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Insulin and GLP-1 infusions demonstrate the onset of adipose-specific insulin resistance in a large fasting mammal: potential glucogenic role for GLP-1.

Viscarra JA, Rodriguez R, Vazquez-Medina JP, Lee A, Tift MS, Tavoni SK, Crocker DE, Ortiz RM - Physiol Rep (2013)

Bottom Line: However, fasting mammals exhibit hypoinsulinemia, suggesting that the insulin resistance-like conditions they experience may actually result from reduced pancreatic sensitivity to glucose/capacity to secrete insulin.To determine whether fasting results in insulin resistance or in pancreatic dysfunction, we infused early- and late-fasted seals (naturally adapted to prolonged fasting) with insulin (0.065 U/kg), and a separate group of late-fasted seals with low (10 pM/kg) or high (100 pM/kg) dosages of glucagon-like peptide-1 (GLP-1) immediately following a glucose bolus (0.5g/kg), and measured the systemic and cellular responses.Despite the dose-dependent increases in insulin and increased glucose clearance (high dose), both GLP-1 dosages produced increases in plasma cortisol and glucagon, which may have contributed to the glucogenic role of GLP-1.

View Article: PubMed Central - PubMed

Affiliation: School of Natural Sciences, University of California, Merced.

ABSTRACT
Prolonged food deprivation increases lipid oxidation and utilization, which may contribute to the onset of the insulin resistance associated with fasting. Because insulin resistance promotes the preservation of glucose and oxidation of fat, it has been suggested to be an adaptive response to food deprivation. However, fasting mammals exhibit hypoinsulinemia, suggesting that the insulin resistance-like conditions they experience may actually result from reduced pancreatic sensitivity to glucose/capacity to secrete insulin. To determine whether fasting results in insulin resistance or in pancreatic dysfunction, we infused early- and late-fasted seals (naturally adapted to prolonged fasting) with insulin (0.065 U/kg), and a separate group of late-fasted seals with low (10 pM/kg) or high (100 pM/kg) dosages of glucagon-like peptide-1 (GLP-1) immediately following a glucose bolus (0.5g/kg), and measured the systemic and cellular responses. Because GLP-1 facilitates glucose-stimulated insulin secretion, these infusions provide a method to assess pancreatic insulin-secreting capacity. Insulin infusions increased the phosphorylation of insulin receptor and Akt in adipose and muscle of early and late fasted seals; however the timing of the signaling response was blunted in adipose of late fasted seals. Despite the dose-dependent increases in insulin and increased glucose clearance (high dose), both GLP-1 dosages produced increases in plasma cortisol and glucagon, which may have contributed to the glucogenic role of GLP-1. Results suggest that fasting induces adipose-specific insulin resistance in elephant seal pups, while maintaining skeletal muscle insulin sensitivity, and therefore suggests that the onset of insulin resistance in fasting mammals is an evolved response to cope with prolonged food deprivation.

No MeSH data available.


Related in: MedlinePlus

Mean (±SE) plasma (A) glucagon-like peptide-1 (GLP-1), (B) cortisol, (C) glucagon, and (D) insulin in response to low- (LDG, n = 3) and high-dose (HDG, n = 4) GLP-1 infusions in late-fasted (7 weeks postweaning) elephant seal pups. *denotes significantly (P < 0.05) different from baseline (T0); †denotes significantly (P < 0.05) different from late-fasting GTT; ‡denotes significantly (P < 0.05) different from LDG. Late GTT insulin values adapted from (Viscarra et al. 2011a).
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fig04: Mean (±SE) plasma (A) glucagon-like peptide-1 (GLP-1), (B) cortisol, (C) glucagon, and (D) insulin in response to low- (LDG, n = 3) and high-dose (HDG, n = 4) GLP-1 infusions in late-fasted (7 weeks postweaning) elephant seal pups. *denotes significantly (P < 0.05) different from baseline (T0); †denotes significantly (P < 0.05) different from late-fasting GTT; ‡denotes significantly (P < 0.05) different from LDG. Late GTT insulin values adapted from (Viscarra et al. 2011a).

Mentions: Figure 4A confirms that GLP-1 infusions maintained elevated circulating GLP-1 levels throughout the sampling period and that a dose-dependent response was achieved. Both LDG and HDG induced a dose-dependent increase in mean plasma cortisol by 10 min with levels remaining elevated throughout the sampling period (Fig. 4B) despite our previous data demonstrating that GTT alone suppressed plasma cortisol within this time point suggesting that adrenal responsiveness is highly sensitive to GLP-1. HDG increased the peak plasma cortisol concentration by 430% compared with LDG (296 ± 65 vs. 56 ± 21% from baseline) (Fig. 4B). HDG and LDG increased mean plasma glucagon within 10 min with peak levels increased 51% and 34%, respectively, and remaining elevated throughout the sampling period (Fig. 4C). While a dose-dependent effect of GLP-1 on plasma glucagon was not detected, the trend is suggestive of an effect, which would imply that the pancreas is sensitive to GLP-1 levels. This is corroborated by the dose-dependent response of plasma insulin to GLP-1 (Fig. 4D). While all treatments (including late-fasting GTT) stimulated insulin secretion, the LDG infusion did not further increase the GSIS beyond the late-fasting GTT (Fig. 4D). However, HDG nearly doubled the increase in mean plasma insulin compared with LDG and late-fasting GTT (Viscarra et al. 2011a), with this increase persisting throughout the sampling period (Fig. 4D).


Insulin and GLP-1 infusions demonstrate the onset of adipose-specific insulin resistance in a large fasting mammal: potential glucogenic role for GLP-1.

Viscarra JA, Rodriguez R, Vazquez-Medina JP, Lee A, Tift MS, Tavoni SK, Crocker DE, Ortiz RM - Physiol Rep (2013)

Mean (±SE) plasma (A) glucagon-like peptide-1 (GLP-1), (B) cortisol, (C) glucagon, and (D) insulin in response to low- (LDG, n = 3) and high-dose (HDG, n = 4) GLP-1 infusions in late-fasted (7 weeks postweaning) elephant seal pups. *denotes significantly (P < 0.05) different from baseline (T0); †denotes significantly (P < 0.05) different from late-fasting GTT; ‡denotes significantly (P < 0.05) different from LDG. Late GTT insulin values adapted from (Viscarra et al. 2011a).
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC3755502&req=5

fig04: Mean (±SE) plasma (A) glucagon-like peptide-1 (GLP-1), (B) cortisol, (C) glucagon, and (D) insulin in response to low- (LDG, n = 3) and high-dose (HDG, n = 4) GLP-1 infusions in late-fasted (7 weeks postweaning) elephant seal pups. *denotes significantly (P < 0.05) different from baseline (T0); †denotes significantly (P < 0.05) different from late-fasting GTT; ‡denotes significantly (P < 0.05) different from LDG. Late GTT insulin values adapted from (Viscarra et al. 2011a).
Mentions: Figure 4A confirms that GLP-1 infusions maintained elevated circulating GLP-1 levels throughout the sampling period and that a dose-dependent response was achieved. Both LDG and HDG induced a dose-dependent increase in mean plasma cortisol by 10 min with levels remaining elevated throughout the sampling period (Fig. 4B) despite our previous data demonstrating that GTT alone suppressed plasma cortisol within this time point suggesting that adrenal responsiveness is highly sensitive to GLP-1. HDG increased the peak plasma cortisol concentration by 430% compared with LDG (296 ± 65 vs. 56 ± 21% from baseline) (Fig. 4B). HDG and LDG increased mean plasma glucagon within 10 min with peak levels increased 51% and 34%, respectively, and remaining elevated throughout the sampling period (Fig. 4C). While a dose-dependent effect of GLP-1 on plasma glucagon was not detected, the trend is suggestive of an effect, which would imply that the pancreas is sensitive to GLP-1 levels. This is corroborated by the dose-dependent response of plasma insulin to GLP-1 (Fig. 4D). While all treatments (including late-fasting GTT) stimulated insulin secretion, the LDG infusion did not further increase the GSIS beyond the late-fasting GTT (Fig. 4D). However, HDG nearly doubled the increase in mean plasma insulin compared with LDG and late-fasting GTT (Viscarra et al. 2011a), with this increase persisting throughout the sampling period (Fig. 4D).

Bottom Line: However, fasting mammals exhibit hypoinsulinemia, suggesting that the insulin resistance-like conditions they experience may actually result from reduced pancreatic sensitivity to glucose/capacity to secrete insulin.To determine whether fasting results in insulin resistance or in pancreatic dysfunction, we infused early- and late-fasted seals (naturally adapted to prolonged fasting) with insulin (0.065 U/kg), and a separate group of late-fasted seals with low (10 pM/kg) or high (100 pM/kg) dosages of glucagon-like peptide-1 (GLP-1) immediately following a glucose bolus (0.5g/kg), and measured the systemic and cellular responses.Despite the dose-dependent increases in insulin and increased glucose clearance (high dose), both GLP-1 dosages produced increases in plasma cortisol and glucagon, which may have contributed to the glucogenic role of GLP-1.

View Article: PubMed Central - PubMed

Affiliation: School of Natural Sciences, University of California, Merced.

ABSTRACT
Prolonged food deprivation increases lipid oxidation and utilization, which may contribute to the onset of the insulin resistance associated with fasting. Because insulin resistance promotes the preservation of glucose and oxidation of fat, it has been suggested to be an adaptive response to food deprivation. However, fasting mammals exhibit hypoinsulinemia, suggesting that the insulin resistance-like conditions they experience may actually result from reduced pancreatic sensitivity to glucose/capacity to secrete insulin. To determine whether fasting results in insulin resistance or in pancreatic dysfunction, we infused early- and late-fasted seals (naturally adapted to prolonged fasting) with insulin (0.065 U/kg), and a separate group of late-fasted seals with low (10 pM/kg) or high (100 pM/kg) dosages of glucagon-like peptide-1 (GLP-1) immediately following a glucose bolus (0.5g/kg), and measured the systemic and cellular responses. Because GLP-1 facilitates glucose-stimulated insulin secretion, these infusions provide a method to assess pancreatic insulin-secreting capacity. Insulin infusions increased the phosphorylation of insulin receptor and Akt in adipose and muscle of early and late fasted seals; however the timing of the signaling response was blunted in adipose of late fasted seals. Despite the dose-dependent increases in insulin and increased glucose clearance (high dose), both GLP-1 dosages produced increases in plasma cortisol and glucagon, which may have contributed to the glucogenic role of GLP-1. Results suggest that fasting induces adipose-specific insulin resistance in elephant seal pups, while maintaining skeletal muscle insulin sensitivity, and therefore suggests that the onset of insulin resistance in fasting mammals is an evolved response to cope with prolonged food deprivation.

No MeSH data available.


Related in: MedlinePlus