Hypothalamic protein kinase C regulates glucose production

Diabetes. 2008 Aug;57(8):2061-5. doi: 10.2337/db08-0206. Epub 2008 May 28.


Objective: A selective rise in hypothalamic lipid metabolism and the subsequent activation of SUR1/Kir6.2 ATP-sensitive K(+) (K(ATP)) channels inhibit hepatic glucose production. The mechanisms that link the ability of hypothalamic lipid metabolism to the activation of K(ATP) channels remain unknown.

Research design and methods: To examine whether hypothalamic protein kinase C (PKC) mediates the ability of central nervous system lipids to activate K(ATP) channels and regulate glucose production in normal rodents, we first activated hypothalamic PKC in the absence or presence of K(ATP) channel inhibition. We then inhibited hypothalamic PKC in the presence of lipids. Tracer-dilution methodology in combination with the pancreatic clamp technique was used to assess the effect of hypothalamic administrations on glucose metabolism in vivo.

Results: We first reported that direct activation of hypothalamic PKC via direct hypothalamic delivery of PKC activator 1-oleoyl-2-acetyl-sn-glycerol (OAG) suppressed glucose production. Coadministration of hypothalamic PKC-delta inhibitor rottlerin with OAG prevented the ability of OAG to activate PKC-delta and lower glucose production. Furthermore, hypothalamic dominant-negative Kir6.2 expression or the delivery of the K(ATP) channel blocker glibenclamide abolished the glucose production-lowering effects of OAG. Finally, inhibition of hypothalamic PKC eliminated the ability of lipids to lower glucose production.

Conclusions: These studies indicate that hypothalamic PKC activation is sufficient and necessary for lowering glucose production.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Acetophenones / administration & dosage
  • Acetophenones / pharmacology
  • Animals
  • Benzopyrans / administration & dosage
  • Benzopyrans / pharmacology
  • Diglycerides / administration & dosage
  • Diglycerides / pharmacology
  • Enzyme Activation / drug effects
  • Glucose / biosynthesis*
  • Glyburide / administration & dosage
  • Glyburide / pharmacology
  • Hypoglycemic Agents / administration & dosage
  • Hypoglycemic Agents / pharmacology
  • Hypothalamus / drug effects
  • Hypothalamus / enzymology
  • Hypothalamus / metabolism*
  • KATP Channels / antagonists & inhibitors
  • Male
  • Protein Kinase C / antagonists & inhibitors
  • Protein Kinase C / metabolism*
  • Protein Kinase C-delta / antagonists & inhibitors
  • Protein Kinase C-delta / metabolism
  • Protein Transport / drug effects
  • Rats
  • Rats, Sprague-Dawley


  • 1-oleoyl-2-acetoyl-sn-glycerol
  • Acetophenones
  • Benzopyrans
  • Diglycerides
  • Hypoglycemic Agents
  • KATP Channels
  • rottlerin
  • Protein Kinase C
  • Protein Kinase C-delta
  • Glucose
  • Glyburide