Effect of modernized collaborative care for depression on depressive symptoms and cardiovascular disease risk biomarkers: eIMPACT randomized controlled trial.

Although depression is a risk and prognostic factor for cardiovascular disease (CVD), clinical trials treating depression in patients with CVD have not demonstrated cardiovascular benefits. We proposed a novel explanation for the null results for CVD-related outcomes: the late timing of depression treatment in the natural history of CVD. Our objective was to determine whether successful depression treatment before, versus after, clinical CVD onset reduces CVD risk in depression. We conducted a single-center, parallel-group, assessor-blinded randomized controlled trial. Primary care patients with depression and elevated CVD risk from a safety net healthcare system (N = 216, Mage = 59 years, 78% female, 50% Black, 46% with income <$10,000/year) were randomized to 12 months of the eIMPACT intervention (modernized collaborative care involving internet cognitive-behavioral therapy [CBT], telephonic CBT, and/or select antidepressants) or usual primary care for depression (primary care providers supported by embedded behavioral health clinicians and psychiatrists). Outcomes were depressive symptoms and CVD risk biomarkers at 12 months. Intervention participants, versus usual care participants, exhibited moderate-to-large (Hedges' g = -0.65, p < 0.01) improvements in depressive symptoms. Clinical response data yielded similar results - 43% of intervention participants, versus 17% of usual care participants, had a ≥ 50% reduction in depressive symptoms (OR = 3.73, 95% CI: 1.93-7.21, p < 0.01). However, no treatment group differences were observed for the CVD risk biomarkers - i.e., brachial flow-mediated dilation, high-frequency heart rate variability, interleukin-6, high-sensitivity C-reactive protein, ß-thromboglobulin, and platelet factor 4 (Hedges' gs = -0.23 to 0.02, ps ≥ 0.09). Our modernized collaborative care intervention - which harnessed technology to maximize access and minimize resources - produced clinically meaningful improvements in depressive symptoms. However, successful depression treatment did not lower CVD risk biomarkers. Our findings indicate that depression treatment alone may not be sufficient to reduce the excess CVD risk of people with depression and that alternative approaches are needed. In addition, our effective intervention highlights the utility of eHealth interventions and centralized, remote treatment delivery in safety net clinical settings and could inform contemporary integrated care approaches. Trial Registration:ClinicalTrials.gov Identifier: NCT02458690.

Almond consumption decreases android fat mass percentage in adults with high android subcutaneous adiposity but does not change HbA1c in a randomised controlled trial.

The purpose of this study was to determine if the mixed evidence of almond consumption on HbA1c stems from testing people with different body fat distributions (BFD) associated with different risks of glucose intolerance. A 6-month randomised controlled trial in 134 adults was conducted. Participants were randomly assigned to the almond (A) or control (C) group based on their BFD. Those in the almond group consumed 1·5 oz of almonds with their breakfast and as their afternoon snack daily. Those in the control group continued their habitual breakfast and afternoon snack routines. Body weight and composition were measured and blood samples were collected for determination of HbA1c, glycaemia and lipaemia at 0 and 6 months. Appetite ratings, energy intake and diet quality were collected at 0, 2, 4 and 6 months. Participants consuming almonds ingested 816 (sem 364) kJ/d more than participants in the control group (P = 0·03), but this did not result in any differences in body weight (A: -0·3 (sem 0·4), C: -0·4 (sem 0·4); P > 0·3). Participants in the almond, high android subcutaneous adipose tissue (SAT) group had a greater reduction in android fat mass percentage (A: -1·0 (sem 0·6), C: 1·1 (sem 0·6); P = 0·04), preserved android lean mass percentage (A: 0·9 (sem 0·6), C: -1 (sem 0·6); P = 0·04) and tended to decrease android visceral adipose tissue mass (A: -13 (sem 53) g, C: 127 (sem 53) g; P = 0·08) compared with those in the control, high SAT group. There were no differences in HbA1c between groups (A: 5·4 (sem 0·04), C: 5·5 (sem 0·04); P > 0·05). Thus, BFD may not explain the mixed evidence on almond consumption and HbA1c. Long-term almond consumption has limited ability to improve cardiometabolic health in those who are overweight and obese but otherwise healthy.

Associations of somatic depressive symptoms with body mass index, systemic inflammation, and insulin resistance in primary care patients with depression.

The somatic depressive symptom cluster (including appetite and sleep disturbances) is more strongly associated with insulin resistance (a diabetes risk marker) than other depressive symptom clusters. Utilizing baseline data from 129 primary care patients with depression but no diabetes in the eIMPACT trial (Mage = 59 years, 78% female, 50% Black), we examined associations of somatic depressive symptoms with insulin resistance (HOMA-IR), body mass index (BMI), and high-sensitivity C-reactive protein (hsCRP). We tested BMI and hsCRP as mediators and race as a moderator of these relationships. Hyperphagia was positively associated HOMA-IR (ß = 0.19, p = .048) and BMI (ß = 0.30, p < .001); poor appetite was negatively associated with HOMA-IR (ß = -0.24, p = .02); hypersomnia was positively associated with HOMA-IR (ß = 0.28, p = .003), BMI (ß = 0.26, p = .003), and hsCRP (ß = 0.23, p = .01); and disturbed sleep was positively associated with hsCRP (ß = 0.21, p = .04). BMI partially mediated hyperphagia and hypersomnia's associations with HOMA-IR; hsCRP partially mediated the hypersomnia-HOMA-IR association; and race moderated the hyperphagia-HOMA-IR association (positive for White participants but null for Black participants). People with depression experiencing hyperphagia and/or hypersomnia may be a subgroup with greater insulin resistance; BMI and hsCRP are likely pathways in these relationships. This study highlights the importance of considering the direction of somatic depressive symptoms in the context of cardiometabolic disease risk.

Saturated fat ingestion stimulates proatherogenic inflammation in polycystic ovary syndrome.

Inflammation and dyslipidemia are often present in polycystic ovary syndrome (PCOS). We determined the effect of saturated fat ingestion on circulating heat shock protein-70 (HSP-70) and mononuclear cell (MNC) toll-like receptor-2 (TLR2) gene expression, activator protein-1 (AP-1) activation, and matrix matalloproteinase-2 (MMP-2) protein in women with PCOS. Twenty reproductive-age women with PCOS (10 lean, 10 with obesity) and 20 ovulatory controls (10 lean, 10 with obesity) participated in the study. HSP-70 was measured in serum and TLR2 mRNA and protein, AP-1 activation, and MMP-2 protein were quantified in MNC from blood drawn while fasting and 2, 3, and 5 h after saturated fat ingestion. Insulin sensitivity was derived from an oral glucose tolerance test (ISOGTT). Androgen secretion was assessed from blood drawn while fasting and 24, 48, and 72 h after human chorionic gonadotropin (HCG) administration. In response to saturated fat ingestion, serum HSP-70, TLR2 gene expression, activated AP-1, and MMP-2 protein were greater in lean women with PCOS compared with lean controls and in women with PCOS and obesity compared with controls with obesity. Both PCOS groups exhibited lower ISOGTT and greater HCG-stimulated androgen secretion compared with control subjects of their respective weight classes. Lipid-stimulated proatherogenic inflammation marker responses were negatively correlated with ISOGTT and positively correlated with abdominal adiposity and HCG-stimulated androgen secretion. In PCOS, saturated fat ingestion stimulates proatherogenic inflammation independent of obesity. This effect is greater when PCOS is combined with obesity compared with obesity alone. Abdominal adiposity and hyperandrogenism may perpetuate proatherogenic inflammation.NEW & NOTEWORTHY This paper demonstrates that in polycystic ovary syndrome (PCOS), ingestion of saturated fat triggers a molecular pathway of inflammation known to drive atherogenesis. This effect is independent of obesity as it occurs in lean women with PCOS and not in lean ovulatory control subjects. Furthermore, the combined effects of PCOS and obesity are greater compared with obesity alone.

The linearized disposition index augments understanding of treatment effects in diabetes.

The disposition index, calculated by multiplying measures of insulin secretion and insulin sensitivity, is widely applied as a sensitivity-adjusted measure of insulin secretion. We have recently shown that linearizing the underlying relationship uniquely permits identification of terms relating to maximal insulin secretion capacity and the secretion-coupling relationship, with both terms separately contributing to differences in the secretion-sensitivity relationship across gradations of glycemia. Here, we demonstrate the application of this linearized equation to the evaluation of treatment-induced changes in the insulin secretion-sensitivity relationship. We applied a combination of repeated-measures multivariate linear regression (evaluating treatment-induced changes in the joint relationship of insulin sensitivity and secretion) plus mixed-model repeated measures (evaluating treatment effects on maximal secretion capacity and on the secretion-sensitivity coupling slope) and compared against a usual application of the disposition index calculated from the same measurements. This novel approach allows a more informative description of treatment-induced changes compared with the usual disposition index, including isolating the source of change within the mutually adjusted relationship and identifying treatment-induced changes in the secretion-sensitivity coupling slope and in maximal insulin secretion. Application of this linearized approach provides an expanded understanding of treatment-induced changes in the insulin sensitivity-secretion relationship.NEW & NOTEWORTHY The linearized insulin secretion-sensitivity relationship allows separate evaluation of the secretion-sensitivity slope and of maximal insulin secretion. Here, we demonstrate the application of this methodology to the evaluation of clinical trial data, showing that it provides an expanded understanding of treatment-induced changes compared with the disposition index.

Treatment With Treprostinil and Metformin Normalizes Hyperglycemia and Improves Cardiac Function in Pulmonary Hypertension Associated With Heart Failure With Preserved Ejection Fraction.

OBJECTIVE: Pulmonary hypertension (PH) due to left heart disease (group 2), especially in the setting of heart failure with preserved ejection fraction (HFpEF), is the most common cause of PH worldwide; however, at present, there is no proven effective therapy available for its treatment. PH-HFpEF is associated with insulin resistance and features of metabolic syndrome. The stable prostacyclin analog, treprostinil, is an effective and widely used Food and Drug Administration-approved drug for the treatment of pulmonary arterial hypertension. While the effect of treprostinil on metabolic syndrome is unknown, a recent study suggests that the prostacyclin analog beraprost can improve glucose intolerance and insulin sensitivity. We sought to evaluate the effectiveness of treprostinil in the treatment of metabolic syndrome-associated PH-HFpEF. Approach and Results: Treprostinil treatment was given to mice with mild metabolic syndrome-associated PH-HFpEF induced by high-fat diet and to SU5416/obese ZSF1 rats, a model created by the treatment of rats with a more profound metabolic syndrome due to double leptin receptor defect (obese ZSF1) with a vascular endothelial growth factor receptor blocker SU5416. In high-fat diet-exposed mice, chronic treatment with treprostinil reduced hyperglycemia and pulmonary hypertension. In SU5416/Obese ZSF1 rats, treprostinil improved hyperglycemia with similar efficacy to that of metformin (a first-line drug for type 2 diabetes mellitus); the glucose-lowering effect of treprostinil was further potentiated by the combined treatment with metformin. Early treatment with treprostinil in SU5416/Obese ZSF1 rats lowered pulmonary pressures, and a late treatment with treprostinil together with metformin improved pulmonary artery acceleration time to ejection time ratio and tricuspid annular plane systolic excursion with AMPK (AMP-activated protein kinase) activation in skeletal muscle and the right ventricle. CONCLUSIONS: Our data suggest a potential use of treprostinil as an early treatment for mild metabolic syndrome-associated PH-HFpEF and that combined treatment with treprostinil and metformin may improve hyperglycemia and cardiac function in a more severe disease.

Salicylate administration suppresses the inflammatory response to nutrients and improves ovarian function in polycystic ovary syndrome.

Oxidative stress (OS) and inflammation are often present in polycystic ovary syndrome (PCOS). We examined the effects of salsalate treatment on nutrient-induced OS and inflammation, ovarian androgen secretion, ovulation, and insulin sensitivity in PCOS. Eight lean insulin-sensitive women with PCOS and eight age- and body composition-matched ovulatory controls for baseline comparison participated in the study. The women with PCOS underwent a 12-wk treatment of salsalate, a nonsteroidal anti-inflammatory drug, at a dose of 3 g daily. Markers of OS and inflammation were quantified in mononuclear cells (MNC) and plasma from blood drawn fasting and 2 h after saturated fat ingestion before and after treatment. Ovarian androgen secretion was assessed from blood drawn fasting and 24, 48, and 72 h after human chorionic gonadotropin (HCG) administration before and after treatment. Ovulation was documented based on biphasic basal body temperatures and luteal range progesterone elevations. A two-step pancreatic clamp was performed pre- and posttreatment to measure basal endogenous glucose production (EGP) and the steady-state glucose disposal rate (GDR) during the euglycemic phase and markers of OS and inflammation in MNC and plasma during the hyperglycemic phase. Salsalate administration suppressed lipid- and glucose-stimulated reactive oxygen species generation, activated nuclear factor-κB and circulating tumor necrosis factor-α, normalized basal androgen levels, and lowered HCG-stimulated androgen secretion without altering EGP or GDR. Four salsalate-treated subjects responded with two consecutive ovulations. We conclude that in PCOS, salsalate-induced suppression of OS and inflammation ameliorates ovarian androgen hypersecretion and may induce ovulation while maintaining insulin action.

Oligomeric collagen as an encapsulation material for islet/ß-cell replacement: effect of islet source, dose, implant site, and administration format.

Replacement of islets/ß-cells that provide long-lasting glucose-sensing and insulin-releasing functions has the potential to restore extended glycemic control in individuals with type 1 diabetes. Unfortunately, persistent challenges preclude such therapies from widespread clinical use, including cumbersome administration via portal vein infusion, significant loss of functional islet mass upon administration, limited functional longevity, and requirement for systemic immunosuppression. Previously, fibril-forming type I collagen (oligomer) was shown to support subcutaneous injection and in situ encapsulation of syngeneic islets within diabetic mice, with rapid (<24 h) reversal of hyperglycemia and maintenance of euglycemia for beyond 90 days. Here, we further evaluated this macroencapsulation strategy, defining effects of islet source (allogeneic and xenogeneic) and dose (500 and 800 islets), injection microenvironment (subcutaneous and intraperitoneal), and macrocapsule format (injectable and preformed implantable) on islet functional longevity and recipient immune response. We found that xenogeneic rat islets functioned similarly to or better than allogeneic mouse islets, with only modest improvements in longevity noted with dosage. Additionally, subcutaneous injection led to more consistent encapsulation outcomes along with improved islet health and longevity, compared with intraperitoneal administration, whereas no significant differences were observed between subcutaneous injectable and preformed implantable formats. Collectively, these results document the benefits of incorporating natural collagen for islet/ß-cell replacement therapies.

Inquiry into the short- and long-term effects of Roux-en-Y gastric bypass on the glomerular filtration rate.

Bariatric surgery is known to attenuate glomerular hyperfiltration over the long term and thereby protect the kidney from mechanical damage. Whether this effect is directly related to weight loss or is independent of weight as are some of its other beneficial metabolic effects is not known. We explored this question in a preliminary study that directly measured glomerular filtration rate (GFR) before, immediately after, and again many months after Roux-en-Y gastric bypass after large weight loss had occurred. We simultaneously measured stimulated circulating glucagon-like peptide-1, which is upregulated after Roux-en-Y gastric bypass and is a putative mediator of GFR after bariatric surgery. We found no weight-independent effect of Roux-en-Y gastric bypass on GFR nor an association between circulating GLP-1 levels and GFR. These findings, if confirmed in larger studies, will help steer future enquiries in this area.

In situ type I oligomeric collagen macroencapsulation promotes islet longevity and function in vitro and in vivo.

Widespread use of pancreatic islet transplantation for treatment of type 1 diabetes (T1D) is currently limited by requirements for long-term immunosuppression, limited donor supply, and poor long-term engraftment and function. Upon isolation from their native microenvironment, islets undergo rapid apoptosis, which is further exacerbated by poor oxygen and nutrient supply following infusion into the portal vein. Identifying alternative strategies to restore critical microenvironmental cues, while maximizing islet health and function, is needed to advance this cellular therapy. We hypothesized that biophysical properties provided through type I oligomeric collagen macroencapsulation are important considerations when designing strategies to improve islet survival, phenotype, and function. Mouse islets were encapsulated at various Oligomer concentrations (0.5 -3.0 mg/ml) or suspended in media and cultured for 14 days, after which viability, protein expression, and function were assessed. Oligomer-encapsulated islets showed a density-dependent improvement in in vitro viability, cytoarchitecture, and insulin secretion, with 3 mg/ml yielding values comparable to freshly isolated islets. For transplantation into streptozotocin-induced diabetic mice, 500 islets were mixed in Oligomer and injected subcutaneously, where rapid in situ macroencapsulation occurred, or injected with saline. Mice treated with Oligomer-encapsulated islets exhibited rapid (within 24 h) diabetes reversal and maintenance of normoglycemia for 14 (immunocompromised), 90 (syngeneic), and 40 days (allogeneic). Histological analysis showed Oligomer-islet engraftment with maintenance of islet cytoarchitecture, revascularization, and no foreign body response. Oligomer-islet macroencapsulation may provide a useful strategy for prolonging the health and function of cultured islets and has potential as a subcutaneous injectable islet transplantation strategy for treatment of T1D.

Aspartame Consumption for 12 Weeks Does Not Affect Glycemia, Appetite, or Body Weight of Healthy, Lean Adults in a Randomized Controlled Trial.

Background: Low-calorie sweeteners are often used to moderate energy intake and postprandial glycemia, but some evidence indicates that they may exacerbate these aims. Objective: The trial's primary aim was to assess the effect of daily aspartame ingestion for 12 wk on glycemia. Effects on appetite and body weight were secondary aims. Methods: One hundred lean [body mass index (kg/m2): 18-25] adults aged 18-60 y were randomly assigned to consume 0, 350, or 1050 mg aspartame/d (ASP groups) in a beverage for 12 wk in a parallel-arm design. At baseline, body weight and composition were determined, a 240-min oral-glucose-tolerance test (OGTT) was administered, and measurements were made of appetite and selected hormones. Participants also collected a 24-h urine sample. During the intervention, the 0-mg/d ASP group consumed capsules containing 680 mg dextrose and 80 mg para-amino benzoic acid. For the 350-mg/d ASP group, the beverage contained 350 mg aspartame and the 1050-mg/d ASP group consumed the same beverage plus capsules containing 680 mg dextrose and 700 mg aspartame. Body weight, blood pressure, heart rate, and waist circumference were measured weekly. At weeks 4, 8, and 12, participants collected 24-h urine samples and kept appetite logs. Baseline measurements were repeated at week 12. Results: With the exception of the baseline OGTT glucose concentration at 60 min (and resulting area under the curve value), there were no group differences for glucose, insulin, resting leptin, glucagon-like peptide 1, or gastric inhibitory peptide at baseline or week 12. There also were no effects of aspartame ingestion on appetite, body weight, or body composition. Compliance with the beverage intervention was ∼95%. Conclusions: Aspartame ingested at 2 doses for 12 wk had no effect on glycemia, appetite, or body weight among healthy, lean adults. These data do not support the view that aspartame is problematic for the management of glycemia, appetite, or body weight. This trial was registered at www.clinicaltrials.gov as NCT02999321.

Hematopoietic IKBKE limits the chronicity of inflammasome priming and metaflammation.

Obesity increases the risk of developing life-threatening metabolic diseases including cardiovascular disease, fatty liver disease, diabetes, and cancer. Efforts to curb the global obesity epidemic and its impact have proven unsuccessful in part by a limited understanding of these chronic progressive diseases. It is clear that low-grade chronic inflammation, or metaflammation, underlies the pathogenesis of obesity-associated type 2 diabetes and atherosclerosis. However, the mechanisms that maintain chronicity and prevent inflammatory resolution are poorly understood. Here, we show that inhibitor of κB kinase epsilon (IKBKE) is a novel regulator that limits chronic inflammation during metabolic disease and atherosclerosis. The pathogenic relevance of IKBKE was indicated by the colocalization with macrophages in human and murine tissues and in atherosclerotic plaques. Genetic ablation of IKBKE resulted in enhanced and prolonged priming of the NLRP3 inflammasome in cultured macrophages, in hypertrophic adipose tissue, and in livers of hypercholesterolemic mice. This altered profile associated with enhanced acute phase response, deregulated cholesterol metabolism, and steatoheptatitis. Restoring IKBKE only in hematopoietic cells was sufficient to reverse elevated inflammasome priming and these metabolic features. In advanced atherosclerotic plaques, loss of IKBKE and hematopoietic cell restoration altered plaque composition. These studies reveal a new role for hematopoietic IKBKE: to limit inflammasome priming and metaflammation.

Genetic and environmental influences on the prospective correlation between systemic inflammation and coronary heart disease death in male twins.

OBJECTIVE: Because of lack of evidence, we aimed to examine to what degree low-grade systemic inflammation and coronary heart disease (CHD) death shared common genetic and environmental substrates. APPROACH AND RESULTS: From the 41-year prospective National Heart, Lung, and Blood Institute Twin Study, we included 950 middle-aged male twins at baseline (1969-1973). Low-grade systemic inflammation was measured with plasma levels of interleukin-6 (IL-6) and C-reactive protein. Univariate and bivariate structural equation models were used, adjusted for a risk score for CHD death. The score-adjusted heritability was 19% for IL-6, 27% for C-reactive protein, and 22% for CHD death. The positive phenotypic correlation of IL-6 with CHD death (radjusted=0.27; 95% confidence interval [CI], 0.08-0.43) was driven by additive genetic factors (contribution [relative contribution], 0.30 [111%]) but attenuated by unique environment (-0.03 [-11%]). The genetic correlation between IL-6 and CHD death was 0.74 (95% CI, 0.21-1.00), whereas the unique environmental correlation was -0.05 (95% CI, -0.35 to 0.25). The proportion of genetic variance for CHD death shared with that for IL-6 was 74%. The phenotypic correlation of C-reactive protein with CHD death (radjusted=0.10; 95% CI, -0.02 to 0.22) was explained by additive genetic factors (0.20 [149%]) but was attenuated by the unique environment (-0.09 [-49%]). The genetic correlation of C-reactive protein with CHD death was 0.63 (95% CI, -0.07 to 1.00), whereas the unique environmental correlation was -0.07 (95% CI, -0.29 to 0.17). CONCLUSIONS: Low-grade systemic inflammation, measured by IL-6, and long-term CHD death share moderate genetic substrates that augment both traits.

Acute Changes in Sleep Duration on Eating Behaviors and Appetite-Regulating Hormones in Overweight/Obese Adults.

There is considerable interest in the role of sleep in weight regulation, yet few studies have examined this relationship in overweight/obese (OW/OB) adults. Using a within-subject, counterbalanced design, 12 OW/OB women were studied in lab with two nights of short (5 hr time in bed [TIB]) and two nights of long (9 hr TIB) sleep. Hunger, consumption at a buffet, and fasting hormone levels were obtained. Significant polysomnographic differences occurred between conditions in total sleep time and sleep architecture (ps < .001). Percent energy from protein at the buffet increased following short sleep. No differences were observed for total energy intake or measured hormones. Further research is needed to determine how lengthening sleep impacts weight regulation in OW/OB adults.

Hepatocyte growth factor regulates neovascularization in developing fat pads.

In this study, we used lentiviral-delivered shRNA to generate a clonal line of 3T3-F442A preadipocytes with stable silencing of hepatocyte growth factor (HGF) expression and examined the long-term consequence of this modification on fat pad development. HGF mRNA expression was reduced 94%, and HGF secretion 79% (P < 0.01), compared with preadipocytes treated with nontargeting shRNA. Fat pads derived from HGF knockdown preadipocytes were significantly smaller (P < 0.01) than control pads beginning at 3 days postinjection (0.022 ± 0.003 vs. 0.037 ± 0.004 g), and further decreased in size at day 7 (0.015 ± 0.004 vs. 0.037 ± 0.003 g) and day 14 (0.008 ± 0.002 vs. 0.045 ± 0.007 g). Expression of the endothelial cell genes TIE1 and PECAM1 increased over time in control fat pads (1.6 ± 0.4 vs. 11.4 ± 1.7 relative units at day 3 and 14, respectively; P < 0.05) but not in HGF knockdown fat pads (1.1 ± 0.5 vs. 5.9 ± 2.2 relative units at day 3 and 14). Contiguous vascular structures were observed in control fat pads but were much less developed in HGF knockdown fat pads. Differentiation of preadipocytes to mature adipocytes was significantly attenuated in HGF knockdown fat pads. Fat pads derived from preadipocytes with knockdown of the HGF receptor c-MET were smaller than control pads at day 3 postinjection (0.034 ± 0.002 vs. 0.049 ± 0.004 g; P < 0.05), and remained the same size through day 14. c-MET knockdown fat pads developed a robust vasculature, and preadipocytes differentiated to mature adipocytes. Overall these data suggest that preadipocyte-secreted HGF is an important regulator of neovascularization in developing fat pads.

Profound defects in ß-cell function in screen-detected type 2 diabetes are not improved with glucose-lowering treatment in the Early Diabetes Intervention Program (EDIP).

BACKGROUND: Few studies have measured the ability of interventions to affect declining ß-cell function in screen-detected type 2 diabetes. The Early Diabetes Intervention Programme (ClinicalTrials.gov NCT01470937) was a randomized study based on the hypothesis that improving postprandial glucose excursions with acarbose would slow the progression of fasting hyperglycaemia in screen-detected type 2 diabetes. In the Early Diabetes Intervention Programme, the effect of acarbose plus lifestyle advice on progression of fasting hyperglycaemia over a 5-year period was not greater than that of placebo. However, there was an early glucose-lowering effect of the trial. The objective of the current secondary analysis was to describe ß-cell function changes in response to glucose lowering. METHODS: Participants were overweight adult subjects with screen-detected type 2 diabetes. ß-cell function was measured using hyperglycaemic clamps and oral glucose tolerance testing. The primary outcome was the change in ß-cell function from baseline to year 1, the time point where the maximal glucose-lowering effect was seen. RESULTS: At baseline, participants exhibited markedly impaired first-phase insulin response. Despite significant reductions in weight, fasting plasma glucose (PG) and 2-h PG, there was no clinically significant improvement in the first-phase insulin response. Late-phase insulin responses declined despite beneficial glycaemic effects of interventions. CONCLUSIONS: Insulin secretion is already severely impaired in early, screen-detected type 2 diabetes. Effective glucose-lowering intervention with acarbose was not sufficient to improve insulin secretion or halt the decline of ß-cell function.

Predictors of glycemic worsening in the next year in adults with screen-detected type 2 diabetes.

Background and Aims: Identifying simple markers of risk for worsening glucose can allow care providers to target therapeutic interventions according to risk of worsening glycemic control. We aimed to determine which routine clinical measures herald near-term glycemic worsening in early type 2 diabetes(T2D). Methods: The Early Diabetes Intervention Program (EDIP) was a clinical trial in individuals with screendetected T2D [HbA1C 6.3+0.63%(45+5mmol/mol)]. During the trial some participants experienced worsening fasting blood glucose (FBG). We investigated the time course of FBG, HbA1c, weight, and other clinical factors to determine which might herald glycemic worsening over the next year. Results: Progressors (62/219, 28.5%) had higher FBG than non-progressors at baseline [118 vs 130mg/dL (6.6 vs 7.2 mmol/L), p=<0.001]. FBG was stable except in the year of progression, when progressors exhibited a large 1-year rise [mean change 14.2mg/dL(0.79 mmol/L)]. Current FBG and antecedent year change in FBG were associated with progression(p<0.01), although the magnitude of change was too small to be of clinical utility (0.19 mg/dL; 0.01 mmol/L). Current or antecedent year change in HbA1c, weight, TG or HDL were not associated with progression. In the year of glycemic worsening, rising glucose was strongly associated with a concurrent increase in weight (p<0.001). Conclusions: Elevated FBG but not HbA1c identified individuals at risk for imminent glycemic worsening; the subsequent large rise in glucose was associated with a short-term increase in weight. Glucose and weight surveillance provide actionable information for those caring for patients with early diabetes.

Genetic variation of GPLD1 associates with serum GPI-PLD levels: a preliminary study.

HDL is a heterogeneous mixture of lipoprotein particles varying in composition, size, and function. We and others have described a small (7.0nm), minor (0.1% of total apolipoprotein AI) particle containing apolipoprotein AI, AIV and glycosylphosphatidylinositol-specific phospholipase D (GPI-PLD) in humans the function of which is not entirely known. Circulating GPI-PLD levels are regulated by multiple factors including genetics. To determine if genetic variation in GPLD1 affects circulating GPI-PLD levels, we examined the relationship between 32 SNPS upstream, within, and downstream of GPLD1 and circulating GPI-PLD levels in Caucasians (n=77) and African-Americans (n=99). The genotype distribution among races differed at 13 SNPs. Nine SNPS were associated with circulating GPI-PLD levels in Caucasians but not African-Americans. These results suggest that genetic variation of GPLD1 appears to associate with circulating GPI-PLD levels. This article is part of a Special Issue entitled Advances in High Density Lipoprotein Formation and Metabolism: A Tribute to John F. Oram (1945-2010).

Impaired cardiometabolic responses to glucagon-like peptide 1 in obesity and type 2 diabetes mellitus.

Glucagon-like peptide 1 (GLP-1) has insulin-like effects on myocardial glucose uptake which may contribute to its beneficial effects in the setting of myocardial ischemia. Whether these effects are different in the setting of obesity or type 2 diabetes (T2DM) requires investigation. We examined the cardiometabolic actions of GLP-1 (7-36) in lean and obese/T2DM humans, and in lean and obese Ossabaw swine. GLP-1 significantly augmented myocardial glucose uptake under resting conditions in lean humans, but this effect was impaired in T2DM. This observation was confirmed and extended in swine, where GLP-1 effects to augment myocardial glucose uptake during exercise were seen in lean but not in obese swine. GLP-1 did not increase myocardial oxygen consumption or blood flow in humans or in swine. Impaired myocardial responsiveness to GLP-1 in obesity was not associated with any apparent alterations in myocardial or coronary GLP1-R expression. No evidence for GLP-1-mediated activation of cAMP/PKA or AMPK signaling in lean or obese hearts was observed. GLP-1 treatment augmented p38-MAPK activity in lean, but not obese cardiac tissue. Taken together, these data provide novel evidence indicating that the cardiometabolic effects of GLP-1 are attenuated in obesity and T2DM, via mechanisms that may involve impaired p38-MAPK signaling.

Effect of modernized collaborative care for depression on brain-derived neurotrophic factor (BDNF) and depressive symptom clusters: Data from the eIMPACT trial.

Brain-derived neurotrophic factor (BDNF) levels are lower in people with depression and are normalized following pharmacological treatment. However, it is unknown if psychological treatments for depression improve BDNF and if change in BDNF is a mediator of intervention effects on depressive symptoms. Therefore, using data from the eIMPACT trial, we sought to determine the effect of modernized collaborative care for depression on 12-month changes in BDNF and cognitive/affective and somatic depressive symptom clusters and to examine whether BDNF changes mediate intervention effects on depressive symptoms. 216 primary care patients with depression from a safety net healthcare system were randomized to 12 months of the eIMPACT intervention (internet cognitive-behavioral therapy [CBT], telephonic CBT, and select antidepressant medications) or usual primary care. Plasma BDNF was measured with commercially available kits, and depressive symptom clusters were assessed by the Patient Health Questionnaire-9. The intervention did not influence BDNF but did improve both the cognitive/affective and somatic clusters over 12 months. Changes in BDNF did not mediate the intervention effect on either cluster. Our findings suggest that modernized collaborative care is an effective treatment for both the cognitive/affective and somatic symptoms of depression and that the mechanism of action is not improvements in BDNF. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT02458690.