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Publication
Liver glycogen-induced enhancements in hypoglycemic counterregulation require
neuroglucopenia.
Authors Warner SO, Wadian AM, Smith M, Farmer B, Dai Y, Sheanon N, Edgerton DS, Winnick
JJ
Submitted By Submitted Externally on 12/3/2021
Status Published
Journal American journal of physiology. Endocrinology and metabolism
Year 2021
Date Published 5/1/2021
Volume : Pages 320 : E914 - E924
PubMed Reference 33779306
Abstract Iatrogenic hypoglycemia is a prominent barrier to achieving optimal glycemic
control in patients with diabetes, in part due to dampened counterregulatory
hormone responses. It has been demonstrated that elevated liver glycogen content
can enhance these hormonal responses through signaling to the brain via afferent
nerves, but the role that hypoglycemia in the brain plays in this liver glycogen
effect remains unclear. During the first 4 h of each study, the liver glycogen
content of dogs was increased by using an intraportal infusion of fructose to
stimulate hepatic glucose uptake (HG; n = 13), or glycogen was maintained near
fasting levels with a saline infusion (NG; n = 6). After a 2-h control period,
during which the fructose/saline infusion was discontinued, insulin was infused
intravenously for an additional 2 h to bring about systemic hypoglycemia in all
animals, whereas brain euglycemia was maintained in a subset of the HG group by
infusing glucose bilaterally into the carotid and vertebral arteries (HG-HeadEu;
n = 7). Liver glycogen content was markedly elevated in the two HG groups (43 ±
4, 73 ± 3, and 75 ± 7 mg/g in NG, HG, and HG-HeadEu, respectively). During the
hypoglycemic period, arterial plasma glucose levels were indistinguishable
between groups (53 ± 2, 52 ± 1, and 51 ± 1 mg/dL, respectively), but jugular
vein glucose levels were kept euglycemic (88 ± 5 mg/dL) only in the HG-HeadEu
group. Glucagon and epinephrine responses to hypoglycemia were higher in HG
compared with NG, whereas despite the increase in liver glycogen, neither
increased above basal in HG-HeadEu. These data demonstrate that the enhanced
counterregulatory hormone secretion that accompanies increased liver glycogen
content requires hypoglycemia in the brain.NEW & NOTEWORTHY It is well known
that iatrogenic hypoglycemia is a barrier to optimal glycemic regulation in
patients with diabetes. Our data confirm that increasing liver glycogen content
75% above fasting levels enhances hormonal responses to insulin-induced
hypoglycemia and demonstrate that this enhanced hormonal response does not occur
in the absence of hypoglycemia in the brain. These data demonstrate that
information from the liver regarding glycogen availability is integrated in the
brain to optimize the counterregulatory response.




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