Effects of unbalanced diets on cerebral glucose metabolism in the adult rat
From the Departments of Neurology (Drs. Al-Mudallal and Harik) and Neurological Surgery (Dr. Lust), Case Western Reserve University School of Medicine, Cleveland, OH; and the Neurology Service (Dr. Levin), VA Medical Center, and Department of Neurosciences, New Jersey School of Medicine and Dentistry, Newark, NJ.
Supported in part by USPHS grants HL 35617 and AM 30066 and by the Research Service of the Department of Veterans Administration.
Received December 6, 1994. Accepted in final form March 28, 1995.
Address correspondence and reprint requests to Dr. Sami I. Harik, Department of Neurology, University of Arkansas for Medical Sciences, 4301 West Markham Street, Slot 500, Little Rock, AR 72205.
We measured regional cerebral metabolic rates for glucose and selected cerebral metabolites in rats fed one of the following diets for 6 to 7 weeks1) regular laboratory chow; (2) high-fat, carbohydrate-free ketogenic diet deriving 10% of its caloric value from proteins and 90% from fat; and (3) high-carbohydrate diet deriving 10% of its caloric value from proteins, 78% from carbohydrates, and 12% from fat. In preliminary experiments, we found that moderate ketosis could not be achieved by diets deriving less than about 90% of their caloric value from fat. Rats maintained on the ketogenic diet had moderately elevated blood beta-hydroxybutyrate (0.4 mM) and acetoacetate (0.2 mM), and a five- to 10-fold increase in their cerebral beta-hydroxybutyrate level. Cerebral levels of glucose, glycogen, lactate, and citrate were similar in all groups. 2-Deoxyglucose studies showed that the ketogenic diet did not significantly alter regional brain glucose utilization. However, rats maintained on the high-carbohydrate diet had a marked decrease in their brain glucose utilization and increased cerebral concentrations of glucose 6-phosphate. These findings indicate that long-term moderate ketonemia does not significantly alter brain glucose phosphorylation. However, even marginal protein dietary deficiency, when coupled with a carbohydrate-rich diet, depresses cerebral glucose utilization to a degree often seen in metabolic encephalopathies. Our results support the clinical contention that protein dietary deficiency coupled with increased carbohydrate intake can lead to CNS dysfunction.
"Our hypothesis was that the metabolic syndrome is really a problem with how we store energy from food," Shulman explained. "The idea is that insulin resistance in muscle changes the pattern of energy storage."
After providing the study's subjects with two meals high in carbohydrates, Shulman and his colleagues turned to magnetic resonance spectroscopy to measure the production of liver and muscle triglyceride, the storage form of fat, and of glycogen, the storage form of carbohydrates. "What we found is that (insulin) sensitive individuals took the energy from carbohydrate in the meals and stored it away as glycogen in both liver and muscle," said Shulman.
In the insulin resistant subjects, the energy obtained from their carbohydrates rich meals was rerouted to liver triglyceride production, elevating triglycerides in the blood by as much as 60 percent and lowering HDL cholesterol (the good cholesterol) by 20 percent. "In contrast to the young, lean, insulin-sensitive subjects, who stored most of their ingested energy as liver and muscle glycogen, the young, lean, insulin-resistant subjects had a marked defect in muscle glycogen synthesis and diverted much more of their ingested carbohydrate into liver fat production," Shulman and his colleagues reported.
"What we see," he noted, "is alterations in patterns of energy storage. An additional key point is that the insulin resistance, in these young, lean, insulin resistant individuals, was if MS independent of abdominal obesity and circulating plasma adipocytokines, suggesting that these abnormalities develop later in the development of the metabolic syndrome."
The new findings promise to help untangle the early molecular events of a syndrome at the root of one of the world's most significant health issues. "Knowing how insulin resistance alters energy storage before it leads to more serious problems can help those susceptible prevent the onset of the metabolic syndrome," Shulman said.
Another key observation was that skeletal muscle insulin resistance precedes the development of insulin resistance in liver cells, and that fat production in the liver is increased. "These findings also have important implications for understanding the pathogenesis of nonalcoholic fatty liver disease, one of the most prevalent liver diseases in both adults and children Shulman said.
An American study has shown that glucosamine (often prescribed for joint problems) may cause insulin resistance.
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