Hostname: page-component-586b7cd67f-rdxmf Total loading time: 0 Render date: 2024-12-01T00:39:35.636Z 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 [email protected]
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.

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