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      Medium-Chain Fatty Acids Improve Cognitive Function in Intensively Treated Type 1 Diabetic Patients and Support In Vitro Synaptic Transmission During Acute Hypoglycemia

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          Abstract

          OBJECTIVE

          We examined whether ingestion of medium-chain triglycerides could improve cognition during hypoglycemia in subjects with intensively treated type 1 diabetes and assessed potential underlying mechanisms by testing the effect of β-hydroxybutyrate and octanoate on rat hippocampal synaptic transmission during exposure to low glucose.

          RESEARCH DESIGN AND METHODS

          A total of 11 intensively treated type 1 diabetic subjects participated in stepped hyperinsulinemic- (2 mU · kg −1 · min −1) euglycemic- (glucose ∼5.5 mmol/l) hypoglycemic (glucose ∼2.8 mmol/l) clamp studies. During two separate sessions, they randomly received either medium-chain triglycerides or placebo drinks and performed a battery of cognitive tests. In vitro rat hippocampal slice preparations were used to assess the ability of β-hydroxybutyrate and octanoate to support neuronal activity when glucose levels are reduced.

          RESULTS

          Hypoglycemia impaired cognitive performance in tests of verbal memory, digit symbol coding, digit span backwards, and map searching. Ingestion of medium-chain triglycerides reversed these effects. Medium-chain triglycerides also produced higher free fatty acids and β-hydroxybutyrate levels compared with placebo. However, the increase in catecholamines and symptoms during hypoglycemia was not altered. In hippocampal slices β-hydroxybutyrate supported synaptic transmission under low-glucose conditions, whereas octanoate could not. Nevertheless, octanoate improved the rate of recovery of synaptic function upon restoration of control glucose concentrations.

          CONCLUSIONS

          Medium-chain triglyceride ingestion improves cognition without adversely affecting adrenergic or symptomatic responses to hypoglycemia in intensively treated type 1 diabetic subjects. Medium-chain triglycerides offer the therapeutic advantage of preserving brain function under hypoglycemic conditions without causing deleterious hyperglycemia.

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          Most cited references47

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          Hypoglycemia in the Diabetes Control and Complications Trial. The Diabetes Control and Complications Trial Research Group.

          (1997)
          A total of 1,441 patients with IDDM were randomly assigned to receive either intensive (n = 711) or conventional (n = 730) diabetes therapy in the Diabetes Control and Complications Trial (DCCT). The patients were followed for an average of 6.5 years. Subjects were instructed to report all episodes of suspected severe hypoglycemia to their health care team. In addition, at quarterly follow-up visits, each subject was asked about the occurrence of severe hypoglycemia. There were 3,788 episodes of severe hypoglycemia (requiring assistance); 1,027 of these episodes were associated with coma and/or seizure. A total of 65% percent of patients in the intensive group vs. 35% of patients in the conventional group had at least one episode of severe hypoglycemia by the study end; the overall rates of severe hypoglycemia were 61.2 per 100 patient-years vs. 18.7 per 100 patient-years in the intensive and conventional treatment groups, respectively, with a relative risk (RR) of 3.28. The relative risk for coma and/or seizure was 3.02 for intensive therapy. The increased risk with intensive treatment persisted over each of the 9 years of follow-up in the DCCT and over the calendar years 1984-1993 during which the study was conducted. When baseline patient characteristics were examined for effects on the risk of severe hypoglycemia, the relative risk of hypoglycemia for intensive versus conventional treatment was > or = 2 for all subgroups. Several subgroups defined by baseline characteristics, including males, adolescents, and subjects with no residual C-peptide or with a prior history of hypoglycemia, had a particularly high risk of severe hypoglycemia in both treatment groups. Analyses of the cumulative incidence of successive episodes indicated that intensive treatment was also associated with an increased risk of multiple episodes within the same patient (e.g., 22% experienced five or more episodes of severe hypoglycemia within the first 5 years of follow-up vs. 4% in the conventional group). Within both treatment groups, patients who experienced severe hypoglycemia were at increased risk of subsequent episodes. Approximately 30% of patients in each group experienced a second episode within the 4 months following the first episode of severe hypoglycemia. Within each treatment group, the number of prior episodes of hypoglycemia was the strongest predictor of the risk of future episodes, followed closely by the current HbA1c value. After adjustment for the current quarterly HbA1c level, intensive treatment was still associated with a significantly increased risk of hypoglycemia, indicating that the increased risk with intensive treatment is not completely explained by differences in HbA1c values.
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            Physiological effects of medium-chain triglycerides: potential agents in the prevention of obesity.

            Marie-Pierre St-Onge, Peter J H Jones (2002)
            Medium chain fatty acids (MCFA) are readily oxidized in the liver. Animal and human studies have shown that the fast rate of oxidation of MCFA leads to greater energy expenditure (EE). Most animal studies have also demonstrated that the greater EE with MCFA relative to long-chain fatty acids (LCFA) results in less body weight gain and decreased size of fat depots after several months of consumption. Furthermore, both animal and human trials suggest a greater satiating effect of medium-chain triglycerides (MCT) compared with long-chain triglycerides (LCT). The aim of this review is to evaluate existing data describing the effects of MCT on EE and satiety and determine their potential efficacy as agents in the treatment of human obesity. Animal studies are summarized and human trials more systematically evaluated because the primary focus of this article is to examine the effects of MCT on human energy metabolism and satiety. Hormones including cholescytokinin, peptide YY, gastric inhibitory peptide, neurotensin and pancreatic polypeptide have been proposed to be involved in the mechanism by which MCT may induce satiety; however, the exact mechanisms have not been established. From the literature reviewed, we conclude that MCT increase energy expenditure, may result in faster satiety and facilitate weight control when included in the diet as a replacement for fats containing LCT.
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              Lactate: the ultimate cerebral oxidative energy substrate?

              Avital Schurr (2005)
              Research over the past two decades has renewed the interest in lactate, no longer as a useless end product of anaerobic glycolysis in brain (and other tissues), but as an oxidative substrate for energy metabolism. While this topic would be considered blasphemy only three decades ago, much recent evidence indicates that lactate does play a major role in aerobic energy metabolism in the brain, the heart, skeletal muscle, and possibly in any other tissue and organ. Nevertheless, this concept has challenged the old dogma and ignited a fierce debate, especially among neuroscientists, pitting the supporters of glucose as the major oxidative energy substrate against those who support lactate as a possible alternative to glucose under certain conditions. Meanwhile, researchers working on energy metabolism in skeletal muscle have taken great strides toward bridging between these two extreme positions, while avoiding the high decibels of an emotional debate. Employing their findings along with the existing old and new data on cerebral energy metabolism, it is postulated here that lactate is the only major product of cerebral (and other tissues) glycolysis, whether aerobic or anaerobic, neuronal or astrocytic, under rest or during activation. Consequently, this postulate entails that lactate is a major, if not the only, substrate for the mitochondrial tricarboxylic acid cycle. If proven true, this hypothesis could provide better understanding of the biochemistry and physiology of (cerebral) energy metabolism, while holding important implications in the field of neuroimaging. Concomitantly, it could satisfy both 'glucoseniks' and 'lactatians' in the ongoing debate.
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                Author and article information

                Journal
                Journal ID (nlm-ta): Diabetes
                Journal ID (hwp): diabetes
                Journal ID (pmc): diabetes
                Journal ID (publisher-id): Diabetes
                Title: Diabetes
                Publisher: American Diabetes Association
                ISSN (Print): 0012-1797
                ISSN (Electronic): 1939-327X
                Publication date (Print): May 2009
                Publication date (Electronic): 17 February 2009
                Volume: 58
                Issue: 5
                Pages: 1237-1244
                Affiliations
                [1] 1Section of Endocrinology, Yale School of Medicine, New Haven, Connecticut;
                [2] 2Department of Neurosurgery, Yale School of Medicine, New Haven, Connecticut;
                [3] 3Winthrop University Hospital, Long Island, New York;
                [4] 4Department of Psychology, State University of New York, University at Albany, Albany, New York; and
                [5] 5Yale Center for Clinical Investigation, New Haven, Connecticut.
                Author notes
                Corresponding author: Kathleen A. Page, kathleen.page@ 123456yale.edu .
                Article
                Publisher ID: 1557
                DOI: 10.2337/db08-1557
                PMC ID: 2671041
                PubMed ID: 19223595
                SO-VID: 1f7b5a9e-65dd-48c7-84f3-892313cda3af
                Copyright © © 2009 by the American Diabetes Association.
                License:

                Readers may use this article as long as the work is properly cited, the use is educational and not for profit, and the work is not altered. See http://creativecommons.org/licenses/by-nc-nd/3.0/ for details.

                History
                Date received : 10 November 2008
                Date accepted : 4 February 2009
                Funding
                Funded by: National Institutes of Health
                Award ID: R37 DK20495
                Funded by: National Institutes of Health
                Award ID: RO1NA045792
                Funded by: National Institutes of Health
                Award ID: DK069831
                Categories
                Subject: Original Article
                Subject: Complications

                ScienceOpen disciplines: Endocrinology & Diabetes
                Data availability:
                ScienceOpen disciplines: Endocrinology & Diabetes

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