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Mechanisms of insulin resistance after insulin-induced hypoglycemia in humans: the role of lipolysis.

Lucidi P, Rossetti P, Porcellati F, Pampanelli S, Candeloro P, Andreoli AM, Perriello G, Bolli GB, Fanelli CG - Diabetes (2010)

Bottom Line: We conducted a series of studies in eight healthy volunteers using acipimox, an inhibitor of lipolysis.Plasma adrenaline, norepinephrine, growth hormone, and cortisol levels were unchanged (P > 0.2).The effect was largely removed by blockade of lipolysis during hypoglycemia in study 3 (28.9 +/- 2.6 micromol/kg/min, P > 0.2 vs. study 1) and largely reproduced by replacement of FFA in study 4 (22.3 +/- 2.8 micromol/kg/min, P < 0.03 vs. study 1).

View Article: PubMed Central - PubMed

Affiliation: Department of Internal Medicine, Section of Internal Medicine, Endocrinology and Metabolism, University of Perugia, Perugia, Italy.

ABSTRACT

Objective: Changes in glucose metabolism occurring during counterregulation are, in part, mediated by increased plasma free fatty acids (FFAs), as a result of hypoglycemia-activated lipolysis. However, it is not known whether FFA plays a role in the development of posthypoglycemic insulin resistance as well.

Research design and methods: We conducted a series of studies in eight healthy volunteers using acipimox, an inhibitor of lipolysis. Insulin action was measured during a 2-h hyperinsulinemic-euglycemic clamp (plasma glucose [PG] 5.1 mmo/l) from 5:00 p.m. to 7:00 p.m. or after a 3-h morning hyperinsulinemic-glucose clamp (from 10 a.m. to 1:00 p.m.), either euglycemic (study 1) or hypoglycemic (PG 3.2 mmol/l, studies 2-4), during which FFA levels were allowed to increase (study 2), were suppressed by acipimox (study 3), or were replaced by infusing lipids (study 4). [6,6-(2)H(2)]-Glucose was infused to measure glucose fluxes.

Results: Plasma adrenaline, norepinephrine, growth hormone, and cortisol levels were unchanged (P > 0.2). Glucose infusion rates (GIRs) during the euglycemic clamp were reduced by morning hypoglycemia in study 2 versus study 1 (16.8 +/- 2.3 vs. 34.1 +/- 2.2 micromol/kg/min, respectively, P < 0.001). The effect was largely removed by blockade of lipolysis during hypoglycemia in study 3 (28.9 +/- 2.6 micromol/kg/min, P > 0.2 vs. study 1) and largely reproduced by replacement of FFA in study 4 (22.3 +/- 2.8 micromol/kg/min, P < 0.03 vs. study 1). Compared with study 2, blockade of lipolysis in study 3 decreased endogenous glucose production (2 +/- 0.3 vs. 0.85 +/- 0.1 micromol/kg/min, P < 0.05) and increased glucose utilization (16.9 +/- 1.85 vs. 28.5 +/- 2.7 micromol/kg/min, P < 0.05). In study 4, GIR fell by approximately 23% (22.3 +/- 2.8 micromol/kg/min, vs. study 3, P = 0.058), indicating a role of acipimox per se on insulin action.

Conclusion: Lipolysis induced by hypoglycemia counterregulation largely mediates posthypoglycemic insulin resistance in healthy subjects, with an estimated overall contribution of approximately 39%.

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Plasma nonglucose substrates free fatty acids, glycerol, β-OH-butyrate, lactate, and alanine in study 1 (euglycemia), study 2 (hypoglycemia), study 3 (hypoglycemia + acipimox), and study 4 (hypoglycemia + acipimox + heparin + intralipid). The diagonal area depicts t1 (0–180 min, euglycemia or hypoglycemia), the white area depicts t2 (180–420 min, euglycemia or recovery to hypoglycemia), and the dotted area depicts t3 (420–540 min, euglycemic clamp) of each study.
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Figure 4: Plasma nonglucose substrates free fatty acids, glycerol, β-OH-butyrate, lactate, and alanine in study 1 (euglycemia), study 2 (hypoglycemia), study 3 (hypoglycemia + acipimox), and study 4 (hypoglycemia + acipimox + heparin + intralipid). The diagonal area depicts t1 (0–180 min, euglycemia or hypoglycemia), the white area depicts t2 (180–420 min, euglycemia or recovery to hypoglycemia), and the dotted area depicts t3 (420–540 min, euglycemic clamp) of each study.

Mentions: In t1, plasma FFAs decreased after initiation of insulin infusion from an averaged baseline of 0.40 ± 0.03 to a nadir of 0.09 ± 0.02 mmol/l at 180 min with no differences in studies 1–3 (Fig. 4). After discontinuing insulin infusion (180 min), plasma FFAs returned to values similar to those of baseline by 420 min of t2. In the same segment of t2, plasma FFA levels were at all times less suppressed in study 2 compared with studies 1 and 3 (P < 0.05). Finally, replacement of FFAs and glycerol in study 4 reproduced plasma FFA concentrations similar to those of study 2 and greater than those of studies 1 and 3 (P < 0.05).


Mechanisms of insulin resistance after insulin-induced hypoglycemia in humans: the role of lipolysis.

Lucidi P, Rossetti P, Porcellati F, Pampanelli S, Candeloro P, Andreoli AM, Perriello G, Bolli GB, Fanelli CG - Diabetes (2010)

Plasma nonglucose substrates free fatty acids, glycerol, β-OH-butyrate, lactate, and alanine in study 1 (euglycemia), study 2 (hypoglycemia), study 3 (hypoglycemia + acipimox), and study 4 (hypoglycemia + acipimox + heparin + intralipid). The diagonal area depicts t1 (0–180 min, euglycemia or hypoglycemia), the white area depicts t2 (180–420 min, euglycemia or recovery to hypoglycemia), and the dotted area depicts t3 (420–540 min, euglycemic clamp) of each study.
© Copyright Policy - creative-commons
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC2874695&req=5

Figure 4: Plasma nonglucose substrates free fatty acids, glycerol, β-OH-butyrate, lactate, and alanine in study 1 (euglycemia), study 2 (hypoglycemia), study 3 (hypoglycemia + acipimox), and study 4 (hypoglycemia + acipimox + heparin + intralipid). The diagonal area depicts t1 (0–180 min, euglycemia or hypoglycemia), the white area depicts t2 (180–420 min, euglycemia or recovery to hypoglycemia), and the dotted area depicts t3 (420–540 min, euglycemic clamp) of each study.
Mentions: In t1, plasma FFAs decreased after initiation of insulin infusion from an averaged baseline of 0.40 ± 0.03 to a nadir of 0.09 ± 0.02 mmol/l at 180 min with no differences in studies 1–3 (Fig. 4). After discontinuing insulin infusion (180 min), plasma FFAs returned to values similar to those of baseline by 420 min of t2. In the same segment of t2, plasma FFA levels were at all times less suppressed in study 2 compared with studies 1 and 3 (P < 0.05). Finally, replacement of FFAs and glycerol in study 4 reproduced plasma FFA concentrations similar to those of study 2 and greater than those of studies 1 and 3 (P < 0.05).

Bottom Line: We conducted a series of studies in eight healthy volunteers using acipimox, an inhibitor of lipolysis.Plasma adrenaline, norepinephrine, growth hormone, and cortisol levels were unchanged (P > 0.2).The effect was largely removed by blockade of lipolysis during hypoglycemia in study 3 (28.9 +/- 2.6 micromol/kg/min, P > 0.2 vs. study 1) and largely reproduced by replacement of FFA in study 4 (22.3 +/- 2.8 micromol/kg/min, P < 0.03 vs. study 1).

View Article: PubMed Central - PubMed

Affiliation: Department of Internal Medicine, Section of Internal Medicine, Endocrinology and Metabolism, University of Perugia, Perugia, Italy.

ABSTRACT

Objective: Changes in glucose metabolism occurring during counterregulation are, in part, mediated by increased plasma free fatty acids (FFAs), as a result of hypoglycemia-activated lipolysis. However, it is not known whether FFA plays a role in the development of posthypoglycemic insulin resistance as well.

Research design and methods: We conducted a series of studies in eight healthy volunteers using acipimox, an inhibitor of lipolysis. Insulin action was measured during a 2-h hyperinsulinemic-euglycemic clamp (plasma glucose [PG] 5.1 mmo/l) from 5:00 p.m. to 7:00 p.m. or after a 3-h morning hyperinsulinemic-glucose clamp (from 10 a.m. to 1:00 p.m.), either euglycemic (study 1) or hypoglycemic (PG 3.2 mmol/l, studies 2-4), during which FFA levels were allowed to increase (study 2), were suppressed by acipimox (study 3), or were replaced by infusing lipids (study 4). [6,6-(2)H(2)]-Glucose was infused to measure glucose fluxes.

Results: Plasma adrenaline, norepinephrine, growth hormone, and cortisol levels were unchanged (P > 0.2). Glucose infusion rates (GIRs) during the euglycemic clamp were reduced by morning hypoglycemia in study 2 versus study 1 (16.8 +/- 2.3 vs. 34.1 +/- 2.2 micromol/kg/min, respectively, P < 0.001). The effect was largely removed by blockade of lipolysis during hypoglycemia in study 3 (28.9 +/- 2.6 micromol/kg/min, P > 0.2 vs. study 1) and largely reproduced by replacement of FFA in study 4 (22.3 +/- 2.8 micromol/kg/min, P < 0.03 vs. study 1). Compared with study 2, blockade of lipolysis in study 3 decreased endogenous glucose production (2 +/- 0.3 vs. 0.85 +/- 0.1 micromol/kg/min, P < 0.05) and increased glucose utilization (16.9 +/- 1.85 vs. 28.5 +/- 2.7 micromol/kg/min, P < 0.05). In study 4, GIR fell by approximately 23% (22.3 +/- 2.8 micromol/kg/min, vs. study 3, P = 0.058), indicating a role of acipimox per se on insulin action.

Conclusion: Lipolysis induced by hypoglycemia counterregulation largely mediates posthypoglycemic insulin resistance in healthy subjects, with an estimated overall contribution of approximately 39%.

Show MeSH
Related in: MedlinePlus