Lipid rather than glucose metabolism is implicated in altered insulin secretion caused by oleate in INS-1 cells

1999 ◽  
Vol 277 (3) ◽  
pp. E521-E528 ◽  
Author(s):  
Laura Segall ◽  
Nathalie Lameloise ◽  
Françoise Assimacopoulos-Jeannet ◽  
Enrique Roche ◽  
Pamela Corkey ◽  
...  
Keyword(s):  
Fatty Acids ◽  
Insulin Secretion ◽  
Fatty Acid ◽  
Glucose Metabolism ◽  
Acid Oxidation ◽  
Β Cells ◽  
Malonyl Coa ◽  
Basal Insulin Secretion ◽  
Low Glucose ◽  
Glucose Fatty Acid Cycle

A comprehensive metabolic study was carried out to understand how chronic exposure of pancreatic β-cells to fatty acids causes high basal secretion and impairs glucose-induced insulin release. INS-1 β-cells were exposed to 0.4 mM oleate for 3 days and subsequently incubated at 5 or 25 mM glucose, after which various parameters were measured. Chronic oleate promoted triglyceride deposition, increased fatty acid oxidation and esterification, and reduced malonyl-CoA at low glucose in association with elevated basal O2 consumption and redox state. Oleate caused a modest (25%) reduction in glucose oxidation but did not affect glucose usage, the glucose 6-phosphate and citrate contents, and the activity of pyruvate dehydrogenase of INS-1 cells. Thus changes in glucose metabolism and a Randle-glucose/fatty acid cycle do not explain the altered secretory properties of β-cells exposed to fatty acids. The main response of INS-1 cells to chronic oleate, which is to increase the oxidation and esterification of fatty acids, may contribute to cause high basal insulin secretion via increased production of reducing equivalents and/or the generation of complex lipid messenger molecule(s).

scholarly journals Adenovirus-mediated overexpression of liver carnitine palmitoyltransferase I in INS1E cells: effects on cell metabolism and insulin secretion

2002 ◽  
Vol 364 (1) ◽  
pp. 219-226 ◽  
Author(s):  
Blanca RUBÍ ◽  
Peter A. ANTINOZZI ◽  
Laura HERRERO ◽  
Hisamitsu ISHIHARA ◽  
Guillermina ASINS ◽  
...  
Keyword(s):  
Fatty Acids ◽  
Insulin Secretion ◽  
Fatty Acid ◽  
Fatty Acid Oxidation ◽  
Fold Increase ◽  
Acid Oxidation ◽  
Β Cells ◽  
Β Cell ◽  
Carnitine Palmitoyltransferase I ◽  
Cpt I

Lipid metabolism in the β-cell is critical for the regulation of insulin secretion. Pancreatic β-cells chronically exposed to fatty acids show higher carnitine palmitoyltransferase I (CPT I) protein levels, higher palmitate oxidation rates and an altered insulin response to glucose. We examined the effect of increasing CPT I levels on insulin secretion in cultured β-cells. We prepared a recombinant adenovirus containing the cDNA for the rat liver isoform of CPT I. The overexpression of CPT I in INS1E cells caused a more than a 5-fold increase in the levels of CPT I protein (detected by Western blotting), a 6-fold increase in the CPT activity, and an increase in fatty acid oxidation at 2.5mM glucose (1.7-fold) and 15mM glucose (3.1-fold). Insulin secretion was stimulated in control cells by 15mM glucose or 30mM KCl. INS1E cells overexpressing CPT I showed lower insulin secretion on stimulation with 15mM glucose (−40%; P<0.05). This decrease depended on CPT I activity, since the presence of etomoxir, a specific inhibitor of CPT I, in the preincubation medium normalized the CPT I activity, the fatty-acid oxidation rate and the insulin secretion in response to glucose. Exogenous palmitate (0.25mM) rescued glucose-stimulated insulin secretion (GSIS) in CPT I-overexpressing cells, indicating that the mechanism of impaired GSIS was through the depletion of a critical lipid. Depolarizing the cells with KCl or intermediary glucose concentrations (7.5mM) elicited similar insulin secretion in control cells and cells overexpressing CPT I. Glucose-induced ATP increase, glucose metabolism and the triacylglycerol content remained unchanged. These results provide further evidence that CPT I activity regulates insulin secretion in the β-cell. They also indicate that up-regulation of CPT I contributes to the loss of response to high glucose in β-cells exposed to fatty acids.

scholarly journals The prolyl hydroxylase PHD3 maintains β-cell glucose metabolism during fatty acid excess

2020 ◽  
Author(s):  
Daniela Nasteska ◽  
Federica Cuozzo ◽  
Alpesh Thakker ◽  
Rula Bany Bakar ◽  
Rebecca Westbrook ◽  
...  
Keyword(s):  
Fatty Acids ◽  
Insulin Secretion ◽  
Fatty Acid ◽  
Glucose Metabolism ◽  
High Fat Diet ◽  
High Fat ◽  
Β Cells ◽  
Β Cell ◽  
Cell Glucose ◽  
Fuel Source

ABSTRACTThe alpha ketoglutarate-dependent dioxygenase, prolyl-4-hydroxylase 3 (PHD3), is a hypoxia-inducible factor target that uses molecular oxygen to hydroxylate proline. While PHD3 has been reported to influence cancer cell metabolism and liver insulin sensitivity, relatively little is known about effects of this highly conserved enzyme in insulin-secreting β-cells. Here, we show that deletion of PHD3 specifically in β-cells (βPHD3KO) is associated with impaired glucose homeostasis in mice fed high fat diet. In the early stages of dietary fat excess, βPHD3KO islets energetically rewire, leading to defects in the management of pyruvate fate and a shift away from glycolysis. However, βPHD3KO islets are able to maintain oxidative phosphorylation and insulin secretion by increasing utilization of fatty acids to supply the tricarboxylic acid cycle. This nutrient-sensing switch cannot be sustained and βPHD3KO islets begin to show signs of failure in response to prolonged metabolic stress, including impaired glucose-stimulated ATP/ADP rises, Ca2+ fluxes and insulin secretion. Thus, PHD3 might be a pivotal component of the β-cell glucose metabolism machinery by suppressing the use of fatty acids as a primary fuel source, under obesogenic and insulin resistant states.SIGNIFICANCE STATEMENTProlyl-4-hydroxylase 3 (PHD3) is involved in the oxygen-dependent regulation of cell phenotype. A number of recent studies have shown that PHD3 might operate at the interface between oxygen availability and metabolism. To understand how PHD3 influences insulin secretion, which depends on intact glucose metabolism, we generated mice lacking PHD3 specifically in pancreatic β-cells. These mice, termed βPHD3KO, are apparently normal until fed high fat diet at which point their β-cells switch to fatty acids as a fuel source. This switch cannot be tolerated and β-cells in βPHD3KO mice eventually fail. Thus, PHD3 maintains glucose-stimulated insulin secretion in β-cells during states of fatty acid excess, such as diabetes and obesity.

Short-chain 3-hydroxyacyl-CoA dehydrogenase deficiency associated with hyperinsulinism: a novel glucose–fatty acid cycle?

2003 ◽  
Vol 31 (6) ◽  
pp. 1137-1139 ◽  
Author(s):  
S. Eaton ◽  
I. Chatziandreou ◽  
S. Krywawych ◽  
S. Pen ◽  
P.T. Clayton ◽  
...  
Keyword(s):  
Insulin Secretion ◽  
Fatty Acid ◽  
Fatty Acid Oxidation ◽  
Dehydrogenase Deficiency ◽  
Short Chain ◽  
Acid Oxidation ◽  
Β Cells ◽  
Molecular Defects ◽  
Glucose Fatty Acid Cycle ◽  
Hydroxyacyl Coa Dehydrogenase

Hyperinsulinism of infancy is caused by inappropriate insulin secretion in pancreatic β-cells, even when blood glucose is low. Several molecular defects are known to cause hyperinsulinism of infancy, such as KATP channelopathies and regulatory defects of glucokinase and glutamate dehydrogenase. Although defects of fatty acid oxidation have not previously been known to cause hyperinsulinism, patients with deficiency in SCHAD (short-chain 3-hydroxyacyl-CoA dehydrogenase; an enzyme of mitochondrial β-oxidation) have hyperinsulinism. A novel link between fatty acid oxidation and insulin secretion may explain hyperinsulinism in these patients.

Improved energy homeostasis of the heart in the metabolic state of exercise

2000 ◽  
Vol 279 (4) ◽  
pp. H1490-H1501 ◽  
Author(s):  
Gary W. Goodwin ◽  
Heinrich Taegtmeyer ◽  
Keyword(s):  
Fatty Acids ◽  
Fatty Acid ◽  
Fatty Acid Oxidation ◽  
Energy Homeostasis ◽  
Acid Oxidation ◽  
High Fat ◽  
Nonesterified Fatty Acids ◽  
Malonyl Coa ◽  
Metabolic Conditions ◽  
High Lactate

We postulate that metabolic conditions that develop systemically during exercise (high blood lactate and high nonesterified fatty acids) are favorable for energy homeostasis of the heart during contractile stimulation. We used working rat hearts perfused at physiological workload and levels of the major energy substrates and compared the metabolic and contractile responses to an acute low-to-high work transition under resting versus exercising systemic metabolic conditions (low vs. high lactate and nonesterified fatty acids in the perfusate). Glycogen preservation, resulting from better maintenance of high-energy phosphates, was a consequence of improved energy homeostasis with high fat and lactate. We explained the result by tighter coupling between workload and total β-oxidation. Total fatty acid oxidation with high fat and lactate reflected increased availability of exogenous and endogenous fats for respiration, as evidenced by increased long-chain fatty acyl-CoA esters (LCFA-CoAs) and by an increased contribution of triglycerides to total β-oxidation. Triglyceride turnover (synthesis and degradation) also appeared to increase. Elevated LCFA-CoAs caused high total β-oxidation despite increased malonyl-CoA. The resulting bottleneck at mitochondrial uptake of LCFA-CoAs stimulated triglyceride synthesis. Our results suggest the following. First, both malonyl-CoA and LCFA-CoAs determine total fatty acid oxidation in heart. Second, concomitant stimulation of peripheral glycolysis and lipolysis should improve cardiac energy homeostasis during exercise. We speculate that high lactate contributes to the salutary effect by bypassing the glycolytic block imposed by fatty acids, acting as an anaplerotic substrate necessary for high tricarbocylic acid cycle flux from fatty acid-derived acetyl-CoA.

scholarly journals Increased Glucose Metabolism and Glycerolipid Formation by Fatty Acids and GPR40 Receptor Signaling Underlies the Fatty Acid Potentiation of Insulin Secretion

2014 ◽  
Vol 289 (19) ◽  
pp. 13575-13588 ◽  
Author(s):  
Mahmoud El-Azzouny ◽  
Charles R. Evans ◽  
Mary K. Treutelaar ◽  
Robert T. Kennedy ◽  
Charles F. Burant
Keyword(s):  
Fatty Acids ◽  
Insulin Secretion ◽  
Fatty Acid ◽  
Glucose Metabolism ◽  
Receptor Signaling

Effect of fatty acids on insulin release: role of chain length and degree of unsaturation

1994 ◽  
Vol 266 (4) ◽  
pp. E635-E639 ◽  
Author(s):  
E. C. Opara ◽  
M. Garfinkel ◽  
V. S. Hubbard ◽  
W. M. Burch ◽  
O. E. Akwari
Keyword(s):  
Fatty Acids ◽  
Insulin Secretion ◽  
Fatty Acid ◽  
Insulin Release ◽  
Glucose Concentration ◽  
Basal Insulin ◽  
Degree Of Unsaturation ◽  
Structural Differences ◽  
Basal Insulin Secretion

The purpose of the present study was to examine the role played by structural differences among fatty acids in their effect on insulin secretion by isolated perifused murine islets. Insulin secretion measured by radioimmunoassay was assessed either as total insulin output (ng.6 islets-1.20 min-1) or as percent of basal insulin secretion. Raising the glucose concentration from a basal 5.5 to 27.7 mM caused an increase of insulin output from 6.69 +/- 1.59 to 19.92 +/- 4.99 ng.6 islets-1.20 min-1 (P < 0.05) in control (untreated) islets. However, after 20-min exposure of islets to 5 mM 16:0 or 18:2, the effect of 27.7 mM glucose was enhanced or diminished, respectively. Basal insulin output (100% basal) changed to 44 +/- 10% basal (P < 0.005) with the addition of 5 mM 4:0 but was not altered when 4:0 was replaced by 6:0. Insulin output increased modestly with 5 mM 8:0 but significantly (P < 0.05) with 10:0 until a maximal of 280 +/- 24% basal with 12:0 (P < 0.01), then fell to 110 +/- 18 and 93 +/- 15% basal (P < 0.05) with 14:0 and 16:0, respectively. The addition of 5 mM 18:0 inhibited insulin secretion to 30 +/- 10% of basal (P < 0.003), and this effect was not caused by fatty acid interference with insulin assay.(ABSTRACT TRUNCATED AT 250 WORDS)

Malonyl CoA control of fatty acid oxidation in the newborn heart in response to increased fatty acid supply

2006 ◽  
Vol 84 (11) ◽  
pp. 1215-1222 ◽  
Author(s):  
Arzu Onay-Besikci ◽  
Nandakumar Sambandam
Keyword(s):  
Fatty Acids ◽  
Fatty Acid ◽  
Fatty Acid Oxidation ◽  
Acid Oxidation ◽  
Acetyl Coa Carboxylase ◽  
Myocardial Fatty Acid ◽  
Acetyl Coa ◽  
Tissue Levels ◽  
Post Surgery ◽  
Malonyl Coa

The concentration of fatty acids in the blood or perfusate is a major determinant of the extent of myocardial fatty acid oxidation. Increasing fatty acid supply in adult rat increases myocardial fatty acid oxidation. Plasma levels of fatty acids increase post-surgery in infants undergoing cardiac bypass operation to correct congenital heart defects. How a newborn heart responds to increased fatty acid supply remains to be determined. In this study, we examined whether the tissue levels of malonyl CoA decrease to relieve the inhibition on carnitine palmitoyltransferase (CPT) I when the myocardium is exposed to higher concentrations of long-chain fatty acids in newborn rabbit heart. We then tested the contribution of the enzymes that regulate tissue levels of malonyl CoA, acetyl CoA carboxylase (ACC), and malonyl CoA decarboxylase (MCD). Our results showed that increasing fatty acid supply from 0.4 mmol/L (physiological) to 1.2 mmol/L (pathological) resulted in an increase in cardiac fatty acid oxidation rates and this was accompanied by a decrease in tissue malonyl CoA levels. The decrease in malonyl CoA was not related to any alterations in total and phosphorylated acetyl CoA carboxylase protein or the activities of acetyl CoA carboxylase and malonyl CoA decarboxylase. Our results suggest that the regulatory role of malonyl CoA remained when the hearts were exposed to high levels of fatty acids.

Potential mechanisms and consequences of cardiac triacylglycerol accumulation in insulin-resistant rats

2003 ◽  
Vol 284 (5) ◽  
pp. E923-E930 ◽  
Author(s):  
Laura L. Atkinson ◽  
Ray Kozak ◽  
Sandra E. Kelly ◽  
Arzu Onay-Besikci ◽  
James C. Russell ◽  
...  
Keyword(s):  
Fatty Acid ◽  
Glucose Metabolism ◽  
Fatty Acid Oxidation ◽  
Acid Oxidation ◽  
Fatty Acid Binding ◽  
Insulin Resistant ◽  
Lean Control ◽  
Malonyl Coa ◽  
Significant Difference ◽  
Ampk Activity

The accumulation of intracellular triacylglycerol (TG) is highly correlated with muscle insulin resistance. However, it is controversial whether the accumulation of TG is the result of increased fatty acid supply, decreased fatty acid oxidation, or both. Because abnormal fatty acid metabolism is a key contributor to the pathogenesis of diabetes-related cardiovascular dysfunction, we examined fatty acid and glucose metabolism in hearts of insulin-resistant JCR:LA-cp rats. Isolated working hearts from insulin-resistant rats had glycolytic rates that were reduced to 50% of lean control levels ( P < 0.05). Cardiac TG content was increased by 50% ( P < 0.05) in the insulin-resistant rats, but palmitate oxidation rates remained similar between the insulin-resistant and lean control rats. However, plasma fatty acids and TG levels, as well as cardiac fatty acid-binding protein (FABP) expression, were significantly increased in the insulin-resistant rats. AMP-activated protein kinase (AMPK) plays a major role in the regulation of cardiac fatty acid and glucose metabolism. When activated, AMPK increases fatty acid oxidation by inhibiting acetyl-CoA carboxylase (ACC) and reducing malonyl-CoA levels, and it decreases TG content by inhibiting glycerol-3-phosphate acyltransferase (GPAT), the rate-limiting step in TG synthesis. The activation of AMPK also stimulates cardiac glucose uptake and glycolysis. We thus investigated whether a decrease in AMPK activity was responsible for the reduced cardiac glycolysis and increased TG content in the insulin-resistant rats. However, we found no significant difference in AMPK activity. We also found no significant difference in various established downstream targets of AMPK: ACC activity, malonyl-CoA levels, carnitine palmitoyltransferase I activity, or GPAT activity. We conclude that hearts from insulin-resistant JCR:LA-cp rats accumulate substantial TG as a result of increased fatty acid supply rather than from reduced fatty acid oxidation. Furthermore, the accumulation of cardiac TG is associated with a reduction in insulin-stimulated glucose metabolism.

scholarly journals Adipose differentiation-related protein regulates lipids and insulin in pancreatic islets

2010 ◽  
Vol 299 (2) ◽  
pp. E249-E257 ◽  
Author(s):  
D. M. Faleck ◽  
K. Ali ◽  
R. Roat ◽  
M. J. Graham ◽  
R. M. Crooke ◽  
...  
Keyword(s):  
Fatty Acids ◽  
Insulin Secretion ◽  
Fatty Acid ◽  
Lipid Metabolism ◽  
Acid Uptake ◽  
Mrna Levels ◽  
Related Protein ◽  
Β Cells ◽  
Adipose Differentiation ◽  
Increase Insulin Secretion

The excess accumulation of lipids in islets is thought to contribute to the development of diabetes in obesity by impairing β-cell function. However, lipids also serve a nutrient function in islets, and fatty acids acutely increase insulin secretion. A better understanding of lipid metabolism in islets will shed light on complex effects of lipids on β-cells. Adipose differentiation-related protein (ADFP) is localized on the surface of lipid droplets in a wide range of cells and plays an important role in intracellular lipid metabolism. We found that ADFP was highly expressed in murine β-cells. Moreover, islet ADFP was increased in mice on a high-fat diet (3.5-fold of control) and after fasting (2.5-fold of control), revealing dynamic changes in ADFP in response to metabolic cues. ADFP expression was also increased by addition of fatty acids in human islets. The downregulation of ADFP in MIN6 cells by antisense oligonucleotide (ASO) suppressed the accumulation of triglycerides upon fatty acid loading (56% of control) along with a reduction in the mRNA levels of lipogenic genes such as diacylglycerol O-acyltransferase-2 and fatty acid synthase. Fatty acid uptake, oxidation, and lipolysis were also reduced by downregulation of ADFP. Moreover, the reduction of ADFP impaired the ability of palmitate to increase insulin secretion. These findings demonstrate that ADFP is important in regulation of lipid metabolism and insulin secretion in β-cells.

Circulating lipids are lowered but pancreatic islet lipid metabolism and insulin secretion are unaltered in exercise-trained female rats

2007 ◽  
Vol 32 (2) ◽  
pp. 241-248 ◽  
Author(s):  
Julien Lamontagne ◽  
Pellegrino Masiello ◽  
Mariannick Marcil ◽  
Viviane Delghingaro-Augusto ◽  
Yan Burelle ◽  
...  
Keyword(s):  
Fatty Acids ◽  
Insulin Secretion ◽  
Fatty Acid ◽  
Lipid Metabolism ◽  
Free Fatty Acids ◽  
Fatty Acid Oxidation ◽  
Female Rats ◽  
Acid Oxidation ◽  
Β Cell ◽  
Glucose Stimulated Insulin Secretion

Deteriorating islet β-cell function is key in the progression of an impaired glucose tolerance state to overt type 2 diabetes (T2D), a transition that can be delayed by exercise. We have previously shown that trained rats are protected from heart ischemia–reperfusion injury in correlation with an increase in cardiac tissue fatty-acid oxidation. This trained metabolic phenotype, if induced in the islet, could also prevent β-cell failure in the pathogenesis of T2D. To assess the effect of training on islet lipid metabolism and insulin secretion, female Sprague–Dawley rats were exercised on a treadmill for 90 min/d, 4 d/week, for 10 weeks. Islet fatty-acid oxidation, the expression of key lipid metabolism genes, and glucose-stimulated insulin secretion were determined in freshly isolated islets from trained and sedentary control rats after a 48 h rest period from the last exercise. Although this moderate training reduced plasma glycerol, free fatty acids, and triglyceride levels by about 40%, consistent with reduced lipolysis from adipose tissue, it did not alter islet fatty-acid oxidation, nor the islet expression of key transcription factors and enzymes of lipid metabolism. The training also had no effect on glucose-stimulated insulin secretion or its amplification by free fatty acids. In summary, chronic exercise training did not cause an intrinsic change in islet lipid metabolism. Training did, however, substantially reduce the exposure of islets to exogenous lipid, thereby providing a potential mechanism by which exercise can prevent islet β-cell failure leading to T2D.

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