Time of Day When Type 1 Diabetes Patients With Eating Disorder Symptoms Most Commonly Restrict Insulin.

OBJECTIVE: Restricting insulin to lose weight is a significant problem in the clinical management of type 1 diabetes (T1D). Little is known about this behavior or how to effectively intervene. Identifying when insulin restriction occurs could allow clinicians to target typical high-risk times or formulate hypotheses regarding factors that influence this behavior. The current study investigated the frequency of insulin restriction by time of day. METHODS: Fifty-nine adults with T1D and eating disorder symptoms completed 72 hours of real-time reporting of eating and insulin dosing with continuous glucose monitoring. We used a generalized estimating equation model to test the global hypothesis that frequency of insulin restriction (defined as not taking enough insulin to cover food consumed) varied by time of day, and examined frequency of insulin restriction by hour. We also examined whether patterns of insulin restriction for 72 hours corresponded with patients' interview reports of insulin restriction for the past 28 days. RESULTS: Frequency of insulin restriction varied as a function of time (p = .016). Insulin restriction was the least likely in the morning hours (6:00-8:59 AM), averaging 6% of the meals/snacks consumed. Insulin restriction was more common in the late afternoon (3:00-5:59 PM), peaking at 29%. Insulin was restricted for 32% of the meals/snacks eaten overnight (excluding for hypoglycemia); however, overnight eating was rare. Insulin restriction was associated with higher 120-minute postprandial blood glucose (difference = 44.4 mg/dL, 95% confidence interval = 22.7-68.5, p < .001) and overall poorer metabolic control (r = 0.43-0.62, p's < .01). Patients reported restricting insulin for a greater percentage of meals and snacks for the past 28 days than during the 72 hour real-time assessment; however, the reports were correlated (Spearman's ρ = 0.46, p < .001) and accounted for similar variance in HbA1c (34% versus 35%, respectively). CONCLUSIONS: Findings suggest that insulin restriction may be less likely in the morning, and that late afternoon is a potentially important time for additional therapeutic support. Results also suggest that systematic clinical assessment and treatment of overnight eating might improve T1D management.

Injectable protease-operated depots of glucagon-like peptide-1 provide extended and tunable glucose control.

Peptide drugs are an exciting class of pharmaceuticals increasingly used for the treatment of a variety of diseases; however, their main drawback is a short half-life, which dictates multiple and frequent injections and an undesirable "peak-and-valley" pharmacokinetic profile, which can cause undesirable side-effects. Synthetic prolonged release formulations can provide extended release of biologically active native peptide, but their synthetic nature can be an obstacle to production and utilization. Motivated by these limitations, we have developed a new and entirely genetically encoded peptide delivery system--Protease Operated Depots (PODs)--to provide sustained and tunable release of a peptide drug from an injectable s.c. depot. We demonstrate proof-of-concept of PODs, by fusion of protease cleavable oligomers of glucagon-like peptide-1, a type-2 diabetes drug, and a thermally responsive, depot-forming elastin-like-polypeptide that undergoes a thermally triggered inverse phase transition below body temperature, thereby forming an injectable depot. We constructed synthetic genes for glucagon-like peptide-1 PODs and demonstrated their high-yield expression in Escherichia coli and facile purification by a nonchromatographic scheme we had previously developed. Remarkably, a single injection of glucagon-like peptide-1 PODs was able to reduce blood glucose levels in mice for up to 5 d, 120 times longer than an injection of the native peptide drug. These findings demonstrate that PODs provide the first genetically encoded alternative to synthetic peptide encapsulation schemes for sustained delivery of peptide therapeutics.

Forty-Year Trends in Tooth Loss Among American Adults With and Without Diabetes Mellitus: An Age-Period-Cohort Analysis.

INTRODUCTION: This study aimed to assess the trends in tooth loss among adults with and without diabetes mellitus in the United States and racial/ethnic disparities in tooth loss patterns, and to evaluate trends in tooth loss by age, birth cohorts, and survey periods. METHODS: Data came from 9 waves of the National Health and Nutrition Examination Survey (NHANES) from 1971 through 2012. The trends in the estimated tooth loss in people with and without diabetes were assessed by age groups, survey periods, and birth cohorts. The analytical sample was 37,609 dentate (ie, with at least 1 permanent tooth) adults aged 25 years or older. We applied hierarchical age-period-cohort cross-classified random-effects models for the trend analysis. RESULTS: The estimated number of teeth lost among non-Hispanic blacks with diabetes increased more with age than that among non-Hispanic whites with diabetes (z = 4.05, P < .001) or Mexican Americans with diabetes (z = 4.38, P < .001). During 1971-2012, there was a significant decreasing trend in the number of teeth lost among non-Hispanic whites with diabetes (slope = -0.20, P < .001) and non-Hispanic blacks with diabetes (slope = -0.37, P < .001). However, adults with diabetes had about twice the tooth loss as did those without diabetes. CONCLUSION: Substantial differences in tooth loss between adults with and without diabetes and across racial/ethnic groups persisted over time. Appropriate dental care and tooth retention need to be further promoted among adults with diabetes.

Risk vs benefit in diabetes pharmacotherapy: a rational approach to choosing pharmacotherapy in type 2 diabetes.

Type 2 diabetes now affects more than 1 in 10 US adults and is a leading cause of morbidity, mortality, and healthcare expense. There are increasing numbers of available pharmacotherapies, with established agents as well as newer drugs developed from hormones in the incretin pathway, among others. New data are accumulating continuously with respect to potential benefits of both long-standing and new agents, as well as risks identified through post-marketing surveillance. Here we review the commonly prescribed pharmacotherapy options with attention to recently published information and provide a rational approach to choice of therapy.

Severe hypoglycemia symptoms, antecedent behaviors, immediate consequences and association with glycemia medication usage: Secondary analysis of the ACCORD clinical trial data.

BACKGROUND: Hypoglycemia is a common complication of diabetes treatment. This paper describes symptoms, predecessors, consequences and medications associated with the first episode of severe hypoglycemia among ACCORD participants with type 2 diabetes, and compares these between intensive (Int: goal A1C <6.0%) and standard (Std, goal A1C 7-7.9%) glycemia intervention groups. METHODS: Information about symptoms, antecedents, and consequences was collected at the time participants reported an episode of severe hypoglycemia. Data on medications prescribed during the clinical trial was used to determine the association of particular diabetes drug classes and severe hypoglycemia. RESULTS: The most frequently reported symptoms in both glycemia group were weakness/fatigue (Int 29%; Std 30%) and sweating (Int 26%; Std 27%), followed by confusion/disorientation (Int 22%; Std 29%) and shakiness (Int 21%; Std 19%). Approximately half of all events were preceded by a variation in food intake (Int 48%; Std 58%). The most common consequences were confusion (Int 37%; Std 34%), loss of consciousness (Int 25%; Std 25%), and hospitalization (Int 18%; Std 24%). The highest rates of hypoglycemia were found among those participants treated with insulin only (Int 6.09/100 person yrs; Std 2.64/100 person yrs) while the lowest were among those prescribed oral agents only (Int 1.93/100 person yrs; Std 0.20/100 person yrs). CONCLUSIONS: Severe hypoglycemia episodes were frequently preceded by a change in food intake, making many episodes potentially preventable. Symptoms of confusion/disorientation and loss of consciousness were frequently seen. The highest rates of hypoglycemia were seen with prescription of insulin, either alone or in combination with other medications. CLINICAL TRIAL REGISTRATION: Number: NCT00000620.

Robertsite, Ca(2)Mn(III) (3)O(2)(PO(4))(3)·3H(2)O.

Robertsite, ideally Ca(2)Mn(3)O(2)(PO(4))(3)·3H(2)O [calcium manganese(III) tris-(orthophosphate) trihydrate], can be associated with the arseniosiderite structural group characterized by the general formula Ca(2)A(3)O(2)(TO(4))(3)·nH(2)O, with A = Fe, Mn; T = As, P; and n = 2 or 3. In this study, single-crystal X-ray diffraction data were used to determine the robertsite structure from a twinned crystal from the type locality, the Tip Top mine, Custer County, South Dakota, USA, and to refine anisotropic displacement parameters for all atoms. The general structural feature of robertsite resembles that of the other two members of the arseniosiderite group, the structures of which have previously been reported. It is characterized by sheets of [MnO(6)] octa-hedra in the form of nine-membered pseudo-trigonal rings. Located at the center of each nine-membered ring is a PO(4) tetra-hedron, and the other eight PO(4) tetra-hedra sandwich the Mn-oxide sheets. The six different Ca(2+) ions are seven-coordinated in form of distorted penta-gonal bipyramids, [CaO(5)(H(2)O)(2)], if Ca-O distances less than 2.85 Šare considered. Along with hydrogen bonding involving the water mol-ecules, they hold the manganese-phosphate sheets together. All nine [MnO(6)] octa-hedra are distorted by the Jahn-Teller effect.

Effects of pregabalin on heart rate variability in patients with painful diabetic neuropathy.

UNLABELLED: Many studies have demonstrated that low heart rate variability (HRV) is a risk for high mortality and morbidity in patients with cardiovascular diseases. The primary purpose of the study was to evaluate whether pregabalin improves HRV in patients with diabetes and painful peripheral neuropathy. Resting heart rates were collected by using the LifeShirt System, developed by VivoMetrics (Ventura, Calif), at baseline and at the end of a 4-week intervention of pregabalin or placebo in patients with painful diabetic peripheral neuropathy. Heart rate variability analysis was performed on the collected R-R intervals using the Vivo- VMLA-036-00 3 Logic of the LifeShirt system. Of the 40 patients enrolled in the study, 70% completed the end of 4-week assessments (n = 15 in pregabalin and n = 14 in placebo). Compared with placebo, pregabalin treatment resulted in significant improvement in HRV measured by frequency domain analysis, that is, a reduction in low frequency-high frequency ratio (-1.30 ± 2.89 vs 0.37 ± 0.33, P = 0.03) and power of normalized low frequency (-0.049 ± 0.092 vs 0.0066 ± 0.023, P = 0.02), as well as an increase in power of normalized high frequency (0.039 ± 0.094 vs -0.038 ± 0.066, P = 0.02). Furthermore, pregabalin resulted in greater reduction of pain and symptoms of anxiety and greater improvement of quality of life. The improvement of HRV measures were not correlated with change of those measures. In conclusion, 4-week pregabalin treatment improved HRV in patients with painful diabetic peripheral neuropathy. TRIAL REGISTRATION: NCT00573261 (clinicaltrials.gov).

An open trial of app-assisted acceptance and commitment therapy (iACT) for eating disorders in type 1 diabetes.

BACKGROUND: Eating disorders (EDs) among individuals with type 1 diabetes (T1D) increase the risk of early and severe diabetes-related medical complications and premature death. Conventional eating disorder (ED) treatments have been largely ineffective for T1D patients, indicating the need to tailor treatments to this patient population and the unique conditions under which ED symptoms emerge (in the context of a chronic illness with unrelenting demands to control blood glucose, diet and exercise). The current study was a pilot open trial of iACT, a novel intervention for EDs in T1D grounded in Acceptance and Commitment Therapy (ACT). iACT was based on the premise that ED symptoms emerge as individuals attempt to cope with T1D and related emotional distress. iACT taught acceptance and mindfulness as an alternative to maladaptive avoidance and control, and leveraged personal values to increase willingness to engage in T1D management, even when it was upsetting (e.g., after overeating). A tailored mobile application ("app") was used in between sessions to facilitate the application of ACT skills in the moment that individuals are making decisions about their diabetes management. METHODS: Adults with T1D who met criteria for an ED completed 12 sessions of iACT (with three optional tapering sessions). In addition to examining whether treatment was acceptable and feasible (the primary aim of the study), the study also examined whether iACT was associated with increased psychological flexibility (i.e., the ability to have distressing thoughts/feelings about diabetes while pursuing personally meaningful values), and improvements in ED symptoms, diabetes management and diabetes distress. RESULTS: Treatment was acceptable to T1D patients with EDs and feasible to implement. Participants reported increased psychological flexibility with diabetes-related thoughts/feelings, and less obstruction and greater progress in pursuing personal values. There were large effects for change in ED symptoms, diabetes self-management and diabetes distress from baseline to end-of-treatment (Cohen's d = .90-1.79). Hemoglobin A1c also improved, but the p-value did not reach statistical significance, p = .08. CONCLUSIONS: Findings provide preliminary evidence for iACT to improve outcomes for T1D patients with EDs and support further evaluation of this approach in a controlled trial. TRIAL REGISTRATION: NCT02980627 . Registered 8 July 2016.

Non-invasive wearables for remote monitoring of HbA1c and glucose variability: proof of concept.

INTRODUCTION: Diabetes prevalence continues to grow and there remains a significant diagnostic gap in one-third of the US population that has pre-diabetes. Innovative, practical strategies to improve monitoring of glycemic health are desperately needed. In this proof-of-concept study, we explore the relationship between non-invasive wearables and glycemic metrics and demonstrate the feasibility of using non-invasive wearables to estimate glycemic metrics, including hemoglobin A1c (HbA1c) and glucose variability metrics. RESEARCH DESIGN AND METHODS: We recorded over 25 000 measurements from a continuous glucose monitor (CGM) with simultaneous wrist-worn wearable (skin temperature, electrodermal activity, heart rate, and accelerometry sensors) data over 8-10 days in 16 participants with normal glycemic state and pre-diabetes (HbA1c 5.2-6.4). We used data from the wearable to develop machine learning models to predict HbA1c recorded on day 0 and glucose variability calculated from the CGM. We tested the accuracy of the HbA1c model on a retrospective, external validation cohort of 10 additional participants and compared results against CGM-based HbA1c estimation models. RESULTS: A total of 250 days of data from 26 participants were collected. Out of the 27 models of glucose variability metrics that we developed using non-invasive wearables, 11 of the models achieved high accuracy (<10% mean average per cent error, MAPE). Our HbA1c estimation model using non-invasive wearables data achieved MAPE of 5.1% on an external validation cohort. The ranking of wearable sensor's importance in estimating HbA1c was skin temperature (33%), electrodermal activity (28%), accelerometry (25%), and heart rate (14%). CONCLUSIONS: This study demonstrates the feasibility of using non-invasive wearables to estimate glucose variability metrics and HbA1c for glycemic monitoring and investigates the relationship between non-invasive wearables and the glycemic metrics of glucose variability and HbA1c. The methods used in this study can be used to inform future studies confirming the results of this proof-of-concept study.

Engineering digital biomarkers of interstitial glucose from noninvasive smartwatches.

Prediabetes affects one in three people and has a 10% annual conversion rate to type 2 diabetes without lifestyle or medical interventions. Management of glycemic health is essential to prevent progression to type 2 diabetes. However, there is currently no commercially-available and noninvasive method for monitoring glycemic health to aid in self-management of prediabetes. There is a critical need for innovative, practical strategies to improve monitoring and management of glycemic health. In this study, using a dataset of 25,000 simultaneous interstitial glucose and noninvasive wearable smartwatch measurements, we demonstrated the feasibility of using noninvasive and widely accessible methods, including smartwatches and food logs recorded over 10 days, to continuously detect personalized glucose deviations and to predict the exact interstitial glucose value in real time with up to 84% and 87% accuracy, respectively. We also establish methods for designing variables using data-driven and domain-driven methods from noninvasive wearables toward interstitial glucose prediction.

Comparative risk of musculoskeletal adverse reactions among new users of dipeptidyl peptidase-4 inhibitors: A retrospective cohort study.

Background: The effects of dipeptidyl peptidase-4 inhibitors (DPP4Is) on joint pain have been controversial. Objective: To assess the comparative musculoskeletal (MSk) risk of DPP4Is vs. non-DPP4Is. Methods: This study used a national claims database from January 2007 to December 2014. Exposure included the initiation of DPP4Is against the initiation of non-DPP4Is: metformin, sulfonylureas, thiazolidinediones, meglitinides, and glucagonlike peptide-1 receptor agonists (GLP-1 RAs). Insulin was not included in this study. Outcomes were newly diagnosed MSk conditions (arthralgia, arthropathy, and rheumatoid arthritis or other inflammatory polyarthropathies). Individuals exposed to DPP4Is were matched to those exposed to non-DPP4Is using a propensity score (PS). Balance between the DPP4I's group and the non-DPP4I's group was assessed using standardized differences for both continuous and categorical variables. Cox regressions were used to estimate hazard ratios (HRs) for MSk conditions. Results: Among PS-matched cohorts, incidence rates (IRs) for MSk conditions did not differ between DPP4I initiators and non-DPP4I initiators (HR = 1.01, 95% CI: 0.97-1.05). After stratifying non-DPP4Is by drug class, the results still showed that DPP4I initiators had similar MSk risk when compared to initiators of metformin, sulfonylureas, meglitinides, and GLP-1 RAs. However, thiazolidinedione initiators had higher risk of MSk conditions than DPP4I initiators (HR = 1.05, 95% CI: 1.00-1.10). Conclusions: This head-to-head comparison study estimated comparative MSk risks among different antidiabetic drugs. The risk of MSk conditions among DPP4I initiators were not significantly higher than non-DPP4I initiators.

Hostility and minimal model of glucose kinetics in African American women.

OBJECTIVE: To explore the underlying physiology of hostility (HOST) and to test the hypothesis that HOST has a greater impact on fasting glucose in African American (AA) women than it does on AA men or white men or women, using an intravenous glucose tolerance test (IVGTT) and the minimal model of glucose kinetics. METHODS: A total of 115 healthy subjects selected for high or low scores on the 27 item Cook Medley HOST Scale underwent an IVGTT. Fasting nonesterified fatty acids (NEFA) levels were measured before the IVGTT. Catecholamine levels were measured 10 minutes into the IVGTT. RESULTS: Moderation by group (AA women versus others) of HOST was found for glucose effectiveness (Sg, p = .02), acute insulin response (AIRg, p = .02), and disposition index (DI, p = .02). AA women showed a negative association between HOST and both Sg (beta = -0.45, p = .04) and DI (beta = -0.49, p = .02), controlling for age and body mass index. HOST was also associated with changes in epinephrine (beta = 0.39, p = .05) and fasting NEFA (beta = 0.44, p = .02) in the AA women. Controlling for fasting NEFA reduced the effect of HOST on both Sg and DI. CONCLUSIONS: This study shows that HOST is related to decreased DI, a measure of pancreatic compensation for increased insulin resistance as well as decreased Sg, a measure of noninsulin-mediated glucose transport compared in AA women. These effects are partly mediated by the relationship of HOST to fasting NEFA.

Hostility and fasting glucose in African American women.

OBJECTIVE: To examine whether the relationship of hostility (HOST) to fasting glucose indices is moderated by sex and race. HOST has been associated with abnormalities in glucose metabolism. Prior studies suggested that this association may be more prevalent in women and in African American (AA) individuals. METHODS: A total of 565 healthy AA and white (W) men and women (mean age = 33 +/- 6 years) were assessed. HOST was measured by the 27-item version of the Cook Medley HOST Scale. The moderating effects of sex and race were evaluated for the associations of HOST to fasting glucose, insulin, and insulin sensitivity (HOMA-IR). RESULTS: Analysis showed a moderating effect of sex and race on the association of HOST to fasting glucose (p = .03), but not for insulin (p = .12). Analysis of HOMA-IR revealed a trend (p = .06) for the interaction. Stratified analyses by race and sex revealed a positive association between HOST and fasting glucose only in AA women, which remained significant after controlling for age and body mass index. CONCLUSION: A relationship between HOST and fasting glucose was evident in AA women only, a group that has twice the risk of developing Type 2 diabetes compared with W women. Further studies are needed to elucidate the mechanisms by which HOST may affect glucose metabolism in AA women.

The growing burden of diabetes mellitus in the US elderly population.

BACKGROUND: The prevalence of diabetes mellitus is growing worldwide. Consequently, there has been increased emphasis on primary and secondary prevention of diabetes. To our knowledge, whether there have been actual improvements in outcomes in the last decade or so has not been documented in a nationally representative sample. METHODS: We undertook this study to examine trends in rates of occurrence of diabetes and its complications in persons older than 65 years in the United States. National longitudinal analysis of Medicare claims and other Medicare program data for persons first diagnosed as having diabetes during 1994 (n=33 164), 1999 (n=31 722), or 2003 (n=40 058) were compared with 2 control groups of persons of approximately equal sample size who were not diagnosed as having diabetes, alternatively during 1994, 1999, or 2003 or for the entire period from 1994 to 1999 or from 1999 to 2004. The main outcome measures were death and complications of diabetes including cardiovascular, cerebrovascular, ophthalmic, renal, and lower extremity events. RESULTS: The annual incidence of diabetes increased by 23% between 1994-1995 and 2003-2004, and prevalence increased by 62%. The mortality rate after diagnosis in persons having diagnosed diabetes decreased by 8.3% compared with that in the control groups. Complication rates among persons diagnosed as having diabetes generally increased or stayed the same compared with those in the control groups during 1994 to 2004 except for ophthalmic diseases associated with diabetes. Rates for some major complications were high; for example, the rate for congestive heart failure in the diabetes group during 1999 to 2004 was 475 per 1000 persons. In some cases, most notably renal events, including the most serious complications, there were increases in prevalence in both the diabetes and control groups. CONCLUSION: The burden of financing and providing medical care for persons older than 65 in the United States having diagnosed diabetes is growing rapidly as a result of increased incidence and, especially, prevalence of diagnosed diabetes, decreased mortality, and overall lack of improvement in rates of complications in persons having diagnosed diabetes.

Longitudinal incidence and prevalence of adverse outcomes of diabetes mellitus in elderly patients.

BACKGROUND: The natural history of type 2 diabetes mellitus (DM) in the elderly has not been previously described in a national longitudinal sample. METHODS: This national longitudinal analysis (January 1, 1991, to December 31, 2004) examines mortality and morbidity rates in a representative sample of elderly patients newly diagnosed as having DM. Medicare beneficiaries diagnosed as having DM in 1994 (n=33,772) were compared with a control group (n=25,563) regarding death, lower extremity complications, nephropathy, retinopathy, cardiovascular complications, and cerebrovascular complications. RESULTS: The DM group had excess mortality of 9.2% by year 11 compared with the control group. By 2004, 91.8% of the DM group experienced an adverse complication compared with 72.0% of the control group. The DM group had a higher prevalence and incidence of microvascular and macrovascular complications at all time points compared with controls. Patients with DM were at increased risk for all lower extremity complications, particularly those requiring surgical intervention (gangrene, debridement, and amputation). Cardiovascular complications were a leading cause of morbidity, with 57.6% of the DM group diagnosed as having heart failure compared with 34.1% of the controls. CONCLUSION: Elderly persons newly diagnosed as having DM experienced high rates of complications during 10-year follow-up, far in excess of elderly persons without this diagnosis, implying a substantial burden on the individual and on the health care system.

New combination treatments in the management of diabetes: focus on sitagliptin-metformin.

Type 2 diabetes mellitus is an increasingly prevalent condition worldwide. The complications of this disease are known to significantly increase the morbidity and mortality of those affected, resulting in substantial direct and indirect costs. Although good glycemic control has been shown to reduce the incidence and progression of diabetes-related microvascular complications, blood glucose levels are not adequately controlled in most individuals with diabetes. The reasons for this are many, and include issues such as poor adherence to complex medication regimes; costs of prescribed therapies; and the failure of traditionally prescribed medications to preserve beta cell function over time. However, our armamentarium of glucose-lowering drugs has expanded recently with the development of medications that act via the incretin pathway. Sitagliptin, the first commercially available dipeptidyl peptidase-4 inhibitor, inhibits the metabolism and inactivation of the incretin hormones GLP-1 and GIP. The subsequent elevation in levels of these hormones and associated prolongation of their actions has been shown to increase insulin secretion and suppress glucagon secretion in a glucose-appropriate fashion. Sitagliptin therapy in individuals with type 2 diabetes has been found to lower significantly hemoglobin A1c (Hb1c) levels with a minimum of adverse side effects such as weight gain or hypoglycemia. Use of sitagliptin in conjunction with the insulin-sensitizing medication metformin has been shown to decrease HbAlc levels more significantly than does either drug alone. This combination of medications is generally well tolerated, with no adverse effects on weight and a very low likelihood of treatment-related hypoglycemia. Use of both drugs will positively affect many of the underlying metabolic abnormalities associated with type 2 diabetes, including the disordered secretion of insulin and glucagon as well as impaired sensitivity to insulin which are known to accompany this disease. Animal studies also suggest that dipeptidyl peptidase-4 inhibitor treatment may help to preserve beta cell mass; however, it is unclear at present whether or not this will prove to be the case in humans.

Glycemia treatment strategies in the Action to Control Cardiovascular Risk in Diabetes (ACCORD) trial.

There is an independent progressive epidemiologic relation between glycemia and cardiovascular disease (CVD) events; however, whether lowering glucose levels with currently available therapies can reduce CVD events remains unknown. The Action to Control Cardiovascular Risk in Diabetes (ACCORD) trial is designed to answer this question in high-risk patients with type 2 diabetes mellitus. In ACCORD, 10,251 patients with type 2 diabetes and other CVD risk factors or CVD were randomly allocated to intensive glycemic control, targeting a glycosylated hemoglobin (HbA1c) level <6%, or standard glycemic control, targeting an HbA1c level of 7.0%-7.9%. All participants are provided with diabetes education, glucose-monitoring equipment, and antidiabetic medications. All participants in the intensive glycemic control group are started on > or = 2 classes of agents. Doses are intensified or a new medication class is added every month if HbA1c levels are > or = 6% or if >50% of premeal or postmeal capillary glucose readings are >5.6 mmol/L (100 mg/dL) or >7.8 mmol/L (140 mg/dL), respectively. All drug combinations are permitted, and drugs are reduced only because of side effects or contraindications. Annual training, menus of approaches for intensification, regular electronic messaging, audits of achieved glycemia, and central feedback to sites support glycemic intensification strategies in intensive participants. In participants in the standard glycemic control group, therapy is intensified whenever HbA1c is > or = 8%, and antihyperglycemic drugs that promote hypoglycemia (ie, insulin or insulin secretagogues) are reduced if HbA1c persistently decreases to <7% in the setting of hypoglycemia. ACCORD addresses the hypothesis that aggressive glucose lowering prevents CVD events in patients with type 2 diabetes. It is focused on the levels of glycemia achieved using a variety of strategies, not on the specific therapies used. It will also provide information on how to safely approach near-normal levels of glucose control in clinical practice and evidence to support future clinical guidelines for diabetes management in older adults.

Changes in depressive symptoms and glycemic control in diabetes mellitus.

OBJECTIVE: To investigate if changes in depressive symptoms would be associated with changes in glycemic control over a 12-month period in patients with Type 1 and Type 2 diabetes. METHODS: Ninety (Type 1 diabetes, n = 28; Type 2 diabetes, n = 62) patients having Beck Depression Inventory (BDI) levels of >10 were enrolled in the study. Of those 90 patients, 65 patients completed a 12-week cognitive behavioral therapy intervention. BDI was assessed at baseline and thereafter biweekly during 12 months. Hemoglobin (HbA1c) and fasting blood glucose levels were assessed at baseline and at four quarterly in-hospital follow-up visits. Linear mixed-model analysis was applied to determine the effects of time and diabetes type on depressive symptoms, HbA1c levels, and fasting glucose levels. RESULTS: Mean and standard deviation baseline BDI and HbA1c levels were 17.9 +/- 5.8 and 7.6 +/- 1.6, respectively, with no significant difference between patients with Type 1 and Type 2 diabetes. Mixed-model regression analysis found no difference between the groups with Type 1 and Type 2 diabetes in the within-subject effect of BDI score on HbA1c or fasting glucose levels during the study. Depressive symptoms decreased significantly (p = .0001) and similarly over a 12-month period in both patients with Type 1 and Type 2 diabetes, whereas HbA1c and fasting glucose levels did not change significantly over time in either group. CONCLUSION: Changes in depressive symptoms were not associated with changes in HbA1c or fasting glucose levels over a 1-year period in either patients with Type 1 or Type 2 diabetes.

One-week glucose control via zero-order release kinetics from an injectable depot of glucagon-like peptide-1 fused to a thermosensitive biopolymer.

Stimulation of the glucagon-like peptide-1 (GLP1) receptor is a useful treatment strategy for type 2 diabetes because of pleiotropic effects, including the regulation of islet hormones and the induction of satiety. However, the native ligand for the GLP1 receptor has a short half-live owing to enzymatic inactivation and rapid clearance. Here, we show that a subcutaneous depot formed after a single injection of GLP1 recombinantly fused to a thermosensitive elastin-like polypeptide results in zero-order release kinetics and circulation times of up to 10 days in mice and 17 days in monkeys. The optimized pharmacokinetics leads to 10 days of glycemic control in three different mouse models of diabetes, as well as to the reduction of glycosylated hemoglobin levels and weight gain in ob/ob mice treated once weekly for 8 weeks. Our results suggest that the optimized GLP1 formulation could enhance therapeutic outcomes by eliminating peak-and-valley pharmacokinetics and improving overall safety and tolerability. The design principles that we established should be broadly applicable for improving the pharmacological performance of other peptide and protein therapeutics.

Effect of Intensive Versus Standard Blood Pressure Treatment According to Baseline Prediabetes Status: A Post Hoc Analysis of a Randomized Trial.

OBJECTIVE: To determine whether the effects of intensive (<120 mmHg) compared with standard (<140 mmHg) systolic blood pressure (SBP) treatment are different among those with prediabetes versus those with fasting normoglycemia at baseline in the Systolic Blood Pressure Intervention Trial (SPRINT). RESEARCH DESIGN AND METHODS: This was a post hoc analysis of SPRINT. SPRINT participants were categorized by prediabetes status, defined as baseline fasting serum glucose ≥100 mg/dL versus those with normoglycemia (fasting serum glucose <100 mg/dL). The primary outcome was a composite of myocardial infarction, acute coronary syndrome not resulting in myocardial infarction, stroke, acute decompensated heart failure, or death from cardiovascular causes. Cox regression was used to calculate hazard ratios for study outcomes with intensive compared with standard SBP treatment among those with prediabetes and normoglycemia. RESULTS: Among 9,361 participants randomized (age 67.9 ± 9.4 years; 35.5% female), 3,898 and 5,425 had baseline prediabetes and normoglycemia, respectively. After a median follow-up of 3.26 years, the hazard ratio for the primary outcome was 0.69 (95% CI 0.53, 0.89) and 0.83 (95% CI 0.66, 1.03) among those with prediabetes and normoglycemia, respectively (P value for interaction 0.30). For all-cause mortality, the hazard ratio with intensive SBP treatment was 0.77 (95% CI 0.55, 1.06) for prediabetes and 0.71 (95% CI 0.54, 0.94) for normoglycemia (P value for interaction 0.74). Effects of intensive versus standard SBP treatment on prespecified renal outcomes and serious adverse events were similar for prediabetes and normoglycemia (all interaction P > 0.05). CONCLUSIONS: In SPRINT, the beneficial effects of intensive SBP treatment were similar among those with prediabetes and fasting normoglycemia.