Evaluation of the specific effects of intranasal glucagon on glucose production and lipid concentration in healthy men during a pancreatic clamp

Dash, Satya; Xiao, Changting; Stahel, Priska; Koulajian, Khajag; Giacca, Adria; Lewis, Gary F.

doi:10.1111/dom.13069

Cited by 7 publications

(16 citation statements)

References 33 publications

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“…We observed a transient increase in plasma glucagon and insulin, with no apparent rise in plasma glucose. Notably, we have previously shown that ING attenuates the increase in endogenous glucose production under conditions of hyperglucagonaemia with a pancreatic clamp 20. The transient insulin elevation with ING is therefore attributable to glucagon potentiation of insulin secretion rather than enhanced clearance.…”

mentioning

confidence: 91%

“…REE was increased upon glucagon injection into the paraventricular nucleus of the hypothalamus of rats and this was attributed to increased thermogenesis and carbohydrate oxidation. 19,20 Most notably, 1 mg ING attenuated the increase in hepatic glucose production in healthy, lean adults under conditions of hyperglucagonaemia in the setting of a pancreatic clamp. In addition, CNS glucagon action in the mediobasal hypothalamus and dorsal vagal complex has been shown to lower hepatic glucose production.…”

Section: Introductionmentioning

confidence: 98%

“…15 Intra-cerebroventricular glucagon in rats reduced food intake dependent on glucagon signalling in the AgRP neurons of the hypothalamus. 20 Nasal glucagon, therefore, has metabolic effects independent of plasma glucagon which may potentially be CNS-mediated. 16,17 In humans, several intranasally administered small peptide hormones have been shown to increase cerebrospinal fluid (CSF) concentration of the administered peptide, with no discernible effect on serum levels.…”

Section: Introductionmentioning

confidence: 99%

“…In addition, CNS glucagon action in the mediobasal hypothalamus and dorsal vagal complex has been shown to lower hepatic glucose production. 20 Whether ING can be used to target other metabolic processes has not been studied before. 18 This suggests that intranasal administration can potentially be used to preferentially deliver small peptide hormones to the CNS.…”

Section: Introductionmentioning

confidence: 99%

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Intranasal glucagon acutely increases energy expenditure without inducing hyperglycaemia in overweight/obese adults

Stahel

Lee

Sud

et al. 2019

Diabetes Obesity Metabolism

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Aim: To assess the acute effects of 0.7 mg intranasal glucagon (ING) vs intranasal placebo (INP) on food intake and resting energy expenditure (REE).Methods: A single-blind, crossover study was conducted in 19 overweight/obese adults (15 men, 4 women). REE was assessed by indirect calorimetry over 90 minutes, after which appetite was assessed using a visual analogue scale, and ad libitum caloric intake was assessed. Plasma samples were obtained at baseline and at 15-minute intervals post-treatment up to 90 minutes.Results: ING increased total REE (INP 61.5 ± 1.2 kcal vs ING 69.4 ± 1.2 kcal; P = 0.027). There were no between-treatment differences in blood glucose, food intake and appetite. There were no adverse effects.Conclusion: ING acutely increases REE without increasing plasma glucose. Longer term studies with multiple daily dosing will establish whether this affects body weight.

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confidence: 91%

Section: Introductionmentioning

confidence: 98%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

Intranasal glucagon acutely increases energy expenditure without inducing hyperglycaemia in overweight/obese adults

Stahel

Lee

Sud

et al. 2019

Diabetes Obesity Metabolism

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“…Delays, errors, or failure to administer glucagon during severe hypoglycaemia may negatively impact patient outcomes . Recently, a study has shown that reconstituted recombinant glucagon delivered intranasally in euglycaemic individuals is rapidly absorbed into the systemic circulation and acts to increase blood glucose . A form of glucagon that does not require reconstitution could be more beneficial, as it could be administered more quickly.…”

Section: Introductionmentioning

confidence: 99%

Effects of common cold and concomitant administration of nasal decongestant on the pharmacokinetics and pharmacodynamics of nasal glucagon in otherwise healthy participants: A randomized clinical trial

Guzmán

Dulude²,

Piché³

et al. 2017

Diabetes Obesity Metabolism

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AimsNasal glucagon (NG) is a nasally‐administered glucagon powder, absorbed through the nasal mucosa, designed for treatment of severe hypoglycaemia. This study evaluated the safety, pharmacokinetics (PK) and pharmacodynamics (PD) of NG in otherwise healthy participants with common colds and after recovery from cold symptoms, with and without concomitant nasal decongestant.Materials and MethodsThis was a single‐centre, open‐label study. Cohort 1 participants (N = 18) received 2 doses of NG: one while experiencing nasal congestion and another after recovery from cold symptoms. Cohort 2 participants (N = 18), who also had colds with nasal congestion, received a single dose of NG 2 hours after treatment with the decongestant oxymetazoline. Total symptoms score and other safety measures were assessed before and after NG administration.ResultsNG was well tolerated, without serious adverse events. Common adverse events (transient lacrimation, nasal discomfort, rhinorrhea and nausea) were more frequent in both Cohorts 1 and 2 during nasal congestion. Glucagon levels peaked 18 minutes post‐dose and glucose levels peaked 30 to 42 minutes post‐dose in all groups. Nasal congestion, with or without concomitant nasal decongestant, did not significantly affect PK of NG. Although glucose AUECs0‐t was different between Cohort 1 with nasal congestion and Cohort 2, glucose concentrations at 30 minutes appeared similar in all groups.ConclusionsThere were no clinically relevant differences in safety or PK/PD of NG associated with nasal congestion or concomitant administration of nasal decongestant, suggesting that NG can be used to treat severe hypoglycaemia in individuals experiencing nasal congestion.

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Intestinal lipid absorption and transport in type 2 diabetes

Vergès

2022

Diabetologia

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Postprandial hyperlipidaemia is an important feature of diabetic dyslipidaemia and plays an important role in the development of cardiovascular disease in individuals with type 2 diabetes. Postprandial hyperlipidaemia in type 2 diabetes is secondary to increased chylomicron production by the enterocytes and delayed catabolism of chylomicrons and chylomicron remnants. Insulin and some intestinal hormones (e.g. glucagon-like peptide-1 [GLP-1]) influence intestinal lipid metabolism. In individuals with type 2 diabetes, insulin resistance and possibly reduced GLP-1 secretion are involved in the pathophysiology of postprandial hyperlipidaemia. Several factors are involved in the overproduction of chylomicrons: (1) increased expression of microsomal triglyceride transfer protein, which is a key enzyme in chylomicron synthesis; (2) higher stability and availability of apolipoprotein B-48; and (3) increased de novo lipogenesis. Individuals with type 2 diabetes present with disorders of cholesterol metabolism in the enterocytes with reduced absorption and increased synthesis. The increased production of chylomicrons in type 2 diabetes is also associated with a reduction in their catabolism, mostly because of a reduction in activity of lipoprotein lipase. Modification of the microbiota, which is observed in type 2 diabetes, may also generate disorders of intestinal lipid metabolism, but human data remain limited. Some glucose-lowering treatments significantly influence intestinal lipid absorption and transport. Postprandial hyperlipidaemia is reduced by metformin, pioglitazone, alpha-glucosidase inhibitors, dipeptidyl peptidase 4 inhibitors and GLP-1 agonists. The most pronounced effect is observed with GLP-1 agonists, which reduce chylomicron production significantly in individuals with type 2 diabetes and have a direct effect on the intestine by reducing the expression of genes involved in intestinal lipoprotein metabolism. The effect of sodium-glucose cotransporter 2 inhibitors on intestinal lipid metabolism needs to be clarified.

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Evaluation of the specific effects of intranasal glucagon on glucose production and lipid concentration in healthy men during a pancreatic clamp

Cited by 7 publications

References 33 publications

Intranasal glucagon acutely increases energy expenditure without inducing hyperglycaemia in overweight/obese adults

Intranasal glucagon acutely increases energy expenditure without inducing hyperglycaemia in overweight/obese adults

Effects of common cold and concomitant administration of nasal decongestant on the pharmacokinetics and pharmacodynamics of nasal glucagon in otherwise healthy participants: A randomized clinical trial

Intestinal lipid absorption and transport in type 2 diabetes

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