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  • 1
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    Gut-liver interaction in triglyceride-rich lipoprotein metabolism
    American Physiological Society ; 2011
    In:  American Journal of Physiology-Endocrinology and Metabolism Vol. 301, No. 3 ( 2011-09), p. E429-E446
    Details
    In: American Journal of Physiology-Endocrinology and Metabolism, American Physiological Society, Vol. 301, No. 3 ( 2011-09), p. E429-E446
    Abstract: The liver and intestine have complementary and coordinated roles in lipoprotein metabolism. Despite their highly specialized functions, assembly and secretion of triglyceride-rich lipoproteins (TRL; apoB-100-containing VLDL in the liver and apoB-48-containing chylomicrons in the intestine) are regulated by many of the same hormonal, inflammatory, nutritional, and metabolic factors. Furthermore, lipoprotein metabolism in these two organs may be affected in a similar fashion by certain disorders. In insulin resistance, for example, overproduction of TRL by both liver and intestine is a prominent component of and underlies other features of a complex dyslipidemia and increased risk of atherosclerosis. The intestine is gaining increasing recognition for its importance in affecting whole body lipid homeostasis, in part through its interaction with the liver. This review aims to integrate recent advances in our understanding of these processes and attempts to provide insight into the factors that coordinate lipid homeostasis in these two organs in health and disease.
    Type of Medium: Online Resource
    ISSN: 0193-1849 , 1522-1555
    URL: Article
    DOI: 10.1152/ajpendo.00178.2011
    Language: English
    Publisher: American Physiological Society
    Publication Date: 2011
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  • 2
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    Acute enhancement of insulin secretion by FFA in humans is lost with prolonged FFA elevation
    American Physiological Society ; 1999
    In:  American Journal of Physiology-Endocrinology and Metabolism Vol. 276, No. 6 ( 1999-06-01), p. E1055-E1066
    Details
    In: American Journal of Physiology-Endocrinology and Metabolism, American Physiological Society, Vol. 276, No. 6 ( 1999-06-01), p. E1055-E1066
    Abstract: The in vivo effect of elevated free fatty acids (FFA) on β-cell function in humans remains extremely controversial. We examined, in healthy young men, the acute (90 min) and chronic (48 h) effects of an approximately twofold elevation of plasma FFA vs. control on glucose-stimulated insulin secretion (GSIS). GSIS was studied in response to a graded intravenous glucose infusion (peak plasma glucose, ∼10 mmol/l, n = 8) and a two-step hyperglycemic clamp (10 and 20 mmol/l, n = 8). In the acute studies, GSIS was significantly higher, insulin sensitivity index (S I ) was lower, and disposition index (DI = insulin sensitivity × insulin secretion) was unchanged with elevated FFA vs. control [2-step clamp: DI = 8.9 ± 1.4 × 10 −3 l 2 ⋅ kg −1 ⋅ min −2 in control vs. 10.0 ± 1.9 × 10 −3 l 2 ⋅ kg −1 ⋅ min −2 with high FFA, P = nonsignificant (NS)]. In the chronic studies, there was no difference in absolute GSIS between control and high FFA studies, but there was a reduction in S I and a loss of the expected compensatory increase in insulin secretion as assessed by the DI (2-step clamp: DI = 10.0 ± 1.2 × 10 −3 l 2 ⋅ kg −1 ⋅ min −2 in control vs. 6.1 ± 0.7 × 10 −3 l 2 ⋅ kg −1 ⋅ min −2 with high FFA, P = 0.01). In summary, 1) acute and chronic FFA elevation induces insulin resistance; 2) with acute FFA elevation, this insulin resistance is precisely countered by an FFA-induced increase in insulin secretion, such that DI does not change; and 3) chronic FFA elevation disables this β-cell compensation.
    Type of Medium: Online Resource
    ISSN: 0193-1849 , 1522-1555
    URL: Article
    DOI: 10.1152/ajpendo.1999.276.6.E1055
    Language: English
    Publisher: American Physiological Society
    Publication Date: 1999
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  • 3
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    Lipid-induced pancreatic β-cell dysfunction: focus on in vivo studies
    American Physiological Society ; 2011
    In:  American Journal of Physiology-Endocrinology and Metabolism Vol. 300, No. 2 ( 2011-02), p. E255-E262
    Details
    In: American Journal of Physiology-Endocrinology and Metabolism, American Physiological Society, Vol. 300, No. 2 ( 2011-02), p. E255-E262
    Abstract: The phenomenon of lipid-induced pancreatic β-cell dysfunction (“lipotoxicity”) has been very well documented in numerous in vitro experimental systems and has become widely accepted. In vivo demonstration of β-cell lipotoxicity, on the other hand, has not been consistently demonstrated, and there remains a lack of consensus regarding the in vivo effects of chronically elevated free fatty acids (FFA) on β-cell function. Much of the disagreement relates to how insulin secretion is quantified in vivo and in particular whether insulin secretion is assessed in relation to whole body insulin sensitivity, which is clearly reduced by elevated FFA. By correcting for changes in in vivo insulin sensitivity, we and others have shown that prolonged elevation of FFA impairs β-cell secretory function. Prediabetic animal models and humans with a positive family history of type 2 diabetes are more susceptible to this impairment, whereas those with severe impairment of β-cell function (such as individuals with type 2 diabetes) demonstrate no additional impairment of β-cell function when FFA are experimentally raised. Glucolipotoxicity (i.e., the combined β-cell toxicity of elevated glucose and FFA) has been amply demonstrated in vitro and in some animal studies but not in humans, perhaps because there are limitations in experimentally raising plasma glucose to sufficiently high levels for prolonged periods of time. We and others have shown that therapies directed toward diminishing oxidative stress and ER stress have the potential to reduce lipid-induced β-cell dysfunction in animals and humans. In conclusion, lipid-induced pancreatic β-cell dysfunction is likely to be one contributor to the complex array of genetic and metabolic insults that result in the relentless decline in pancreatic β-cell function in those destined to develop type 2 diabetes, and mechanisms involved in this lipotoxicity are promising therapeutic targets.
    Type of Medium: Online Resource
    ISSN: 0193-1849 , 1522-1555
    URL: Article
    DOI: 10.1152/ajpendo.00416.2010
    Language: English
    Publisher: American Physiological Society
    Publication Date: 2011
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  • 4
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    Role of free fatty acids and glucagon in the peripheral effect of insulin on glucose production in humans
    American Physiological Society ; 1998
    In:  American Journal of Physiology-Endocrinology and Metabolism Vol. 275, No. 1 ( 1998-07-01), p. E177-E186
    Details
    In: American Journal of Physiology-Endocrinology and Metabolism, American Physiological Society, Vol. 275, No. 1 ( 1998-07-01), p. E177-E186
    Abstract: We have shown previously that the greater suppression of endogenous glucose production (GP) with equimolar peripheral vs. portal insulin cannot be detected or is minimally reversed when the insulin-induced suppression of either free fatty acids (FFA) or glucagon alone is prevented. The present experiments were designed to minimize the insulin suppression of both glucagon and FFA in an attempt to further examine the mechanism of insulin’s peripheral effect on GP. In nine healthy men, we investigated the effect of limiting the insulin suppression of both FFA and glucagon by infusing heparin (250 U/h), Intralipid 10% (25 ml/h), and glucagon (0.65 ng ⋅ kg −1 ⋅ min −1 ) during 1) portal ( n = 9), 2) equimolar peripheral ( n = 9), and 3) half-dose peripheral insulin delivery ( n = 4) by use of our previously published tolbutamide infusion method, with calculation and matching of insulin secretion rate. GP decreased by 57.2 ± 2.6% with portal, 39.0 ± 4.1% with equimolar peripheral, and 31.5 ± 2.7% with half-dose peripheral insulin delivery ( P 〈 0.001 for portal vs. peripheral and P 〈 0.001 for portal vs. half-dose peripheral). In contrast, in six control subjects in whom glucagon and FFA were not replaced, GP decreased by 62.6 ± 2.4% with portal ( n = 6), 75.7 ± 3.0% with peripheral ( n = 6), and 56.3 ± 3.0% with half-dose peripheral ( n = 4) insulin delivery ( P 〈 0.01 for portal vs. peripheral and P = not significant for portal vs. half-dose peripheral). In summary, the greater suppression of GP with equimolar peripheral vs. portal insulin is eliminated and markedly reversed if the acute insulin-induced suppression of both plasma FFA and glucagon is minimized. This suggests that the insulin-induced suppression of glucagon and FFA has additive or cooperative effects in mediating the acute extrahepatic effect of insulin on GP.
    Type of Medium: Online Resource
    ISSN: 0193-1849 , 1522-1555
    URL: Article
    DOI: 10.1152/ajpendo.1998.275.1.E177
    Language: English
    Publisher: American Physiological Society
    Publication Date: 1998
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  • 5
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    Increased postprandial nonesterified fatty acid efflux from adipose tissue in prediabetes is offset by enhanced dietary fatty acid adipose trapping
    American Physiological Society ; 2021
    In:  American Journal of Physiology-Endocrinology and Metabolism Vol. 320, No. 6 ( 2021-06-01), p. E1093-E1106
    Details
    In: American Journal of Physiology-Endocrinology and Metabolism, American Physiological Society, Vol. 320, No. 6 ( 2021-06-01), p. E1093-E1106
    Abstract: The mechanism of increased postprandial nonesterified fatty acid (NEFA) appearance in the circulation in impaired glucose tolerance (IGT) is due to increased adipose tissue lipolysis but could also be contributed to by reduced adipose tissue (AT) dietary fatty acid (DFA) trapping and increased “spillover” into the circulation. Thirty-one subjects with IGT (14 women, 17 men) and 29 with normal glucose tolerance (NGT, 15 women, 14 men) underwent a meal test with oral and intravenous palmitate tracers and the oral [ 18 F]-fluoro-thia-heptadecanoic acid positron emission tomography method. Postprandial palmitate appearance (Ra palmitate ) was higher in IGT versus NGT ( P 〈 0.001), driven exclusively by Ra palmitate from obesity-associated increase in intracellular lipolysis ( P = 0.01), as Ra palmitate from DFA spillover was not different between the groups ( P = 0.19) and visceral AT DFA trapping was even higher in IGT versus NGT ( P = 0.02). Plasma glycerol appearance was lower in IGT ( P = 0.01), driven down by insulin resistance and increased insulin secretion. Thus, we found higher AT DFA trapping, limiting spillover to lean organs and in part offsetting the increase in Ra palmitate from intracellular lipolysis. Whether similar findings occur in frank diabetes, a condition also characterized by insulin resistance but relative insulin deficiency, requires further investigation (Clinicaltrials.gov: NCT04088344, NCT02808182). NEW & NOTEWORTHY We found higher adipose tissue dietary fatty acid trapping, limiting spillover to lean organs, that in part offsets the increase in appearance rate of palmitate from intracellular lipolysis in prediabetes. These results point to the adaptive nature of adipose tissue trapping and dietary fatty acid spillover as a protective mechanism against excess obesity-related palmitate appearance rate from intracellular adipose tissue lipolysis.
    Type of Medium: Online Resource
    ISSN: 0193-1849 , 1522-1555
    URL: Article
    DOI: 10.1152/ajpendo.00619.2020
    Language: English
    Publisher: American Physiological Society
    Publication Date: 2021
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  • 6
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    Enteral glucose, absorbed and metabolized, potently enhances mesenteric lymph flow in chow- and high-fat-fed rats
    American Physiological Society ; 2022
    In:  American Journal of Physiology-Gastrointestinal and Liver Physiology Vol. 323, No. 4 ( 2022-10-01), p. G331-G340
    Details
    In: American Journal of Physiology-Gastrointestinal and Liver Physiology, American Physiological Society, Vol. 323, No. 4 ( 2022-10-01), p. G331-G340
    Abstract: A portion of absorbed dietary triglycerides (TG) is retained in the intestine after the postprandial period, within intracellular and extracellular compartments. This pool of TG can be mobilized in response to several stimuli, including oral glucose. The objective of this study was to determine whether oral glucose must be absorbed and metabolized to mobilize TG in rats and whether high-fat feeding, a model of insulin resistance, alters the lipid mobilization response to glucose. Lymph flow, TG concentration, TG output, and apolipoprotein B48 (apoB48) concentration and output were assessed after an intraduodenal lipid bolus in rats exposed to the following intraduodenal administrations 5 h later: saline (placebo), glucose, 2-deoxyglucose (2-DG, absorbed but not metabolized), or glucose + phlorizin (intestinal glucose absorption inhibitor). Glucose alone, but not 2-DG or glucose + phlorizin treatments, stimulated lymph flow, TG output, and apoB48 output compared with placebo. The effects of glucose in high-fat-fed rats were similar to those in chow-fed rats. In conclusion, glucose must be both absorbed and metabolized to enhance lymph flow and intestinal lipid mobilization. This effect is qualitatively and quantitatively similar in high-fat- and chow-fed rats. The precise signaling mechanism whereby enteral glucose enhances lymph flow and mobilizes enteral lipid remains to be determined. NEW & NOTEWORTHY Glucose potently enhances mesenteric lymph flow in chow- and high-fat-fed rats. The magnitude of glucose effect on lymph flow is no different in chow- and high-fat-fed rats. Glucose must be absorbed and metabolized to enhance lymph flow and mobilize intestinal lipid.
    Type of Medium: Online Resource
    ISSN: 0193-1857 , 1522-1547
    URL: Article
    DOI: 10.1152/ajpgi.00095.2022
    Language: English
    Publisher: American Physiological Society
    Publication Date: 2022
    detail.hit.zdb_id: 1477329-6
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  • 7
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    Mechanisms of the free fatty acid-induced increase in hepatic glucose production
    American Physiological Society ; 2003
    In:  American Journal of Physiology-Endocrinology and Metabolism Vol. 284, No. 5 ( 2003-05-01), p. E863-E873
    Details
    In: American Journal of Physiology-Endocrinology and Metabolism, American Physiological Society, Vol. 284, No. 5 ( 2003-05-01), p. E863-E873
    Abstract: The associations between obesity, insulin resistance, and type 2 diabetes mellitus are well documented. Free fatty acids (FFA), which are often elevated in obesity, have been implicated as an important link in these associations. Contrary to muscle glucose metabolism, the effects of FFA on hepatic glucose metabolism and the associated mechanisms have not been extensively investigated. It is still controversial whether FFA have substantial effects on hepatic glucose production, and the mechanisms responsible for these putative effects remain unknown. We review recent progress in this area and try to clarify controversial issues regarding the mechanisms responsible for the FFA-induced increase in hepatic glucose production in the postabsorptive state and during hyperinsulinemia.
    Type of Medium: Online Resource
    ISSN: 0193-1849 , 1522-1555
    URL: Article
    DOI: 10.1152/ajpendo.00033.2003
    Language: English
    Publisher: American Physiological Society
    Publication Date: 2003
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  • 8
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    Lipid-induced β-cell dysfunction in vivo in models of progressive β-cell failure
    American Physiological Society ; 2007
    In:  American Journal of Physiology-Endocrinology and Metabolism Vol. 292, No. 2 ( 2007-02), p. E549-E560
    Details
    In: American Journal of Physiology-Endocrinology and Metabolism, American Physiological Society, Vol. 292, No. 2 ( 2007-02), p. E549-E560
    Abstract: We determined the effect of 48-h elevation of plasma free fatty acids (FFA) on insulin secretion during hyperglycemic clamps in control female Wistar rats ( group a) and in the following female rat models of progressive β-cell dysfunction: lean Zucker diabetic fatty (ZDF) rats, both wild-type ( group b) and heterozygous for the fa mutation in the leptin receptor gene ( group c); obese (fa/fa) Zucker rats (nonprediabetic; group d); obese prediabetic (fa/fa) ZDF rats ( group e); and obese (fa/fa) diabetic ZDF rats ( group f). FFA induced insulin resistance in all groups but increased C-peptide levels (index of absolute insulin secretion) only in obese prediabetic ZDF rats. Insulin secretion corrected for insulin sensitivity using a hyperbolic or power relationship (disposition index or compensation index, respectively, both indexes of β-cell function) was decreased by FFA. The decrease was greater in normoglycemic heterozygous lean ZDF rats than in Wistar controls. In obese “prediabetic” ZDF rats with mild hyperglycemia, the FFA-induced decrease in β-cell function was no greater than that in obese Zucker rats. However, in overtly diabetic obese ZDF rats, FFA further impaired β-cell function. In conclusion, 1) the FFA-induced impairment in β-cell function is accentuated in the presence of a single copy of a mutated leptin receptor gene, independent of hyperglycemia. 2) In prediabetic ZDF rats with mild hyperglycemia, lipotoxicity is not accentuated, as the β-cell mounts a partial compensatory response for FFA-induced insulin resistance. 3) This compensation is lost in diabetic rats with more marked hyperglycemia and loss of glucose sensing.
    Type of Medium: Online Resource
    ISSN: 0193-1849 , 1522-1555
    URL: Article
    DOI: 10.1152/ajpendo.00255.2006
    Language: English
    Publisher: American Physiological Society
    Publication Date: 2007
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  • 9
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    The effect of high-dose sodium salicylate on chronically elevated plasma nonesterified fatty acid-induced insulin resistance and β-cell dysfunction in overweight and obese nondiabetic men
    American Physiological Society ; 2009
    In:  American Journal of Physiology-Endocrinology and Metabolism Vol. 297, No. 5 ( 2009-11), p. E1205-E1211
    Details
    In: American Journal of Physiology-Endocrinology and Metabolism, American Physiological Society, Vol. 297, No. 5 ( 2009-11), p. E1205-E1211
    Abstract: Prolonged elevation of plasma nonesterified fatty acids (NEFA) induces insulin resistance and impairs pancreatic β-cell adaptation to insulin resistance. Studies in rodents suggest that inflammation may play a role in this “lipotoxicity.” We studied the effects of sodium salicylate, an anti-inflammatory agent, on lipid-induced alterations in β-cell function and insulin sensitivity in six overweight and obese nondiabetic men. Each subject underwent four separate studies, 4–6 wk apart, in random order: 1) SAL, 1-wk placebo followed by intravenous (iv) infusion of saline for 48 h; 2) IH, 1-wk placebo followed by iv infusion of intralipid plus heparin for 48 h to raise plasma NEFA approximately twofold; 3) IH + SS, 1-wk sodium salicylate (4.5 g/day) followed by 48-h IH infusion; and 4) SS, 1-wk oral sodium salicylate followed by 48-h saline infusion. After 48-h saline or lipid infusion, insulin secretion and sensitivity were assessed by hyperglycemic clamp and euglycemic hyperinsulinemic clamp, respectively, in sequential order. Insulin sensitivity was reduced by lipid infusion (IH = 67% of SAL) and was not improved by salicylate (IH + SS = 56% of SAL). Lipid infusion also reduced the disposition index ( P 〈 0.05), which was not prevented by sodium salicylate. Salicylate reduced insulin clearance. These data suggest that oral sodium salicylate at this dose impairs insulin clearance but does not ameliorate lipid-induced insulin resistance and β-cell dysfunction in overweight and obese nondiabetic men.
    Type of Medium: Online Resource
    ISSN: 0193-1849 , 1522-1555
    URL: Article
    DOI: 10.1152/ajpendo.00313.2009
    Language: English
    Publisher: American Physiological Society
    Publication Date: 2009
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  • 10
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    Short-term oral α-lipoic acid does not prevent lipid-induced dysregulation of glucose homeostasis in obese and overweight nondiabetic men
    American Physiological Society ; 2011
    In:  American Journal of Physiology-Endocrinology and Metabolism Vol. 301, No. 4 ( 2011-10), p. E736-E741
    Details
    In: American Journal of Physiology-Endocrinology and Metabolism, American Physiological Society, Vol. 301, No. 4 ( 2011-10), p. E736-E741
    Abstract: Prolonged elevation of plasma free fatty acids (FFAs) induces insulin resistance and impairs pancreatic β-cell adaptation to insulin resistance. The mechanisms whereby lipid induces these impairments are not fully defined but may involve oxidative stress, inflammation, and endoplasmic reticulum stress. α-Lipoic acid (ALA), a commonly used health supplement with antioxidant, anti-inflammatory, and AMPK-activating properties, has been shown to have therapeutic value in type 2 diabetes and its complications. Here we examined the effects of ALA on insulin sensitivity and secretion in humans under the conditions of 24-h iv lipid infusion to elevate plasma FFAs. Eight overweight and obese male subjects underwent four randomized studies each, 4–6 wk apart: 1) SAL, 2-wk oral placebo followed by 24-h iv infusion of saline; 2) IH, 2-wk placebo followed by 24-h iv infusion of intralipid plus heparin to raise plasma FFAs approximately twofold; 3) IH + ALA, 2-wk ALA (1,800 mg/day) followed by 24-h infusion of intralipid plus heparin; and 4) ALA, 2-wk ALA followed by 24-h infusion of saline. Insulin secretion rates (ISR) and insulin sensitivity were assessed with a 2-h, 20-mmol/l hyperglycemic clamp and a hyperinsulinemic euglycemic clamp, respectively. ISR was not significantly different between treatments. Lipid infusion impaired insulin sensitivity with and without ALA pretreatment. These results indicate that ALA, administered orally at this dose for 2 wk, does not protect against lipid-induced insulin resistance in overweight and obese humans.
    Type of Medium: Online Resource
    ISSN: 0193-1849 , 1522-1555
    URL: Article
    DOI: 10.1152/ajpendo.00183.2011
    Language: English
    Publisher: American Physiological Society
    Publication Date: 2011
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