application) Obesity is a well-established risk factor for the development of type-2 diabetes, hyperlipidemia, and hypertension. The prevalence of obesity has increased progressively over the past two decades. Available evidence suggests that dietary intake of fructose has also increased. Whereas glucose stimulates insulin and leptin production, fructose does not. Both insulin and leptin act as long-term peripheral signals of energy status to the central nervous system (CNS), and are involved in the regulation of food intake and energy expenditure. We have found that meals with a high fat content and a low amount of glucose-containing carbohydrate lead to lower circulating leptin levels over a 24-hour period than do low fat, high carbohydrate meals. Since fructose administration does not stimulate either leptin or insulin, we hypothesize that energy (calories) consumed as fructose essentially are unrecognized by the CNS and the appropriate adjustments of appetite and energy expenditure do not occur. Fructose also increases triglyceride levels in both humans and animals and induces hypertension in rodents. Comprehensive long-term studies of the effects of fructose consumption have not been conducted in humans or in nonhuman primates. We hypothesize that, over time, a diet high in fructose would promote weight gain, obesity and hyperlipidemia, resulting in an increased risk for type-2 diabetes. However, it is first critical to establish the effects of high-fructose versus high-glucose meals on circulating insulin and leptin levels in humans, and to determine if differences in insulin and leptin subsequently affect appetite and food intake. To test this hypothesis in human subjects, we propose to measure and compare 24-hour circulating leptin levels and appetite parameters in normal weight men and women during a 24-hour period during which the subjects consume 3 meals with 30% of calories as either free fructose or free glucose in a randomized crossover design. We expect that leptin concentrations will be lower over 24 hours when the subjects consume the high fructose meals. To examine the impact of the changes in leptin, we will then assess the effects of prior dietary carbohydrate type on appetite and caloric intake over a subsequent 24-hour period. We expect that the subjects will report greater sensation of hunger and eat more after consuming the fructose meals than after consuming the glucose meals. Together, these results will provide critical background data and additional rationale for controlled long-term studies on the effects of dietary fructose on body adiposity, energy expenditure, insulin sensitivity, lipids, and blood pressure in humans.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Small Research Grants (R03)
Project #
5R03DK058108-02
Application #
6517795
Study Section
Diabetes, Endocrinology and Metabolic Diseases B Subcommittee (DDK)
Program Officer
Robuck, Patricia R
Project Start
2001-07-01
Project End
2004-06-30
Budget Start
2002-07-01
Budget End
2004-06-30
Support Year
2
Fiscal Year
2002
Total Cost
$74,250
Indirect Cost
Name
University of California Davis
Department
Nutrition
Type
Schools of Earth Sciences/Natur
DUNS #
094878337
City
Davis
State
CA
Country
United States
Zip Code
95618
Bremer, Andrew A; Stanhope, Kimber L; Graham, James L et al. (2011) Fructose-fed rhesus monkeys: a nonhuman primate model of insulin resistance, metabolic syndrome, and type 2 diabetes. Clin Transl Sci 4:243-52
Teff, Karen L; Grudziak, Joanne; Townsend, Raymond R et al. (2009) Endocrine and metabolic effects of consuming fructose- and glucose-sweetened beverages with meals in obese men and women: influence of insulin resistance on plasma triglyceride responses. J Clin Endocrinol Metab 94:1562-9
Stanhope, Kimber L; Havel, Peter J (2008) Endocrine and metabolic effects of consuming beverages sweetened with fructose, glucose, sucrose, or high-fructose corn syrup. Am J Clin Nutr 88:1733S-1737S
Teff, Karen L; Petrova, Maja; Havel, Peter J et al. (2007) 48-h glucose infusion in humans: effect on hormonal responses, hunger and food intake. Physiol Behav 90:733-43
Griffen, Steven C; Oostema, Kimberly; Stanhope, Kimber L et al. (2006) Administration of Lispro insulin with meals improves glycemic control, increases circulating leptin, and suppresses ghrelin, compared with regular/NPH insulin in female patients with type 1 diabetes. J Clin Endocrinol Metab 91:485-91
Quinn, Lebris S; Strait-Bodey, Lena; Anderson, Barbara G et al. (2005) Interleukin-15 stimulates adiponectin secretion by 3T3-L1 adipocytes: evidence for a skeletal muscle-to-fat signaling pathway. Cell Biol Int 29:449-57
Havel, Peter J (2005) Dietary fructose: implications for dysregulation of energy homeostasis and lipid/carbohydrate metabolism. Nutr Rev 63:133-57
Teff, Karen L; Elliott, Sharon S; Tschop, Matthias et al. (2004) Dietary fructose reduces circulating insulin and leptin, attenuates postprandial suppression of ghrelin, and increases triglycerides in women. J Clin Endocrinol Metab 89:2963-72
Lindsay, Robert S; Walker, James D; Havel, Peter J et al. (2003) Adiponectin is present in cord blood but is unrelated to birth weight. Diabetes Care 26:2244-9
Faraj, May; Havel, Peter J; Phelis, Steve et al. (2003) Plasma acylation-stimulating protein, adiponectin, leptin, and ghrelin before and after weight loss induced by gastric bypass surgery in morbidly obese subjects. J Clin Endocrinol Metab 88:1594-602