Impaired hepatic counterregulatory response to insulin-induced hypoglycemia in hepatic denervated pigs

Nielsen, Michael Festersen; Roelsgaard, Klaus; Keiding, Susanne; Brodersen, Kathrine; Møller, Niels; Vyberg, Mogens; Vilstrup, Hendrik

doi:10.1016/j.jcte.2015.08.004

Cited by 5 publications

(8 citation statements)

References 35 publications

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“…Notably, urea and glucose concentrations are close to the established range for the species studied (Nielsen et al 2015;Perri et al 2017). These findings are supported by the growth phase of piglets, in which the nutritional and physiological needs are altered, as well as protein levels in the feed, generating lower metabolite concentrations (Perri et al 2017).…”

Section: Blood Metabolitessupporting

confidence: 76%

“…In addition, piglets that are subjected to challenge or show acute clinical signs of disease may undergo a decrease in glucose concentration because they use much of their energy to maintain vital functions. However, the results obtained do not corroborate this idea, and we attribute it to the fact that pigs are animals tolerant to glucose concentrations and hyperinsulinaemic (Nielsen et al 2015).…”

Section: Blood Metabolitescontrasting

confidence: 62%

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Biological response of piglets challenged with Escherichia coli F4 (K88) when fed diets containing intestinal alkaline phosphatase

Rupolo¹,

Melo²,

Azevedo³

et al. 2021

CZECH J ANIM SCI

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The aim of the study was to investigate the effect of intestinal alkaline phosphatase (IAP) added to diets on growth performance, diarrhoea incidence (DI), blood metabolites, relative organ weight, and intestinal morphometry of weaned piglets challenged with enterotoxigenic Escherichia coli F4 (K88). A total of 64 crossbred entire male piglets (25-day-old and 7.16 ± 0.28 kg body weight) were allocated into four treatments: control diet (CD–), CD– + antimicrobial growth promoter (AGP), CD– + 15 mg IAP/kg of diet and CD– + 30 mg IAP/kg of diet, with eight replications. At 15 days, all piglets were orally challenged with 6 ml of a solution containing K88 (106 colony forming units/ml). Microencapsulated IAP in acid solution showed 14.43% solubility and pH values of 1.69, 1.72, 1.51, and 1.52 at the different times measured (0.5 h, 1.0 h, 17.0 h, and 24 h); differently, IAP in basic solution had 4.10% solubility and pH values increased (5.95, 6.10, 6.32 and 6.63) according to the different times, respectively. On days 25–35, piglets that received 30 mg IAP and CD– showed a better feed conversion ratio (P = 0.075) compared to those fed 15 mg IAP. Piglets that consumed 30 mg IAP or CD– had higher (P = 0.004) average daily gain on days 35–44. On days 35–44, the piglet average daily feed intake was lower (P = 0.033) with 15 mg IAP compared to AGP. In the entire period, piglets fed 15 mg IAP showed a reduction in average daily gain (P = 0.040) and average daily feed intake (P = 0.092). Piglets on 30 mg IAP showed an improvement (P ≤ 0.05) in DI in the pre-and post-challenge periods. The relative spleen weight of the piglet increased (P = 0.043) in response to 30 mg IAP. Overall, the addition of 30 mg IAP to diets improves the growth performance, attenuates DI, and promotes an increase in spleen relative weight to maintain the healthy state of piglets.

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Section: Blood Metabolitessupporting

confidence: 76%

Section: Blood Metabolitescontrasting

confidence: 62%

Biological response of piglets challenged with Escherichia coli F4 (K88) when fed diets containing intestinal alkaline phosphatase

Rupolo¹,

Melo²,

Azevedo³

et al. 2021

CZECH J ANIM SCI

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“…It is known that there exists an arteriovenous difference of approximately 1‐2 mmol/L, as higher glucose levels are detected in arterial vs venous blood samples 30 . The arterial plasma glucose levels during the hypoglycaemic clamps in our study could thus have been higher than those reported by others where glucose levels were measured on arterial or arterialized blood, 21,22,25,26 which may account for the relatively low secretion of catecholamines, growth hormones and cortisol. Hence, the present study could have benefited from arterial blood sampling to ensure that the tissues are in fact exposed to glucose levels below 3 mmol/L.…”

Section: Discussioncontrasting

confidence: 67%

“…Thus, these results do not point towards an increased secretion of epinephrine or norepinephrine in response to hypoglycaemia, as reported in humans 21‐24 . Nielsen et al have reported an increased secretion of these hormones in anaesthetized Göttingen minipigs included in hyperinsulinaemic hypoglycaemic clamps of 3 mmol/L, where they showed a significant increase in epinephrine and norepinephrine compared to baseline levels at normoglycaemia (from 0.54 ± 0.14 nmol/L to 2.84 ± 1.6 nmol/L and 0.89 ± 0.1 to 1.7 ± 0.3 nmol) 26 . These findings are more comparable to the results reported in humans.…”

Section: Discussionmentioning

confidence: 91%

The counterregulatory response to hypoglycaemia in the pig

Gradel

Ludvigsen

Porsgaard

et al. 2020

Basic Clin Pharma Tox

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The domestic pig is commonly used as animal model in the pharmaceutical development of new therapeutics for treatment of diabetes. Since a formal definition of hypoglycaemia only exists in humans, the purpose of this study was to assess the counterregulatory response in the domestic pig at glucose levels known to induce symptoms of hypoglycaemia in humans. Six pigs were included in hyperinsulinaemic glucose clamps with plasma glucose targets of 2, 3 and 5 mmol/L in a cross‐over design, and the associated glucose counterregulatory response was assessed by measuring glucose kinetics and levels of glucagon, c‐peptide, catecholamines, cortisol and growth hormone. Results showed that the 2 and 3 vs 5 mmol/L clamps significantly decreased and increased the secretion of c‐peptide and glucagon, respectively (P < .05). This finding was associated with increased rate of glucose appearance (Ra) and decreased rate of glucose disappearance (Rd) (P < .001). No marked differences in the catecholamine, growth hormone or cortisol response were observed. Consequently, like humans, pigs respond to hypoglycaemia by decreasing the pancreatic output of insulin while increasing that of glucagon, with increased glucose mobilization and decreased glucose disposal as a result. The hypoglycaemic clamps did not result in a marked secretion of the other counterregulatory hormones.

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“…The counter-regulatory autonomous response to hypoglycaemia in the clamp protocol induced an approximately 25-fold increase in plasma epinephrine, an increase similar to what has been found in human studies, where autonomous symptoms of hypoglycaemia were also recorded 8 . Release of epinephrine is a counter-regulatory mechanism to hypoglycaemia observed in humans 22 and in rodent models 14 , 15 , but in healthy pigs, no response or only a weak response have been reported 33 , 36 . In the bolus setup, only the healthy group reached hypoglycaemic target to induce an epinephrine response and the lack of response in DIA is likely driven by the low insulin sensitivity, where even a 50% higher insulin dose than given the healthy group was insufficient to induce hypoglycaemia at target level.…”

Section: Discussionmentioning

confidence: 99%

Hyperinsulinaemic hypoglycaemia in non-anaesthetized Göttingen minipigs induces a counter-regulatory endocrine response and electrocardiographic changes

Lyhne

Vegge

Povlsen

et al. 2021

Sci Rep

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The potentially fatal cardiovascular effects of hypoglycaemia are not well understood and large animal models of the counter-regulatory responses and cardiovascular consequences of insulin-induced hypoglycaemia are needed to understand the mechanisms in humans. The aim of this study was to develop a human-like minipig model of hypoglycaemia including healthy and diabetic pigs to investigate endocrine, electrocardiographic and platelet effects. Hypoglycaemia was induced using a hyperinsulinaemic, hypoglycaemic clamp and an insulin bolus protocol. Plasma glucose, glucagon, C-peptide, insulin, epinephrine and platelet aggregation responses were measured before, during and after hypoglycaemia. Continuous electrocardiographic recordings were obtained. Hypoglycaemia at a plasma glucose concentration of 0.8–1.0 mM in the clamp induced 25-fold increase in epinephrine and sixfold and threefold increase in glucagon for healthy and diabetic pigs, respectively. The hypoglycaemic clamp induced QTc-interval prolongation and increase in cardiac arrhythmias. In the bolus approach, the non-diabetic group reached plasma glucose target of 1.5 mM and QTc-interval was prolonged after insulin injection, but before glucose nadir. The diabetic group did not reach hypoglycaemic target, but still demonstrated QTc-interval prolongation. These results demonstrate effects of hyperinsulinaemic hypoglycaemia closely resembling human physiology, indicating the minipig as a translational animal model of counter-regulatory endocrine and myocardial effects of hypoglycaemia.

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Impaired hepatic counterregulatory response to insulin-induced hypoglycemia in hepatic denervated pigs

Cited by 5 publications

References 35 publications

Biological response of piglets challenged with Escherichia coli F4 (K88) when fed diets containing intestinal alkaline phosphatase

Biological response of piglets challenged with Escherichia coli F4 (K88) when fed diets containing intestinal alkaline phosphatase

The counterregulatory response to hypoglycaemia in the pig

Hyperinsulinaemic hypoglycaemia in non-anaesthetized Göttingen minipigs induces a counter-regulatory endocrine response and electrocardiographic changes

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