in the standard group (HR 1.00, 95% CI 0.88-1.14; p=1.00), and the second composite outcome was noted in 1591 of 5107 versus 1659 of 5108 (0.96, 0.89-1.02; p=0.19). Results were similar at study end (first composite outcome 556 of 5119 vs 586 of 5115 [HR 0.95, 95% CI 0.85-1.07, p=0.42]; and second 1956 of 5119 vs 2046 of 5115, respectively [0.95, 0.89-1.01, p=0.12]). Intensive therapy did not reduce the risk of advanced measures of microvascular outcomes, but delayed the onset of albuminuria and some measures of eye complications and neuropathy. Seven secondary measures at study end favoured intensive therapy (p<0.05)., Interpretation: Microvascular benefits of intensive therapy should be weighed against the increase in total and cardiovascular disease-related mortality, increased weight gain, and high risk for severe hypoglycaemia., Funding: US National Institutes of Health; National Heart, Lung, and Blood Institute; National Institute of Diabetes and Digestive and Kidney Diseases; National Institute on Aging; National Eye Institute; Centers for Disease Control and Prevention; and General Clinical Research Centers., (Copyright 2010 Elsevier Ltd. All rights reserved.)

Objective: To determine if baseline subgroups in the Action to Control Cardiovascular Risk in Diabetes (ACCORD) trial can be identified for whom intensive compared with standard glycemia treatment had different effects on all-cause mortality., Research Design and Methods: Exploratory post hoc intention-to-treat comparisons were made between intensive and standard glycemia groups on all-cause mortality by subgroups defined by baseline characteristics., Results: There were few significant interactions between baseline characteristics and effects of intensive versus standard glycemia treatment on mortality: self-reported history of neuropathy (hazard ratio [HR] 1.95, 95% CI 1.41-2.69) versus no history of neuropathy (0.99, 0.79-1.26; P value for interaction 0.0008), higher A1C (A1C >8.5%: HR 1.64, 95% CI 1.22-2.22; A1C 7.5-8.4%: 1.00, 0.75-1.34; A1C <7.5%: 1.00, 0.67-1.50; P value for interaction 0.04), and aspirin use (HR 1.45, 95% CI 1.13-1.85, compared with 0.96, 0.72-1.27, in nonusers; P value for interaction 0.03)., Conclusions: We found a remarkable similarity of effect from intensive compared with standard glycemia treatment on mortality across most baseline subgroups. No differential effect was found in subgroups defined by variables anticipated to have an interaction: age, duration of diabetes, and previous history of cardiovascular disease. The three baseline characteristics that defined subgroups for which there was a differential effect on mortality may help identify patients with type 2 diabetes at higher risk of mortality from intensive regimens for glycemic control. Further research is warranted.

Aims/hypothesis: The aim of the study was to examine the determinants of oral glucose tolerance in 602 persons with impaired glucose tolerance (IGT) who participated in the Actos Now for Prevention of Diabetes (ACT NOW) study., Methods: In addition to the 602 IGT participants, 115 persons with normal glucose tolerance (NGT) and 50 with impaired fasting glucose (IFG) were identified during screening and included in this analysis. Insulin secretion and insulin sensitivity indices were derived from plasma glucose and insulin during an OGTT. The acute insulin response (AIR) (0-10 min) and insulin sensitivity (S(I)) were measured with the frequently sampled intravenous glucose tolerance test (FSIVGTT) in a subset of participants., Results: At baseline, fasting plasma glucose, 2 h postprandial glucose (OGTT) and HbA(1c) were 5.8 +/- 0.02 mmol/l, 10.5 +/- 0.05 mmol/l and 5.5 +/- 0.04%, respectively, in participants with IGT. Participants with IGT were characterised by defects in early (DeltaI (0-30)/DeltaG (0-30) x Matsuda index, where DeltaI is change in insulin in the first 30 min and DeltaG is change in glucose in the first 30 min) and total (DeltaI(0-120)/DeltaG(0-120) x Matsuda index) insulin secretion and in insulin sensitivity (Matsuda index and S(I)). Participants with IGT in whom 2 h plasma glucose was 7.8-8.3 mmol/l had a 63% decrease in the insulin secretion/insulin resistance (disposition) index vs participants with NGT and this defect worsened progressively as 2 h plasma glucose rose to 8.9-9.94 mmol/l (by 73%) and 10.0-11.05 mmol/l (by 80%). The Matsuda insulin sensitivity index was reduced by 40% in IGT compared with NGT (p < 0.005). In multivariate analysis, beta cell function was the primary determinant of glucose AUC during OGTT, explaining 62% of the variance., Conclusion: Our results strongly suggest that progressive beta cell failure is the main determinant of progression of NGT to IGT.

Aim: To assess the efficacy and tolerability of vildagliptin compared with thiazolidinediones (TZDs) as an add on to metformin treatment in a primary care patient population with type 2 diabetes., Methods: This was a randomized, 12-week, open-label study comparing vildagliptin (100 mg, n = 1653) and TZD (agent and dose at the investigators' discretion, n = 825) add-on therapy in patients inadequately controlled [haemoglobin A(1C) (HbA(1c)): 7-10%] on a stable dose of metformin (> or =1000 mg/day). The primary objective was to test non-inferiority of vildagliptin to TZDs for the difference in change in HbA(1c) from baseline [established if the upper limit of the two-sided 95% confidence intervals (CI) did not exceed 0.4%]., Results: Mean (+/- s.e.) change in HbA(1c) from baseline to study endpoint was -0.68 +/- 0.02% in the vildagliptin group and -0.57 +/- 0.03% in the TZD group. The difference between groups was -0.11% (95% CI: -0.17% and -0.04%), establishing the non-inferiority of vildagliptin (p = 0.001) after 3 months of treatment. Vildagliptin was non-inferior to TZDs for subgroups of race, age and body mass index. Body weight increased in the TZD group (0.33 +/- 0.11 kg) and decreased in the vildagliptin group (mean: -0.58 +/- 0.09 kg; p < 0.001 for difference). Adverse events occurred in similar proportions of patients in both groups (vildagliptin: 39.5% and TZD: 36.3%) Hypoglycaemia and abnormal changes in liver enzymes were uncommon., Conclusions: This short-term study suggests that vildagliptin is as effective as TZDs after 3-month treatment as an add-on to metformin in a primary care population that included diverse patient subgroups.

Aim: To compare the efficacy and tolerability of vildagliptin vs. placebo in patients with type 2 diabetes mellitus (T2DM) who are inadequately controlled [haemoglobin A(1c) (HbA(1c)) 7.5 to 11%] with prior sulphonylurea (SU) monotherapy., Methods: This 24-week, multicentre, randomized, double-blind, placebo-controlled study assessed the effects of the dipeptidyl peptidase-4 inhibitor vildagliptin (50 mg given once or twice daily) vs. placebo added to glimepiride (4 mg once daily) in 515 patients with T2DM. Adjusted mean changes from baseline to end-point (AMDelta) in HbA(1c), fasting plasma glucose, fasting lipids and body weight were compared by analysis of covariance., Results: The between-group difference (vildagliptin - placebo) in AMDelta HbA(1c) was -0.6 +/- 0.1% in patients receiving vildagliptin 50 mg daily and -0.7 +/- 0.1% in those receiving 100 mg daily (p < 0.001 vs. placebo for both). Greater efficacy was seen in patients > or =65 years of age (-0.7 +/- 0.1% and -0.8 +/- 0.2% for 50 and 100 mg daily respectively) and in patients with baseline HbA(1c) > 9% (Delta = -1.0 +/- 0.2% and -0.9 +/- 0.2% for 50 and 100 mg daily respectively). Relative to placebo, patients receiving vildagliptin also had improvements in beta-cell function and postprandial glucose, with small changes in fasting lipids and body weight. The incidences of adverse events (AEs) (67.1, 66.3 and 64.2%) and serious AEs (2.9, 2.4 and 5.1%) were similar in patients receiving 50 mg vildagliptin, 100 mg vildagliptin or placebo respectively. The incidence of hypoglycaemic events was low but slightly higher in the group receiving vildagliptin 100 mg (3.6%) than in the group receiving vildagliptin 50 mg (1.2%) or placebo (0.6%)., Conclusions: In patients with T2DM inadequately controlled with prior SU monotherapy, addition of vildagliptin (50 or 100 mg daily) to glimepiride (4 mg once daily) improves glycaemic control and is well tolerated. Addition of vildagliptin 50 mg daily to SU monotherapy may be a particularly attractive therapy in elderly patients.

Aim: To assess the effects of 24-week treatment with vildagliptin on measures of beta-cell function in a broad spectrum of drug-naïve patients with type 2 diabetes (T2DM)., Methods: Data from all double-blind, multicentre, randomized, placebo- or active-controlled trials conducted in drug-naïve patients with T2DM were pooled from all patients receiving monotherapy with vildagliptin (100 mg daily: 50 mg twice daily or 100 mg once daily, n = 1855) or placebo (n = 347). Fasting measures of beta-cell function [homeostasis model assessment of beta-cell function (HOMA-B) and proinsulin : insulin ratio] were assessed in the overall pooled monotherapy population. Standard meal tests were performed at baseline and week 24 in a subset of patients, and effects of vildagliptin (100 mg daily, n = 227) on dynamic (meal test-derived) measures of beta-cell function [insulin secretion rate relative to glucose (ISR/G) and insulinogenic indices] were assessed relative to baseline and vs. placebo (n = 29)., Results: In the overall population, vildagliptin significantly increased HOMA-B both relative to baseline [adjusted mean change (AMDelta) = 10.3 +/- 1.5] and vs. placebo (between-treatment difference in AMDelta = 11.5 +/- 4.5, p = 0.01) and significantly decreased the proinsulin : insulin ratio relative to baseline (AMDelta = -0.05 +/- 0.01) and vs. placebo (between-treatment difference in AMDelta = -0.09 +/- 0.02, p < 0.001). Relative to baseline, vildagliptin monotherapy significantly increased all meal test-derived parameters, and ISR/G (between-treatment difference in AMDelta = 9.8 +/- 2.8 pmol/min/m(2)/mM, p < 0.001) and the insulinogenic index(0-peak glucose) (between-treatment difference in AMDelta = 0.24 +/- 0.05 pmol/mmol, p = 0.045) were significantly increased vs. placebo., Conclusions: Vildagliptin monotherapy consistently produced robust improvements in both fasting and meal test-derived measures of beta-cell function across a broad spectrum of drug-naïve patients with T2DM. All Phase III trials described (NCT 00099905, NCT 00099866, NCT 00099918, NCT 00101673, NCT 00101803 and NCT 00120536) are registered with ClinicalTrials.gov.

Objective: The purpose of this study was to evaluate the efficacy and safety of vildagliptin in elderly patients with type 2 diabetes., Research Design and Methods: Efficacy data from five double-blind, randomized, placebo- or active-controlled trials of >or=24 weeks' duration were pooled. Effects of 24-week vildagliptin monotherapy (100 mg daily) were compared in younger (<65 years, n = 1,231) and older (>or=65 years, n = 238) patients. Safety data from eight controlled clinical trials of >or=12-weeks' duration were pooled; adverse event profiles in younger (n = 1,890) and older (n = 374) patients were compared., Results: Mean baseline A1C and fasting plasma glucose (FPG) were significantly lower in older (70 years: 8.3 +/- 0.1% and 9.6 +/- 0.1 mmol/l, respectively) than in younger (50 years: 8.7 +/- 0.0% and 10.5 +/- 0.1 mmol/l, respectively) patients. Despite this, the adjusted mean change from baseline (AMDelta) in A1C was -1.2 +/- 0.1% in older and -1.0 +/- 0.0% in younger vildagliptin-treated patients (P = 0.092), and the AMDelta in FPG was significantly larger in older (-1.5 +/- 0.2 mmol/l) than in younger (-1.1 +/- 0.1 mmol/l, P = 0.035) patients. Body weight was significantly lower at baseline in older (83.4 +/- 1.0 kg) than in younger (92.0 +/- 0.6 kg) patients. Weight decreased significantly in the older subgroup (AMDelta -0.9 +/- 0.3 kg, P = 0.007), whereas smaller, nonsignificant decreases occurred in younger patients (AMDelta -0.2 +/- 0.1 kg). Adverse event rates were slightly higher in older than in younger subgroups but were lower among older, vildagliptin-treated subjects (63.6%) than in the pooled active comparator group (68.1%). Vildagliptin treatment did not increase adverse events among older patients with mild renal impairment (62.0%). Hypoglycemia was rare (0.8%) in the elderly patients, and no severe events occurred., Conclusions: Vildagliptin monotherapy was effective and well tolerated in treatment-naive elderly patients.

Stress is a risk factor for chronic illnesses such as obesity, type 2 diabetes, and hypertension and has been postulated to cause the metabolic syndrome via perturbation of the hypothalamo-pituitary-adrenal (HPA) axis. In our model of early-life stress (variable foraging demand [VFD]), food insecurity is imposed on monkey mothers for 16 weeks beginning when their nursing offspring are 3-5 months of age. Under VFD, food availability is never restricted, and the infant's growth is unaffected. VFD rearing does, however, cause a range of neurobiological abnormalities, including dysregulation of the HPA axis, manifested in abnormal cerebrospinal fluid cortisol and corticotropin-releasing factor levels. We previously reported spontaneous occurrence of metabolic syndrome in 14% of normally reared peripubertal bonnet macaques given ad libitum access to standard monkey chow. Here, we show that compared with normally reared monkeys, peripubertal VFD juveniles exhibit greater weight, BMI, abdominal circumference, and glucagon-like peptide-1 and decreased glucose disposal rates during hyperinsulinemic-euglycemic clamps. Our data suggest that early-life stress during a critical period of neuro development can result in the peripubertal emergence of obesity and insulin resistance.

Obesity is the most common metabolic disease globally. It is increasingly a problem of children and individuals in poor countries characterized by food insecurity. This is of great concern as childhood obesity predicts increased future adult obesity. To curb the epidemic of obesity, it is essential to understand the regulation of appetite. Energy stores and nutrient homeostasis are maintained by hypothalamic regulation of energy balance. The hypothalamus receives neural and endocrine signals from the gut, adipose tissue and pancreas in response to food intake. These are integrated, interpreted and directed to other centers in the brain and peripheral organs to orchestrate energy homeostasis. This brain-gut axis is disrupted in obesity. This review discusses the various hormones involved in the regulation of energy balance both at the level of the gut and in the central nervous system.

Complementary and alternative medicine (CAM) describes a diverse group of medical and health care systems, practices, and products not currently considered to be part of conventional medicine. Inadequacies in current treatments for diabetes have led 2 to 3.6 million Americans to use CAM for diabetes treatment, despite limited studies of safety and efficacy of CAM methods. CAM is used mostly by West Indians, Africans, Indians, Latin Americans, or Asians. Prayer, acupuncture, massage, hot tub therapy, biofeedback, and yoga have been used as well as various plant remedies for treating diabetes. Several CAM practices and herbal remedies are promising for diabetes treatment, but further rigorous study is needed in order to establish safety, efficacy, and mechanism of action. In the meantime, it is important to be aware that many patients with diabetes may be using CAM and to consider potential interactions with conventional medicines being used.

We have previously demonstrated abnormalities in insulin secretion in adolescents with type 2 diabetes mellitus (DM2) in response to the mixed meal test and to glucagon. In order to further assess beta-cell function in DM2, we measured insulin and C-peptide responses to oral glucose in adolescents with DM2 in comparison to non-diabetic obese and lean adolescents. We studied 20 patients with DM2, 25 obese adolescents with matching body mass index (BMI) (33.8 +/- 1.4 vs 34.3 +/- 1.0 kg/m2), and 12 non-obese control adolescents (BMI 22.6 +/- 0.6 kg/m2). Mean age, sex and sexual maturation did not differ between the three groups. All adolescents with DM2 had negative islet cell antibodies (ICA); five patients were on diet and 15 on insulin treatment. Fasting lipid profiles were determined in all participants. Plasma glucose and serum C-peptide and insulin levels were measured at 0, 30, 60, 90, and 120 min after an oral glucose load. The C-peptide increment (deltaCP) was calculated as peak minus fasting C-peptide. Area under the curve (AUC) was estimated using the trapezoid method. Insulin resistance was estimated using the HOMA model (HOMA-IR). The first phase of insulin secretion (PH1) was computed using a previously published formula. Serum triglyceride levels were significantly higher in the patients with DM2 compared to the non-obese controls (1.4 +/- 0.1 vs 0.9 +/- 0.1 mmol/l; p = 0.02). Plasma glucose AUC was greater in the patients with DM2 compared to the obese and non-obese control groups (1,660 +/- 130 vs 717 +/- 17 vs 647 +/- 14 mmol/l x min; p < 0.0001). ACP was lower in adolescents with DM2 than in obese and non-obese adolescents (761 +/- 132 vs 1,721 +/- 165 vs 1,225 +/- 165 pmol/l; p < 0.001). Insulin AUC was lower in the patients with DM2 compared to obese controls (888 +/- 206 vs 1,606 +/- 166 pmol/l x h; p = 0.009), but comparable to that of the non-obese controls (888 +/- 206 vs 852 +/- 222 pmol/l x h; p = 0.9). Insulin AUC was also higher in the obese than in the non-obese group (p = 0.05). PH1 was significantly higher in the obese group compared to the patients with DM2 as well as to the non-obese controls (2,614 +/- 2,47.9 vs 929.6 +/- 403.5 vs 1,946 +/- 300.6 pmol/l, respectively; p = 0.001). PH1 was also higher in the non-obese controls than in the patients with DM2 (p = 0.05). HOMA-IR was three-fold higher in the patients with DM2 than in the BMI-matched obese group, and five-fold higher than in the lean controls (14.3 +/- 1.2 vs 5.4 +/- 0.8 vs 2.9 +/- 0.4; p = 0.0002). Adolescents with DM2 have dyslipidemia, a significant cardiovascular risk factor. Decreased beta-cell function is characteristic of adolescents with DM2 in the presence of severe insulin resistance.