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Clinical Care/Education/Nutrition/Psychosocial Research ORIGINAL ARTICLE Effect of Oral Sebacic Acid on Postprandial Glycemia, Insulinemia, and Glucose Rate of Appearance in Type 2 Diabetes 1 1 AMERIGO IACONELLI, MD ANGELA FAVUZZI, MD beneficial in terms of reduction of circu- 2 3 AMALIA GASTALDELLI, PHD CHRISTOPHE BINNERT, PHD lating levels of glucose, insulin, and free 1 3 CHIARA CHIELLINI, PHD KATHERINE MACE´, PHD 1 1 fatty acids in type 2 diabetes. Thus, the DONATELLA GNIULI, MD GELTRUDE MINGRONE, MD, PHD availability of snacks poor in fat and that do not induce hyperglycemia and/or overstimulate insulin secretion would be OBJECTIVE — Dicarboxylic acids are natural products with the potential of being an alter- a good tool in the diet of insulin-resistant, nate dietary source of energy. We aimed to evaluate the effect of sebacic acid (a 10-carbon type 2 diabetic subjects. dicarboxylic acid; C10) ingestion on postprandial glycemia and glucose rate of appearance (Ra) in healthy and type 2 diabetic subjects. Furthermore, the effect of C10 on insulin-mediated Dicarboxylic acids are naturally oc- glucose uptake and on GLUT4 expression was assessed in L6 muscle cells in vitro. curring substances produced by both higher plants and animals via ␻-oxidation RESEARCH DESIGN AND METHODS — Subjects ingested a mixed meal (50% car- of fatty acids (6,7). In plants, long-chain bohydrates, 15% proteins, and 35% lipids) containing 0 g (control) or 10 g C10 in addition to dicarboxylic acids are components of nat- the meal or 23 g C10 as a substitute of fats. ural protective polymers, cutin and RESULTS — In type 2 diabetic subjects, the incremental glucose area under the curve (AUC) suberin, which support biopolyesters in- decreased by 42% (P Ͻ 0.05) and 70% (P Ͻ 0.05) in the 10 g C10 and 23 g C10 groups, volved in waterproofing the leaves and respectively. At the largest amounts used, C10 reduced the glucose AUC in healthy volunteers fruits, regulating the flow of nutrients also. When fats were substituted with 23 g C10, AUC of Ra was significantly reduced on the order among various plant cells and organs, and of 18% (P Ͻ 0.05) in both healthy and diabetic subjects. The insulin-dependent glucose uptake minimizing the deleterious impact of Ϯ Ϯ ϭ by L6 cells was increased in the presence of C10 (38.7 10.3 vs. 11.4 5.4%; P 0.026). This pathogens (7). In animals and humans, increase was associated with a 1.7-fold raise of GLUT4. medium chain dicarboxylic acids, which CONCLUSIONS — Sebacic acid significantly reduced hyperglycemia after a meal in type 2 include prevalently sebacic (C10) and do- decanedioic (C12) acids, derive from the diabetic subjects. This beneficial effect was associated with a reduction in glucose Ra, probably due to lowered hepatic glucose output and increased peripheral glucose disposal. ␤-oxidation of longer chain dicarboxylic acids (8). Long-chain dicarboxylic acids, Diabetes Care 33:2327–2332, 2010 in turn, are formed from the correspon- dent fatty acids by ␻-oxidation in the mi- he World Health Report launched in sis of glycogen of ϳ25–45% compared crosomal membranes (9) or are taken in 2002 by the World Health Organi- with that in nondiabetic subjects (2). In- with a diet rich in vegetables (7). T zation advised that more than 1 bil- creased hepatic gluconeogenesis has been We have shown previously that me- lion adults worldwide are overweight and considered to be responsible for elevated dium-chain dicarboxylic acids represent a at least 300 million are clinically obese. hepatic glucose output in type 2 diabetes suitable alternate energy substrate to glu- Type 2 diabetes can be considered a (3). When glycogen is available in ade- cose in clinical conditions with marked threatening obesity-related disease be- quate amounts, there is an autolimitation insulin resistance and/or impaired aero- cause hyperglycemia causes relevant of hepatic glucose production. In diabe- bic glycolysis (10). Interestingly, in type 2 complications such as micro- and mac- tes, a breakdown of this autoregulation diabetes, medium-chain dicarboxylic ac- roangiopathy. Patients with type 2 diabe- may occur if glycogenolysis is limited by ids are rapidly oxidized, do not stimulate tes exhibit increased hepatic glucose glycogen depletion (4). insulin secretion, and reduce muscle fa- output, which is identified as the main Jenkins et al. (5) have shown that tigue (11). Nevertheless, the effect of C10 cause of fasting hyperglycemia and is as- spreading the nutrient load over a longer or C12, not as a substitute but in addition sociated with impaired plasma glucose period of time by increased meal fre- clearance (1) and reduced hepatic synthe- quency, the so-called nibbling diet, is to available carbohydrates, on glucose ho- meostasis has never been studied. ●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●● On this basis, our aim was to investi- From the 1Department of Internal Medicine, Catholic University of Rome, Rome, Italy; the 2Institute of gate the effect of oral administration of Clinical Physiology, Consiglio Nazionale delle Ricerche Pisa, Pisa, Italy; and the 3Nestle´ Research Centre, C10 on postprandial glycemia, insuline- Lausanne, Switzerland. mia, and glucose rate of appearance (Ra) Corresponding author: Geltrude Mingrone, [email protected]. Received 9 April 2010 and accepted 6 August 2010. Published ahead of print at http://care.diabetesjournals. in type 2 diabetic subjects compared with org on 19 August 2010. DOI: 10.2337/dc10-0663. that in healthy volunteers. To further elu- © 2010 by the American Diabetes Association. Readers may use this article as long as the work is properly cidate the mechanism of action of sebacic cited, the use is educational and not for profit, and the work is not altered. See http://creativecommons. acid in diabetes, insulin-mediated glucose org/licenses/by-nc-nd/3.0/ for details. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby uptake and GLUT4 protein expression marked “advertisement” in accordance with 18 U.S.C. Section 1734 solely to indicate this fact. were assessed in L6 cells in vitro. care.diabetesjournals.org DIABETES CARE, VOLUME 33, NUMBER 11, NOVEMBER 2010 2327 Oral sebacic acid in type 2 diabetes RESEARCH DESIGN AND Table 1—Mixed meal composition METHODS — From October 2006 to September 2007, 10 obese type 2 diabetic Carbohydrates Proteins Lipids Sebacic acid subjects and 10 healthy volunteers were enrolled. Women in fertile age were asked Control (450 kcal) 50 15 35 0 to avoid pregnancy during the study pro- 10 g C10 (450 kcal ϩ 60 kcal from C10 44 13 31 12 tocol. In addition, before starting each ex- 23 g C10 (450 kcal) 50 15 0 35 perimental session a pregnancy test was Data are kcal%. performed, and pregnant women were excluded from the investigation. All women were studied in the follicular Blood samples for the determination monitored, and enrichment was calcu- phase of their menstrual cycle. None of of 6,6-D-glucose enrichment, plasma C- lated as the ratio of 202 to 200. C10 anal- the subjects previously or currently had peptide, and plasma insulin concentra- ysis was performed as described major endocrinological, renal, cardiac, tions were obtained before the tracer previously (14). respiratory, liver, or gastrointestinal infusion was started and every 10 min disorders. during the last 20 min of the 2 h preced- Calculations All subjects underwent a 75-g oral ing the meal ingestion (equilibration pe- A physiological and isotopic steady state glucose tolerance test to measure the Mat- riod). Starting from the meal ingestion was achieved during the last 20 min of the suda index, as an index of insulin resis- time, plasma samples were obtained every basal period and of the meal period; tance (12). None of the diabetic subjects 20 min for 5 h. Therefore, overall the therefore, the glucose rate of appearance were taking oral hypoglycemic agents or study duration was7hor420min. (Ra), which is equivalent to endogenous were diagnosed with type 2 diabetes 2–5 Each subject voided to empty his/her glucose production, and rate of disap- years before the study and their A1C was bladder before starting the experimental pearance (Rd) were calculated as the 5.5–7.5%. protocol. The subsequent 24-h urine tracer infusion rate divided by the tracer- The protocol was approved by the samples were collected in a container with to-tracee ratio. During the meal, glucose ethics committee of the Catholic Univer- 0.1% sodium azide to prevent bacterial non–steady-state conditions prevail, and, sity, School of Medicine, in Rome, Italy. growth. thus, Ra and Rd were calculated using the All of the subjects signed a written in- Steele equation (15). Glucose flux rates formed consent form before starting the Body composition are expressed per kilogram of body study. After subjects voided and were weighed, weight. Glucose clearance was calculated body composition was assessed by dual- as Rd divided by plasma glucose concen- Chemicals x-ray absorptiometry (Lunar Prodigy; GE tration. AUCs of glucose and insulin con- Sebacic acid was purchased from Sigma- Lunar, Madison, WI) to measure fat-free centrations and of glucose Ra and Aldrich (St. Louis, MO) and purified by mass, fat mass, and percentage of fat mass. clearance were calculated using the trap- Real s.r.l. (Como, Italy). It was pyrogen- ezoidal method. AUC of meal glucose free and contaminant-free with a degree Analytical methods clearance was normalized to AUC of insu- of purification (gas-liquid chromatogra- Plasma insulin and C-peptide were mea- lin to account for different insulin con- phy/mass spectrometry) of 99.5%. 6,6-D- sured in duplicate by double-antibody ra- centrations observed during the three Glucose was purchased from Mass Trace dioimmunoassays (Linco Research, St.

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