In the Absence of Counterregulatory Hormones, the Increase in Hepatic Glucose Production During Insulin-Induced Hypoglycemia in the Dog Is Initiated in the Liver Rather Than the Brain

Connolly, Cynthia C.; Myers, S. R.; Neal, Doss W.; Hastings, Jon R.; Cherrington, Alan D.

doi:10.2337/diab.45.12.1805

Cited by 10 publications

(5 citation statements)

References 57 publications

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“…Both groups switched from net hepatic uptake of glucose during the control period (systemic euglycemic hyperinsulinemia) to net hepatic release of glucose during the hypoglycemic period, with no difference in response between groups (change in net hepatic glucose balance ,12 mmol/kg per min in both groups). Thus maintenance of cerebral euglycemia did not prevent the rise in hepatic glucose release caused by the low blood glucose, and consequently liver hypoglycemia must have stimulated net hepatic glucose release (45). The results of this study do not rule out a role for the nervous system in the response observed (i.e.…”

Section: Autoregulation In Response To Hypoglycemiacontrasting

confidence: 71%

“…Stimulation of the ventromedial hypothalamus results in enhancement of hepatic glycogenolysis and gluconeogenesis (43,44). To separate the possible effects of glucopenia at the level of the central nervous system from direct effects of glucopenia on the liver Connolly et al (45) conducted further studies in the conscious dog model. The dogs underwent adrenalectomy 2 weeks prior to experimentation, as in the previous investigation (38).…”

Section: Autoregulation In Response To Hypoglycemiamentioning

confidence: 99%

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Autoregulation of hepatic glucose production

Moore

Connolly

Cherrington

1998

European Journal of Endocrinology

102

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In vitro evidence indicates that the liver responds directly to changes in circulating glucose concentrations with reciprocal changes in glucose production and that this autoregulation plays a role in maintenance of normoglycemia. Under in vivo conditions it is dif®cult to separate the effects of glucose on neural regulation mediated by the central nervous system from its direct effect on the liver. Nevertheless, it is clear that nonhormonal mechanisms can cause signi®cant changes in net hepatic glucose balance. In response to hyperglycemia, net hepatic glucose output can be decreased by as much as 60±90% by nonhormonal mechanisms. Under conditions in which hepatic glycogen stores are high (i.e. the overnight-fasted state), a decrease in the glycogenolytic rate and an increase in the rate of glucose cycling within the liver appear to be the explanation for the decrease in hepatic glucose output seen in response to hyperglycemia. During more prolonged fasting, when glycogen levels are reduced, a decrease in gluconeogenesis may occur as a part of the nonhormonal response to hyperglycemia.A substantial role for hepatic autoregulation in the response to insulin-induced hypoglycemia is most clearly evident in severe hypoglycemia (#2.8 mmol/l). The nonhormonal response to hypoglycemia apparently involves enhancement of both gluconeogenesis and glycogenolysis and is capable of supplying enough glucose to meet at least half of the requirement of the brain. The nonhormonal response can include neural signaling, as well as autoregulation. However, even in the absence of the ability to secrete counterregulatory hormones (glucocorticoids, catecholamines, and glucagon), dogs with denervated livers (to interrupt neural pathways between the liver and brain) were able to respond to hypoglycemia with increases in net hepatic glucose output. Thus, even though the endocrine system provides the primary response to changes in glycemia, autoregulation plays an important adjunctive role. European Journal of Endocrinology 138 240±248

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Section: Autoregulation In Response To Hypoglycemiacontrasting

confidence: 71%

Section: Autoregulation In Response To Hypoglycemiamentioning

confidence: 99%

Autoregulation of hepatic glucose production

Moore

Connolly

Cherrington

1998

European Journal of Endocrinology

102

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“…This may be an independent effect as it was associated with a diminution of adrenaline release. The B2AR antagonist might have also acted directly on the hypothalamus to diminish HGP independent of counter-regulatory hormone secretion [22, 23]. The latter possibility is consistent with data suggesting that noradrenaline neurotransmission acts locally to stimulate VMH neurons and in turn counter-regulatory responses during hypoglycaemia [11, 12].…”

Section: Discussionsupporting

confidence: 57%

β2-Adrenergic receptor agonist administration promotes counter-regulatory responses and recovery from hypoglycaemia in rats

2013

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Aims/hypothesis We have previously reported that local activation of β2-adrenergic receptors (B2ARs) in the ventromedial hypothalamus (VMH) enhances hypoglycaemic counter-regulation. This study examines whether peripheral delivery of a selective B2AR agonist could also promote counter-regulatory responses and thereby has potential therapeutic value to limit hypoglycaemia risk. Methods Conscious male Sprague–Dawley rats received an intra-arterial injection of the B2AR specific agonist, formoterol, or a control solution either before a hyperinsulinaemic–hypoglycaemic clamp study or immediately before recovery from insulin-induced hypoglycaemia. In addition, the capacity of a VMH-targeted microinjection of a B2AR antagonist to limit the anti-insulin effect of the B2AR agonist was assessed. Results Systemic delivery of B2AR agonist markedly reduced the exogenous glucose infusion rate (GIR) required during the hypoglycaemic clamp study. This effect was mediated by blockade of insulin’s inhibitory effect on endogenous glucose production. Local blockade of B2ARs within the VMH using a specific antagonist partially diminished the effect of systemic activation of B2ARs during hypoglycaemia at least in part by diminishing the adrenaline (epinephrine) response to hypoglycaemia. Peripheral B2AR agonist injection also enhanced glucose recovery from insulin-induced hypoglycaemia. Conclusions/interpretation Systemic B2AR agonist administration acts to limit insulin-induced hypoglycaemia by offsetting insulin’s inhibitory effect on hepatic glucose production. This effect appears to be predominately mediated via a direct effect on liver B2ARs, but a small stimulatory effect on B2ARs within the VMH cannot be excluded. Our data suggest that formoterol may have therapeutic value to limit the risk of hypoglycaemia in patients with diabetes.

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“…More importantly, a hepato-preferential insulin puts the primary burden of hypoglycemia on the organ best suited to cope because hepatic insulin signaling is markedly reduced in the presence of hypoglycemia; i.e., the insulin receptor is essentially disengaged (34). Even when overinsulinized and deprived of increases in counterregulatory hormones and central neural stimuli, the liver is capable of responding directly to hypoglycemia by increasing its glucose output (35–37). …”

Section: Discussionmentioning

confidence: 99%

Novel PEGylated Basal Insulin LY2605541 Has a Preferential Hepatic Effect on Glucose Metabolism

et al. 2014

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The impact of the novel basal insulin LY2605541 (LY) on hepatic and nonhepatic glucose uptake (non-HGU) was evaluated. Conscious dogs underwent euglycemic clamps with tracer and hepatic balance measurements. Clamp period infusions were peripheral venous regular insulin (0.1 nmol ⋅ kg−1 ⋅ h−1 [control], n = 6) or LY (bolus [nmol/kg], continuous [nmol ⋅ kg−1 ⋅ h−1]: 0.5, 0.5 [n = 6]; 0.375, 0.375 [n = 5]; 0.25, 0.25 [n = 4]), somatostatin, and glucose, as well as intraportal glucagon (basal). During the clamp, the dogs switched from net hepatic glucose output to uptake (rates reached 2.1 ± 1.2, 0.9 ± 2.1, 8.6 ± 2.3, and 6.0 ± 1.1 µmol ⋅ kg−1 ⋅ min−1 within 5 h in control, LY0.25, LY0.375, and LY0.5, respectively). Non-HGU in LY increased less than in control; the ratio of change from basal in non-HGU to change in net hepatic glucose balance, calculated when glucose infusion rates (GIRs) were ~20 µmol ⋅ kg-1 ⋅ min−1 in all groups, was higher in control (1.17 ± 0.38) versus LY0.25 (0.39 ± 0.33), LY0.375 (−0.01 ± 0.13), and LY0.5 (−0.09 ± 0.07). Likewise, the change from baseline in glucose Rd-to-Ra ratio was greatest in control (1.4 ± 0.3 vs. 0.6 ± 0.4, 0.5 ± 0.2, and 0.6 ± 0.2 in LY0.25, LY0.375, and LY0.5, respectively). In contrast to exogenously administered human insulin, LY demonstrated preferential hepatic effects, similar to endogenously secreted insulin. Therefore, the analog might reduce complications associated with current insulin therapy.

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In the Absence of Counterregulatory Hormones, the Increase in Hepatic Glucose Production During Insulin-Induced Hypoglycemia in the Dog Is Initiated in the Liver Rather Than the Brain

Cited by 10 publications

References 57 publications

Autoregulation of hepatic glucose production

Autoregulation of hepatic glucose production

β2-Adrenergic receptor agonist administration promotes counter-regulatory responses and recovery from hypoglycaemia in rats

Novel PEGylated Basal Insulin LY2605541 Has a Preferential Hepatic Effect on Glucose Metabolism

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