@phdthesis{Kehlenbrink2010,
  author    = {Kehlenbrink, Sylvia},
  title     = {Inhibiting Gluconeogenesis (GNG) Prevents the Effects of Free Fatty Acids (FFA) on Hepatic Glucose Effectiveness (GE)},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-48389},
  school      = {Universit{\"a}t W{\"u}rzburg},
  year      = {2010},
  abstract  = {Free fatty acids (FFA) modulate the effectiveness of glucose to suppress endogenous glucose production (EGP), and increased FFA levels contribute importantly to the loss of glucose effectiveness in type 2 diabetes mellitus (T2DM). Elevating FFA levels in nondiabetic (ND) subjects for at least 6h both increases gluconeogenesis (GNG) and impairs glucose effectiveness. Therefore, we wished to define the extent to which an increase in GNG is responsible for the loss of glucose effectiveness and whether EGP can be inhibited in the presence of elevated plasma FFA by inhibiting GNG with ethanol. To determine the effect of inhibiting GNG on glucose effectiveness, EGP ([3-3H]-glucose) was measured during three separate 7h normoglycemic/hyperglycemic pancreatic clamp studies (somatostatin; basal glucagon/GH/insulin replacement) in n=7 ND subjects (1F/6M; age=45±5 yr; BMI=27.6±3.0 kg/m2). Following an initial 210 min interval of euglycemia (5 mmol/l), blood glucose levels were raised to hyperglycemic levels (10 mmol/l) from t=210-420 min. The first pancreatic clamp study was a baseline study with saline infusions (Lip-/Et-). Lipid emulsion (Liposyn 20\%) was infused throughout the second and third study types (Lip+ and Lip+/Et+) to increase FFA to T2DM levels (~ 500 mmol/l). In addition to Liposyn, ethanol (Et) was infused during hyperglycemia in the third study type (Lip+/Et+), using a pharmacokinetic algorithm to attain GNG-inhibiting ethanol levels of 80 mg/dl within 20 min. Under baseline conditions, hyperglycemia suppressed EGP by 61\%. After raising plasma FFA to T2DM levels, suppression of EGP by hyperglycemia was impaired in Lip+ (34\% decrease). During the Lip+/Et+ co-infusion studies the infusion of ethanol enhanced suppression of EGP by hyperglycemia (65.8\% decrease, P=0.004 vs. Lip+) and thus restored glucose effectiveness (P=0.6 vs. Lip-/Et-). Thus, our results confirm the striking effects of elevated plasma FFA to impair glucose effectiveness and suggest that increased GNG contributes importantly to this loss of regulation. Inhibiting GNG could be an effective means of lowering EGP and improving glucose effectiveness in T2DM.},
  subject      = {Gluconeogenese},
  language  = {en}
}