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Naloxone, but not valsartan, preserves responses to hypoglycemia after antecedent hypoglycemia: role of metabolic reprogramming in counterregulatory failure.

Poplawski MM, Mastaitis JW, Mobbs CV - Diabetes (2010)

Bottom Line: Hypoglycemia-associated autonomic failure (HAAF) constitutes one of the main clinical obstacles to optimum treatment of type 1 diabetes.On the other hand, clinical studies have demonstrated that the opioid receptor blocker naloxone ameliorates HAAF.Responsiveness of a subset of these genes was preserved by naloxone but not valsartan.

View Article: PubMed Central - PubMed

Affiliation: Fishberg Center for Neurobiology, Mount Sinai School of Medicine, New York, New York, USA.

ABSTRACT

Objective: Hypoglycemia-associated autonomic failure (HAAF) constitutes one of the main clinical obstacles to optimum treatment of type 1 diabetes. Neurons in the ventromedial hypothalamus are thought to mediate counterregulatory responses to hypoglycemia. We have previously hypothesized that hypoglycemia-induced hypothalamic angiotensin might contribute to HAAF, suggesting that the angiotensin blocker valsartan might prevent HAAF. On the other hand, clinical studies have demonstrated that the opioid receptor blocker naloxone ameliorates HAAF. The goal of this study was to generate novel hypothalamic markers of hypoglycemia and use them to assess mechanisms mediating HAAF and its reversal.

Research design and methods: Quantitative PCR was used to validate a novel panel of hypothalamic genes regulated by hypoglycemia. Mice were exposed to one or five episodes of insulin-induced hypoglycemia, with or without concurrent exposure to valsartan or naloxone. Corticosterone, glucagon, epinephrine, and hypothalamic gene expression were assessed after the final episode of hypoglycemia.

Results: A subset of hypothalamic genes regulated acutely by hypoglycemia failed to respond after repetitive hypoglycemia. Responsiveness of a subset of these genes was preserved by naloxone but not valsartan. Notably, hypothalamic expression of four genes, including pyruvate dehydrogenase kinase 4 and glycerol 3-phosphate dehydrogenase 1, was acutely induced by a single episode of hypoglycemia, but not after antecedent hypoglycemia; naloxone treatment prevented this failure. Similarly, carnitine palmitoyltransferase-1 was inhibited after repetitive hypoglycemia, and this inhibition was prevented by naloxone. Repetitive hypoglycemia also caused a loss of hypoglycemia-induced elevation of glucocorticoid secretion, a failure prevented by naloxone but not valsartan.

Conclusions: Based on these observations we speculate that acute hypoglycemia induces reprogramming of hypothalamic metabolism away from glycolysis toward β-oxidation, HAAF is associated with a reversal of this reprogramming, and naloxone preserves some responses to hypoglycemia by preventing this reversal.

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Blood glucose concentration throughout the study for all experimental groups: Eu, 1XH, 5XH, Eu-V, 1XH-V, 5XH-V, 5XH-N. The x-axis indicates the day and time points of the study (with insulin or saline injected at time 0, and for the 5XH-N group, naloxone was injected 15 min prior). Data are means ± SE (n = 10 for all groups).
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Figure 1: Blood glucose concentration throughout the study for all experimental groups: Eu, 1XH, 5XH, Eu-V, 1XH-V, 5XH-V, 5XH-N. The x-axis indicates the day and time points of the study (with insulin or saline injected at time 0, and for the 5XH-N group, naloxone was injected 15 min prior). Data are means ± SE (n = 10 for all groups).

Mentions: Animals were randomly assigned to one of seven groups (n = 10), designated in Figure 1: Eu (saline-injected euglycemic), 1XH (acute insulin-induced hypoglycemia without antecedent hypoglycemia), 5XH (acute hypoglycemia with four antecedent days of hypoglycemia), Eu-V (euglycemic group with oral valsartan 40 mg/kg/day), 1XH-V (acute hypoglycemia with oral valsartan), 5XH-V (acute hypoglycemia with four antecedent days of hypoglycemia maintained on oral valsartan), 5XH-N (acute hypoglycemia with four antecedent days of hypoglycemia with 2 mg/kg naloxone injected intraperitoneally 15 min before every insulin injection). Antecedent hypoglycemia (5XH) consisted of four consecutive days of insulin-induced hypoglycemia (3 h), followed on the 5th day with the final episode of acute hypoglycemia and the animals killed 4 h after insulin injection. The group exposed to acute insulin–induced hypoglycemia without antecedent hypoglycemia (1XH) received physiological saline injections for 4 days, followed by acute hypoglycemia on the 5th day. The euglycemic group (Eu) received saline injections for five consecutive days. The valsartan groups (1XH-V, 5XH-V) ingested 40 mg/kg/day oral valsartan starting 5 days prior to commencing the 5-day injection protocol and continued on oral valsartan throughout the study. Before the 40-mg/kg/day dose, the valsartan groups received a 20-mg/kg/day dose for a 2-day adjustment period. The naloxone group (5XH-N) received an injection of naloxone (2 mg/kg, intraperitoneally) 15 min before every insulin injection. Therefore, the 5XH-N group received a total of 5 days of insulin injections preceded on each day by an injection of naloxone.


Naloxone, but not valsartan, preserves responses to hypoglycemia after antecedent hypoglycemia: role of metabolic reprogramming in counterregulatory failure.

Poplawski MM, Mastaitis JW, Mobbs CV - Diabetes (2010)

Blood glucose concentration throughout the study for all experimental groups: Eu, 1XH, 5XH, Eu-V, 1XH-V, 5XH-V, 5XH-N. The x-axis indicates the day and time points of the study (with insulin or saline injected at time 0, and for the 5XH-N group, naloxone was injected 15 min prior). Data are means ± SE (n = 10 for all groups).
© Copyright Policy - creative-commons
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC3012195&req=5

Figure 1: Blood glucose concentration throughout the study for all experimental groups: Eu, 1XH, 5XH, Eu-V, 1XH-V, 5XH-V, 5XH-N. The x-axis indicates the day and time points of the study (with insulin or saline injected at time 0, and for the 5XH-N group, naloxone was injected 15 min prior). Data are means ± SE (n = 10 for all groups).
Mentions: Animals were randomly assigned to one of seven groups (n = 10), designated in Figure 1: Eu (saline-injected euglycemic), 1XH (acute insulin-induced hypoglycemia without antecedent hypoglycemia), 5XH (acute hypoglycemia with four antecedent days of hypoglycemia), Eu-V (euglycemic group with oral valsartan 40 mg/kg/day), 1XH-V (acute hypoglycemia with oral valsartan), 5XH-V (acute hypoglycemia with four antecedent days of hypoglycemia maintained on oral valsartan), 5XH-N (acute hypoglycemia with four antecedent days of hypoglycemia with 2 mg/kg naloxone injected intraperitoneally 15 min before every insulin injection). Antecedent hypoglycemia (5XH) consisted of four consecutive days of insulin-induced hypoglycemia (3 h), followed on the 5th day with the final episode of acute hypoglycemia and the animals killed 4 h after insulin injection. The group exposed to acute insulin–induced hypoglycemia without antecedent hypoglycemia (1XH) received physiological saline injections for 4 days, followed by acute hypoglycemia on the 5th day. The euglycemic group (Eu) received saline injections for five consecutive days. The valsartan groups (1XH-V, 5XH-V) ingested 40 mg/kg/day oral valsartan starting 5 days prior to commencing the 5-day injection protocol and continued on oral valsartan throughout the study. Before the 40-mg/kg/day dose, the valsartan groups received a 20-mg/kg/day dose for a 2-day adjustment period. The naloxone group (5XH-N) received an injection of naloxone (2 mg/kg, intraperitoneally) 15 min before every insulin injection. Therefore, the 5XH-N group received a total of 5 days of insulin injections preceded on each day by an injection of naloxone.

Bottom Line: Hypoglycemia-associated autonomic failure (HAAF) constitutes one of the main clinical obstacles to optimum treatment of type 1 diabetes.On the other hand, clinical studies have demonstrated that the opioid receptor blocker naloxone ameliorates HAAF.Responsiveness of a subset of these genes was preserved by naloxone but not valsartan.

View Article: PubMed Central - PubMed

Affiliation: Fishberg Center for Neurobiology, Mount Sinai School of Medicine, New York, New York, USA.

ABSTRACT

Objective: Hypoglycemia-associated autonomic failure (HAAF) constitutes one of the main clinical obstacles to optimum treatment of type 1 diabetes. Neurons in the ventromedial hypothalamus are thought to mediate counterregulatory responses to hypoglycemia. We have previously hypothesized that hypoglycemia-induced hypothalamic angiotensin might contribute to HAAF, suggesting that the angiotensin blocker valsartan might prevent HAAF. On the other hand, clinical studies have demonstrated that the opioid receptor blocker naloxone ameliorates HAAF. The goal of this study was to generate novel hypothalamic markers of hypoglycemia and use them to assess mechanisms mediating HAAF and its reversal.

Research design and methods: Quantitative PCR was used to validate a novel panel of hypothalamic genes regulated by hypoglycemia. Mice were exposed to one or five episodes of insulin-induced hypoglycemia, with or without concurrent exposure to valsartan or naloxone. Corticosterone, glucagon, epinephrine, and hypothalamic gene expression were assessed after the final episode of hypoglycemia.

Results: A subset of hypothalamic genes regulated acutely by hypoglycemia failed to respond after repetitive hypoglycemia. Responsiveness of a subset of these genes was preserved by naloxone but not valsartan. Notably, hypothalamic expression of four genes, including pyruvate dehydrogenase kinase 4 and glycerol 3-phosphate dehydrogenase 1, was acutely induced by a single episode of hypoglycemia, but not after antecedent hypoglycemia; naloxone treatment prevented this failure. Similarly, carnitine palmitoyltransferase-1 was inhibited after repetitive hypoglycemia, and this inhibition was prevented by naloxone. Repetitive hypoglycemia also caused a loss of hypoglycemia-induced elevation of glucocorticoid secretion, a failure prevented by naloxone but not valsartan.

Conclusions: Based on these observations we speculate that acute hypoglycemia induces reprogramming of hypothalamic metabolism away from glycolysis toward β-oxidation, HAAF is associated with a reversal of this reprogramming, and naloxone preserves some responses to hypoglycemia by preventing this reversal.

Show MeSH
Related in: MedlinePlus