FFA cause hepatic insulin resistance by inhibiting insulin suppression of glycogenolysis

2002 ◽  
Vol 283 (1) ◽  
pp. E12-E19 ◽  
Author(s):  
Guenther Boden ◽  
Peter Cheung ◽  
T. Peter Stein ◽  
Karen Kresge ◽  
Maria Mozzoli
Keyword(s):  
Insulin Resistance ◽  
Fatty Acids ◽  
Insulin Infusion ◽  
Glucose Production ◽  
Endogenous Glucose Production ◽  
Hepatic Insulin Resistance ◽  
Elevated Plasma ◽  
Heparin Infusion ◽  
Plasma Ffa ◽  
Endogenous Glucose

Free fatty acids (FFA) have been shown to inhibit insulin suppression of endogenous glucose production (EGP). To determine whether this is the result of stimulation by FFA of gluconeogenesis (GNG) or glycogenolysis (GL) or a combination of both, we have determined rates of GNG and GL (with2H2O) and EGP in 16 healthy nondiabetic volunteers (11 males, 5 females) during euglycemic-hyperinsulinemic (∼450 pM) clamping performed either with or without simultaneous intravenous infusion of lipid plus heparin. During insulin infusion, FFA decreased from 571 to 30 μmol/l ( P < 0.001), EGP from 15.7 to 2.0 μmol · kg−1 · min−1( P < 0.01), GNG from 8.2 to 3.7 μmol · kg−1 · min−1( P < 0.05), and GL from 7.4 to −1.7 μmol · kg−1 · min−1( P < 0.02). During insulin plus lipid/heparin infusion, FFA increased from 499 to 1,247 μmol/l ( P< 0.001). EGP decreased 64% less than during insulin alone (−5.1 ± 0.7 vs. −13.7 ± 3.4 μmol · kg−1 · min−1). The decrease in GNG was not significantly different from the decrease of GNG during insulin alone (−2.6 vs. −4.5 μmol · kg−1 · min−1, not significant). In contrast, GL decreased 66% less than during insulin alone (−3.1 vs. −9.2 μmol · kg−1 · min−1, P < 0.05). We conclude that insulin suppressed EGP by inhibiting GL more than GNG and that elevated plasma FFA levels attenuated the suppression of EGP by interfering with insulin suppression of GL.

Peripheral and hepatic resistance to insulin and hepatic resistance to glucagon in uraemic subjects

1988 ◽  
Vol 118 (1) ◽  
pp. 125-134 ◽  
Author(s):  
Ole Schmitz
Keyword(s):  
Insulin Resistance ◽  
Insulin Infusion ◽  
Serum Insulin ◽  
Hepatic Glucose Production ◽  
Glucose Production ◽  
Endogenous Glucose Production ◽  
Hepatic Insulin Resistance ◽  
Glucose Disposal ◽  
Peripheral Tissues ◽  
Endogenous Glucose

Abstract. To characterize endogenous glucose production in uraemia, nondialyzed uraemic patients and controls were exposed to two major modulating hormones, insulin and glucagon. Nineteen uraemic and 15 healthy subjects underwent either a 2-step (insulin infusion rates: 0.45 and 1.0 mU·kg−1·min−1) or a 3-step (insulin infusion rates: 0.1, 0.2 and 0.3 mU·kg−1·min−1 sequential euglycaemic insulin clamp. Average steady state serum insulin concentrations were almost identical during all five infusion rates in uraemic patients (16,22, 26, 31 and 66 mU/l) and controls (15, 19, 24, 33 and 68 mU/l). At all steps, insulin infusion was accompanied by significantly lower glucose disposal rates ([3−3H]glucose) in uraemic patients compared with controls (P < 0.05 or less). Moreover, the restraining potency of insulin on endogenous glucose production was much more prominent in healthy than in uraemic subjects at the lowest three infusion rates (0.6 ± 1.0 versus 1.4 ± 0.3 (mean ± 1 sd), −0.3 ± 0.7 versus 0.7 ± 0.3, and −1.1 ± 0.7 versus 0.2 ± 0.6 mg·kg−1·min−1; P < 0.05, P < 0.01 and P < 0.01, respectively), implying a shift to the right of the dose-response curve in uraemia. In contrast, basal values were comparable (2.4 ± 0.3 versus 2.2 ± 0.6 mg·kg−1·min−1) as the difference vanished at higher infusion rates, i.e. peripheral insulinaemia above ≈30 mU/l. Another 7 uraemic patients and 7 controls were infused with glucagon at constant rates of 4 or 6 ng·kg−1·min−1, respectively, for 210 min concomitant with somatostatin (125 μg/h) and tritiated glucose. The ability of glucagon to elevate plasma glucose was markedly attenuated in uraemic patients compared with controls during the initial 60 min of glucagon exposure. This difference was entirely due to diminished hepatic glucose production (3.5 ± 0.8 versus 4.8 ± 1.0 mg·kg−1·min−1; P < 0.05). In conclusion, in addition to insulin resistance in peripheral tissues, uraemia is also associated with hepatic insulin resistance. Furthermore, glucagon challenge implies impaired early endogenous glucose release in uraemia suggesting a superimposed hepatic resistance to glucagon.

scholarly journals Effects of Growth Hormone and Free Fatty Acids on Insulin Sensitivity in Patients with Type 1 Diabetes

2009 ◽  
Vol 94 (9) ◽  
pp. 3297-3305 ◽  
Author(s):  
Burak Salgin ◽  
Maria L. Marcovecchio ◽  
Rachel M. Williams ◽  
Sarah J. Jackson ◽  
Leslie J. Bluck ◽  
...  
Keyword(s):  
Insulin Resistance ◽  
Fatty Acids ◽  
Growth Hormone ◽  
Type 1 Diabetes ◽  
Insulin Sensitivity ◽  
Glucose Uptake ◽  
Glucose Production ◽  
Endogenous Glucose Production ◽  
Endogenous Glucose

Context: Because GH stimulates lipolysis, an increase in circulating free fatty acid levels, as opposed to a direct effect of high GH levels, could underlie the development of insulin resistance in type 1 diabetes (T1D). Our aim was to explore the relative contributions of GH and free fatty acids to the development of insulin resistance in patients with T1D. Patients: Seven (four females, three males) nonobese patients with T1D aged 21–30 yr were studied on four occasions in random order. On each visit, overnight endogenous GH production was suppressed by octreotide. Three 1-h pulses of recombinant human GH (rhGH) or placebo were administered on two visits each. Acipimox, an antilipolytic drug, or a placebo were ingested every 4 h on two visits each. Stable glucose and glycerol isotopes were used to assess glucose and glycerol turnover. The overnight protocol was concluded by a two-step hyperinsulinemic euglycemic clamp on each visit. Main Outcome: rhGH administration led to increases in the insulin infusion rate required to maintain euglycemia overnight (P = 0.008), elevated basal endogenous glucose production (P = 0.007), decreased basal peripheral glucose uptake (P = 0.03), and reduced glucose uptake during step 1 of the clamp (P &lt; 0.0001). Coadministration of rhGH and acipimox reversed these effects and suppression of lipolysis in the absence of GH replacement led to further increases in insulin sensitivity. Results: GH pulses were associated with an increase in endogenous glucose production and decreased rates of peripheral glucose uptake, which was entirely reversed by acipimox. Therefore, GH-driven decreases in insulin sensitivity are mainly determined by the effect of GH on lipolysis. Growth hormone decreases insulin sensitivity through increases in free fatty acid levels.

Inhibition of lipolysis causes suppression of endogenous glucose production independent of changes in insulin

2000 ◽  
Vol 279 (3) ◽  
pp. E630-E637 ◽  
Author(s):  
Steven D. Mittelman ◽  
Richard N. Bergman
Keyword(s):  
Fatty Acids ◽  
Free Fatty Acids ◽  
Insulin Infusion ◽  
Glucose Production ◽  
Endogenous Glucose Production ◽  
Significant Rise ◽  
Endogenous Glucose

We have shown that insulin controls endogenous glucose production (EGP) indirectly, via suppression of adipocyte lipolysis. Free fatty acids (FFA) and EGP are suppressed proportionately, and when the decline in FFA is prevented during insulin infusion, suppression of EGP is also prevented. The present study tested the hypothesis that suppression of lipolysis under conditions of constant insulin would yield a suppression of EGP. N 6-cyclohexyladenosine (CHA) was used to selectively suppress adipocyte lipolysis during euglycemic clamps in conscious male dogs. FFA suppression by CHA caused suppression of EGP. Liposyn control experiments, which maintained FFA levels above basal during CHA infusion, completely prevented the decline in EGP, whereas glycerol control experiments, which maintained glycerol levels close to basal, did not prevent a decline in EGP. These controls suggest that the EGP suppression was secondary to the suppression of FFA levels specifically. A difference in the sensitivity of FFA and EGP suppression (FFA were suppressed ∼85% whereas EGP only declined ∼40%) was possibly caused by confounding effects of CHA, including an increase in catecholamine and glucagons levels during CHA infusion. Thus suppression of lipolysis under constant insulin causes suppression of EGP, despite a significant rise in catecholamines.

1898-P: Colonic Short-Chain Fatty Acids Lower Endogenous Glucose Production

Diabetes ◽  
2020 ◽  
Vol 69 (Supplement 1) ◽  
pp. 1898-P
Author(s):  
ADELINA I.L. LANE ◽  
SAVANNA N. WENINGER ◽  
FRANK DUCA
Keyword(s):  
Fatty Acids ◽  
Glucose Production ◽  
Short Chain Fatty Acids ◽  
Endogenous Glucose Production ◽  
Short Chain ◽  
Endogenous Glucose ◽  
Chain Fatty Acids

Acute inhibition of lipolysis does not affect postprandial suppression of endogenous glucose production

2005 ◽  
Vol 289 (6) ◽  
pp. E941-E947 ◽  
Author(s):  
Peter E. Carey ◽  
Jean Gerrard ◽  
Gary W. Cline ◽  
Chiara Dalla Man ◽  
Philip T. English ◽  
...  
Keyword(s):  
Fatty Acids ◽  
Glucose Homeostasis ◽  
Plasma Glucose ◽  
Peak Plasma ◽  
Serum Insulin ◽  
Glucose Production ◽  
Significant Negative Correlation ◽  
Endogenous Glucose Production ◽  
Liver Fat ◽  
Endogenous Glucose

To test the hypothesis that intrahepatic availability of fatty acid could modify the rate of suppression of endogenous glucose production (EGP), acipimox or placebo was administered before and during a test meal. We used a modified isotopic methodology to measure EGP in 11 healthy subjects, and 1H magnetic resonance spectroscopic measurement of hepatic triglyceride stores was also undertaken. Acipimox suppressed plasma free fatty acids markedly before the meal (0.05 ± 0.01 mmol/l at −10 min, P = 0) and throughout the postprandial period (0.03 ± 0.01 mmol/l at 150 min). Mean peak plasma glucose was significantly lower after the meal on acipimox days (8.9 ± 0.4 vs. 10.1 ± 0.5 mmol/l, P < 0.01), as was mean peak serum insulin (653.1 ± 99.9 vs. 909 ± 118 pmol/l, P < 0.01). Fasting EGP was similar (11.15 ± 0.58 μmol·kg−1·min−1 placebo vs. 11.17 ± 0.89 mg·kg−1·min−1 acipimox). The rate of suppression of EGP after the meal was almost identical on the 2 test days (4.36 ± 1.52 vs. 3.69 ± 1.21 μmol·kg−1·min−1 at 40 min). There was a significant negative correlation between the acipimox-induced decrease in peak plasma glucose and liver triglyceride content ( r = −0.827, P = 0.002), suggesting that, when levels of liver fat were low, inhibition of lipolysis was able to affect glucose homeostasis. Acute pharmacological sequestration of fatty acids in triglyceride stores improves postprandial glucose homeostasis without effect on the immediate postprandial suppression of EGP.

Activation of liver G-6-Pase in response to insulin-induced hypoglycemia or epinephrine infusion in the rat

2002 ◽  
Vol 282 (4) ◽  
pp. E905-E910 ◽  
Author(s):  
Isabelle Bady ◽  
Carine Zitoun ◽  
Ludovic Guignot ◽  
Gilles Mithieux
Keyword(s):  
Insulin Infusion ◽  
Glucose Production ◽  
Endogenous Glucose Production ◽  
Epinephrine Infusion ◽  
Liver Lobe ◽  
Endogenous Glucose ◽  
Tracer Dilution ◽  
Glucose Supply ◽  
Adrenalectomized Rats ◽  
Stimulation Of

This study was conducted to test the hypothesis of the activation of glucose-6-phosphatase (G-6-Pase) in situations where the liver is supposed to sustain high glucose supply, such as during the counterregulatory response to hypoglycemia. Hypoglycemia was induced by insulin infusion in anesthetized rats. Despite hyperinsulinemia, endogenous glucose production (EGP), assessed by [3-3H]glucose tracer dilution, was paradoxically not suppressed in hypoglycemic rats. G-6-Pase activity, assayed in a freeze-clamped liver lobe, was increased by 30% in hypoglycemia ( P < 0.01 vs. saline-infused controls). Infusion of epinephrine (1 μg · kg−1 · min−1) in normal rats induced a dramatic 80% increase in EGP and a 60% increase in G-6-Pase activity. In contrast, infusion of dexamethasone had no effect on these parameters. Similar insulin-induced hypoglycemia experiments performed in adrenalectomized rats did not induce any stimulation of G-6-Pase. Infusion of epinephrine in adrenalectomized rats restored a stimulation of G-6-Pase similar to that triggered by hypoglycemia in normal rats. These results strongly suggest that specific activatory mechanisms of G-6-Pase take place and contribute to EGP in situations where the latter is supposed to be sustained.

Role of free fatty acids in hepatic insulin resistance during late pregnancy in conscious rabbits

1991 ◽  
Vol 260 (6) ◽  
pp. E938-E945 ◽  
Author(s):  
M. Gilbert ◽  
M. C. Pere ◽  
A. Baudelin ◽  
F. C. Battaglia
Keyword(s):  
Insulin Resistance ◽  
Fatty Acids ◽  
Free Fatty Acids ◽  
Hepatic Glucose Production ◽  
Glucose Production ◽  
Hepatic Uptake ◽  
Hepatic Insulin Resistance ◽  
Euglycemic Hyperinsulinemic Clamp ◽  
Lipid Infusion ◽  
Hepatic Glucose

This study addresses whether elevated free fatty acids (FFA) contribute to the hepatic insulin resistance of pregnancy. We applied a euglycemic hyperinsulinemic clamp with or without Intralipid plus heparin infusion in conscious virgin and pregnant rabbits after an 18-h fast coupled with chronic catheterization of the hepatic and portal veins and femoral artery. A primed constant infusion of [3-3H]glucose was used to determine glucose fluxes. Insulin was infused into a mesenteric vein for 140 min. In pregnant rabbits, basal net hepatic uptake of lactate was almost two times that of nonpregnant rabbits. During a euglycemic hyperinsulinemic clamp there was a decline of approximately 65% in hepatic lactate uptake in nonpregnant rabbits at 80 min, whereas a similar decrease was observed only at 140 min in pregnant rabbits. This effect was blocked by lipid infusion. In the basal state the hepatic uptake of FFA was greater in pregnant than in nonpregnant animals. During the hyperinsulinemic clamp the hepatic uptake dropped by approximately 70 and approximately 30% in nonpregnant and pregnant females, respectively. Lipid infusion did not prevent the hepatic FFA uptake and hepatic ketone body output from decreasing. Hepatic glucose production was totally suppressed in the control period in nonpregnant animals but not during lipid infusion (approximately 65%). Hepatic glucose production was not significantly different between pregnant and nonpregnant rabbits during lipid infusion. Glucose utilization was markedly reduced in nonpregnant animals during lipid infusion to levels comparable with that in pregnant animals.(ABSTRACT TRUNCATED AT 250 WORDS)

Insulin sensitivity of glucose and fat metabolism in severe sepsis

2000 ◽  
Vol 99 (4) ◽  
pp. 321-328 ◽  
Author(s):  
Cécile CHAMBRIER ◽  
Martine LAVILLE ◽  
Khalid RHZIOUAL BERRADA ◽  
Michelle ODEON ◽  
Paul BOULÉTREAU ◽  
...  
Keyword(s):  
Severe Sepsis ◽  
Insulin Infusion ◽  
Glucose Utilization ◽  
Fat Metabolism ◽  
Glucose Production ◽  
Normal Subjects ◽  
Endogenous Glucose Production ◽  
Exogenous Insulin ◽  
Control Subjects ◽  
Endogenous Glucose

In order to quantify the changes in insulin sensitivity, particularly of endogenous glucose production and fat metabolism, in patients with severe sepsis, a prospective study was conducted in five normal subjects and in five patients with severe sepsis hospitalized in an intensive care unit. The responses of endogenous glucose production, glucose utilization, plasma fatty acids and ketone body concentrations to progressive increase in plasma insulin levels (exogenous insulin infusion rates of 0, 0.5, 1 and 2 m-unitsċmin-1ċkg-1) were measured using the isoglycaemic clamp technique. Total glucose turnover was determined with D-[6,6-2H2]glucose. In each group, plasma glucose was maintained at basal levels (control subjects, 4.32±0.22 mmolċl-1; patients with sepsis, 7.10±2.29 mmolċl-1; P < 0.05). Plasma insulin concentrations were comparable in the two groups at an insulin infusion rate of 0.4 m-unitċmin-1ċkg-1 for controls and 0.5 m-unitċmin-1ċkg-1 for patients with sepsis, but differed following infusion at 2 m-unitċmin-1ċkg-1 (control subjects, 102±13.4 m-unitsċl-1; patients with sepsis, 124.8±19.7 m-unitsċl-1; P < 0.05). Endogenous glucose production was completely suppressed in control subjects by the first insulin infusion (0.4 m-unitċmin-1ċkg-1), but was only suppressed during infusion at 1 m-unitċmin-1ċkg-1 insulin in patients with sepsis. The glucose utilization rate increased significantly with exogenous insulin infusion in control subjects, but did not increase in patients with sepsis. Plasma non-esterified (free) fatty acid and ketone body levels were significantly decreased in both groups by the infusion of exogenous insulin, but the sensitivity of lipolysis was impaired in patients with sepsis. In conclusion, sepsis impaired to a varying extent the action of insulin on endogenous glucose production, glucose utilization, lipolysis and ketogenesis. Whole-body glucose uptake was the most affected, with a total lack of response to the elevated insulin levels obtained in this study. Suppression of endogenous glucose production and lipolysis could only be achieved with higher doses of insulin than those required in normal subjects.

Insulin regulation of renal glucose metabolism in humans

1999 ◽  
Vol 276 (1) ◽  
pp. E78-E84 ◽  
Author(s):  
Eugenio Cersosimo ◽  
Peter Garlick ◽  
John Ferretti
Keyword(s):  
Glucose Metabolism ◽  
Insulin Infusion ◽  
Glucose Utilization ◽  
Glucose Production ◽  
Endogenous Glucose Production ◽  
Saline Infusion ◽  
Saline Control ◽  
Control Group ◽  
Renal Gluconeogenesis ◽  
Endogenous Glucose

Eighteen healthy subjects had arterialized hand and renal veins catheterized after an overnight fast. Systemic and renal glucose and glycerol kinetics were measured with [6,6-2H2]glucose and [2-13C]glycerol before and after 180-min peripheral infusions of insulin at 0.125 (LO) or 0.25 (HI) mU ⋅ kg−1 ⋅ min−1with variable [6,6-2H2]dextrose or saline (control). Renal plasma flow was determined by plasma p-aminohippurate clearance. Arterial insulin increased from 37 ± 8 to 53 ± 5 (LO) and to 102 ± 10 pM (HI, P < 0.01) but not in control (35 ± 8 pM). Arterial glucose did not change and averaged 5.2 ± 0.1 (control), 4.7 ± 0.2 (LO), and 5.1 ± 0.2 (HI) μmol/ml; renal vein glucose decreased from 4.8 ± 0.2 to 4.5 ± 0.2 μmol/ml (LO) and from 5.3 ± 0.2 to 4.9 ± 0.1 μmol/ml (HI) with insulin but not saline infusion (5.3 ± 0.1 μmol/ml). Endogenous glucose production decreased from 9.9 ± 0.7 to 6.9 ± 0.5 (LO) and to 5.7 ± 0.5 (HI) μmol ⋅ kg−1 ⋅ min−1; renal glucose production decreased from 2.5 ± 0.6 to 1.5 ± 0.5 (LO) and to 1.2 ± 0.6 (HI) μmol ⋅ kg−1 ⋅ min−1, whereas renal glucose utilization increased from 1.5 ± 0.6 to 2.6 ± 0.7 (LO) and to 2.9 ± 0.7 (HI) μmol ⋅ kg−1 ⋅ min−1after insulin infusion (all P < 0.05 vs. baseline). Neither endogenous glucose production (10.0 ± 0.4), renal glucose production (1.1 ± 0.4), nor renal glucose utilization (0.8 ± 0.4) changed in the control group. During insulin infusion, systemic gluconeogenesis from glycerol decreased from 0.67 ± 0.05 to 0.18 ± 0.02 (LO) and from 0.60 ± 0.04 to 0.20 ± 0.02 (HI) μmol ⋅ kg−1 ⋅ min−1( P < 0.01), and renal gluconeogenesis from glycerol decreased from 0.10 ± 0.02 to 0.02 ± 0.02 (LO) and from 0.15 ± 0.03 to 0.09 ± 0.03 (HI) μmol ⋅ kg−1 ⋅ min−1( P < 0.05). In contrast, during saline infusion, systemic (0.66 ± 0.03 vs. 0.82 ± 0.05 μmol ⋅ kg−1 ⋅ min−1) and renal gluconeogenesis from glycerol (0.11 ± 0.02 vs. 0.41 ± 0.04 μmol ⋅ kg−1 ⋅ min−1) increased ( P < 0.05 vs. baseline). We conclude that glucose production and utilization by the kidney are important insulin-responsive components of glucose metabolism in humans.

Inhibition by insulin of hepatic glucose production in the normal dog

1965 ◽  
Vol 208 (2) ◽  
pp. 301-306 ◽  
Author(s):  
R. Steele ◽  
J. S. Bishop ◽  
A. Dunn ◽  
N. Altszuler ◽  
I. Rathgeb ◽  
...  
Keyword(s):  
Production Rate ◽  
Insulin Infusion ◽  
Hepatic Glucose Production ◽  
Glucose Production ◽  
Endogenous Glucose Production ◽  
Glucose Release ◽  
Endogenous Insulin ◽  
Intravenous Insulin ◽  
Hepatic Glucose ◽  
Endogenous Glucose

Glucose-C14 was given intravenously in trace amount as an initial dose followed by continuous infusion to tag the circulating glucose of normal unanesthetized dogs in the post-absorptive state. The rate of dilution of this circulating tagged glucose by new (C12) glucose produced endogenously was measured. The release to the blood of such new glucose, presumably almost entirely from liver, was reduced by half during the 1st hr of intravenous insulin infusion at 0.1 U/kg per hr or more, provided that enough glucose was also infused to limit hypoglycemia. During the 2nd hr new glucose release was reduced by three-quarters or more. Insulin infusion at lower rates (02–.04 U/kg per hr), along with glucose, produced smaller effects. Glucose alone, infused intravenously in amounts sufficient to raise plasma glucose concentration, and hence presumed to enhance endogenous insulin secretion, reduced new glucose release by half during the 1st hr of infusion at one-half to one and one-half times the resting endogenous glucose production rate In the 2nd or 3rd hr, with glucose infusion increased to two to five times the resting endogenous glucose production rate, new glucose release was reduced by three-fourths or more.

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