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Effects of Free Fatty Acids Per Se on Glucose Production, Gluconeogenesis, and Glycogenolysis Peter Staehr,1 Ole Hother-Nielsen,1 Bernard R

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Effects of Free Fatty Acids Per Se on Glucose Production, Gluconeogenesis, and Glycogenolysis Peter Staehr,1 Ole Hother-Nielsen,1 Bernard R Effects of Free Fatty Acids Per Se on Glucose Production, Gluconeogenesis, and Glycogenolysis Peter Staehr,1 Ole Hother-Nielsen,1 Bernard R. Landau,2 Visvanathan Chandramouli,2 Jens Juul Holst,3 and Henning Beck-Nielsen1 Insulin-independent effects of a physiological increase thermore, in clamp studies of type 2 diabetic patients, in free fatty acid (FFA) levels on fasting glucose pro- impaired suppression of glucose production by insulin duction, gluconeogenesis, and glycogenolysis were appears related to impaired suppression of plasma FFA 2 assessed by administering [6,6- H2]-glucose and deuteri- levels (6). However, in vivo effects of FFA on glucose 2 ated water ( H2O) in 12 type 1 diabetic patients, during production, gluconeogenesis, and glycogenolysis in the 6-h infusions of either saline or a lipid emulsion. Insulin fasted state are less clear. ؍ was either fully replaced (euglycemic group, n 6), or The in vivo studies are complicated by the fact that During .(6 ؍ underreplaced (hyperglycemic group, n saline infusions, plasma FFA levels remained un- FFAs are potent insulin secretagogues (1). Since glycogen- changed. Glucose concentrations decreased from 6.7 ؎ olysis, in particular, is very sensitive to insulin (7,8), even to 5.3 ؎ 0.4 mmol/l and 11.9 ؎ 1.0 to 10.5 ؎ 1.0 small changes in its levels may bias studies on the effects 0.4 mmol/l in the euglycemic and hyperglycemic group, re- of FFAs. To assess the direct effects of FFA per se on these spectively. Accordingly, glucose production declined pathways, endogenous insulin secretion has therefore ؊ ؊ from 84 ؎ 5to63؎ 5mg⅐ m 2 ⅐ min 1 and from 84 ؎ 5 been inhibited in a number of studies by administering ؊2 ؊1 to 68 ؎ 4mg⅐ m ⅐ min , due to declining rates of somatostatin (SRIF) (9–14), but conclusions still differ glycogenolysis but unaltered rates of gluconeogenesis. (Table 1). During lipid infusions, plasma FFA levels increased twofold. In the euglycemic group, plasma glucose in- In some studies, an insulin-independent direct relation- creased from 6.8 ؎ 0.3 to 7.8 ؎ 0.8 mmol/l. Glucose ship between plasma FFA levels and fasting glucose production declined less in the lipid study than in the production rates was found, i.e., glucose production in- saline study due to a stimulation of gluconeogenesis by creased when FFA levels were elevated by lipid/heparin 1mg⅐ m؊2 ⅐ min؊1 and a decline in glycogenolysis infusions (9–11) and decreased when FFA levels were ؎ 6 ؊ ؊ ,that was 6 ؎ 2mg⅐ m 2 ⅐ min 1 less in the lipid study lowered by N6-cyclohexyladenosine (12). In other studies than in the saline study. In contrast, in the hyperglyce- there was no significant effect of elevated FFA levels on mic group, there were no significant effects of elevated glucose production (13,14). In two studies, individual FFA on glucose production, gluconeogenesis, or glyco- genolysis. In conclusion, a physiological elevation of contributions of gluconeogenesis and glycogenolysis were plasma FFA levels stimulates glycogenolysis as well as determined, and a stimulating effect of FFA on gluconeo- gluconeogenesis and causes mild fasting hyperglycemia. genesis was reported in both. In one of the studies (13) These effects of FFA appear attenuated in the presence glycogenolysis was unaltered by elevating FFA levels, of hyperglycemia. Diabetes 52:260–267, 2003 while in the other (14) glycogenolysis was inhibited. An important question is: does an increase in glucose production induced by elevated FFA levels result in in- creased glucose levels? The answer is of particular interest ree fatty acids (FFAs) are believed to play an with regard to type 2 diabetic patients, in whom elevated important role in the regulation of glucose pro- fasting FFA levels are suggested to lead to hyperglycemia duction (1). Supporting this view, in vitro stud- by increasing glucose production. In several previous Fies suggest that FFAs increase gluconeogenesis studies, glucose levels were clamped (9,11,12). Plasma through stimulation of key-gluconeogenic enzymes (2–4). glucose levels were allowed to change freely in response In vivo, elevation of FFA levels in hyperinsulinemic clamp to changes in FFA levels in only two studies in humans. studies (by lipid/heparin infusions) impair the insulin- Boden et al. (10) found that production, as well as plasma mediated suppression of glucose production (1,5). Fur- glucose levels, increased upon elevating FFA levels. Roden et al. (13) also observed an increase in plasma glucose From the 1Medical Department M, Odense University Hospital, Odense, levels in response to elevated FFA levels. However, there Denmark; the 2Departments of Medicine and Biochemistry, Case Western was no change in glucose production rates, suggesting that Reserve University, Cleveland, Ohio; and the 3Department of Medical Physi- ology, Panum Institute, University of Copenhagen, Copenhagen, Denmark. FFA affected glucose levels via another mechanism (13). Address correspondence and reprint requests to Peter Staehr, MD, Depart- A methodological issue of potential significance is in the ment of Endocrinology M, Odense University Hospital, Kloevervaenget 6 (3rd floor), DK-5000 Odense C, Denmark. E-mail: [email protected]. use of SRIF. SRIF may reduce splanchnic blood flow (15) Received for publication 22 August 2002 and accepted in revised form 14 and stimulate peripheral glucose clearance (16). More November 2002. importantly, SRIF acutely reduces portal insulin levels. FFA, free fatty acid; HMT, hexamethylene-tetramine; HSI, hepatic sinusoi- dal insulin; MCR, metabolic clearance rate; RIA, radioimmunosorbent assay; That is because insulin is replaced by peripheral infusion SRIF, somatostatin. in most in vivo studies (and in all human studies). There- 260 DIABETES, VOL. 52, FEBRUARY 2003 P. STAEHR AND ASSOCIATES TABLE 1 Studies that have assessed the effects of FFA per se on glucose production (GP), gluconeogenesis (GNG), and glycogenolysis (GGL) Change in Change in Change in Change in Change in Ref. Species FFA plasma glucose GP GNG GGL no. Ferrannini 1983 Human Increase Clamped 3 ——9 Boden 1991 Human Increase Increase 3 ——10 Rebrin 1996 Dogs Increase Clamped 3 ——11 Mittelman 2000 Dogs Decrease Clamped 2 ——12 Roden 2000 Human Increase Increase No change 3 No change 13 Chu 2002 Dogs Increase No change No change 3214 fore, because insulin is normally secreted into the portal 5:30 A.M., and 1.25 ml/kg at 6:15 A.M. (17,18). Otherwise, they rested undis- turbed throughout the night. vein, peripheral insulin levels remain essentially unaltered 2 At 6:30 A.M., a primed-continous infusion of [6,6- H2]glucose was begun. while portal insulin levels are lower than normal. Since The priming dose equaled the amount infused in 100 min times the fasting glycogenolysis is sensitive to very small changes in insulin plasma glucose concentration (mmol/l) divided by 5 mmol/l (adjusted priming levels (7,8), acute reduction in portal insulin during SRIF [19,20]). The infusion rate was constant at 75 mg/h. A baseline period of 120 infusion could then alter the sensitivity of the liver to FFA. min was allowed for tracer equlibration. At 8:30 A.M., an infusion of either saline at 45 ml/h or a 20% lipid emulsion (Intralipid; Kabi Pharmacia) at 45 ml/h In any case, the stimulating effect of FFA on glucose was started and continued for 300 min. production in humans appears primarily to have been Blood was collected every 15–60 min for determination of the enrichments detected under acutely reduced portal insulin levels. of the two hydrogens bound to carbon 6 of blood glucose and the plasma We therefore assessed the effects of a physiological concentrations of glucose, FFA, triglyceride, insulin, C-peptide, and glucagon. elevation of FFA levels on glucose production, gluconeo- Blood for determining the enrichments of the hydrogens bound to carbons 2 and 5 of blood glucose were collected at Ϫ30, 0, 270, and 300 min. Blood genesis, and glycogenolysis in otherwise healthy type 1 samples were immediately centrifuged and plasma stored at Ϫ20°C until diabetic patients to determine whether elevated FFA lev- assay. els increase glucose production in the absence of acute Assays. Plasma glucose concentrations were determined using a glucose reductions in portal insulin levels brought about by SRIF. oxidase method (Beckman Glucose Analyzer II, Fullerton, CA). Enrichments of the hydrogens bound to carbons 2, 5, and 6 of blood glucose were If so, we asked whether changes in both gluconeogenesis determined as previously described (17,18). Briefly, the supernatant, obtained and glycogenolysis occur. Studies were performed both after deproteinizing a blood sample with ZnSO4-Ba(OH)2, was deionized by after overnight replacement and underreplacement of in- passage through cation- and anion-exchange resins. Glucose in the effluent sulin to further explore the importance of prevailing was isolated by high-performance liquid chromatography. To determine the 2 insulin levels on the effects of FFA. percentage of glucose molecules with two H atoms at carbon 6, a sample of the glucose was oxidized with periodate. The formaldehyde formed, which contains carbon 6 with its two hydrogens, was converted to hexamethylene- RESEARCH DESIGN AND METHODS tetramine (HMT) by the addition of ammonia. The HMT was analyzed by gas Subjects. A total of 12 lean male type 1 diabetic patients were recruited from chromatography–mass spectrometry for mass m ϩ 2. the outpatient clinic. They were in good glycemic control (Table 2) and To determine the enrichment of the hydrogen bound to carbon 2, carbon 1 without signs of diabetic retinopathy, nephropathy, neuropathy, or macrovas- of a portion of the glucose was removed to yield ribulose-5-P. The ribulose-5-P cular complications. All were treated with short-acting insulin (Actrapid; was reduced to a mixture of polyol phosphates. These were oxidized with Novo, Bagsvaerd, Denmark) three times a day and long-acting insulin (Insu- periodate, yielding formaldehyde, which contains carbon 2 with its hydrogen.
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