Xenin-25 delays gastric emptying and reduces postprandial glucose levels in humans with and without type 2 diabetes.

Xenin-25 (Xen) is a neurotensin-related peptide secreted by a subset of glucose-dependent insulinotropic polypeptide (GIP)-producing enteroendocrine cells. In animals, Xen regulates gastrointestinal function and glucose homeostasis, typically by initiating neural relays. However, little is known about Xen action in humans. This study determines whether exogenously administered Xen modulates gastric emptying and/or insulin secretion rates (ISRs) following meal ingestion. Fasted subjects with normal (NGT) or impaired (IGT) glucose tolerance and Type 2 diabetes mellitus (T2DM; n = 10-14 per group) ingested a liquid mixed meal plus acetaminophen (ACM; to assess gastric emptying) at time zero. On separate occasions, a primed-constant intravenous infusion of vehicle or Xen at 4 (Lo-Xen) or 12 (Hi-Xen) pmol · kg(-1) · min(-1) was administered from zero until 300 min. Some subjects with NGT received 30- and 90-min Hi-Xen infusions. Plasma ACM, glucose, insulin, C-peptide, glucagon, Xen, GIP, and glucagon-like peptide-1 (GLP-1) levels were measured and ISRs calculated. Areas under the curves were compared for treatment effects. Infusion with Hi-Xen, but not Lo-Xen, similarly delayed gastric emptying and reduced postprandial glucose levels in all groups. Infusions for 90 or 300 min, but not 30 min, were equally effective. Hi-Xen reduced plasma GLP-1, but not GIP, levels without altering the insulin secretory response to glucose. Intense staining for Xen receptors was detected on PGP9.5-positive nerve fibers in the longitudinal muscle of the human stomach. Thus Xen reduces gastric emptying in humans with and without T2DM, probably via a neural relay. Moreover, endogenous GLP-1 may not be a major enhancer of insulin secretion in healthy humans under physiological conditions.

Pilot study of pioglitazone and exercise training effects on basal myocardial substrate metabolism and left ventricular function in HIV-positive individuals with metabolic complications.

BACKGROUND: Individuals with HIV infection and peripheral metabolic complications have impaired basal myocardial insulin sensitivity that is related to left ventricular (LV) diastolic dysfunction. It is unknown whether interventions shown to be effective in improving peripheral insulin sensitivity can improve basal myocardial insulin sensitivity and diastolic function in people with HIV and peripheral metabolic complications. OBJECTIVE: In a pilot study, we evaluated whether the peroxisome proliferator-activated receptor-gamma (PPAR-γ) agonist pioglitazone or combined endurance and resistance exercise training improves basal myocardial insulin sensitivity and diastolic function in HIV+ adults with peripheral metabolic complications. DESIGN: Twenty-four HIV+ adults with metabolic complications including peripheral insulin resistance were randomly assigned to 4 months of pioglitazone (PIO; 30 mg/d) or supervised, progressive endurance and resistance exercise training (EXS; 90-120 min/d, 3 d/wk). Basal myocardial substrate metabolism was quantified by radioisotope tracer methodology and positron emission tomography (PET) imaging, and LV function was measured by echocardiography. RESULTS: Twenty participants completed the study. Neither PIO nor EXS resulted in a detectable improvement in basal myocardial insulin sensitivity or diastolic function. Post hoc analyses revealed sample sizes of more than 100 participants are needed to detect significant effects of these interventions on basal myocardial insulin sensitivity and function. CONCLUSIONS: PIO or EXS alone did not significantly increase basal myocardial insulin sensitivity or LV diastolic function in HIV+ individuals with peripheral metabolic complications.

Exercise training augments the peripheral insulin-sensitizing effects of pioglitazone in HIV-infected adults with insulin resistance and central adiposity.

The prevalence and incidence of insulin resistance and type 2 diabetes mellitus (DM) are higher in people treated for human immunodeficiency virus-1 (HIV) infection than in the general population. Identifying safe and effective interventions is a high priority. We evaluated whether the peroxisome proliferator-activated receptor-γ agonist pioglitazone with exercise training improves central and peripheral insulin sensitivity more than pioglitazone alone in HIV-infected adults with insulin resistance and central adiposity. Forty-four HIV-infected adults with baseline insulin resistance and central adiposity were randomly assigned to 4 mo of pioglitazone (30 mg/day) with or without supervised, progressive aerobic, and resistance exercise training (1.5-2 h/day, 3 days/wk). The hyperinsulinemic euglycemic clamp was used to evaluate alterations in central and peripheral insulin sensitivity. Thirty-nine participants completed the study. Hepatic insulin sensitivity improved similarly in both groups. Exercise training augmented the beneficial effects of pioglitazone on peripheral insulin sensitivity. Greater improvements in peripheral insulin sensitivity were associated with reductions in total body and limb adipose content rather than increases in limb adiposity or pioglitazone-induced increases in adiponectin concentration. We conclude that supplementing pioglitazone with increased physical activity improved insulin sensitivity more effectively than pioglitazone alone in HIV-infected adults with insulin resistance and central adiposity. Pioglitazone alone did not significantly increase limb adipose content. Potential cardiovascular benefits of these interventions in HIV need investigation.

Sitagliptin Reduces Inflammation and Chronic Immune Cell Activation in HIV+ Adults With Impaired Glucose Tolerance.

CONTEXT: HIV infection is associated with a greater risk for fasting hyperinsulinemia, impaired glucose tolerance, and higher incidence rates for vascular disease, myocardial infarction, or stroke despite effective combination antiretroviral therapy (cART). The underlying mechanism(s) may involve chronic low-grade systemic inflammation and immune cell activation. Dipeptidyl peptidase-4 inhibitors (sitagliptin) improve glucose tolerance and may possess immunomodulatory effects because leukocyte CD26 cell surface receptors express dipeptidyl peptidase-4 activity. OBJECTIVE: Sitagliptin will reduce inflammatory and immune cell activation markers known to be elevated in cART-treated HIV-infected (HIV+) adults with impaired glucose tolerance. DESIGN: This was designed as a prospective, randomized, placebo-controlled, double-blind trial of sitagliptin in HIV+ adults. SETTING: The setting was an academic medical center. PATIENTS: Patients were cART-treated HIV+ men and women (n = 36) with stable HIV disease and impaired glucose tolerance. INTERVENTIONS: Interventions included sitagliptin 100 mg/d or placebo for 8 weeks. MAIN OUTCOME MEASURES: At baseline and week 8, plasma high-sensitivity C-reactive protein and C-X-C motif chemokine 10 concentrations (ELISA), oral glucose tolerance, and abdominal sc adipose mRNA expression for M1 macrophage markers (monocyte chemotactic protein-1, EGF-like module-containing, mucin-like hormone receptor 1). RESULTS: Sitagliptin reduced glucose area under the curve (P = .002) and improved oral glucose insulin sensitivity index (P = .04) more than placebo. Sitagliptin reduced plasma high-sensitivity C-reactive protein and C-X-C motif chemokine 10 levels more than placebo (P < .009). Adipose tissue monocyte chemotactic protein-1 mRNA abundance declined significantly more (P = .01), and adipose EGF-like module-containing, mucin-like hormone receptor 1 mRNA expression tended to decline more (P = .19) in sitagliptin than placebo. CONCLUSION: Sitagliptin had beneficial systemic and adipose anti-inflammatory effects in cART-treated HIV+ adults with impaired glucose tolerance. Large-scale, long-term studies should determine whether sitagliptin reduces cardiovascular risk and events in HIV+ adults.

Global biochemical profiling identifies ß-hydroxypyruvate as a potential mediator of type 2 diabetes in mice and humans.

Glucose-dependent insulinotropic polypeptide (GIP) and GLP-1 are incretins secreted by respective K and L enteroendocrine cells after eating and amplify glucose-stimulated insulin secretion (GSIS). This amplification has been termed the "incretin response." To determine the role(s) of K cells for the incretin response and type 2 diabetes mellitus (T2DM), diphtheria toxin-expressing (DT) mice that specifically lack GIP-producing cells were backcrossed five to eight times onto the diabetogenic NONcNZO10/Ltj background. As in humans with T2DM, DT mice lacked an incretin response, although GLP-1 release was maintained. With high-fat (HF) feeding, DT mice remained lean but developed T2DM, whereas wild-type mice developed obesity but not diabetes. Metabolomics identified biochemicals reflecting impaired glucose handling, insulin resistance, and diabetes complications in prediabetic DT/HF mice. ß-Hydroxypyruvate and benzoate levels were increased and decreased, respectively, suggesting ß-hydroxypyruvate production from d-serine. In vitro, ß-hydroxypyruvate altered excitatory properties of myenteric neurons and reduced islet insulin content but not GSIS. ß-Hydroxypyruvate-to-d-serine ratios were lower in humans with impaired glucose tolerance compared with normal glucose tolerance and T2DM. Earlier human studies unmasked a neural relay that amplifies GIP-mediated insulin secretion in a pattern reciprocal to ß-hydroxypyruvate-to-d-serine ratios in all groups. Thus, K cells may maintain long-term function of neurons and ß-cells by regulating ß-hydroxypyruvate levels.

Dipeptidyl peptidase IV inhibition does not adversely affect immune or virological status in HIV infected men and women: a pilot safety study.

CONTEXT: People infected with HIV have a higher risk for developing insulin resistance, diabetes, and cardiovascular disease than the general population. Dipeptidyl peptidase IV (DPP4) inhibitors are glucose-lowering medications with pleiotropic actions that may particularly benefit people with HIV, but the immune and virological safety of DPP4 inhibition in HIV is unknown. OBJECTIVE: DPP4 inhibition will not reduce CD4+ T lymphocyte number or increase HIV viremia in HIV-positive adults. DESIGN: This was a randomized, placebo-controlled, double-blind safety trial of sitagliptin in HIV-positive adults. SETTING: The study was conducted at an academic medical center. PARTICIPANTS: Twenty nondiabetic HIV-positive men and women (9.8 ± 5.5 years of known HIV) taking antiretroviral therapy and with stable immune (625 ± 134 CD4+ T cells per microliter) and virological (<48 copies HIV RNA per milliliter) status. INTERVENTION: The intervention included sitagliptin (100 mg/d) vs matching placebo for up to 24 weeks. MAIN OUTCOME MEASURES: CD4+ T cell number and plasma HIV RNA were measured every 4 weeks; fasting serum regulated upon activation normal T-cell expressed and secreted (RANTES), stromal derived factor (SDF)-1α, Soluble TNF receptor II, and oral glucose tolerance were measured at baseline, week 8, and the end of study. ANOVA was used for between-group comparisons; P < .05 was considered significant. RESULTS: Compared with placebo, sitagliptin did not reduce CD4+ T cell count, plasma HIV RNA remained less than 48 copies/mL, RANTES and soluble TNF receptor II concentrations did not increase. SDF1α concentrations declined (P < .0002) in the sitagliptin group. The oral glucose tolerance levels improved in the sitagliptin group at week 8. CONCLUSIONS: Despite lowering SDF1α levels, sitagliptin did not adversely affect immune or virological status, or increase immune activation, but did improve glycemia in healthy, nondiabetic HIV-positive adults. These safety data allow future efficacy studies of sitagliptin in HIV-positive people with cardiometabolic complications.

18FDG PET-CT imaging detects arterial inflammation and early atherosclerosis in HIV-infected adults with cardiovascular disease risk factors.

BACKGROUND: Persistent vascular inflammation has been implicated as an important cause for a higher prevalence of cardiovascular disease (CVD) in HIV-infected adults. In several populations at high risk for CVD, vascular 18Fluorodeoxyglucose (18FDG) uptake quantified using 3D-positron emission-computed tomography (PET-CT) has been used as a molecular level biomarker for the presence of metabolically active proinflammatory macrophages in rupture-prone early atherosclerotic plaques. We hypothesized that 18FDG PET-CT imaging would detect arterial inflammation and early atherosclerosis in HIV-infected adults with modest CVD risk. METHODS: We studied 9 HIV-infected participants with fully suppressed HIV viremia on antiretroviral therapy (8 men, median age 52 yrs, median BMI 29 kg/m2, median CD4 count 655 cells/µL, 33% current smokers) and 5 HIV-negative participants (4 men, median age 44 yrs, median BMI 25 kg/m2, no current smokers). Mean Framingham Risk Scores were higher for HIV-infected persons (9% vs. 2%, p < 0.01). 18FDG (370 MBq) was administered intravenously. 3D-PET-CT images were obtained 3.5 hrs later. 18FDG uptake into both carotid arteries and the aorta was compared between the two groups. RESULTS: Right and left carotid 18FDG uptake was greater (P < 0.03) in the HIV group (1.77 ±0.26, 1.33 ±0.09 target to background ratio (TBR)) than the control group (1.05 ± 0.10, 1.03 ± 0.05 TBR). 18FDG uptake in the aorta was greater in HIV (1.50 ±0.16 TBR) vs control group (1.24 ± 0.05 TBR), but did not reach statistical significance (P = 0.18). CONCLUSIONS: Carotid artery 18FDG PET-CT imaging detected differences in vascular inflammation and early atherosclerosis between HIV-infected adults with CVD risk factors and healthy HIV-seronegative controls. These findings confirm the utility of this molecular level imaging approach for detecting and quantifying glucose uptake into inflammatory macrophages present in metabolically active, rupture-prone atherosclerotic plaques in HIV infected adults; a population with increased CVD risk.