Ulrik B. Andersen

2-Oleoyl Glycerol Is a GPR119 Agonist and Signals GLP-1 Release in Humans

OBJECTIVE Dietary fat is thought to stimulate release of incretin hormones via activation of fatty acid receptors in the intestine. However, dietary fat (triacylglycerol) is digested to 2-monoacylglycerol and fatty acids. Activation of G protein-coupled receptor 119 (GPR119) stimulates glucagon-like peptide-1 (GLP-1) release from the intestinal L-cells. We aimed to investigate if 2-oleoyl glycerol (2OG) can activate GPR119 in vitro and stimulate GLP-1 secretion in vivo. RESEARCH DESIGN AND METHODS Agonist activity for various lipids was tested on transiently expressed human GPR119 in COS-7 cells. The effect of a jejunal bolus of 2 g 2OG on plasma levels of GLP-1 was evaluated in eight healthy human volunteers. The effect of 2OG was compared to an equimolar amount of oleic acid, a degradation product from 2OG, and the vehicle, glycerol. Digestion of 5 ml olive oil with pancreatic lipase will result in formation of approximately 2 g 2OG and 3.2 g oleic acid. RESULTS 2OG and other 2-monoacylglycerols increased intracellular concentrations of cAMP in GPR119-expressing COS-7 cells (2OG EC(50) = 2.5 μm). Administration of 2OG to humans significantly increased plasma GLP-1 (0-25 min) when compared to the two controls, oleic acid and vehicle. Plasma levels of glucose-dependent insulinotropic polypeptide also increased. CONCLUSION 2OG and other 2-monoacylglycerols formed during fat digestion can activate GPR119 and cause incretin release from the human intestine. This mechanism is likely to contribute to the known stimulatory effect of dietary fat on incretin secretion, and it indicates that GPR119 is a fat sensor.

The effect of Glucagon-Like Peptide-2 on mesenteric blood flow and cardiac parameters in end-jejunostomy short bowel patients.

BACKGROUND Exogenous Glucagon-Like Peptide-2 (GLP-2) treatment improves intestinal wet weight absorption in short bowel syndrome (SBS) patients. In healthy subjects, administration of GLP-2 increases small intestinal blood flow. The aim of the study was to evaluate the effect of GLP-2 on mesenteric blood flow and dynamic changes in cardiac parameters in SBS patients with jejunostomy and varying length of remnant small intestine. METHODS 8 SBS patients with end-jejunostomy and less than 200 cm small intestine were given GLP-2, 1600 μg subcutaneously (SC), or isotonic saline in a double blinded manner. At 0, 30 and 60 min plasma GLP-2 was measured, and from 0 to 90 min, blood flow in the superior mesenteric artery (SMA) and the celiac artery (CA) was measured using Doppler ultrasound (US), and cardiovascular variables were measured by continuous impedance cardiography and finger plethysmography. RESULTS Plasma GLP-2 concentrations increased significantly in the GLP-2 group, whereas no changes were seen in the placebo group. Compared to baseline, GLP-2 SC elicited a 19.4% decrease (p<0.01) in the resistance index (RI) and a 97.6% increase in time averaged maximal velocity (TAMV) in the SMA (P<0.01). In the CA there were no significant changes in RI or TAMV in the GLP-2 or placebo group. Blood flow and length of remaining intestine were correlated (RI: y=0.14+4.3, R=0.83, p=0.01 and TAMV: y=1.21+21.3, R=0.63, p=0.09). GLP-2 non significantly increased cardiac output (CO), stroke volume (SV) and significantly increased heart rate (HR) compared to baseline. CONCLUSION Subcutaneous GLP-2 increased SMA blood flow in end-jejunostomy SBS patients with less than 200 cm of remaining small intestine. The increase in blood flow correlated with the length of remaining intestine, suggesting that the increase is coupled to the metabolic actions of GLP-2 on the gut rather than effects on the vasculature.

Long-term treatment with losartan versus atenolol improves insulin sensitivity in hypertension: ICARUS, a LIFE substudy.

Objective Hypertension and insulin resistance might be associated through peripheral vascular hypertrophy/rarefaction which compromises skeletal muscle blood flow and decreases glucose uptake, inducing insulin resistance. We hypothesized that treatment with losartan as compared to atenolol would improve insulin sensitivity through regression of peripheral vascular hypertrophy/rarefaction. Methods In 70 hypertensive patients with electrocardiographic left ventricular hypertrophy, we measured minimal forearm vascular resistance (MFVR) by plethysmography and insulin sensitivity (M/IG) by a 2-h isoglycemic hyperinsulinemic clamp at baseline and after 1, 2 and 3 years of blinded treatment with atenolol- or losartan-based regimens. Results Blood pressures were reduced similarly in the two treatment groups. After 3 years, MFVR was increased (3.7 versus 3.2 mmHg × min × 100, P < 0.05) and M/IG decreased (8.6 versus 12.1 l2/kg × mmol × min, P < 0.05) in patients treated with atenolol, whereas MFVR and M/IG were unchanged (3.5 versus 3.5 mmHg × min × 100 and 12.6 versus 11.1 l2/kg × mmol × min, both P = NS) in patients treated with losartan. As compared to atenolol, losartan treatment was associated with less increase in MFVR (4.3 versus 27%, P < 0.05) and less decrease in M/IG (24 versus −14%, P < 0.01). The relative change in M/IG was inversely associated with the relative change in MFVR (r = −0.16, P < 0.05) independently of the relative change in body mass index (r = −0.29, P < 0.001). Conclusions As compared to atenolol, losartan treatment was associated with less peripheral vascular hypertrophy/rarefaction and higher insulin sensitivity. The relative change in MFVR and M/IG were inversely related, supporting the hypothesis that peripheral vascular changes in hypertension may induce insulin resistance. The ability of losartan to preserve insulin sensitivity may explain the lower incidence of new onset diabetes in patients treated with losartan in the LIFE study.

Lipodystrophy in human immunodeficiency virus patients impairs insulin action and induces defects in β-cell function

The pathophysiology of insulin resistance in human immunodeficiency virus (HIV)-associated lipodystrophy syndrome (HALS) is not fully clarified. We investigated 18 men with HALS and 18 HIV-positive males without lipodystrophy (control subjects). Duration and modality of antiretroviral therapy were similar between study groups. A hyperinsulinemic euglycemic clamp showed an impaired glucose disposal rate (GDR) in HALS patients (5.6 v 8.3 mg glucose/min. kg(FFM), P =.0006). As demonstrated by indirect calorimetry, HALS patients showed an impaired nonoxidative glucose metabolism (NOGM, 2.2 v 4.2, P =.006), whereas levels of basal and insulin-stimulated oxidative glucose metabolism (OGM) (2.4 v 2.3, P =.55, and 3.3 v 4.0, P =.064, respectively) were not significantly different between groups. Despite comparable total fat masses, dual energy x-ray absorptiometry (DEXA) scans showed that the percentage of limb fat (ie, peripheral-fat-mass/[peripheral-fat-mass + trunk-fat-mass]. 100%) was reduced in HALS patients (36% v 46%, P =.0002). Multiple linear regression analysis indicated that percentage of limb fat explained 53% of the variability of GDR and 45% of the variability of NOGM in HALS patients. In HALS patients, leg fat mass correlated positively with NOGM (r =.51, P <.05), whereas abdominal fat mass and NOGM did not correlate (P =.91). Analyzing the relationship between first phase insulin secretion and insulin sensitivity, 6 HALS patients compared with none of the control subjects exhibited impaired insulin secretion (P <.05). Our data suggest that fat redistribution independently of antiretroviral therapy is highly related to insulin resistance in HALS patients. Furthermore, in HALS patients, impaired glucose metabolism most likely relates to decreased NOGM and to defects in beta-cell function.

Relative influence of insulin resistance versus blood pressure on vascular changes in longstanding hypertension. ICARUS, a LIFE sub study

Background Insulin resistance is associated with hypertension. The relative influences of hyperinsulinaemia and high blood pressure on vascular hypertrophy and carotid distensibility is unclear in patients with longstanding hypertension. Methods In 88 unmedicated patients with stage II–III hypertension and left ventricular hypertrophy on electrocardiogram we measured blood pressure, minimal forearm vascular resistance (MFVR) using plethysmography, intima–media thickness (IMT) and the wall distensibility of the common carotid arteries using ultrasound, and insulin sensitivity using a 2-h isoglycaemic hyperinsulinaemic clamp. Results IMT was positively correlated to systolic blood pressure (r = 0.26, P < 0.05), whole body glucose uptake index (M/IG; r = 0.22, P < 0.05), age (r = 0.24, P < 0.05) and negatively correlated to body mass index (r = −0.24, P < 0.05); IMT did not correlate to fasting serum insulin (r = −0.14, NS). In men (n = 64) MFVR was positively correlated to systolic blood pressure (r = 0.30, P < 0.05), but was unrelated to M/G and serum insulin. The distensibility of the common carotid arteries was negatively correlated to systolic blood pressure (r = −0.40, P < 0.001) and in untreated patients (n = 22) positively correlated to M/IG (r = 0.47, P < 0.05). Conclusions High systolic blood pressure was related to vascular hypertrophy, whereas hyperinsulinaemia and insulin resistance were not, suggesting that longstanding high blood pressure is a far more important determinant for structural vascular changes than insulin resistance at this stage of the hypertensive disease. However, hyperinsulinaemia and insulin resistance were associated with low distensibility of the common carotid arteries in the subgroup of never treated hypertensive patients.

Relative Atrial Natriuretic Peptide Deficiency and Inadequate Renin and Angiotensin II Suppression in Obese Hypertensive Men

Obesity is a strong risk factor for hypertension, but the mechanisms by which obesity leads to hypertension are incompletely understood. On this background, we assessed dietary sodium intake, serum levels of natriuretic peptides (NPs), and the activity of the renin–angiotensin system in 63 obese hypertensive men (obeseHT: body mass index, ≥30.0 kg/m2; 24-hour ambulatory blood pressure, ≥130/80 mm Hg), in 40 obese normotensive men (obeseNT: body mass index, ≥30.0 kg/m2; 24-hour ambulatory blood pressure, <130/80 mm Hg), and in 27 lean normotensive men (leanNT: body mass index, 20.0–24.9 kg/m2; 24-hour ambulatory blood pressure, <130/80 mm Hg). All study subjects were medication free. As a surrogate estimate for dietary sodium intake, we measured sodium excretion in a 24-hour urine collection and we measured serum levels of midregional proatrial NP and plasma levels of renin and angiotensin II. The obese men had higher mean (±SD) urinary sodium excretion (obeseHT, 213.6±85.2 mmol; obeseNT, 233.0±70.0 mmol) than the lean normotensive men (leanNT, 155.5±51.7 mmol; P=0.003). ObeseHT had lower (median [interquartile range]) serum midregional proatrial NP levels (49.2 [37.3–64.7] pmol/L) than leanNT (69.3 [54.3–82.9] pmol/L; P=0.003), whereas obeseNT had midregional proatrial NP levels in between (54.1 [43.2–64.7] pmol/L); obeseNT had lower (median [interquartile range]) plasma levels of renin (5.0 [3.0–8.0] mIU/L versus 9.0 [4.0–18.0]) and angiotensin II (2.4 [1.5–3.5] pmol/L versus 4.2 [2.2–7.9]) than obeseHT (P⩽0.049), whereas obeseHT had similar plasma levels of renin and angiotensin II as leanNT (P≥0.19). Thus, despite a high sodium intake and a high blood pressure, obese hypertensive men have a relative NP deficiency and an inadequate renin–angiotensin system suppression.

β-Cell dysfunction and low insulin clearance in insulin-resistant human immunodeficiency virus (HIV)-infected patients with lipodystrophy

Objective  To obtain a better understanding of the physiological aspects of glucose homeostasis in human immunodeficiency virus (HIV)‐infected patients with lipodystrophy, we evaluated separately β‐cell function and insulin sensitivity after an oral glucose load.

The effect of glucagon-like peptide-2 on arterial blood flow and cardiac parameters.

BACKGROUND Glucagon-like peptide-2 (GLP-2) is known to increase mesenteric blood flow. The aim of the study was to evaluate the effect of GLP-2 on blood flow in different vascular sites, and dynamic changes in cardiac parameters. METHODS 10 healthy volunteers were given 450 nmol subcutaneous (SC) GLP-2 or isotonic saline (5 subjects) in a single blinded manner. During the following 90 min, blood flow in the superior mesenteric artery (SMA), celiac artery (CA), renal artery (RA), common carotid artery (CCA) was measured using Doppler ultrasound (US), and cardiovascular variables were measured by impedance cardiography and finger plethysmography. Plasma GLP-2 was measured at times 0, 30 and 60 min. RESULTS Compared to the placebo group, GLP-2 elicited a 27% decrease in the resistance index (RI) and a 269.4% increase in Time Averaged Maximal Velocity (TAMV) in the SMA (P<0.01). CA, RA and CCA: There were no significant changes in RI or TAMV in the GLP-2 or placebo group, and no change in CA diameter. Cardiac parameters: GLP-2 increased cardiac output (CO), stroke volume (SV) and heart rate (HR) compared to baseline (respectively: 15.3, 4.81 and 8.2% (P<0.001, P<0.01 and P<0.01)). The CO, SV and HR changes were not significantly different from the placebo group. Mean plasma GLP-2 serum levels in the placebo group at times 0, 30 and 60 min were 22.8, 23.4 and 23.2 pmol/l. In the GLP-2 group 20.3, 1273 and 1725 pmol/l. CONCLUSION SC GLP-2 increased SMA blood flow, as previously shown, but elicited no changes in other vascular sites. CO and HR increased significantly, presumably due to the increased mesenteric blood flow.

Flash pulmonary edema in patients with renal artery stenosis--the Pickering Syndrome.

Abstract Aim. We report the prevalence of flash pulmonary edema in patients consecutively referred for balloon angioplasty of unior bilateral renal artery stenosis (PTRA), and describe the characteristics of this special fraction of the patients. We further report two unusual cases. Methods and material. Review of medical records from 60 patients consecutively referred for unior bilateral PTRA from 2004–2005 in Copenhagen County. Results. Eight out of 60 patients had one or more episodes of flash pulmonary edema before PTRA. Compared with the remaining patients, they had a higher prevalence of bilateral stenosis (50% vs 27%) and coronary artery disease (75% vs 28%). However, only one of eight had severe systolic dysfunction of the left ventricle. After PTRA, two recurrences of flash pulmonary edema were observed. One was caused by severe restenosis and did not recur after aorto-renal bypass surgery. The other one was caused by rapid atrial fibrillation and did not recur after pacemaker and medical treatment. Conclusion. Flash pulmonary edema can be observed in patients with unilateral as well as bilateral stenosis. The prognosis is usually excellent upon treatment of the stenoses. Recurrences are rare unless restenosis occurs, and therefore, regular control, e.g. by Doppler-ultrasound examination is recommended.

Different growth hormone sensitivity of target tissues and growth hormone response to glucose in HIV-infected patients with and without lipodystrophy

Growth hormone (GH)-secretion in HIV-lipodystrophy is impaired; however, GH-sensitivity of GH-target tissues remains to be evaluated. We measured overnight fasting concentrations of GH-sensitive insulin-like growth-factor-I (IGF-I) and IGF binding protein-3 (IGFBP-3) including GH binding protein (GHBP), a marker of GH-receptor sensitivity, in antiretroviral treated HIV-infected patients with (LIPO) and without lipodystrophy (NONLIPO) and antiretroviral naïve HIV-infected patients (NAÏVE). Three h GH-suppression tests using oral glucose were undertaken to determine dynamics of GH-secretion. IGF-I and IGFBP-3 were increased in LIPO compared with NONLIPO (p<0.05), but did not differ significantly between NONLIPO and NAÏVE. Area under the curve of GH (AUC-GH) during the GH-suppression test was decreased in LIPO compared with NONLIPO (p<0.05). Ratio of limb to trunk fat, which was decreased in LIPO compared to NONLIPO and NAÏVE (p<0.001), correlated positively with AUC-GH and rebound-GH (p<0.05). All groups displayed suppression of GH during the suppression test (p<0.05) and all groups, except LIPO, displayed a rebound of GH (p<0.05), which probably is explained by persistently increased plasma glucose in LIPO compared with NONLIPO and NAÏVE (p<0.01). GHBP was inversely correlated with AUC-GH (p<0.01). Our data suggest that GH-target tissues in LIPO are at least as GH-sensitive as in HIV-infected patients without lipodystrophy.