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The Journal of Clinical Endocrinology & Metabolism Vol. 89, No. 12 6193-6197
Copyright © 2004 by The Endocrine Society

A Low-Carbohydrate/High-Fat Diet Improves Glucoregulation in Type 2 Diabetes Mellitus by Reducing Postabsorptive Glycogenolysis

Gideon Allick1, Peter H. Bisschop1, Mariette T. Ackermans, Erik Endert, Alfred J. Meijer, Folkert Kuipers, Hans P. Sauerwein and Johannes A. Romijn

Departments of Endocrinology and Metabolism (G.A., P.H.B., H.P.S.), Clinical Chemistry (M.T.A., E.E.), Laboratory of Endocrinology, and Biochemistry (A.J.M.), Academic Medical Center, University of Amsterdam, 1100 DD Amsterdam, The Netherlands; Center for Liver, Digestive, and Metabolic Diseases (F.K.), Department of Pediatrics, University Hospital Groningen, 9713 GZ Groningen, The Netherlands; and Department of Endocrinology (P.H.B., J.A.R.), Leiden University Medical Center, 2300 RC Leiden, The Netherlands

Address all correspondence and requests for reprints to: G. Allick, Department of Endocrinology and Metabolism (F5), Academic Medical Center, University of Amsterdam, P.O. BOX 22660, 1100 DD Amsterdam, The Netherlands. E-mail: g.allick{at}amc.uva.nl.


   Abstract
Top
 Abstract
Introduction
 Subjects and Methods
 Results
 Discussion
 References
 
The aim of this study was to examine the mechanisms by which dietary carbohydrate and fat modulate fasting glycemia. We compared the effects of an eucaloric high-carbohydrate (89% carbohydrate) and high-fat (89% fat) diet on fasting glucose metabolism and insulin sensitivity in seven obese patients with type 2 diabetes using stable isotopes and euglycemic hyperinsulinemic clamps. At basal insulin levels glucose concentrations were 148 ± 11 and 123 ± 11 mg/dl (8.2 ± 0.6 and 6.8 ± 0.6 mmol/liter) on the high-carbohydrate and high-fat diet, respectively (P < 0.001), with insulin concentrations of 12 ± 2 and 10 ± 1 µIU/ml (82 ± 11 and 66 ± 10 pmol/liter) (P = 0.08). Glucose production was higher on the high-carbohydrate diet (1.88 ± 0.06 vs. 1.55 ± 0.05 mg/kg·min (10.44 ± 0.33 vs. 8.61 ± 0.28 µmol/kg·min) (P < 0.001) because of higher glycogenolysis. Gluconeogenic rates were not different between the diets. During the use of hyperinsulinemic euglycemic clamps, insulin-mediated suppression of glucose production and stimulation of glucose disposal were not different between the diets. Free fatty concentrations were suppressed by 89 and 62% (P < 0.0001) on the high-carbohydrate and high-fat diet, respectively. We conclude that short-term variations in dietary carbohydrate to fat ratios affect basal glucose metabolism in people with type 2 diabetes merely through modulation of the rate of glycogenolysis, without affecting insulin sensitivity of glucose metabolism.


   Introduction
Top
 Abstract
 Introduction
Subjects and Methods
 Results
 Discussion
 References
 
POSTABSORPTIVE GLUCOSE PRODUCTION is modulated in a dose-dependent manner by dietary carbohydrate content. In healthy subjects endogenous glucose production varies by 34–40% during extreme variations of dietary carbohydrate content, i.e. 0–85% energy, mainly due to adaptations of glycogenolysis (1, 2). Under these conditions changes in gluconeogenesis are much smaller (maximal difference 15%). Despite these relatively large effects of dietary carbohydrate content on glucose production, postabsorptive glucose concentrations are relatively stable and vary less than 10% (1).

Postabsorptive glucose metabolism is altered in type 2 diabetes mellitus. Increased endogenous glucose production contributes to fasting hyperglycemia (3, 4). The increase in endogenous glucose production is due to increases of both gluconeogenesis (5) and glycogenolysis (4). As in healthy subjects, postabsorptive glucose metabolism in type 2 diabetes mellitus is susceptible to dietary manipulation. Short-term dietary energy restriction reduces plasma glucose concentrations and endogenous glucose production by diminishing glycogenolysis (6). However, it is unclear to what extent energy restriction, rather than carbohydrate restriction, contributes to this beneficial effect on glucose metabolism.

Therefore, the aim of the present study was to establish the effects of a maximal variation in dietary carbohydrate content on postabsorptive glucose metabolism in patients with type 2 diabetes mellitus. The patients were studied after 14 d on isocaloric diets with a maximal and minimal carbohydrate content, respectively. To maintain energy intake, we made reciprocal changes in dietary fat content, resulting in a high-carbohydrate/low-fat diet and a low-carbohydrate/high-fat diet. Endogenous glucose production, gluconeogenesis, and glycogenolysis were measured by stable isotopes. In a previous study (7), we found that the low-carbohydrate/high-fat diet induced hepatic, but not peripheral insulin resistance, in healthy subjects. To evaluate to what extent alterations in insulin sensitivity induced by the diets contributed to the outcome, we also assessed hepatic and peripheral insulin sensitivity.


   Subjects and Methods
Top
 Abstract
 Introduction
 Subjects and Methods
Results
 Discussion
 References
 
Subjects

Five females and two males (aged 51–65 yr, body mass index 27–36 kg/m2) with diabetes mellitus type 2 were studied on two separate occasions. Subjects were screened for biochemical evidence of abnormal renal or hepatic functions and had no other systemic disease. All subjects were being treated with a sulfonylurea derivative and/or metformin, which was discontinued 2 wk before the study. All subjects gave written informed consent. This study was approved by the medical ethical committee of the Academic Medical Center.

Diets

The subjects were studied on two different diets. The experiments in each subject were separated by an interval of 8–10 wk, during which period the subjects used their habitual diets. The sequence of the diets was determined by balanced assignment. The diets consisted of liquid formulas and contained identical amounts (11% of energy) and composition of proteins. The fiber content was identical for both diets (30 g). The diets were custom made (Nutricia, Zoetermeer, The Netherlands). In addition to the proteins, the high-carbohydrate diet contained 89% of energy in the form of carbohydrates. The carbohydrates in the diets consisted of 6% monosaccharides, 12% disaccharides, and 82% polysaccharides. The low-carbohydrate diet contained 89% of energy in the form of lipids. Detailed composition of the diets is shown in Table 1Go. The amino acid profile and cholesterol, mineral, and vitamin content were identical for both diets. Energy requirements of each subject were assessed by a dietitian by means of a 3-d dietary journal. Liquid meals with predetermined amounts of energy were taken each day at six fixed time points between 0800 and 2130 h for 14 d. Compliance with the diets was assessed by measuring the respiratory quotient, which reflects the ratio of carbohydrate to fat intake (8). Respiratory quotients were measured after 14 d on each experimental diet after an overnight fast. Subjects refrained from alcohol during the experimental diets, and physical activity was limited to normal daily activities. In addition to the diets, the subjects were allowed to drink only water freely.


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  		TABLE 1. Composition of the tailor-made diets

 
Protocol

In the clinical research center the subjects were studied twice on each diet: the first time after 11 d on the respective diet to measure postabsorptive glucose metabolism at basal insulin concentrations (basal study) and the second time 3 d later to measure glucose metabolism during a hyperinsulinemic euglycemic clamp (clamp study). The basal study was as follows: the night before the study, subjects ingested 2H2O each half-hour between 2000 and 2200 h up to a total dose of 5 g/kg body water. Body water was estimated as 50 and 60% of body weight for females and males, respectively. After ingestion of 2H2O, the subjects were allowed only to drink water that contained 0.5% 2H2O. Urine and blood samples were taken before ingestion of 2H2O to determine background enrichments in glucose and body water. The following morning at 0730 h after an overnight fast of 14 h, a catheter was inserted in an antecubital vein in each arm. One catheter was used for sampling of arterialized blood using a heated hand box (60 C). The other catheter was used for infusion of [6,6-2H2]glucose. At 0800 h after a blood sample for background enrichment of plasma glucose was drawn, a primed-continuous infusion of [6,6-2H2]glucose (>99% enriched, Cambridge Isotopes, Woburn, MA) was started at a rate of 0.06 mg/kg–1·min–1 (0.33 µmol/kg–1·min–1) (prime 4.8 mg/kg–1 (26.4 µmol/kg–1)]. At 1030, 1040, 1050, and 1100 h, blood samples were drawn for determination of basal endogenous glucose production and gluconeogenesis.

For the clamp study, a catheter was inserted in an antecubital vein in each arm. One catheter was used for sampling of arterialized blood using a heated hand box (60 C). The other catheter was used for infusion of insulin, glucose and [6,6-2H2]glucose. Depending on the plasma glucose concentration, a variable infusion of insulin (Actrapid 100 IU/ml; Novo Nordisk Farma B.V., Zoeterwoude, The Netherlands) was started during the night to lower the glucose concentration by 18 mg/h (1 mmol/h) to 90 mg/dl (5 mmol/liter) at 0700 h. At 0700 h, insulin infusion was fixed at 40 mU/m–2 body surface area per min–1, and a primed-continuous infusion of [6,6-2H2]glucose (>99% enriched; Cambridge Isotopes) was started at a rate of 0.04 mg/kg–1·min–1 (0.22 µmol/kg–1·min–1) [prime 3.2 mg/kg–1 (17.6 µmol/kg–1)]. Plasma glucose concentration was measured every 5 min (glucose analyzer 2; Beckman, Palo Alto, CA) and glucose 20% infused at a variable rate to maintain euglycemia at 90 mg/dl (5.0 mmol/liter). [6,6-2H2]Glucose was added to the infusate containing 20% glucose to achieve glucose enrichments of 2% to minimize changes in isotopic enrichment due to changes in the infusion rate of exogenous glucose and thus to allow for accurate quantification of endogenous glucose production (9). Between 0930 and 1030 h, blood samples were drawn every 10 min for isotopic enrichment of plasma glucose and insulin and glucose concentrations.

Indirect calorimetry

Oxygen consumption (VO2) and CO2 production (VCO2) were measured on an energy expenditure unit (model 2900; Sensormedics, Anaheim, CA) with the ventilated hood technique. VO2 and VCO2 were measured continuously during the final 30 min of both the basal and clamp studies. The mean rates of VO2 and VCO2 during the final 20 min were used for calculations of glucose and fat oxidation as described below.

Gas chromatography-mass spectrometry

Enrichments of plasma [6,6-2H2]glucose and deuterium at the C5 position of glucose were determined as described previously (1). Briefly, plasma samples for glucose enrichments of [6,6-2H2]glucose were deproteinized with methanol (10). The aldonitril penta-acetate derivative of glucose (11) was injected into a gas chromatograph/mass spectrometer system. Separation was achieved on a J&W DB17 column (30 m x 0.25 mm, df 0.25 µm; Agilent Technologies Nederland BV, Amstelveen, The Netherlands). Glucose concentrations were determined by gas chromatography using xylose as an internal standard. Glucose was monitored at mass-to-charge ratio 187, 188, and 189. The enrichment of [6,6-2H2]glucose was determined by dividing the peak area of mass-to-charge ratio 189 by the total peak area and correcting for natural enrichments. Gluconeogenesis is quantified by the ratio of deuterium enrichment of C5 of glucose to the deuterium enrichment of body water resulting from 2H2O ingestion. Only glucose produced by gluconeogenesis is labeled with deuterium at the C5 position; therefore, the ratio of C5 and water enrichment reflects the fractional contribution of gluconeogenesis to endogenous glucose production. To measure deuterium enrichment at the C5 position, glucose was converted to hexamethylenetetramine as described by Landau et al.(12). Hexamethylenetetramine was injected into a gas chromatograph mass spectrometer. Separation was achieved on an AT-Amine column (30 m x 0.25 mm, df 0.25 µm; Alltech Nederland BV, Breda, The Netherlands). Deuterium enrichment in body water was measured by an adapted method (13). All isotopic enrichments were measured on a gas chromatograph mass spectrometer (model 6890 gas chromatograph coupled to a model 5973 mass selective detector, equipped with an electron impact ionization mode; Hewlett-Packard, Palo Alto, CA).

Analytical procedures

Plasma insulin concentration was determined by RIA (insulin RIA 100; Pharmacia Diagnostic AB, Uppsala, Sweden), intraassay coefficient of variation (CV) 3–5%, interassay CV 6–9%, and detection limit 2 µIU/ml (15 pmol/liter). C-peptide was determined by RIA (RIA-coat C-peptide; Byk-Sangtec Diagnostica GmbH & Co. KG, Dietzenbach, Germany), intraassay CV 4–6%, interassay CV 6–8%, and detection limit 0.2 ng/ml (50 pmol/liter). Cortisol was measured by enzyme immunoassay on an Immulite analyzer (Diagnostic Products Corp., Los Angeles, CA), intraassay CV 2–4%, interassay CV 3–7%, and detection limit: 1.8 µg/dl (50 nmol/liter). Glucagon was determined by RIA (Linco Research, St. Charles, MO), intraassay CV 3–5%, interassay CV 9–13%, and detection limit 15 ng/liter. Norepinephrine and epinephrine were determined by an in-house HPLC method. Norepinephrine had an intraassay CV 6–8%, interassay CV 7–10%, and detection limit 9 pg/ml (0.05 nmol/liter). Epinephrine had an intraassay CV 6–8%, interassay CV 7–12%, and detection limit: 9 pg/ml (0.05 nmol/liter). Serum free fatty acids (FFAs) were measured by an enzymatic method (NEFAC; Wako Chemicals GmbH, Neuss, Germany), intraassay CV 2–4%, interassay CV 3–6%, and detection limit 0.6 mg/dl (0.02 mmol/liter). Triglycerides, total cholesterol, and high-density lipoprotein cholesterol were measured by an enzymatic method (Roche Diagnostics, Almere, The Netherlands). Low-density lipoprotein cholesterol was calculated using the formula of Friedewald.

Calculations and statistics

Endogenous glucose production (EGP) and glucose disposal were calculated with a modified form of the Steele equations, as described before (7). Fractional gluconeogenesis was calculated by dividing the deuterium enrichment of the C5 position of glucose by deuterium enrichment of body water. Gluconeogenesis was calculated by multiplying fractional gluconeogenesis with endogenous glucose production. Glycogenolysis was calculated by multiplying (1-fractional gluconeogenesis) with endogenous glucose production. Glucose and fat oxidation were calculated from VO2 and VCO2 (14). Differences between the diets were analyzed by the paired-samples t test. P < 0.05 was considered to be statistically different. Data are presented as means ± SE.


   Results
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
Discussion
 References
 
Respiratory quotients were 0.79 ± 0.01 and 0.73 ± 0.01 on the high-carbohydrate/low-fat and low-carbohydrate/high-fat diet, respectively (P = 0.008). Body weights were not different on completion of each diet: 93.1 ± 2.5 and 93.3 ± 2.2 kg.

Basal glucose concentrations were 148 ± 11 and 123 ± 11 mg/dl (8.2 ± 0.6 and 6.8 ± 0.6 mmol/liter) (P < 0.0001) and basal insulin concentrations were 12 ± 2 and 10 ± 1 µIU/ml (82 ± 11 and 66 ± 10 pmol/liter) (P = 0.08) on the high-carbohydrate/low-fat and low-carbohydrate/high-fat diet, respectively. During the euglycemic hyperinsulinemic clamp, glucose and insulin concentrations were not different between the two diets: 92 ± 4 and 96 ± 2 mg/dl (5.1 ± 0.2 and 5.3 ± 0.1 mmol/liter) and 73 ± 4 and 70 ± 3 µIU/ml (506 ± 27 and 483 ± 23 pmol/liter), respectively (Table 2Go).


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  		TABLE 2. Glucose, FFA, and glucoregulatory hormones at basal insulin concentrations and during a hyperinsulinemic clamp in patients with type 2 diabetes (n = 7) on high-carbohydrate and high-fat diets

 
FFA concentrations at basal insulin concentrations were not different between the two diets (P = 0.4; Table 2Go). However, during the hyperinsulinemic clamp, FFA concentrations were lower on the high-carbohydrate diet, compared with the high-fat diet: 1.9 ± 0.6 and 7.9 ± 1.4 mg/dl (0.07 ± 0.02 and 0.28 ± 0.05 mmol/liter), respectively (P < 0.001). Fat oxidation was higher on the high-fat diet, both at basal insulin concentrations [0.60 ± 0.04 and 0.82 ± 0.04 mg/kg·min (0.70 ± 0.05 and 0.95 ± 0.05 µmol/kg·min), high-carbohydrate and high-fat diet, respectively; P = 0.004)] and during the hyperinsulinemic clamp [0.18 ± 0.05 and 0.81 ± 0.07 mg/kg·min (0.21 ± 0.06 and 0.94 ± 0.08 µmol/kg·min), high-carbohydrate and high-fat diet, respectively; P < 0.001)].

EGP at basal insulin concentrations was higher on the high-carbohydrate diet than on the high-fat diet: 1.88 ± 0.06 vs. 1.55 ± 0.05 mg/kg·min (10.44 ± 0.33 vs. 8.61 ± 0.28 µmol/kg·min), respectively (P < 0.001). The higher rate of EGP on the high-carbohydrate diet was caused by an increased rate of glycogenolysis, whereas gluconeogenesis was not different between the diets (Table 3Go). During the hyperinsulinemic euglycemic clamp, suppression of EGP was not different between the high-carbohydrate and high-fat diet (83 ± 6 and 73 ± 4%, respectively; Table 3Go).


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  		TABLE 3. Postabsorptive glucose production and disposal at basal insulin concentrations and during a hyperinsulinemic euglycemic clamp in patients with type 2 diabetes (n = 7) on high-carbohydrate and high-fat diets

 
Glucose disposal at basal insulin concentrations, which equals EGP, was higher on the high-carbohydrate diet. During the euglycemic hyperinsulinemic clamp, glucose disposal increased on both diets but was no longer different between the diets (Table 3Go). Nonoxidative glucose disposal was not different between the diets at basal insulin concentrations but tended to lower on the high-carbohydrate diet during hyperinsulinemia (P = 0.09; Table 3Go). Glucose oxidation was higher on the high-carbohydrate diet, both at basal insulin concentrations (P = 0.007; Table 3Go) and during the hyperinsulinemic clamp (P < 0.001; Table 3Go).


   Discussion
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
 Discussion
References
 
The results of this study show that, in subjects with mild type 2 diabetes mellitus, maximal eucaloric variation in carbohydrate to fat ratio modulates plasma glucose concentration exclusively by alterations in hepatic glucose production. This effect was entirely explained by diet-induced effects on the rate of glycogenolysis because gluconeogenesis remained unaffected. Unexpectedly and in contrast to the situation in healthy subjects (7), short-term variation in dietary carbohydrate to fat ratios did not alter whole-body or hepatic insulin sensitivity of glucose metabolism in type 2 diabetes mellitus.

The diets in this study were designed to maximize the potential effects of dietary carbohydrate to fat ratio on endogenous glucose metabolism and insulin action. The type of carbohydrate in the high-carbohydrate diet and type of fat in the high-fat diet closely resembled that of typical diets consumed in The Netherlands (Dutch Nutritional Survey, 1994, Voedingscentrum, Den Haag, The Netherlands). Energy supply, protein content and composition, and micronutrient and fiber content were identical in both diets. Therefore, the results of this study can be ascribed to the differences in dietary carbohydrate to fat ratio per se. We studied the effects of diets consumed for only 14 d. The question arises as to what extent our results can be applicable to diets consumed for a much longer period than 14 d. Interestingly, the 1-yr follow-up of a recently published, randomized study in obese subjects documented lower hemoglobin A1c values during a low-carbohydrate diet, compared with a conventional weight-loss diet (15). Of these subjects, 83% had type 2 diabetes mellitus or the metabolic syndrome. The beneficial effect on hemoglobin A1c values was not associated with an effect on insulin sensitivity in that study, in accordance with our results obtained after dietary intervention of only 14 d. Therefore, we cannot exclude the possibility that our results may be applicable to diets consumed for a much longer period than the short period used in the present study.

In type 2 diabetes mellitus, postabsorptive glucose concentrations and rates of EGP increased with dietary carbohydrate content, which is not different from the situation previously observed in healthy subjects (1, 2). Hepatic glycogen content is known to influence the relative contribution of glycogenolysis to EGP in obese nondiabetic volunteers (16). Therefore, the differential contribution of glycogenolysis to plasma glucose in our study likely reflects differences in hepatic glycogen stores, which are, at least partially, determined by dietary carbohydrate intake (17, 18).

In patients with type 2 diabetes, the rate of gluconeogenesis was found to be stable despite maximal isocaloric variations in dietary carbohydrate content. The same extent of dietary carbohydrate deprivation stimulated gluconeogenesis in healthy subjects, although by only 15% (1). Differences in plasma FFA concentrations might have contributed to these differential effects on gluconeogenic rates between healthy subjects and those with diabetes. Surprisingly, the low-carbohydrate/high-fat diet did not affect plasma FFA concentrations at basal insulin concentrations in subjects with type 2 diabetes mellitus. In contrast, the same diet increased basal FFA concentrations in healthy subjects compared with the high-carbohydrate diet (19). Because FFAs are known to stimulate gluconeogenesis, these differences in plasma FFA concentrations could have contributed to the altered dietary regulation of gluconeogenesis; in healthy subjects the high-fat diet increased plasma FFA concentrations, whereas FFA concentrations remained unchanged in subjects with type 2 diabetes mellitus.

Although effects of diet composition on insulin resistance have been subject of considerable scientific interest (20), little is known about the consequences of eucaloric dietary fat and carbohydrate interchanges on insulin-mediated glucose metabolism in type 2 diabetes mellitus. In our study, there was no difference between both diets with respect to insulin-mediated suppression of hepatic glucose production in patients with type 2 diabetes mellitus. In contrast, a low-carbohydrate/high-fat diet and high-fat diets in general induce within a short period hepatic insulin resistance in healthy subjects (7) and rodents (21). In rodents the reduction of hepatic insulin sensitivity on a high-fat diet is associated with hepatic steatosis. The notion emerges that the hepatic triglyceride content and, as a consequence, hepatic insulin sensitivity is not fixed in healthy subjects and rodents but to a certain extent flexible in relation to, for instance, dietary composition (22). It is possible that our patients had preexisting hepatic insulin resistance/steatosis, which may have obscured a potential differential effect of the diets on hepatic insulin resistance.

There was no difference between both diets in insulin-mediated glucose disposal, indicating that there is no relation between short-term maximal variation of eucaloric dietary carbohydrate to fat ratios and peripheral insulin sensitivity. This is in accordance with the absence of any effect of the same low-carbohydrate/high-fat diet observations in healthy subjects (7, 23). These observations are in contrast to the effects of lipid infusion on peripheral insulin sensitivity, which reduces insulin-mediated glucose disposal in patients with type 2 diabetes (24). However, it is likely that differences in design may explain this discrepancy. Most studies focusing on the relation between lipids and insulin resistance addressed the consequences of hypercaloric iv lipid administration in an acute setting, whereas our study focused on the postabsorptive effects of short-term eucaloric diets. Apparently results obtained from acute experiments with lipid/heparin administration are not applicable to short-term eucaloric high-fat feeding (25). Nonetheless, our findings support the notion that short-term eucaloric variation of the dietary carbohydrate to fat ratio does not affect peripheral insulin sensitivity with respect to glucose uptake (7, 23).

Although the dietary carbohydrate to fat ratio did not affect insulin-mediated glucose disposal, major effects were found on oxidative and nonoxidative glucose disposal. The low-carbohydrate/high-fat diet reduced carbohydrate oxidation but did not significantly affect nonoxidative glucose disposal. The fact that nonoxidative glucose disposal tended to be higher on the high-fat diet might indicate that insulin stimulates glycogen synthesis more effectively when dietary fat intake increases, as was earlier suggested from the results obtained in healthy lean males (7). Conversely, on the low-carbohydrate/high-fat diet, oxidation of fat was increased both at basal insulin levels and during hyperinsulinemia. After 14 d on this diet, 3 h of hyperinsulinemia were not sufficient to suppress fat oxidation and increase glucose oxidation. Because fatty acid use and oxidation is impaired in patients with type 2 diabetes mellitus, the 14-d high-fat diet seemed to have reversed this defect by forcing fuel selection toward fatty acids as the main energy substrates and maintaining glucose oxidation at a minimum (26, 27). In healthy subjects the same low-carbohydrate/high-fat diet increased fat oxidation and decreased glucose oxidation in a similar fashion (7).

Although postabsorptive plasma FFA concentrations did not differ between the two diets, FFA concentrations were higher during hyperinsulinemic clamp analysis on the high-fat diet. In general there is a positive correlation between plasma FFA concentrations and the rate of lipolysis. Therefore, the increased FFA concentrations during hyperinsulinemia suggest that a low-carbohydrate/high-fat diet decreased insulin sensitivity of lipolysis, even though there was no effect on insulin sensitivity of glucose production and glucose uptake. Remarkably despite the dose-response relationship of FFA and insulin resistance, the increased plasma FFA concentrations failed to affect insulin-mediated glucose metabolism, possibly due to the fact that the increase was relatively modest.

In conclusion, a eucaloric low-carbohydrate/high-fat diet improved glucoregulation in type 2 diabetes mellitus merely by reducing postabsorptive glycogenolysis. Insulin sensitivity of glucose metabolism was not susceptible to the eucaloric, inverse changes in carbohydrate and fat intake, but insulin sensitivity of adipose tissue decreased after low-carbohydrate/high-fat diet consumption.


   Acknowledgments
 
We thank An Ruiter for excellent technical assistance.


   Footnotes
 
This work was supported by the Dutch Diabetes Research Foundation (Grant 96.604).

1 G.A. and P.H.B. contributed equally to this work. Back

Abbreviations: CV, Coefficient of variation; EGP, endogenous glucose prodution; FFA, free fatty acid; VCO2, CO2 production; VO2, oxygen consumption.

Received June 2, 2004.

Accepted September 14, 2004.


   References
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
 Discussion
 References
 

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