Effects of exenatide on circulating glucose, insulin, glucagon, cortisol and catecholamines in healthy volunteers during exercise

Khoo, Eric Yin Hao; Wallis, James; Tsintzas, Kostas; Macdonald, I. A.; Mansell, Peter

doi:10.1007/s00125-009-1579-1

Cited by 21 publications

(20 citation statements)

References 8 publications

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“…In contrast, the epinephrine response to reducing glucose concentration to 3.5 mmol/L was significantly reduced by lixisenatide treatment, whereas the epinephrine response to further reduction in glucose concentration to 2.8 mmol/L was not different between the treatments. A normal epinephrine response to deep hypoglycemia by lixisenatide treatment is supported by studies on GLP-1 (11), exenatide (12), and albiglutide (13), whereas the finding that lixisenatide reduces epinephrine levels at glucose levels of 3.5 mmol/L contrasts with the normal response at this level by exenatide (12) and albiglutide (13), and is in contrast with an increase in epinephrine levels by exenatide during exercise (32). Again, whether this characteristic is due to differences between the GLP-1 receptor agonists, differences in clamp technique, or differences between healthy subjects and subjects with type 2 diabetes treated with oral agents or basal insulin remains to be studied.…”

Section: Discussionmentioning

confidence: 96%

Effect of the GLP-1 Receptor Agonist Lixisenatide on Counterregulatory Responses to Hypoglycemia in Subjects With Insulin-Treated Type 2 Diabetes

2015

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OBJECTIVECounterregulatory responses are critical to prevent hypoglycemia in subjects with type 2 diabetes. This is particularly important in insulin-treated patients. This study explored the effect of the glucagon-like peptide 1 receptor agonist lixisenatide on the hormonal counterregulatory responses to insulin-induced hypoglycemia when added to basal insulin therapy in subjects with type 2 diabetes. RESEARCH DESIGN AND METHODSThe study was a single-center, double-blind, randomized, placebo-controlled crossover study involving 18 subjects with type 2 diabetes (11 males) with a mean age of 55 years, diabetes duration of 12 years, HbA 1c level of 7.7%, fasting blood glucose (FBG) concentration of 9.7 mmol/L, and a BMI of 33 kg/m 2 , who were treated with basal insulin (mean duration 7 years, daily dose 39 units/day) and metformin (mean daily dose 2.1 g). Subjects received treatment with lixisenatide or placebo for 6 weeks in random order, with a 4-week washout period in between. After 6 weeks of treatment, subjects underwent a two-step hyperinsulinemic hypoglycemic clamp at 3.5 and 2.8 mmol/L. RESULTSAfter 6 weeks of treatment, HbA 1c and FBG levels were lower after lixisenatide therapy than after placebo therapy. At the hypoglycemic level of 3.5 mmol/L, glucagon and epinephrine levels were significantly lower during lixisenatide treatment than during placebo treatment, whereas at 2.8 mmol/L glucagon and epinephrine levels did not differ between the subjects. Cortisol, pancreatic polypeptide, and norepinephrine levels did not differ significantly between the treatments. CONCLUSIONSGlucagon and epinephrine levels are reduced by lixisenatide at a concentration of 3.5 mmol/L, but their counterregulatory responses to deep hypoglycemia at a concentration of 2.8 mmol/L are sustained during treatment with lixisenatide in combination with basal insulin. Clinical trial reg. nos. NCT02020629, clinicaltrials .gov, and EudraCT2012-004959-36, https:// www.clinicaltrialsregister.eu/.

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Section: Discussionmentioning

confidence: 96%

Effect of the GLP-1 Receptor Agonist Lixisenatide on Counterregulatory Responses to Hypoglycemia in Subjects With Insulin-Treated Type 2 Diabetes

2015

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“…29 This is in line with previous findings, in which GLP-1 receptor agonists were shown to stimulate SNS activity, measured by heart rate variability, 30,31 or plasma catecholamine levels. 32 Although increased SNS activity is commonly associated with vasoconstriction, several studies have demonstrated that for the microcirculation, SNS activity might be associated with improved perfusion and consequently glucose uptake. 25 For example, in healthy volunteers, clamped hyperinsulinemia increased power in the neurogenic domain, which was associated with increased capillary perfusion and glucose uptake.…”

Section: Discussionmentioning

confidence: 99%

GLP-1–Based Therapies Have No Microvascular Effects in Type 2 Diabetes Mellitus

Smits

Tonneijck

Muskiet

et al. 2016

ATVB

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Objective— To assess the effects of glucagon-like peptide (GLP)-1–based therapies (ie, GLP-1 receptor agonists and dipeptidyl peptidase-4 inhibitors) on microvascular function in patients with type 2 diabetes mellitus. Approach and Results— We studied 57 patients with type 2 diabetes mellitus (mean±SD age: 62.8±6.9 years; body mass index: 31.8±4.1 kg/m 2 ; HbA 1c [glycated hemoglobin] 7.3±0.6%) in an acute and 12-week randomized, placebo-controlled, double-blind trial conducted at the Diabetes Center of the VU University Medical Center. In the acute study, the GLP-1 receptor agonist exenatide (therapeutic concentrations) or placebo (saline 0.9%) was administered intravenously. During the 12-week study, patients received the GLP-1 receptor agonist liraglutide (1.8 mg daily), the dipeptidyl peptidase-4 inhibitor sitagliptin (100 mg daily), or matching placebos. Capillary perfusion was assessed by nailfold skin capillary videomicroscopy and vasomotion by laser Doppler fluxmetry, in the fasting state and after a high-fat mixed meal. In neither study, treatment affected fasting or postprandial capillary perfusion compared with placebo ( P >0.05). In the fasting state, acute exenatide infusion increased neurogenic vasomotion domain power, while reducing myogenic domain power (both P <0.05). After the meal, exenatide increased endothelial domain power ( P <0.05). In the 12-week study, no effects on vasomotion were observed. Conclusions— Despite modest changes in vasomotion, suggestive of sympathetic nervous system activation and improved endothelial function, acute exenatide infusion does not affect skin capillary perfusion in type 2 diabetes mellitus. Twelve-week treatment with liraglutide or sitagliptin has no effect on capillary perfusion or vasomotion in these patients. Our data suggest that the effects of GLP-1–based therapies on glucose are not mediated through microvascular responses.

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“…The function of carnitine in energy metabolism is impaired in diabetes and is also associated with increased lipolysis and the mobilization of free-fatty acids [71]. The metabolic response to exercise is closely regulated via circulating levels of counterregulatory hormones, such as catecholamines, glucagon and cortisol in response to fluctuations in blood glucose and insulin levels [72].…”

Section: Metabolic Hormonal and Autonomic Modulation Of Exercise In mentioning

confidence: 99%

Exercise improves cardiac autonomic function in obesity and diabetes

Voulgari¹,

Pagoni²,

Vinik

et al. 2013

Metabolism

109

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Effects of exenatide on circulating glucose, insulin, glucagon, cortisol and catecholamines in healthy volunteers during exercise

Abstract: In non-diabetic participants given exenatide, blood glucose concentrations rise rather than fall during aerobic exercise with an associated greater catecholamine response.

Cited by 21 publications

References 8 publications

Effect of the GLP-1 Receptor Agonist Lixisenatide on Counterregulatory Responses to Hypoglycemia in Subjects With Insulin-Treated Type 2 Diabetes

Effect of the GLP-1 Receptor Agonist Lixisenatide on Counterregulatory Responses to Hypoglycemia in Subjects With Insulin-Treated Type 2 Diabetes

GLP-1–Based Therapies Have No Microvascular Effects in Type 2 Diabetes Mellitus

Exercise improves cardiac autonomic function in obesity and diabetes

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