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Diabetes Division, Department of Medicine, University of Texas Health Science Center at San Antonio, San Antonio, Texas 78284-7886
Address all correspondence and requests for reprints to: Mandeep Bajaj, M.D., Assistant Professor, Diabetes Division, Department of Medicine, University of Texas Health Science Center at San Antonio, 7703 Floyd Curl Drive, San Antonio, Texas 78284-7886. E-mail: mandeepbajaj{at}hotmail.com.
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Abstract |
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(2.3 ± 0.3 to 2.4 ± 0.3 pg/ml) did not change after acipimox treatment. We concluded that sustained reduction in plasma FFA concentration in subjects with a strong family history of T2DM increases peripheral (muscle) and hepatic insulin sensitivity without increasing adiponectin levels or altering the secretion of other adipocytokines by the adipocyte. These results suggest that lipotoxicity already is well established in individuals who are genetically predisposed to develop T2DM and that drugs that cause a sustained reduction in the elevated plasma FFA concentration may represent an effective modality for the prevention of T2DM in high-risk, genetically predisposed, normal glucose-tolerant individuals despite the lack of an effect on adipocytokine concentrations.
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Introduction |
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It generally has been assumed that accelerated FFA turnover/oxidation in type 2 diabetes is an acquired abnormality that occurs secondary to insulin resistance (early stage of type 2 diabetes), insulin deficiency (later stages of type 2 diabetes), or decompensated metabolic control (1, 2, 3, 4). In Mexican Americans, it has been demonstrated that the normal glucose-tolerant offspring of two type 2 diabetic parents are insulin resistant in muscle and liver and that the defect in insulin action precedes the development of impaired insulin secretion (14, 15). The offspring of two diabetic parents are at especially high risk to develop type 2 diabetes later in life (16). It is especially noteworthy that in these lean, normal glucose-tolerant, insulin-resistant offspring disturbances in FFA metabolism already are well established (14, 15). Basal plasma FFA levels and lipid oxidation are increased and do not suppress normally with insulin. These observations raise the interesting hypothesis that disturbances in FFA metabolism may be primary and that muscle and/or hepatic insulin resistance (1) is acquired, at least in part, secondary to the abnormalities in FFA metabolism (13).
In adipocytes, nicotinic acid reduces lipolysis by inhibiting adenylyl cyclase, resulting in the suppression of hormone-sensitive lipase (17). Santomauro et al. (18) demonstrated that overnight administration of acipimox, a long-acting analog of nicotinic acid, inhibits lipolysis and lowers plasma FFA levels, reduces insulin resistance, increases carbohydrate oxidation, improves oral glucose tolerance, and reduces plasma insulin levels in lean and obese nondiabetic subjects and subjects with impaired glucose tolerance or type 2 diabetes. Similar results were demonstrated by Vaag et al. (19), who showed that an acute reduction in the plasma FFA concentration with acipimox improved peripheral insulin sensitivity and insulin-stimulated nonoxidative glucose disposal, whereas hepatic insulin sensitivity remained unchanged in patients with type 2 diabetes. However, the effect of a chronic reduction in plasma FFA concentration on hepatic/peripheral insulin sensitivity in normal glucose-tolerant subjects with a strong family history of type 2 diabetes has not been examined.
The adipocyte functions, not only a fat depot that releases FFA, but also as an endocrine organ that releases hormones in response to specific extracellular stimuli or changes in metabolic status. These secreted proteins, which include TNF, IL-6, adipsin, leptin, resistin, adiponectin (also known as Acrp30), and others, carry out a variety of diverse functions (20), and they have been referred to collectively as adipocytokines. Plasma levels of adiponectin are reduced in obese rodents and humans (21, 22), offspring of diabetic parents, and patients with type 2 diabetes mellitus (22). It has been suggested that adiponectin functions as an adipostat to regulate energy balance and that adiponectin deficiency might contribute to the development of insulin resistance and type 2 diabetes mellitus (23). In obese rodents, infusion of adiponectin enhances insulin sensitivity (23). Resistin, IL-6, and TNF are adipocytokines that induce insulin resistance, and their concentrations are increased in patients with type 2 diabetes (20, 24, 25). In type 2 diabetic patients, thiazolidinedione therapy is associated with an increase in plasma adiponectin concentration (26, 27); a reduction in plasma resistin (28), IL-6 (29), and TNF (30) levels; and a decrease in circulating plasma FFA levels and FFA turnover (27). Recent studies from our laboratory (27) demonstrated an association between the increase in plasma adiponectin concentration, the reduction in plasma FFA concentration, and the enhancement of hepatic and peripheral insulin sensitivity after pioglitazone treatment in patients with type 2 diabetes. In vitro and in vivo studies (31, 32) in rodents suggest that FFA may independently regulate the gene expression of adipocytokines. However, the effect of a prolonged (>72 h) decrease in plasma FFA concentration with acipimox on plasma adipocytokine levels in humans has not been examined.
The current study was designed to determine the effect of a sustained reduction plasma FFA concentration after 7 d of acipimox treatment on peripheral and hepatic insulin sensitivity, oral glucose tolerance, and adipocytokine concentrations in normal glucose-tolerant subjects with a strong family history of type 2 diabetes.
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Subjects and Methods |
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Eight healthy subjects with at least two first-degree relatives with type 2 diabetes participated in the study. There were five males and three females with a mean age of 40 ± 4 yr and body mass index of 26.5 ± 0.8 kg/m2. One of the three women studied was postmenopausal; the other two were premenopausal, and they were studied during the follicular phase of their menstrual cycle. None of the women were on oral contraceptives. None of the subjects were smokers. The fasting plasma glucose concentration and HbA1c were 5.2 ± 0.1 mmol/liter and 4.5 ± 0.1%, respectively. The mean plasma lipid concentrations were: total cholesterol, 198 ± 12 mg/dl; low-density lipoprotein cholesterol, 135 ± 11 mg/dl; high-density lipoprotein cholesterol, 45 ± 3 mg/dl; and triglycerides, 98 ± 16 mg/dl. None of the subjects had any significant medical problems, and their weight (74.5 ± 3.6 kg) was stable for at least 3 months before the study. No subject was taking any medications known to affect glucose metabolism. None of the subjects participated in any heavy exercise, and they were instructed not to engage in vigorous exercise for at least 3 d before the study. The purpose, nature, and potential risks of the study were explained to all subjects, and written consent was obtained before their participation. The protocol was approved by the Institutional Review Board of the University of Texas Health Science Center at San Antonio.
Study design
Three weeks before study, all subjects met with a dietitian and were instructed to consume a weight-maintaining diet containing 50% carbohydrate, 30% fat, and 20% protein. During the week before the start of acipimox treatment, all subjects received a 75-g oral glucose tolerance test (OGTT) and a euglycemic insulin clamp study (33) in combination with 3-[3H] glucose and indirect calorimetry to examine hepatic and peripheral tissue sensitivity to insulin. All studies were started at 0600 h after a 10- to 12-h overnight fast.
After completion of these studies, subjects were started on acipimox, 250 mg orally every 6 h for 7 d. Adherence to a weight-maintaining diet was reinforced on a second meeting with the dietitian on d 1 of the study. At 1600 h on d 5, all subjects were admitted to the General Clinical Research Center (GCRC) and remained at the GCRC until the completion of the study on d 8. After subjects were admitted to the GCRC, they continued to receive the weight-maintaining diet, and no attempt was made during the study to change dietary instructions. While at the GCRC, subjects were encouraged to ambulate freely, and there was no change in body weight in any subject. The OGTT and euglycemic hyperinsulinemic clamp were repeated on d 7 and 8, respectively, after a 10- to 12-h overnight fast.
OGTT.
Baseline blood samples for determination of plasma glucose, adiponectin, resistin, TNF, IL-6, FFA, and insulin concentrations were drawn at –30, –15, and 0 min. At time 0 subjects ingested 75 g glucose in 300 ml orange-flavored water, and plasma glucose, FFA, and insulin concentrations were measured at 15-min intervals for 2 h.
Hyperinsulinemic euglycemic clamp. Insulin sensitivity was assessed with a euglycemic insulin clamp, as previously described (33). At 0600 h (–120 min), a primed (25 µCi)-continuous (0.25 µCi/min) infusion of 3[3H] glucose was started via catheter placed into an antecubital vein and continued throughout the study. A second catheter was placed retrogradely into a vein on the dorsum of the hand, which was then placed in a heated box (60 C). Baseline arterialized venous blood samples for determination of plasma 3[3H] glucose radioactivity, and plasma glucose, FFA, and insulin concentrations were drawn at –30, –20, –10, –5, and 0 min. At time 0, a prime-continuous infusion of human regular insulin (Novolin; Novo Nordisk Pharmaceuticals, Princeton, NJ) was started at a rate of 80 mU/min–1·m–2 body surface area and continued for 120 min. Arterialized blood samples were collected every 5 min for plasma glucose determination, and a 20% glucose infusion was adjusted to maintain the plasma glucose concentration at each subject’s fasting plasma glucose level. Throughout the insulin clamp, blood samples for determination of plasma glucose concentration were drawn every 5 min, and blood samples for determination of plasma insulin, FFA, and 3[3H] glucose-specific activity were collected every 10–15 min. Continuous indirect calorimetry, using a ventilated hood system (Deltatrac II; Sensor Medics, Yorba Linda, CA), was performed during the last 40 min of the basal period and the last 30 min of the insulin clamp, as previously described (34).
Analytical determinations
Plasma glucose was measured by the glucose oxidase method (Beckman Instruments, Fullerton, CA). Plasma insulin concentration was measured by RIA (Diagnostic Products Corp., Los Angeles, CA). Tritiated glucose-specific activity was determined on deproteinized bariun/zinc plasma samples as previously described (2). Plasma FFA concentration was determined by an enzymatic calorimetric quantification method (Wako Chemicals, Nuess, Germany). Plasma adiponectin concentration was measured by RIA (Linco Research, St. Charles, MO). Plasma resistin concentration was determined by ELISA (U.S. Biologicals, Swampscott, MA). Plasma IL-6 and plasma TNF concentrations were also measured by ELISA (R&D Systems Inc., Minneapolis, MN).
Calculations
Under steady-state postabsorptive conditions, the rate of endogenous glucose appearance (Ra) was calculated as the 3[3H] glucose infusion rate (disintegrations per minute per minute) divided by the steady-state plasma 3[3H] glucose-specific activity (disintegrations per minute per milligram). During the euglycemic insulin clamp, the rate of Ra was calculated using Steele’s equation (35), using a distribution volume of 250 ml/kg. Endogenous (primarily hepatic) glucose production (EGP) was calculated by subtracting the exogenous glucose infusion rate from Ra. The rate of insulin-mediated total body glucose disposal (Rd) was determined by adding the rate of residual EGP to the exogenous glucose infusion rate.
Statistical analysis
Statistical calculations were performed with StatView for Windows (version 5.0; SAS Institute, Cary, NC). Values before and after acipimox treatment were compared with the paired Student’s t test. Data are presented as mean ± SEM. P < 0.05 was considered to be statistically significant. Linear or logarithmic (for nonlinearly distributed data) regression analysis was used to examine the relationships between plasma FFA and adipocytokine concentrations and hepatic/peripheral insulin sensitivity.
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Results |
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After acipimox treatment, the fasting plasma FFA concentration was reduced from 515 ± 64 to 285 ± 58 µM (P < 0.05) without change in the fasting plasma glucose concentration (5.1 ± 0.1 vs. 5.2 ± 0.1) (Fig. 1
). Fasting plasma insulin (42 ± 6 to 42 ± 7 pmol/liter) concentration did not change significantly after acipimox treatment. The mean plasma glucose (7.6 ± 0.5 to 6.9 ± 0.5 mM, P < 0.01) and FFA (263 ± 32 to 151 ± 25 µM, P < 0.05) concentrations during the OGTT were significantly reduced after acipimox treatment. The mean plasma insulin concentration during the OGTT did not change significantly (402 ± 90 to 444 ± 102 pmol/liter) after acipimox treatment (Fig. 1).
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The steady-state plasma glucose concentrations during the 120-min euglycemic insulin clamp were similar before and after acipimox treatment (5.1 ± 0.1 vs. 5.0 ± 0.1 mmol/liter). The steady-state plasma insulin concentrations during the insulin clamp were also similar before and after acipimox (862 ± 66 vs. 828 ± 82 pmol/liter).
The fasting plasma FFA levels before the start of the euglycemic insulin clamp were significantly lower after acipimox treatment (257 ± 65 vs. 560 ± 41 µM, P < 0.01). During the 120-min euglycemic insulin clamp, suppression of plasma FFA concentration was enhanced after acipimox treatment (120 ± 15 vs. 162 ± 18 µM, P < 0.10).
Basal rates of EGP were similar before and after acipimox treatment (1.9 ± 0.1 vs. 2.0 ± 0.1 mg/kg·min). Insulin-mediated suppression of EGP, determined during the 90- to 120-min period of the euglycemic insulin clamp, was significantly enhanced (Fig. 2) after acipimox treatment (0.22 ± 0.09 to 0.01 ± 0.01 mg/kg·min, respectively, P < 0.05). EGP during the 90- to 120-min period tended to correlate with the fasting plasma FFA concentration (r = 0.49, P = 0.06) and correlated significantly with the mean plasma FFA concentration during the insulin clamp (r = 0.52, P < 0.05).
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) was significantly increased (6.8 ± 0.5 vs. 5.6 ± 0.5 mg/kg·min, P < 0.01), due entirely to an increase in insulin-stimulated nonoxidative glucose disposal (2.5 ± 0.4 to 3.5 ± 0.4 mg/kg·min, P < 0.05). The increase in Rd correlated with the decrease in fasting plasma FFA concentration (Fig. 3) after acipimox treatment (r = –0.80, P < 0.02).
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Plasma adiponectin concentration did not change significantly (Fig. 2) after acipimox treatment (7.1 ± 1.0 to 7.2 ± 1.1 µg/ml). Plasma adiponectin concentration correlated positively with insulin-stimulated nonoxidative glucose disposal (r = 0.79, P < 0.03) and correlated with whole-body Rd during the insulin clamp (r = 0.68, P < 0.05) before acipimox treatment. Plasma adiponectin concentration correlated strongly and negatively with EGP during the 90- to 120-min period of the insulin clamp (r = –0.70, P < 0.05) and with the mean plasma FFA concentration during the insulin clamp (r = –0.74, P < 0.05) before acipimox treatment. After acipimox treatment, plasma adiponectin levels did not correlate with Rd (r = 0.31, P = NS), EGP (r = –0.18, P = NS), and plasma FFA concentration (r = 0.42, P = NS) during the insulin clamp.
Plasma resistin, IL-6, and TNF concentrations
Plasma resistin (4.0 ± 0.3 to 3.8 ± 0.3 ng/ml), IL-6 (1.4 ± 0.3 to 1.6 ± 0.4 pg/ml), and TNF (2.3 ± 0.3 to 2.4 ± 0.3 pg/ml) concentrations did not change significantly after acipimox treatment. Taken collectively, before and after treatment, whole-body Rd did not correlate with plasma resistin (r = 0.36, P = NS), IL-6 (r = 0.12, P = NS), or TNF (r = 0.15, P = NS) concentrations. EGP during the insulin clamp also did not correlate with plasma resistin (r = 0.15, P = NS), IL-6 (r = 0.12, P = NS), and TNF (r = 0.12, P = NS) concentrations after acipimox treatment.
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Discussion |
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concentrations.
We previously reported that thiazolidinedione treatment causes a 3-fold increase in plasma adiponectin concentration, which is closely related to increased insulin-mediated suppression of lipolysis and enhanced hepatic and peripheral insulin sensitivity in type 2 diabetic patients (27). We observed a similar relationship between hepatic, peripheral (muscle), and adipocyte (as reflected by suppression of plasma FFA during the insulin clamp) insulin sensitivity and plasma adiponectin concentration in the present study before acipimox treatment. Seven days of acipimox treatment significantly reduced the plasma FFA concentration, improved oral glucose tolerance, and enhanced hepatic and peripheral insulin sensitivity, but it did not increase plasma adiponectin levels. These results demonstrate that adiponectin secretion from the adipocyte is independent of the changes in plasma FFA concentrations. A prolonged reduction of plasma FFA concentration after acipimox treatment, although associated with an improvement in hepatic and peripheral insulin sensitivity, also does not result in a significant change in plasma resistin, IL-6, and TNF concentrations.
During the OGTT, the incremental area under the plasma glucose concentration curve was decreased by 21% (P < 0.03) after acipimox treatment. Because the fasting plasma glucose concentration remained unchanged, the improvement in glycemic control after acipimox-mediated reduction in plasma FFA concentration was accounted for entirely by a decrease in postprandial glucose excursion. The improvement in oral glucose tolerance with acipimox could result from: 1) enhanced peripheral tissue (muscle) sensitivity to insulin; 2) an improvement in hepatic insulin sensitivity, and 3) an increase in insulin secretion. Plasma insulin levels in the fasting state and during the OGTT were unchanged by acipimox therapy. Improved glucose tolerance without a change in the plasma insulin concentration suggests enhanced insulin response to glucose ingestion. In humans and animals, the ß-cell responds to an increment in plasma glucose concentration by an increment in plasma insulin concentration (36). In the present study, enhanced insulin response to glucose ingestion is substantiated by the increase in the insulinogenic index (
I/G from 0 to 120 min) from 134 ± 29 to 228 ± 52 µU/mg (P < 0.05) after acipimox treatment. Previous studies from our laboratory have shown that a sustained reduction in plasma FFA concentrations after acipimox, compared with placebo treatment, improves insulin secretion (as documented by the measurement of the C-peptide response during a hyperglycemic clamp) in subjects with a strong family history of type 2 diabetes (37). The improvement in insulin secretion is more impressive when viewed in light of the decrease in insulin resistance, which would be expected to result in a reduction in glucose-stimulated insulin secretion (38).
During the euglycemic insulin clamp, acipimox significantly enhanced peripheral tissue insulin sensitivity, due entirely to an increase in nonoxidative glucose disposal, which primarily reflects muscle glycogen synthesis (39). The increase in whole-body Rd correlated with the decrease in basal plasma FFA levels after 7 d of acipimox treatment. These observations are consistent with previous results (18, 19) after overnight acipimox administration in individuals with impaired glucose tolerance and type 2 diabetes. Elevated plasma FFA concentrations cause insulin resistance in muscle by substrate competition (increased FFA oxidation restrains glucose oxidation in muscle by altering the redox potential of the cell, i.e. Randle cycle) (40), inhibiting the insulin signal transduction system (41), and impairing glycogen synthesis (9) via direct inhibitory effect of fatty acyltransferase-coenzyme A on glycogen synthase (42, 43). A major defect in insulin-stimulated glycogen synthesis is a characteristic finding in all insulin-resistant states, including obesity, diabetes, and the combination of obesity plus diabetes (6, 44). Impaired nonoxidative glucose disposal also has been demonstrated in the normal-glucose-tolerant offspring of two diabetic parents (14, 45) and in the first-degree relatives of type 2 diabetic individuals (46, 47). Vaag et al. (19) have shown that an acute reduction in plasma FFA concentration with acipimox stimulates skeletal muscle glycogen synthase activity in patients with type 2 diabetes. The results of the present study extend the observations of Vaag et al. by demonstrating that a sustained reduction in plasma FFA with acipimox administration augments insulin-stimulated glycogen synthesis in nonobese, normal-glucose-tolerant subjects with a strong family history of type 2 diabetes. Although correlations do not prove causality, we noted a strong relationship between the decrement in plasma FFA and the increment in insulin-stimulated glycogen synthesis. Furthermore, we observed lower plasma FFA concentrations during the 120-min euglycemic insulin clamp after acipimox treatment. This reduction in plasma FFA levels during the insulin clamp may be the result of enhanced adipocyte insulin sensitivity or simply reflect lower substrate (FFA) availability after acipimox therapy.
Insulin-mediated suppression of EGP during the euglycemic insulin clamp was significantly enhanced after acipimox treatment, and hepatic insulin sensitivity correlated with the fasting plasma FFA concentration as well as the plasma FFA concentration during the insulin clamp. In nondiabetic subjects, an increase in plasma FFA concentration stimulates gluconeogenesis (12, 48) and impairs the insulin-mediated suppression of hepatic glucose production in both diabetic (7) and nondiabetic subjects (49). Rebrin et al. (50) and Cherrington (51) have shown in dogs that a significant portion of the suppressive effect of insulin on hepatic glucose production is mediated via inhibition of lipolysis and a reduction in the circulating plasma FFA concentration. Moreover, FFA infusion in normal humans under conditions that simulate the diabetic state (13) and in obese insulin-resistant subjects (52) enhances hepatic glucose production. Conversely, a reduction in the plasma FFA concentration has been shown to cause a decrease in gluconeogenesis (48). The present results are consistent with these previous observations in dogs (50, 51) and man (48) in demonstrating that a sustained reduction in plasma FFA levels in subjects with a strong family history of type 2 diabetes results in improved insulin-mediated suppression of hepatic glucose production. Because neither the basal rate of EGP nor the fasting plasma glucose concentration was increased, it is not surprising that we did not observe a decline in basal EGP or fasting plasma glucose concentration after acipimox treatment. It is possible that there was a decrease in gluconeogenesis in the postabsorptive state but that this was compensated for by an increase in the rate of glycogenolysis, i.e. hepatic autoregulation (12).
Five of the eight subjects complained of mild itching on the initiation of treatment with acipimox. This itching was self-limited and resolved in 3–4 d. One subject experienced significant itching that required the use of oral antihistaminics. No other side effects of acipimox therapy were reported.
In summary, the results of the present study demonstrate that a sustained reduction in plasma FFA concentration after 7 d of acipimox therapy in nonobese, normal-glucose-tolerant subjects with a strong family history of type 2 diabetes improves insulin-mediated whole-body Rd, enhances insulin-mediated suppression of EGP, increases insulin secretion, and does not significantly alter the concentration of adipocytokines. Improved peripheral and hepatic insulin sensitivity and enhanced insulin secretion contribute to the improvement in oral glucose tolerance in individuals genetically predisposed to develop type 2 diabetes. As a corollary, our observations also suggest that drugs that lower plasma FFA levels and/or target insulin resistance in the adipose tissue (i.e. enhanced inhibition of lipolysis) may be beneficial in preventing type 2 diabetes in high-risk individuals who are genetically predisposed to develop type 2 diabetes later in life.
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Acknowledgments |
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Footnotes |
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M.B. and S.S. contributed equally to this work.
Abbreviations: EGP, Endogenous (primarily hepatic) glucose production; FFA, free fatty acid; OGTT, oral glucose tolerance test; Ra, rate of endogenous glucose appearance; Rd, rate of endogenous glucose disposal.
Received February 8, 2004.
Accepted June 2, 2004.
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and blood cytokine production in type 2 diabetes. Life Sci 67:291–300[CrossRef][Medline]
-activator rosiglitazone reduces MMP-9 serum levels in type 2 diabetic patients with coronary artery disease. Arterioscler Thromb Vasc Biol 23:283–288This article has been cited by other articles:
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