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ObjectivePulmonary 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.ConclusionsOur 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.

Author(s): Aubrey L. Shell [sup.1] , Michelle K. Williams [sup.1] , Jay S. Patel [sup.2] , Elizabeth A. Vrany [sup.3] , Robert V. Considine [sup.4] , Anthony J. Acton [sup.4] [...], 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 (M.sub.age = 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 ([beta] = 0.19, p = .048) and BMI ([beta] = 0.30, p < .001); poor appetite was negatively associated with HOMA-IR ([beta] = -0.24, p = .02); hypersomnia was positively associated with HOMA-IR ([beta] = 0.28, p = .003), BMI ([beta] = 0.26, p = .003), and hsCRP ([beta] = 0.23, p = .01); and disturbed sleep was positively associated with hsCRP ([beta] = 0.21, p = .04). BMI partially mediated hyperphagia and hypersomnia&apos;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.

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. [ABSTRACT FROM AUTHOR]

Abstract Background Nut consumption may reduce the risk of developing type 2 diabetes. The aim of the current study was to measure the acute and second-meal effects of morning almond consumption and determine the contribution of different nut fractions. Methods Fourteen impaired glucose tolerant (IGT) adults participated in a randomized, 5-arm, crossover design study where whole almonds (WA), almond butter (AB), defatted almond flour (AF), almond oil (AO) or no almonds (vehicle - V) were incorporated into a 75 g available carbohydrate-matched breakfast meal. Postprandial concentrations of blood glucose, insulin, non-esterified free fatty acids (NEFA), glucagon-like peptide-1 (GLP-1) and appetitive sensations were assessed after treatment breakfasts and a standard lunch. Results WA significantly attenuated second-meal and daylong blood glucose incremental area under the curve (AUCI) and provided the greatest daylong feeling of fullness. AB and AO decreased blood glucose AUCI in the morning period and daylong blood glucose AUCI was attenuated with AO. WA and AO elicited a greater second-meal insulin response, particularly in the early postprandial phase, and concurrently suppressed the second-meal NEFA response. GLP-1 concentrations did not vary significantly between treatments. Conclusions Inclusion of almonds in the breakfast meal decreased blood glucose concentrations and increased satiety both acutely and after a second-meal in adults with IGT. The lipid component of almonds is likely responsible for the immediate post-ingestive response, although it cannot explain the differential second-meal response to AB versus WA and AO.

Objective: Abnormally elevated proinsulin secretion has been reported in type 2 and early type 1 diabetes when significant C-peptide is present. We questioned whether individuals with long-standing type 1 diabetes and low or absent C-peptide secretory capacity retained the ability to make proinsulin.Research Design and Methods: C-peptide and proinsulin were measured in fasting and stimulated sera from 319 subjects with long-standing type 1 diabetes (≥3 years) and 12 control subjects without diabetes. We considered three categories of stimulated C-peptide: 1) C-peptide positive, with high stimulated values ≥0.2 nmol/L; 2) C-peptide positive, with low stimulated values ≥0.017 but <0.2 nmol/L; and 3) C-peptide <0.017 nmol/L. Longitudinal samples were analyzed from C-peptide-positive subjects with diabetes after 1, 2, and 4 years.Results: Of individuals with long-standing type 1 diabetes, 95.9% had detectable serum proinsulin (>3.1 pmol/L), while 89.9% of participants with stimulated C-peptide values below the limit of detection (<0.017 nmol/L; n = 99) had measurable proinsulin. Proinsulin levels remained stable over 4 years of follow-up, while C-peptide decreased slowly during longitudinal analysis. Correlations between proinsulin with C-peptide and mixed-meal stimulation of proinsulin were found only in subjects with high stimulated C-peptide values (≥0.2 nmol/L). Specifically, increases in proinsulin with mixed-meal stimulation were present only in the group with high stimulated C-peptide values, with no increases observed among subjects with low or undetectable (<0.017 nmol/L) residual C-peptide.Conclusions: In individuals with long-duration type 1 diabetes, the ability to secrete proinsulin persists, even in those with undetectable serum C-peptide. [ABSTRACT FROM AUTHOR]

Objective: Type 2 diabetes is a growing health problem among both adults and adolescents. To better understand the differences in the pathogenesis of diabetes between these groups, we examined differences in β-cell function along the spectrum of glucose tolerance.Research Design and Methods: We evaluated 89 adults and 50 adolescents with normal glucose tolerance (NGT), dysglycemia, or type 2 diabetes. Oral glucose tolerance test results were used for C-peptide and insulin/glucose minimal modeling. Model-derived and direct measures of insulin secretion and insulin sensitivity were compared across glycemic stages and between age-groups at each stage.Results: In adolescents with dysglycemia, there was marked insulin resistance (insulin sensitivity index: adolescents, median [interquartile range] 1.8 [1.1-2.4] × 10-4; adults, 5.0 [2.3-9.9]; P = 0.01). The nature of β-cell dysfunction across stages of dysglycemia differed between the groups. We observed higher levels of secretion among adolescents than adults (total insulin secretion: NGT, 143 [103-284] × 10-9/min adolescent vs. 106 [71-127], P = 0.001); adults showed stepwise impairments in static insulin secretion (NGT, 7.5 [4.0-10.3] × 10-9/min; dysglycemia, 5.0 [2.3-9.9]; type 2 diabetes, 0.7 [0.1-2.45]; P = 0.003), whereas adolescents showed diabetes-related impairment in dynamic secretion (NGT, 1,905 [1,630-3,913] × 10-9; dysglycemia, 2,703 [1,323-3,637]; type 2 diabetes, 1,189 [269-1,410]; P = 0.001).Conclusions: Adults and adolescents differ in the underlying defects leading to dysglycemia, and in the nature of β-cell dysfunction across stages of dysglycemia. These results may suggest different approaches to diabetes prevention in youths versus adults. [ABSTRACT FROM AUTHOR]