Islets in Early Life are Resistant to Detrimental Effects of a High-fat Maternal Diet: A Study in Rats

Abstract

Offspring of rats fed high-fat diets during pregnancy and lactation develop glucose intolerance and islet dysfunction in adulthood. Because other models of developmental programming of glucose intolerance are associated with defective islet development, we investigated whether high-fat exposure during fetal or neonatal life impairs islet development and function, thereby contributing to islet dysfunction in later life. Female rats were fed control or high-fat diets and their pups cross-fostered after birth to represent 4 groups with each combination of control and high-fat diet for the natural and foster mother. In a time course study, pups were kept with the natural mother until weaning. Pancreases were analysed for insulin content, beta cell mass, and islet number. Isolated islets were studied for insulin secretory responses and susceptibility to palmitate-induced apoptosis assessed by caspases 3/9 activity. Pancreatic insulin content and beta cell mass were increased in pups exposed to maternal high-fat diets after birth, whereas glucose-stimulated insulin secretion from islets of high-fat offspring at 5 and 11 days of age was lower than controls. Islets from control rats of 2–14 days of age were resistant to the pro-apoptotic effects of palmitate seen in older animals. The immature beta cell is therefore insensitive to toxic effects of palmitate and may compensate for the inhibitory effects on insulin secretion by increasing beta cell mass. The data suggest that susceptibility to glucose intolerance in offspring of dams fed high-fat diets may not be a consequence of deleterious effects on beta cell mass in early life.

beta cells - diabetes mellitus type 2 - insulin secretion - nutrition

References

• 1 Holemans K, Aerts L, Van Assche FA. Lifetime consequences of abnormal fetal pancreatic development.  J Physiol. 2003;  547 11-20
• 2 Nivoit P, Morens C, Van Assche FA, Jansen E, Poston L, Remacle C, Reusens B. Established diet-induced obesity in female rats leads to offspring hyperphagia, adiposity and insulin resistance.  Diabetologia. 2009;  52 1133-1142
• 3 Ozanne SE, Hales CN. Early programming of glucose-insulin metabolism.  Trends Endocrinol Metab. 2002;  13 368-373
• 4 Samuelsson A-M, Matthews PA, Argenton M, Christie MR, McConnell JM, Jansen EHJM, Piersma AH, Ozanne SE, Twinn FD, Remacle C, Rowlerson A, Poston L, Taylor PD. Diet-induced obesity in female mice leads to offspring hyperphagia, adiposity, hypertension, and insulin resistance. A novel murine model of developmental programming.  Hypertension. 2008;  51 383-392
• 5 Yuan QX, Zhou JY, Teng LP, Liu CP, Guo J, Liu LJ, De W, Xu KF, Mao XD, Liu C. Intrauterine growth retardation leads to the functional change of insulin secretion in the newborn rats.  Horm Metab Res. 2010;  42 491-495
• 6 Garofano A, Czernichow P, Breant B. In utero undernutrition impairs rat beta-cell development.  Diabetologia. 1997;  40 1231-1234
• 7 Armitage JA, Poston L, Taylor PD. Developmental origins of obesity and the metabolic syndrome: the role of maternal obesity.  Front Horm Res. 2008;  36 73-84
• 8 Siemelink M, Verhof A, Dormans JAMA, Span PN, Piersma AH. Dietary fatty acid composition during pregnancy and lactation in the rat programs growth and glucose metabolism in the offspring.  Diabetologia. 2002;  45 1397-1403
• 9 Khan IY, Dekou V, Douglas G, Jensen R, Hanson MA, Poston L, Taylor PD. A high fat diet during rat pregnancy or suckling induced cardiovascular dysfunction in adult offspring.  Am J Physiol Regul Integr Comp Physiol. 2005;  288 R127-R133
• 10 Taylor PD, McConnell J, Khan I Y, Holemans K, Lawrence KM, Asare-Anane H, Persaud SJ, Jones PM, Petrie L, Hanson MA, Poston L. Impaired glucose homeostasis and mitochondrial abnormalities in offspring of rats fed a fat-rich diet in pregnancy.  Am J Physiol Regul Integr Comp Physiol. 2005;  288 R134-R139
• 11 Tschen S, Dhawan S, Gurlo T, Bhushan A. Age-Dependent Decline in β-Cell Proliferation Restricts the Capacity of β-Cell Regeneration in Mice.  Diabetes. 2009;  58 1312-1320
• 12 Cerf ME, Williams K, Nkomo XI, Muller CJ, Du Toit DF, Louw J, Wolfe-Coote SA. Islet cell response in the neonatal rat after exposure to a high fat diet during pregnancy.  Am J Physiol Regul Comp Physiol. 2005;  288 R1122-R1128
• 13 Cerf ME, Williams K, Chapman CS, Louw J. Compromised beta-cell development and beta-cell dysfunction in weanling offspring from dams maintained on a high-fat diet during gestation.  Pancreas. 2007;  34 347-353
• 14 Cerf ME, Louw J. High fat programming induces glucose intolerance in weanling Wistar rats.  Horm Metab Res. 2010;  42 307-310
• 15 Kharroubi I, Ladiere L, Cardozo AK, Dogusan Z, Cnop M, Eizirik DL. Free fatty acids and cytokines induce pancreatic beta-cell apoptosis by different mechanisms: role of nuclear factor kappa B and endoplasmic reticulum stress.  Endocrinology. 2004;  145 5087-5096
• 16 Milburn JL, Hirose H, Lee YH, Nagasawa Y, Ogawa A, Ohneda M, BeltrandelRio H, Newgard CB, Johnson JH, Unger RH. Pancreatic beta cells in obesity. Evidence for induction of functional, morphologic and metabolic abnormalities by increased long chain fatty acids.  J Biol Chem. 1995;  270 1295-1299
• 17 Piro S, Anello M, Di Pietro C, Lizzio MN, Patane G, Rabuazzo AM, Vigneri R, Purrello M, Purrello F. Chronic exposure to free fatty acids or high glucose induces apoptosis in rat pancreatic islets: Possible role of oxidative stress.  Metab Clin Exp. 2002;  51 1340-1347
• 18 Grill V, Lake W, Freinkel N. Generalized diminution in the response to nutrients as insulin-releasing agents during the early neonatal period in the rat.  Diabetes. 1981;  30 56-63
• 19 Lobner K, Steinbrenner H, Roberts GA, Ling Z, Huang GC, Piquer S, Pipeleers DG, Seissler J, Christie MR. Different regulated expression of the tyrosine phosphatase-like proteins IA-2 and phogrin by glucose and insulin in pancreatic islets: relationship to development of insulin secretory responses in early life.  Diabetes. 2002;  51 2982-2988
• 20 Brundstedt J, Nielsen JH, Lernmark A. Hagedorn Study Group .Isolation of islets from mice and rats. In: Larner CL, Pohl S (eds) Methods in Diabetes Research. Laboratory Methods Vol. 1 New York: John Wiley & Sons; 1984: 245-258
• 21 Jones PM, Salmon DM, Howell SL. Protein phosphorylation in electrically permeabilized islets of Langerhans: effects of Ca2+, cyclic AMP, a phorbol ester and noradrenaline.  Biochem J. 1988;  254 397-403
• 22 Christie MR, Ashcroft SJH. Substrates for cyclic AMP-dependent protein kinase in islets of Langerhans.  Biochem J. 1985;  227 727-736
• 23 Scaglia L, Cahill CJ, Finegood DT, Bonner Weir S. Apoptosis participates in the remodelling of the endocrine pancreas in the neonatal rat.  Endocrinology. 1997;  136 1736-1741
• 24 Petrik J, Arany E, McDonald TJ, Hill DJ. Apoptosis in the pancreatic islet cells of the neonatal rat is associated with a reduced expression of insulin-like growth factor II that may act as a survival factor.  Endocrinology. 1998;  139 2994-3004
• 25 Bouret SG, Draper SJ, Simerly RB. Trophic actions of leptin on hypothalamic neurons that regulate feeding.  Science. 2004;  304 108-110
• 26 Pinto S, Roseberry AG, Liu H, Diano S, Shanabrough M, Cai X, Friedman JM, Horvath TL. Rapid rewiring of arcuate nucleus feeding circuits by leptin.  Science. 2004;  304 110-115
• 27 Delahaye F, Breton C, Risold PY, Enache M, Dutriez-Casteloot I, Laborie C, Lesage J, Vieau D. Maternal perinatal undernutrition drastically reduces postnatal leptin surge and affects the development of arcuate nucleus proopiomelanocortin neurons in neonatal male rat pups.  Endocrinology. 2008;  149 470-475
• 28 Kirk SL, Samuelsson A-J Kirk SL, Samuelsson A-M, Argenton M, Dhonye H, Kalamatianos T, Poston L, Taylor PD, Coen CW. Maternal obesity induced by diet in rats permanently influences central processes regulating food intake in offspring.  PLoS ONE. 2009;  4 e5870
• 29 Muhlhauser BS, Adam CL, Findlay PA, Duffield JA, McMillen IC. Increased maternal nutrition alters development of the appetite-regulating network in the brain.  FASEB J. 2006;  20 E556-E565
• 30 Holness MJ, Smith ND, Greenwood GK, Sugden MC. PPAR-alpha activation reverses adverse effects induced by high-saturated-fat feeding on pancreatic beta-cell function in late pregnancy.  Am J Physiol Endocrinol Metab. 2007;  292 E1087-E1094
• 31 Cacho J, Sevillano J, de Castro J, Ramos MP. Validation of simple indexes to assess insulin sensitivity during pregnancy in Wistar and Sprague-Dawley rats.  Am J Physiol Endocrinol Metab. 2008;  295 E1269-E1276
• 32 Leighton B, Dimitriadis GD, Parry-Billings M, Lozeman FL, Newsholme EA. Effects of aging on the responsiveness and sensitivity of glucose metabolism in the incubated soleus muscle isolated from Sprague-Dawley and Wistar rats.  Biochem J. 1989;  26 383-387
• 33 Petrik J, Reusens B, Arany E, Remacle C, Coelho C, Hoet JJ, Hill DJ. A low protein diet alters the balance of islet cell replication in the fetal and neonatal rat and is associated with a reduced pancreatic expression of insulin-like growth factor-II.  Endocrinology. 1999;  140 4861-4873
• 34 El-Assaad W, Buteau J, Peyot ML, Nolan C, Roduit R, Hardy S, Joly E, Dbaibo G, Rosenberg L, Prentki M. Saturated fatty acids synergize with elevated glucose to cause pancreatic beta-cell death.  Endocrinology. 2003;  144 4154-4163
• 35 Cerf ME. High fat diet modulation of glucose sensing in the beta cell.  Med Sci Monit. 2007;  13 RA13-RA17
• 36 Unger RH. How obesity causes diabetes in Zucker Diabetic Fatty rats.  Trends Endocrinol Metab. 1997;  8 276-282
• 37 Hill DJ, Strutt B, Arany E, Coukell S, Graham CF. Increased and persistent circulating insulin-like growth factor II in neonatal transgenic mice suppresses developmental apoptosis in the pancreatic islets.  Endocrinology. 2000;  141 1151-1157

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