Ali Asmar

Fluid Shifts, Vasodilatation and Ambulatory Blood Pressure Reduction During Long Duration Spaceflight

Weightlessness in space induces initially an increase in stroke volume and cardiac output, accompanied by unchanged or slightly reduced blood pressure. It is unclear whether these changes persist throughout months of flight. Here, we show that cardiac output and stroke volume increase by 35–41% between 3 and 6 months on the International Space Station, which is more than during shorter flights. Twenty‐four hour ambulatory brachial blood pressure is reduced by 8–10 mmHg by a decrease in systemic vascular resistance of 39%, which is not a result of the suppression of sympathetic nervous activity, and the nightly dip is maintained in space. It remains a challenge to explore what causes the systemic vasodilatation leading to a reduction in blood pressure in space, and whether the unexpectedly high stroke volume and cardiac output can explain some vision acuity problems encountered by astronauts on the International Space Station.

Renal extraction and acute effects of glucagon-like peptide-1 on central and renal hemodynamics in healthy men

The present experiments were performed to elucidate the acute effects of intravenous infusion of glucagon-like peptide (GLP)-1 on central and renal hemodynamics in healthy men. Seven healthy middle-aged men were examined on two different occasions in random order. During a 3-h infusion of either GLP-1 (1.5 pmol·kg⁻¹·min⁻¹) or saline, cardiac output was estimated noninvasively, and intraarterial blood pressure and heart rate were measured continuously. Renal plasma flow, glomerular filtration rate, and uptake/release of hormones and ions were measured by Ficks Principle after catheterization of a renal vein. Subjects remained supine during the experiments. During GLP-1 infusion, both systolic blood pressure and arterial pulse pressure increased by 5±1 mmHg (P=0.015 and P=0.002, respectively). Heart rate increased by 5±1 beats/min (P=0.005), and cardiac output increased by 18% (P=0.016). Renal plasma flow and glomerular filtration rate as well as the clearance of Na⁺ and Li⁺ were not affected by GLP-1. However, plasma renin activity decreased (P=0.037), whereas plasma levels of atrial natriuretic peptide were unaffected. Renal extraction of intact GLP-1 was 43% (P<0.001), whereas 60% of the primary metabolite GLP-1 9-36amide was extracted (P=0.017). In humans, an acute intravenous administration of GLP-1 leads to increased cardiac output due to a simultaneous increase in stroke volume and heart rate, whereas no effect on renal hemodynamics could be demonstrated despite significant extraction of both the intact hormone and its primary metabolite.

The Gluco- and Liporegulatory and Vasodilatory Effects of Glucose-Dependent Insulinotropic Polypeptide (GIP) Are Abolished by an Antagonist of the Human GIP Receptor

A truncated form of human glucose-dependent insulinotropic polypeptide (GIP), GIP(3–30)NH2, was recently identified as an antagonist of the human GIP receptor. This study examined the ability of GIP(3–30)NH2 to antagonize the physiological actions of GIP in glucose metabolism, subcutaneous abdominal adipose tissue blood flow (ATBF), and lipid metabolism in humans. Eight lean subjects were studied by measuring arteriovenous concentrations of metabolites and ATBF on three different occasions during hyperglycemic-hyperinsulinemic clamps with concomitant infusions of GIP, GIP(3–30)NH2, or both GIP and GIP(3–30)NH2. During infusion of GIP(3–30)NH2 alone and in combination with GIP, insulin levels and the total glucose amount infused to maintain the clamp were lower than during GIP alone. In addition, ATBF remained constant during the antagonist and increased only slightly in combination with GIP, whereas it increased fivefold during GIP alone. Adipose tissue triacylglyceride (TAG) and glucose uptake decreased, and the free fatty acid/glycerol ratio increased during the antagonist alone and in combination with GIP. The changes in glucose infusion rates and plasma insulin levels demonstrate an inhibitory effect of the antagonist on the incretin effect of GIP. In addition, the antagonist inhibited GIP-induced increase in ATBF and decreased the adipose tissue TAG uptake, indicating that GIP also plays a crucial role in lipid metabolism.

The blunted effect of glucose-dependent insulinotropic polypeptide in subcutaneous abdominal adipose tissue in obese subjects is partly reversed by weight loss

Background:Glucose-dependent insulinotropic polypeptide (GIP) appears to have impaired effect on subcutaneous abdominal adipose tissue metabolism in obese subjects. The aim of the present study was to examine whether weight loss may reverse the impaired effect of GIP on subcutaneous abdominal adipose tissue in obese subjects.Methods:Five obese males participated in a 12-week weight loss program, which consisted of caloric restriction (800 Cal day−1) followed by 4 weeks of weight-maintenance diet. Before and after weight loss, subcutaneous adipose tissue lipid metabolism was studied by conducting regional measurements of arterio-venous plasma concentrations of metabolites and blood flow (adipose tissue blood flow, ATBF) across a segment of the abdominal adipose tissue in the fasting state and during GIP infusion (1.5 pmol kg−1 min−1) in combination with a hyperinsulinemic–hyperglycemic clamp.Results:After weight loss (7.5±0.8 kg), glucose tolerance and insulin sensitivity increased significantly as expected. No significant differences were seen in basal ATBF before (1.3±0.4 ml min−1 100 g tissue−1) and after weight loss (2.1±0.4 ml min−1 100 g tissue)−1; however, a tendency to increase was seen. After weight loss, GIP infusion increased ATBF significantly (3.2±0.1 ml min−1 100 g tissue−1) whereas there was no increase before weight loss. Triacylglycerol (TAG) uptake did not change after weight loss. Baseline free fatty acid (FFA) and glycerol output increased significantly after weight loss, P<0.001. During the clamp period, FFA and glycerol output declined significantly, P<0.05, with no differences before and after weight loss. Weight loss increased glucose uptake and decreased FFA/glycerol ratio during the clamp period, P<0.05.Conclusions:In obese subjects, weight loss, induced by calorie restriction, improves the blunted effect of GIP on subcutaneous abdominal adipose tissue metabolism.

Insulin Plays a Permissive Role for the Vasoactive Effect of GIP Regulating Adipose Tissue Metabolism in Humans

CONTEXT AND OBJECTIVE Glucose-dependent insulinotropic polypeptide (GIP) in combination with hyperinsulinemia increases blood flow and triglyceride (TAG) clearance in subcutaneous (sc) abdominal adipose tissue in lean humans. The present experiments were performed to further investigate the role of insulin for the vasoactive effect of GIP in adipose tissue metabolism and whether the vasodilatory effect of GIP is dependent on C-peptide. METHODS Six lean healthy subjects were studied. The sc abdominal adipose tissue metabolism was assessed by Ficks principle during GIP infusion (1.5 pmol/kg/min) in combination with 1) euglycemic-high insulinemic clamp (Eugluc-Hiinsu), raising plasma insulin concentrations to postprandial levels, 2) hyperglycemic-euinsulinemic clamp (Hygluc-Euinsu), and 3) hyperglycemic-hyperinsulinemic clamp, raising plasma insulin concentrations to supraphysiological levels. During the hyperglycemic clamps, endogenous insulin and C-peptide secretion were inhibited by infusion of the somatostatin analogue octreotide. RESULTS During GIP infusion, Eugluc-Hiinsu, and hyperglycemic-hyperinsulinemic clamps, sc abdominal adipose tissue blood flow (ATBF) was similar and increased from 2.1 ± 0.2 and 2.2 ± 0.4 ml min(-1) (100 g tissue)(-1) to 7.1 ± 0.6 and 7.6 ± 0.1 ml min(-1) (100 g tissue)(-1), respectively (P < .01). ATBF remained virtually constant (2.7 ± 0.4 ml min(-1) [100 g tissue](-1)) during Hygluc-Euinsu and GIP infusion. In addition, adipose tissue TAG clearance increased significantly (P = .03), whereas free fatty acid output (P = .01), glycerol output (P = .02) and free fatty acid/glycerol release ratio (P = .04) decreased during the Eugluc-Hiinsu clamp compared to Hygluc-Euinsu clamp with GIP. CONCLUSION In healthy lean humans, insulin is permissive for GIP to induce an increase in blood flow and TAG clearance in sc abdominal adipose tissue. This effect is independent of C-peptide.

Effects of liraglutide on cardiovascular risk factors in patients with type 1 diabetes.

We investigated the short‐term effect of adding liraglutide 1.8 mg once daily to insulin treatment on cardiovascular risk factors in patients with type 1 diabetes. In total, 100 overweight (BMI ≥25 kg/m2) adult patients (age ≥18 years) with type 1 diabetes and HbA1c ≥ 8% (64 mmol/mol) were randomized to liraglutide 1.8 mg or placebo added to insulin treatment in a 24‐week double‐blinded, placebo‐controlled trial. At baseline and after 24 weeks of treatment, 24‐hour blood pressure and heart rate, pulse pressure, pulse wave velocity and carotid intima‐media thickness were evaluated. Compared with placebo, liraglutide increased 24‐hour heart rate by 4.6 beats per minute (BPM); P = .0015, daytime heart rate by 3.7; P = .0240 and night‐time heart rate by 7.5 BPM; P < .001 after 24 weeks. Diastolic nocturnal blood pressure increased by 4 mm Hg; P = .0362 in the liraglutide group compared with placebo. In conclusion, in patients with long‐standing type 1 diabetes, liraglutide as add‐on to insulin increased heart rate and did not improve other cardiovascular risk factors after 24 weeks of treatment.

Blood pressure in Afghan male immigrants to Denmark.

Immigration from a Third‐World society to a Western society can be associated with higher blood pressure and salt sensitivity. We therefore tested whether immigrants from Afghanistan to Denmark compared with non‐immigrant Danes exhibit a (i) higher 24‐h ambulatory blood pressure (24‐h ABP) and (ii) blunted renin response to a change in salt intake.

Hemodynamic responses to mental stress during salt loading.

The purpose was to examine whether prolonged moderate stress associated with a student exam would increase the blood pressure response to a salt load in young healthy normotensive individuals.

Glucagon‐like peptide‐1 elicits vasodilation in adipose tissue and skeletal muscle in healthy men

In healthy subjects, we recently demonstrated that during acute administration of GLP‐1, cardiac output increased significantly, whereas renal blood flow remained constant. We therefore hypothesize that GLP‐1 induces vasodilation in other organs, for example, adipose tissue, skeletal muscle, and/or splanchnic tissues. Nine healthy men were examined twice in random order during a 2‐hour infusion of either GLP‐1 (1.5 pmol kg−1 min−1) or saline. Cardiac output was continuously estimated noninvasively concomitantly with measurement of intra‐arterial blood pressure. Subcutaneous, abdominal adipose tissue blood flow (ATBF) was measured by the 133Xenon clearance technique. Leg and splanchnic blood flow were measured by Ficks Principle, using indocyanine green as indicator. In the GLP‐1 study, cardiac output increased significantly together with a significant increase in arterial pulse pressure and heart rate compared with the saline study. Subcutaneous, abdominal ATBF and leg blood flow increased significantly during the GLP‐1 infusion compared with saline, whereas splanchnic blood flow response did not differ between the studies. We conclude that in healthy subjects, GLP‐1 increases cardiac output acutely due to a GLP‐1‐induced vasodilation in adipose tissue and skeletal muscle together with an increase in cardiac work.

A sandwich ELISA for measurement of the primary glucagon-like peptide-1 metabolite

Glucagon-like peptide-1 (GLP-1) is an incretin hormone secreted from the gastrointestinal tract. It is best known for its glucose-dependent insulinotropic effects. GLP-1 is secreted in its intact (active) form (7-36NH2) but is rapidly degraded by the dipeptidyl peptidase 4 (DPP-4) enzyme, converting >90% to the primary metabolite (9-36NH2) before reaching the targets via the circulation. Although originally thought to be inactive or antagonistic, GLP-1 9-36NH2 may have independent actions, and it is therefore relevant to be able to measure it. Because reliable assays were not available, we developed a sandwich ELISA recognizing both GLP-1 9-36NH2 and nonamidated GLP-1 9-37. The ELISA was validated using analytical assay validation guidelines and by comparing it to a subtraction-based method, hitherto employed for estimation of GLP-1 9-36NH2 Its accuracy was evaluated from measurements of plasma obtained during intravenous infusions (1.5 pmol × kg-1 × min-1) of GLP-1 7-36NH2 in healthy subjects and patients with type 2 diabetes. Plasma levels of the endogenous GLP-1 metabolite increased during a meal challenge in patients with type 2 diabetes, and treatment with a DPP-4 inhibitor fully blocked its formation. Accurate measurements of the GLP-1 metabolite may contribute to understanding its physiology and role of GLP-1 in diabetes.