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Department of Endocrinology and Internal Medicine, Novo Nordisk A/S, NNF center for Basic Metabolic Research, Department of Clinical Biochemistry, Department of Clinical Physiology and Molecular Imaging, Department of Clinical Medicine, Aarhus University Hospital, Norrebrogade 44, DK-8000 Aarhus, Denmark
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Department of Endocrinology and Internal Medicine, Novo Nordisk A/S, NNF center for Basic Metabolic Research, Department of Clinical Biochemistry, Department of Clinical Physiology and Molecular Imaging, Department of Clinical Medicine, Aarhus University Hospital, Norrebrogade 44, DK-8000 Aarhus, Denmark
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The antihypertensive actions of glucagon-like peptide-1 (GLP1) receptor agonists have been linked to the release of atrial natriuretic peptide (ANP) in mice. Whether a GLP1–ANP axis exists in humans is unknown. In this study, we examined 12 healthy young males in a randomized, controlled, double-blinded, single-day, cross-over study to evaluate the effects of a 2-h native GLP1 infusion. Plasma proANP concentrations were measured by an automated mid-region-directed proANP immunoassay and N-terminal pro B-type natriuretic peptide (BNP) on Roche Modular E170. Urine was collected for measurements of sodium excretion. Although GLP1 infusion increased the urinary sodium excretion markedly, there were no significant changes in either proANP or proBNP concentrations. When GLP1 infusion was stopped, sodium excretion declined rapidly. As proANP concentration reflects ANP secretion, our data could not confirm the existence of a GLP1–ANP axis in humans. Especially, the natriuretic effects of GLP1 seem unlikely to be mediated exclusively via ANP.
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Context
Insulin resistance in polycystic ovary syndrome (PCOS) may increase the risk of reactive hypoglycaemia (RH) and decrease glucagon-like peptide-1 (GLP-1) secretion. The possible effects of treatment with oral contraceptives (OCP) and/or metformin on GLP-1 secretion and risk of RH in PCOS is undetermined.
Setting
Outpatient clinic.
Patients and interventions
Randomized, controlled clinical trial. Ninety women with PCOS were randomized to 12-month treatment with OCP (150 mg desogestrel + 30 mg ethinylestradiol), metformin (2 g/day) or metformin + OCP. Five-hour oral glucose tolerance tests (5-h OGTT) measuring fasting and area under the curve (AUC) for GLP-1, glucose, insulin and C-peptide were performed before and after the intervention period. Sixty-five women completed the study and 34 weight-matched healthy women were included as controls.
Main outcome measures
Changes in GLP-1, glucose, insulin and C-peptide during 5-h OGTT.
Results
Fasting GLP-1 levels increased during metformin + OCP vs OCP treatment, whereas AUC GLP-1 levels were unchanged during medical treatment. The prevalence of reactive hypoglycemia increased from 9/65 to 14/65 after intervention (P < 0.01) and was more common after treatment with metformin + OCP (increase from 3/23 to 6/23, P = 0.01). Reactive hypoglycaemia was associated with higher insulin and C-peptide levels during 5-h OGTT, but was unassociated with BMI and AUC GLP-1. GLP-1 levels were comparable in PCOS vs controls. AUC GLP-1 levels were significantly lower in obese vs lean patients and were inversely associated with BMI.
Conclusions
AUC GLP-1 levels were unchanged during treatment. Increased risk of hypoglycemia during metformin + OCP could be associated with increased insulin secretion.
Department of Clinical Physiology and Nuclear Medicine, Bispebjerg and Frederiksberg Hospital, University Hospital of Copenhagen, Copenhagen, Denmark
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Department of Clinical Physiology, Nuclear Medicine and PET, Rigshospitalet, University Hospital of Copenhagen, Copenhagen, Denmark
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Department of Geriatrics, Bispebjerg and Frederiksberg Hospital, University Hospital of Copenhagen, Copenhagen, Denmark
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Department of Biomedical Sciences, University of Copenhagen, Copenhagen, Denmark
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Department of Biomedical Sciences, University of Copenhagen, Copenhagen, Denmark
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Glucose-dependent insulinotropic polypeptide (GIP) in combination with hyperinsulinemia increase blood flow and triglyceride clearance in subcutaneous abdominal adipose tissue in lean humans. The present experiments were performed to determine whether the increase involves capillary recruitment. Eight lean healthy volunteers were studied before and after 1 h infusion of GIP or saline during a hyperglycemic–hyperinsulinemic clamp, raising plasma glucose and insulin to postprandial levels. Subcutaneous abdominal adipose tissue blood flow (ATBF) was measured by the 133Xenon clearance technique, and microvascular blood volume was determined by contrast-enhanced ultrasound imaging. During infusion of saline and the clamp, both ATBF (2.7 ± 0.5 mL/min 100 g/tissue) and microvascular blood volume remained unchanged throughout the experiments. During GIP infusion and the clamp, ATBF increased ~fourfold to 11.4 ± 1.9 mL/min 100 g/tissue, P < 0.001. Likewise, the contrast-enhanced ultrasound signal intensity, a measure of the microvascular blood volume, increased significantly 1 h after infusion of GIP and the clamp (P = 0.003), but not in the control experiments. In conclusion, the increase in ATBF during GIP infusion involves recruitment of capillaries in healthy lean subjects, which probably increases the interaction of circulating lipoproteins with lipoprotein lipase, thus promoting adipose tissue lipid uptake.
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Region Jönköping County, Jönköping, Sweden
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Objective
Glucagon and amino acids may be regulated in a feedback loop called the liver-alpha-cell axis with alanine or glutamine as suggested signal molecules. We assessed this concept in individuals with type 2 diabetes in the fasting state, after ingestion of a protein-rich meal, and during weight loss. Moreover, we investigated if postprandial glucagon secretion and hepatic insulin sensitivity were related.
Methods
This is a secondary analysis of a 12-week weight-loss trial (Paleolithic diet ± exercise) in 29 individuals with type 2 diabetes. Before and after the intervention, plasma glucagon and amino acids were measured in the fasting state and during 180 min after a protein-rich mixed meal. Hepatic insulin sensitivity was measured using the hyperinsulinemic-euglycemic clamp with [6,6-2H2]glucose as a tracer.
Results
The postprandial increase of plasma glucagon was associated with the postprandial increase of alanine and several other amino acids but not glutamine. In the fasted state and after the meal, glucagon levels were negatively correlated with hepatic insulin sensitivity (rS = −0.51/r = −0.58, respectively; both P < 0.05). Improved hepatic insulin sensitivity with weight loss was correlated with decreased postprandial glucagon response (r = −0.78; P < 0.001).
Conclusions
Several amino acids, notably alanine, but not glutamine could be key signals to the alpha cell to increase glucagon secretion. Amino acids may be part of a feedback mechanism as glucagon increases endogenous glucose production and ureagenesis in the liver. Moreover, postprandial glucagon secretion seems to be tightly related to hepatic insulin sensitivity.
Novo Nordisk Foundation Center for Basic Metabolic Research, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
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Novo Nordisk Foundation Center for Basic Metabolic Research, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
Department of Clinical Biochemistry, Rigshospitalet, Copenhagen, Denmark
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Novo Nordisk Foundation Center for Basic Metabolic Research, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
Department of Endocrinology and Nephrology, Nordsjællands University Hospital, Hillerød, Denmark
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Center for Neonatal Screening, Department of Congenital Disorders, Statens Serum Institute, Copenhagen, Denmark
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Department of Clinical Medicine, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
Center for Clinical Metabolic Research, Gentofte Hospital, University of Copenhagen, Hellerup, Denmark
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Steno Diabetes Center Copenhagen, Gentofte, Denmark
Department of Clinical Medicine, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
Center for Clinical Metabolic Research, Gentofte Hospital, University of Copenhagen, Hellerup, Denmark
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Department of Clinical Medicine, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
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Novo Nordisk Foundation Center for Basic Metabolic Research, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
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Novo Nordisk Foundation Center for Basic Metabolic Research, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
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Objective:
Parathyroid hormone (PTH) is a key hormone in regulation of calcium homeostasis and its secretion is regulated by calcium. Secretion of PTH is attenuated during intake of nutrients, but the underlying mechanism(s) are unknown. We hypothesized that insulin acts as an acute regulator of PTH secretion.
Methods:
Intact PTH was measured in plasma from patients with T1D and matched healthy individuals during 4-h oral glucose tolerance tests (OGTT) and isoglycemic i.v. glucose infusions on 2 separate days. In addition, expression of insulin receptors on surgical specimens of parathyroid glands was assessed by immunochemistry (IHC) and quantitative PCR (qPCR).
Results:
The inhibition of PTH secretion was more pronounced in healthy individuals compared to patients with T1D during an OGTT (decrementalAUC0–240min: −5256 ± 3954 min × ng/L and −2408 ± 1435 min × ng/L, P = 0.030). Insulin levels correlated significantly and inversely with PTH levels, also after adjusting for levels of several gut hormones and BMI (P = 0.002). Expression of insulin receptors in human parathyroid glands was detected by both IHC and qPCR.
Conclusion:
Our study suggests that insulin may act as an acute regulator of PTH secretion in humans.
