Hostname: page-component-cb9f654ff-d5ftd Total loading time: 0 Render date: 2025-08-05T10:10:26.511Z Has data issue: false hasContentIssue false

Fatty acids and insulin secretion

Published online by Cambridge University Press:  09 March 2007

Valdemar Grill*
Affiliation:
Department of Internal Medicine, Norwegian University of Science and Technology, Trondheim, Norway
Elisabeth Qvigstad
Affiliation:
Department of Internal Medicine, Norwegian University of Science and Technology, Trondheim, Norway
*
*Corresponding author: Department of Medicine, University Hospital of Trondheim, Trondheim, N-7006 Norway, fax +47 73 86 75 46, email valdemar.grill@medisin.ntnu.no
Rights & Permissions [Opens in a new window]

Abstract

Core share and HTML view are not available for this content. However, as you have access to this content, a full PDF is available via the ‘Save PDF’ action button.

It has long been recognized that acute elevation of non-esterified fatty acids (NEFA) stimulates insulin secretion to a moderate extent both in vitro and in vivo. The effects of longer-term exposure to elevated fatty acids have, however, been investigated only recently. Our own studies in the rat have documented the time dependence of NEFA effects, with inhibition of glucose-induced insulin secretion being apparent after 6–24 h in vivo exposure to Intralipid or in vitro exposure to palmitate, oleate and octanoate. Evidence indicates that the inhibitory effects are coupled to fatty acid oxidation in B-cells, with ensuing reduction in glucose oxidation, in parallel with diminished activity of the pyruvate dehydrogenase enzyme. These findings were essentially confirmed in human pancreatic islets. In the db/db mouse, a model of type 2 diabetes with obesity, evidence was obtained for elevated NEFA playing a significant role in decreased glucose-induced insulin secretion. Evidence also indicates that elevated NEFA inhibit insulin biosynthesis and increase the proinsulin : insulin ratio of secretion. Results on experimentally induced elevations of NEFA in non-diabetic and diabetic humans are thus far inconclusive. Further studies are needed to ascertain the impact of elevated NEFA on insulin secretion in clinical settings.

Information

Type
Research Article
Copyright
Copyright © The Nutrition Society 2000

References

Alstrup, K, Gregersen, S, Jensen, H, Thomsen, J & Hermansen, K (1999) Differential effects of cis and trans fatty acids on insulin release from isolated mouse islets. Metabolism 48, 2229.Google ScholarPubMed
Berglund, O, Frankel, B & Hellman, B (1978) Development of the insulin secretory defect in genetically (db/db) mouse. Acta Endocrinologica 87, 543551.Google ScholarPubMed
Berne, C (1975) The oxidation of fatty acids and ketones in mouse pancreatic islets. Biochemical Journal 152, 661666.CrossRefGoogle ScholarPubMed
Billaudel, B & Sutter, B (1979) Direct effect of corticosterone upon insulin secretion studied by three different techniques. Hormone Metabolic Research 11, 555560.CrossRefGoogle ScholarPubMed
Björklund, A & Grill, V (1999) Enhancing effects of long-term elevated glucose and palmitate on stored and secreted proinsulin-to-insulin ratios in human pancreatic islets. Diabetes 48, 14091415.CrossRefGoogle ScholarPubMed
Boden, G, Chen, X, Rosner, J & Barton, M (1995) Effects of a 48-fat infusion on insulin secretion and glucose utilization. Diabetes 44, 12391242.CrossRefGoogle ScholarPubMed
Bollheimer, C, Skelly, R, Chester, M, McGarry, D & Rhodes, C (1998) Chronic exposure to free fatty acid reduces pancreatic beta cell insulin content by increased basal insulin secretion that is not compensated for by a corresponding increase in proinsulin biosynthesis translation. Journal of Clinical Investigation 101, 10941101.CrossRefGoogle Scholar
Capito, K, Hansen, S, Hedeskov, C & Thams, P (1992) Fat-induced changes in mouse pancreatic islet secretion, insulin biosynthesis and glucose metabolism. Acta Diabetologica 28, 193198.CrossRefGoogle ScholarPubMed
Carlsson, C, Borg, L & Welsh, N (1999) Sodium palmitate induces partial mitochondrial uncoupling and reactive oxygen species in rat pancreatic islets in vitro. Endocrinology 140, 34223428.CrossRefGoogle ScholarPubMed
Carpentier, A, Mittelman, S, Lamarche, B, Bergman, R, Giacca, A & Lewis, G (1999) Acute enhancement of insulin secretion by FFA in humans is lost with prolonged FFA elevation. American Journal of Physiology 276, E1055-E1066.Google ScholarPubMed
Crespin, S, Greenough, W & Steinberg, D (1969) Stimulation of insulin secretion by infusion of free fatty acids. Journal of Clinical Investigation 48, 19341943.CrossRefGoogle ScholarPubMed
Dobbins, RL, Chester, MW, Daniels, MB, McGarry, JD & Stein, DT (1998) Circulating fatty acids are essential for efficient glucose-stimulated insulin secretion after prolonged fasting in humans. Diabetes 47, 16131618.CrossRefGoogle ScholarPubMed
Furukawa, H, Carrol, R, Swift, H & Steiner, D (1999) Long-term elevation of free fatty acids leads to delayed processing of proinsulin and prohormone convertases 2 and 3 in the pancreatic beta-cell line MIN6. Diabetes 48, 13951401.CrossRefGoogle ScholarPubMed
Lee, Y, Hiroshi, H, Ohneda, M, Johnson, J, McGarry, D & Unger, R (1994) Beta cell lipotoxicity in the pathogenesis of non-insulin-dependent diabetes mellitus of obese rats, impairment in adipocyte–beta-cell relationships. Proceedings of the National Academy of Sciences, USA 91, 1087810882.CrossRefGoogle ScholarPubMed
Liang, Y, Buetteger, C, Berner, D & Matschinsky, F (1997) Chronic effect of fatty acids on insulin release is not through the alteration of glucose metabolism in a pancreatic B-cell line (BHC9). Diabetologia 40, 10181027.CrossRefGoogle ScholarPubMed
Malaisse, W, Malaisse-Lagae, F & Wright, P (1967) Effect of fasting upon insulin secretion in the rat. American Journal of Physiology 213, 843848.CrossRefGoogle ScholarPubMed
Malaisse, WJ & Malaisse-Lagae, F (1968) Stimulation of insulin secretion by non-carbohydrate metabolites. Journal of Laboratory and Clinical Medicine 72, 438448.Google Scholar
Malaisse, W, Malaisse-Lagae, F, Sener, A & Hellerström, C (1985) Participation of endogenous fatty acids in the secretory activity of the pancreatic B-cell. Biochemical Journal 227, 9951002.CrossRefGoogle ScholarPubMed
Paolisso, G, Gambardella, A, Amato, L, Tortoriello, R, D'Amore, A & D'Onofrio, F (1995) Opposite effects of short and long term fatty acid infusion on insulin secretion in healthy subjects. Diabetologia 38, 12951299.CrossRefGoogle Scholar
Pelkonen, R, Miettinen, A, Taskinen, M & Nikkilä, A (1968) Effect of acute elevation of plasma triglyceride and FFA levels on glucose utilization and plasma insulin. Diabetes 17, 7682.CrossRefGoogle ScholarPubMed
Priestman, D, Mistry, A, Halsall, A & Randle, P (1994) Role of protein synthesis and of fatty acid metabolism in the longer term regulation of pyruvate dehydrogenase kinase. Biochemical Journal 300, 659666.CrossRefGoogle ScholarPubMed
Ritz-Laser, B, Meda, P, Constant, I, Klages, N, Charollis, A, Morales, A, Magna, C, Ktorza, A & Philippe, J (1999) Glucose-induced preproinsulin gene expression is inhibited by the free fatty acid palmitate. Endocrinology 140, 40054014.CrossRefGoogle ScholarPubMed
Roche, E, Buteau, J, Aniento, I, Reig, J, Soria, B & Prentki, M (1999) Palmitate and oleate induce the immediate-early response genes c-fos and nur-77 in the pancreatic beta-cell line INS-1. Diabetes 48, 20072014.CrossRefGoogle ScholarPubMed
Sako, Y & Grill, V (1990) A 48 h lipid infusion in the rat time-dependently inhibits glucose-induced insulin secretion and B-cell oxidation through a process likely coupled to fatty acid oxidation. Endocrinology 127, 15801589.CrossRefGoogle ScholarPubMed
Sako, Y & Grill, V (1990) Coupling of B-cell desensitization by hyperglycemia to excessive stimulation and circulating insulin in glucose-infused rats. Diabetes 39, 15801583.CrossRefGoogle Scholar
Shimabukuro, M, Zhou, Y-T, Levi, M & Unger, R (1998) Fatty acid-induced apoptosis, a link between obesity and diabetes. Proceedings of the National Academy of Sciences, USA 95, 24982502.CrossRefGoogle ScholarPubMed
Stein, TS, Esser, V, Stevenson, BE, Lane, KE, Whiteside, JH, Daniels, MB & McGarry, JD (1996) Essentiality of circulating fatty acids for glucose-stimulated insulin secretion in the fasted rat. Journal of Clinical Investigation 97, 27282735.CrossRefGoogle ScholarPubMed
Stein, D, Stevenson, B, Chester, M, Basit, M, Daniels, M, Turley, S & McGarry, J (1997) The insulinotropic potency of fatty acids is influenced profoundly by their chain length and degree of saturation. Journal of Clinical Investigation 100, 398403.CrossRefGoogle ScholarPubMed
Tajiri, Y, Möller, C & Grill, V (1997) Long term effects of aminoguanidine on insulin release and biosynthesis. Evidence that the formation of advanced glycosylation end products inhibits B-cell function. Endocrinology 138, 273280.CrossRefGoogle ScholarPubMed
Warnotte, C, Nenquin, M & Henquin, J-C (1999) Unbound rather than total concentration and saturation rather than unsaturation determine the potency of fatty acids on insulin secretion. Molecular and Cellular Endocrinology 153, 147153.CrossRefGoogle ScholarPubMed
Zhou, Y-P & Grill, V (1994) Long term exposure of rat pancreatic islets to fatty acids inhibits glucose-induced insulin secretion and biosynthesis through a glucose fatty acid cycle. Journal of Clinical Investigation 93, 870876.CrossRefGoogle ScholarPubMed
Zhou, Y-P & Grill, V (1995) Long-term exposure to fatty acids and ketones inhibits B-cell functions in human pancreatic islets of Langerhans. Journal of Clinical Endocrinology and Metabolism 80, 15841590.Google ScholarPubMed
Zhou, Y-P & Grill, V (1995) Palmitate-induced B-cell insensitivity to glucose is coupled to decreased pyruvate dehydrogenase activity and enhanced kinase activity in rat pancreatic islets. Diabetes 44, 394399.CrossRefGoogle Scholar
Zhou, Y-P, Berggren, P-O & Grill, V (1996) A fatty acid-induced decrease in pyruvate dehydrogenase activity is an important determinant of B-cell dysfunction in the obese diabetic db/db mouse. Diabetes 45, 580586.CrossRefGoogle Scholar
Zhou, Y-P, Ling, Z-C & Grill, V (1996) Inhibitory effects of fatty acids on glucose-regulated B-cell function, association with increased islet triglyceride stores and altered effect of fatty acid oxidation on glucose metabolism. Metabolism 8, 981986.CrossRefGoogle Scholar
Zhou, Y-P, Priestman, D, Randle, R & Grill, V (1996) Fasting and decreased B-cell sensitivity, important role for fatty acid-induced inhibition of pyruvate dehydrogenase activity. American Journal of Physiology 270, E988-E994.Google Scholar