Key Role for AMP-Activated Protein Kinase in the Ventromedial Hypothalamus in Regulating Counterregulatory Hormone Responses to Acute Hypoglycemia

McCrimmon, Rory J.; Shaw, Margaret; Fan, Xiaoning; Cheng, Hai-Ying Mary; Ding, Yun; Vella, Monica C.; Zhou, Ligang; McNay, Ewan C.; Sherwin, Robert S.

doi:10.2337/db07-0837

Cited by 155 publications

(123 citation statements)

References 54 publications

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“…Consistent with this, down-regulation of a2 in the ventromedial hypothalamus of rats, using short hairpin RNAs delivered by viral vectors, resulted in a defective counter-regulatory response to hypoglycemia, that is, a failure to secrete glucagon from the pancreas and epinephrine from the adrenal medulla (McCrimmon et al 2008). Taken together, these findings suggest that a kinase that evolved to mediate the cell-autonomous response to glucose starvation in singlecelled eukaryotes has retained this function in multicellular organisms.…”

Section: Regulation Of Ampk By Metabolic Stresses Cytokines Drugssupporting

confidence: 65%

Adenosine Monophosphate-Activated Protein Kinase: A Central Regulator of Metabolism with Roles in Diabetes, Cancer, and Viral Infection

Hardie¹

2011

Cold Spring Harbor Symposia on Quantitative Biology

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Adenosine monophosphate -activated protein kinase (AMPK) is a cellular energy sensor activated by metabolic stresses that inhibit catabolic ATP production or accelerate ATP consumption. Once activated, AMPK switches on catabolic pathways, generating ATP, while inhibiting cell growth and proliferation, thus promoting energy homeostasis. AMPK is activated by the antidiabetic drug metformin, and by many natural products including "nutraceuticals" and compounds used in traditional medicines. Most of these xenobiotics activate AMPK by inhibiting mitochondrial ATP production. AMPK activation by metabolic stress requires the upstream kinase, LKB1, whose tumor suppressor effects may be largely mediated by AMPK. However, many tumor cells appear to have developed mechanisms to reduce AMPK activation and thus escape its growthrestraining effects. A similar phenomenon occurs during viral infection. If we can establish how down-regulation occurs in tumors and virus-infected cells, there may be therapeutic avenues to reverse these effects.

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Section: Regulation Of Ampk By Metabolic Stresses Cytokines Drugssupporting

confidence: 65%

Adenosine Monophosphate-Activated Protein Kinase: A Central Regulator of Metabolism with Roles in Diabetes, Cancer, and Viral Infection

Hardie¹

2011

Cold Spring Harbor Symposia on Quantitative Biology

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“…Pioneering studies in the rat have established the important role that the VMH plays in hypoglycemic counterregulation (28)(29)(30). They have also shown that AMPK plays an important role in this "energy sensing" and that, when activated, it increases the secretion of both epinephrine and glucagon (31,32). Of interest, there was no effect of AMPK activation in the VMH on corticosterone levels in the above studies (31,32).…”

Section: Discussionmentioning

confidence: 95%

Hepatic glycogen can regulate hypoglycemic counterregulation via a liver-brain axis

Winnick¹,

Kraft²,

Gregory³

et al. 2016

Journal of Clinical Investigation

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“…Mechanisms for generating defective counterregulation may reside further upstream, perhaps at the level of CRH, urocortin, or CRH receptors. Preliminary rodent data from our laboratory suggest that changes in the activation state of CRH receptors in the ventromedial hypothalamus modulate subsequent counterregulatory hormone responses to hypoglycemia (29).…”

Section: Discussionmentioning

confidence: 99%

Antecedent Hypercortisolemia Is Not Primarily Responsible for Generating Hypoglycemia-Associated Autonomic Failure

et al. 2006

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Hypoglycemia-associated autonomic failure (HAAF) occurs commonly in patients with longstanding diabetes, placing affected patients at increased risk for severe hypoglycemia. Previous studies have suggested that hypoglycemia-induced hypercortisolemia may be responsible for blunting subsequent sympathoadrenal responses to hypoglycemia; however, this view remains highly controversial. In this work, we sought to better define the role of antecedent hypercortisolemia in generating HAAF, using two complimentary experimental models in nondiabetic human subjects: 1) antecedent hydrocortisone infusions (simulating physiologic cortisol responses to hypoglycemia) and 2) antecedent hypoglycemia, with and without concurrent blockade of endogenous cortisol production using oral metyrapone. Our results showed no effect of antecedent hypercortisolemia on epinephrine responses to subsequent hypoglycemia (area under the curve/time 280 ؎ 53 vs. 337 ؎ 57 pg/ml, P ‫؍‬ 0.16). Of particular importance, selective blockade of endogenous cortisol production during antecedent hypoglycemia had no effect on subsequent counterregulatory responses to hypoglycemia. Compared with epinephrine responses following antecedent euglycemia (area under the curve/time 312 ؎ 38 pg/ml), epinephrine responses were comparably blunted following antecedent hypoglycemia, regardless of whether concurrent metyrapone blockade was employed (198 ؎ 28 vs. 192 ؎ 28 pg/ml, P ‫؍‬ NS). Similar results were obtained for glucagon and ACTH levels. Considered together, these observations provide strong evidence that hypoglycemiainduced hypercortisolemia is not primarily responsible for the generation of HAAF. Diabetes 55

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Key Role for AMP-Activated Protein Kinase in the Ventromedial Hypothalamus in Regulating Counterregulatory Hormone Responses to Acute Hypoglycemia

Cited by 155 publications

References 54 publications

Adenosine Monophosphate-Activated Protein Kinase: A Central Regulator of Metabolism with Roles in Diabetes, Cancer, and Viral Infection

Adenosine Monophosphate-Activated Protein Kinase: A Central Regulator of Metabolism with Roles in Diabetes, Cancer, and Viral Infection

Hepatic glycogen can regulate hypoglycemic counterregulation via a liver-brain axis

Antecedent Hypercortisolemia Is Not Primarily Responsible for Generating Hypoglycemia-Associated Autonomic Failure

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