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Nutrition Research 30 (2010) 801 806

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Dietary supplementation with D-tagatose in subjects with type 2 diabetes

leads to weight loss and raises high-density lipoprotein cholesterol
Thomas W. Donner a,, Laurence S. Magder b , Kiarash Zarbalian a
a

Department of Internal Medicine, University of Maryland School of Medicine, Baltimore, MD 21201, USA
b
Department of Epidemiology, University of Maryland School of Medicine, Baltimore, MD 21201, USA
Received 19 May 2010; revised 11 September 2010; accepted 13 September 2010

Abstract
Oral D-tagatose (D-tag) attenuates the rise in plasma glucose during an oral glucose tolerance test
in subjects with type 2 diabetes mellitus (DM) and reduces food intake in healthy human subjects.
A reduction in food consumption and less weight gain occur in rats fed tagatose. This pilot study
explored the metabolic effects of D-tag given daily to 8 human subjects with type 2 DM for 1 year.
We hypothesized that this treatment period would lead to weight loss and improvements in glycated
hemoglobin and the lipid profile. A 2-month run-in period was followed by a 12-month treatment
period when 15 g of oral D-tag was taken 3 times daily with food. No serious adverse effects were
seen during the 12-month treatment period. Ten of the initially12 recruited subjects experienced
gastrointestinal side effects that tended to be mild and transient. When 3 subjects were excluded who
had oral diabetes, medications added and/or dosages increased during the study and mean (SD) body
weight declined from 108.4 (9.0) to 103.3 (7.3) kg (P = .001). Glycated hemoglobin fell
nonsignificantly from 10.6% 1.9% to 9.6% 2.3% (P = .08). High-density lipoprotein cholesterol
progressively rose from a baseline level of 30.5 15.8 to 41.7 12.1 mg/dL at month 12 in the
6 subjects who did not have lipid-modifying medications added during the study (P b .001).
Significant improvements in body weight and high-density lipoprotein cholesterol in this pilot study
suggest that D-tag may be a potentially useful adjunct in the management of patients with type 2 DM.
2010 Elsevier Inc. All rights reserved.
Keywords:
Abbreviations:

Tagatose; Diabetes control; Weight loss agents; HDL cholesterol; Lipid modification; Bulk sweeteners
CHD, coronary heart disease; DM, diabetes mellitus; D-Tag, D-tagatose; GlyHb, glycated hemoglobin; LDL,
low-density lipoprotein.

1. Introduction
Nonnutritive sweeteners are used commonly to help
patients with type 2 diabetes mellitus (DM) reduce
carbohydrate energy intake to affect better glycemic control

Financial support was received from Maryland Industrial Partnerships, Glenn L. Martin Institute of Technology, University of Maryland,
College Park, and Spherix Inc, Beltsville, Md.
Corresponding author. Division of Endocrinology and Metabolism,
Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA.
Tel.: +1 410 955 2908; fax: +1 410 614 9586.
E-mail address: tdonner1@jhmi.edu (T.W. Donner).
0271-5317/$ see front matter 2010 Elsevier Inc. All rights reserved.
doi:10.1016/j.nutres.2010.09.007

and to assist with weight management. D-Tagatose (D-tag) is

a ketohexose bulk sweetener with no net metabolizable
energy when fed to rats [1,2]. D-tagatose received Generally
Recognized as Safe status by the Food and Drug Administration in 2001 and entered the US market as a sweetener in
2003. In subjects with and without type 2 DM, a 75-g oral
D-tag tolerance test led to no changes in plasma glucose or
insulin levels. Pretreatment of type 2 DM subjects with
doses of D-tag ranging from 10 to 75 g attenuated the rise in
plasma glucose during an oral GTT in a dose-dependent
manner [3]. These findings suggest that D-tag could
potentially improve glycemic control in patients with type
2 DM by blunting postprandial hyperglycemia.

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T.W. Donner et al. / Nutrition Research 30 (2010) 801806

The long-term metabolic effects of D-tag have not

previously been studied in humans. In a 90-day study in
rats, D-tag given as 15% to 20% of daily energy intake led to
less weight gain when compared with a control diet [4].
Reduced food intake has been observed in rats fed tagatose
as 20% of daily energy intake [4] and in humans fed a single
29-g dose of tagatose when compared with 29 g of sucrose
added to a breakfast meal [5]. If tagatose causes sustained
reductions in energy intake, beneficial effects on weight,
blood glucose control, and serum lipid profile could be seen.
The objective of this pilot study was to investigate the
metabolic effects of long-term administration of D-tag in
obese subjects with type 2 DM. Following a 2-month run-in
period, subjects had tagatose added to their daily meals
and were followed on an every 2-month basis for 12 months
for changes in weight, blood glucose control, and lipid
profile. We hypothesized that daily oral tagatose would
lower glycated hemoglobin (GlyHb) and lead to weight
loss and improvements in the lipid profile, including lower
low-density lipoprotein (LDL) cholesterol and triglycerides,
and higher high-density lipoprotein (HDL) cholesterol.

2. Methods and materials

2.1. Subjects
Eight subjects (4 male and 4 female) with type 2 DM for
at least 1 year in duration were enrolled and ranged from
35 to 70 years in age. Four of the 12 initially screened
subjects were excluded from analysis because they did not
complete the study. Data analysis was performed on the
8 subjects who completed all 14 months of the study.
Subjects were excluded from study entry if baseline GlyHb
levels were lower than 8% (reference range, 4.4%-7.7%) or
if they had gastrointestinal disorders. All investigational
protocols were approved by the institutional review board of
the University of Maryland for human subjects. Participants
were enrolled only after giving written informed consent.
At entry, 3 subjects were receiving diet therapy for
diabetes, 4 were being treated with a sulfonylurea, and 1 was
being treated with combination metformin and troglitazone.
Those receiving medications had been on stable doses for at
least 10 months before enrollment. Three subjects had oral
diabetes medications added or adjusted by their primary care
providers during the intervention phase of the study. These
3 subjects were included in all outcomes analyses, though
subgroup analyses excluding these subjects were done for
GlyHb and body weight, which are known to be affected by
sulfonylureas and troglitazone.
One subject had glipizide 5 mg added during month 4,
and another subject had her glyburide dosage increased
during month 8 of the intervention phase. The third subject
had glyburide 2.5 mg added during month 3 and had the
troglitazone dose increased from 200 to 400 mg daily during
month 4 of the intervention phase. One subject had
pravastatin added during month 8. A lipid subgroup analysis

was performed, which excluded this subject and the one

whose troglitazone was increased during the study. A
subgroup analysis was also performed on 3 subjects who
had antihypertensive medications added during the study.
2.2. Materials
D -Tagatose was prepared by Spherix Incorporated
(Beltsville, Md). Samples provided to subjects were more
than 99% pure by high-performance liquid chromatography
analysis and were weighed and packaged in the University
of Maryland Pharmacy before administration.

2.3. Study protocol

After a 2-month run-in period, subjects were given 15-g
packages of D -tag to be taken 3 times daily with
nonstandardized meals. Dose-dependent, gastrointestinal
side effects observed with large doses of D-tag have been
attributed to an osmotic effect of this poorly absorbed sugar.
Prior tolerance testing at the University of Maryland has
shown the 15-g dosage to be typically well tolerated with
minimal adverse gastrointestinal effects [3].
The D-tag was dissolved in liquids, used in baking, or
added to prepared foods. For the duration of the 14-month
study period, subjects were encouraged not to otherwise
alter their dietary intake. All subjects enrolled were physically inactive and remained so throughout the 14-month
observation period.
At the initial visit and every 2 months for the next 14
months, body weight and vital signs were recorded, and
fasting blood was sent for glucose, GlyHb, insulin, lipids,
liver and kidney function, uric acid, bilirubin, phosphorus,
calcium, magnesium, bicarbonate, chloride, sodium, potassium, total protein, albumin, and amylase. Subjects were
questioned at each visit about the occurrence of any adverse
events or side effects, and specifically about any gastrointestinal side effects. Compliance with D-tag was confirmed
based on D-tag package counts performed every 2 months.
2.4. Laboratory evaluations
Glycosylated hemoglobin values were measured by the
affinity column method (Helena Glyco-Tek, Beaumont,
Tex), which has a reference range of 4.4% to 7.7% and a
mean intra-assay coefficient of variation of 2.95% [6].
Insulin levels were measured by the Coates-A-count RIA
method (Diagnostics Products Corporation, Los Angeles,
Calif). Chemistry profiles and lipids were performed at the
University of Maryland Chemistry Laboratory using Beckman Coulter laboratory analyzers (Brea, Calif). Sodium,
potassium, chloride, and calcium were measured by ionselective electrode. Bicarbonate was assayed by pH
electrode. Glucose was measured by oxygen sensor. Blood
urea nitrogen was measured by conductivity electrode.
Magnesium was measured by calmagite method and
phosphorous by phospho-molybdate. Uric acid was measured by enzymatic Trinder. Amylase was measured by

T.W. Donner et al. / Nutrition Research 30 (2010) 801806

803

enzymatic DS. Aspartate aminotransferase and alanine

aminotransferase levels were measured by the Henry
method. Total protein, albumin, and creatinine were
measured using the colorimetric methodology [7]. Total
bilirubin levels were assayed by the Jendrassik-Grof
methodology [8].
2.5. Statistical analyses
Mean values of physiologic measurements were calculated at each follow-up time. To assess whether there was a
statistically significant trend in the means over time, we fit
mixed-effects regression models including a random slope
and random intercept for each study subject [9]. Mixedeffects models are alternatives to repeated-measures
analysis of variance that appropriately account for the
repeated measures on the same individuals but allow for
varying numbers of observations per person. P values were
based on Wald tests that based on these models. These
models were fit using the lme software library for the R
system for statistical computation and graphics. Three
subjects had new medications added or medication dosages
adjusted during follow-up that might have had an impact
on their weight, GlyHb, or cholesterol. To avoid the
potential confounding effects of these changes, we did not
include the observations from these subjects that occurred
after the start of the new medications for some of our
analyses. Data are presented as means SD. Associations
with a P value less than .05 are referred to as statistically
significant. Baseline means were calculated by averaging
both pretreatment means.

3. Results
Eight subjects completed the full 14 months of the study
protocol and were included in the efficacy analyses. Of these
8 subjects, 4 were male and 4 female, with a mean age of
50.7 10.9 years. At baseline, study subjects were obese,
with a mean body mass index of 36.7 5.1 kg/m2, and in
poor glycemic control, with a mean GlyHb of 11.2% 2.0%.
Subjects were also dyslipidemic at baseline, with a mean
total cholesterol of 224 28 mg/dL; LDL cholesterol,
146 3) mg/dL; triglycerides, 226 98 mg/dL; and HDL
cholesterol, 31 14 mg/dL.
Four subjects discontinued the study soon after D-tag
therapy was initiated and were not included in data analyses.
Two subjects withdrew during the first week of D-tag
because of persistent gastrointestinal symptoms including
diarrhea, flatulence and/or bloating. One subject with asthma
withdrew after 2 months of daily D-tag because of a
persistent, dry cough. The cough resolved after discontinuation of D-tag and recurred after reinitiation of D-tag. The
fourth subject withdrew after moving to another state.
During the 2-month run-in period, modest increases were
observed for both mean body weight (+0.5 kg) and GlyHb
(+1.1%). Thereafter, body weight and GlyHb remained

Fig. 1. Mean (SEM) weight in all 8 treated subjects and in 5 subjects who
did not have oral diabetes medication changes during the study. P = .01 vs
baseline; #P = .001 vs baseline.

stable for the first 4 months of D-tag supplementation, and

then weight progressively declined (Figs. 1 and 2). Seven of
8 subjects lost weight during the intervention phase, with
a mean fall from 109 14.7 kg at baseline to 105.3 14.4 kg
at month 12 (P = .01). The single subject who gained weight
during the intervention period had been started on a
sulfonylurea and had her troglitazone dose increased during
the study. When this subject and 2 others who had a
sulfonylurea added or dosage increased during the study
were excluded from data analysis, a more substantial weight
loss of 5.1 3.1 kg during the 12-month intervention period
was observed (Fig. 1, P = .001).
After 12 months of D-tag, a decrease in GlyHb was
observed in the 8 subjects who completed the study from
11.2% 2.0% to 9.5% 2.0% (Fig. 2). However, after the
3 subjects in whom hypoglycemic medications were added
or increased during the study were excluded from analysis, a
nonsignificant decrease in GlyHb was seen (10.6% 1.9%
vs 9.6% 2.3%, P = .08). No significant changes were
observed for fasting glucose or insulin levels during the
intervention phase (data not shown).
An increase in HDL cholesterol levels occurred throughout the 12-month intervention period in all 8 subjects
(Fig. 3). Mean baseline HDL cholesterol rose from 31.1
13.9 to 40.5 10.4 mg/dL at month 12 (P = .01). After the

Fig. 2. Mean (SEM) glycohemoglobin in all 8 treated subjects and in

5 subjects who did not have oral diabetes medication changes during
the study.

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T.W. Donner et al. / Nutrition Research 30 (2010) 801806

A 48-year-old man who had experienced a cerebrovascular accident 4 years before study entry had an uncomplicated myocardial infarction 4.5 months into the intervention
phase of the study. D-tagatose was not felt to have played a
role in his myocardial infarction. He had numerous
cardiovascular risk factors before study entry. He was
allowed to restart D-tag after his hospitalization, but was
excluded thereafter from analyses for lipids and blood
pressure, since metoprolol and pravastatin had been added.

Fig. 3. Mean (SEM) HDL cholesterol in all 8 treated subjects and in 6

subjects who did not have lipid-modifying medications added during the
study. P = .01 vs baseline level; #P b .001 vs baseline level.

subjects in whom pravastatin was added (n = 1) or whose

troglitazone dose was increased (n = 1) were excluded from
data analysis, an even greater rise in HDL cholesterol
occurred, from 30.5 15.8 to 41.7 12.1 mg/dL (P b .001).
No changes were observed from baseline to month 12 in total
cholesterol (225 30 mg/dL vs 224 54 mg/dL) or
triglycerides (222 101 mg/dL vs 246 154 mg/dL) in the
6 subjects who did not have medications added that could
affect lipid levels. No change was observed from baseline to
month 12 in LDL cholesterol (154 36 mg/dL vs 155 44
mg/dL)) in 5 subjects who did not have medications added
that could affect lipid levels or whose LDL cholesterol could
not be calculated due to elevated triglycerides. In addition,
no significant changes were observed in blood pressure
during the 12-month intervention period. Three subjects had
cardiovascular medications added during the study, 2 for
hypertension (amlodipine and hydrochlorothiazide), and 1
who was normotensive but postmyocardial infarction
(metoprolol). No significant changes in blood pressure
were observed during the study when these 3 subjects were
excluded from analysis.
D-tagatose was not found to have toxic effects on renal or
hepatic function, measures of which did not change during
the 12-month intervention period. No other changes were
observed in any of the other biochemical parameters tested
during the intervention period (data not shown).
During the first 2 weeks of D-tag therapy, gastrointestinal
symptoms were reported by all 8 subjects who completed the
study and in 10 of 12 subjects who initially enrolled in the
study. These were typically mild and transient and included
flatulence (n = 6), diarrhea (n = 4), and/or nausea (n = 1).
Thereafter, adverse gastrointestinal effects resolved when the
D-tag was taken as directed, with the exception of a single
subject who reported persistent, mild flatulence during the
first 6 months of therapy. Three subjects, including 1 who
was on metformin throughout the study, reported bloating,
flatulence, and/or diarrhea if more than 15 g of D-tag was
consumed at a time or if the doses were spaced less than
3 hours apart. A single subject with chronic constipation
noted more regular bowel habits throughout the 12-month
treatment period.

4. Discussion
This pilot study is the first to investigate the long-term
metabolic effects of D-tag in humans with type 2 DM. No
adverse metabolic or biochemical effects were noted among
the 8 subjects who completed the study. Indeed, significant
and beneficial changes were seen in weight and HDL
cholesterol at the end of the 12-month intervention period, in
the absence of any intentional changes in dietary intake or
physical activity. No significant changes in GlyHb or other
lipid parameters were seen.
The weight loss occurred in 7 of the 8 subjects in the
study. Weight loss occurred in one subject in whom a
sulfonylurea had been added and in another whose
sulfonylurea dosage had been increased. Indeed, the only
subject who gained weight during the study did so only after
being started on a sulfonylurea and having her thiazolidinedione dosage increased, 2 medications known to be
associated with weight gain. When the 5 subjects who did
not have changes in oral diabetes medications made during
the study were separately evaluated, the mean weight
loss observed following 12 months of D-tag was even
greater (5.1 3.1 kg vs 3.7 3.4 kg for all 8 subjects). The
hypothesis that daily tagatose would lead to weight loss
was accepted.
The etiology of weight loss that began after 4 months of
D-tag in our study population is unclear. Subjects participating in the study did not change their dietary habits other than
using D-tag as their sweetener. The 8 subjects were sedentary
and did not modify their physical activity during the study.
Kruger et al [4] reported less weight gain when rats were
fed 15% to 20% of their diet as D-tag for 90 days. In that
study, a decrease in mean weekly food consumption was
reported in the rats fed 20% of their diet as D-tag. In this
study, 3 subjects reported having mild early satiety,
especially during the first month of D-tag use. One subject
felt that this may have decreased his total daily energy
intake throughout the study. Buemann et al similarly
reported a perception of fullness in humans treated with
30 g D-tag/d for 2 weeks [10]. Lee and Storey reported
appetite loss in humans given 20 g D-tag when compared
with sucrose in chocolate [11]. Reduced energy intake has
been reported after oral intake of compounds chemically
similar to tagatose, including fructose in humans [12] and
oligofructose in Wistar rats [13].

T.W. Donner et al. / Nutrition Research 30 (2010) 801806

Two subjects in our study reported a reduction in simple

sugar consumption due to substitution with D-tag. The
reduction in sugar intake may have been underestimated in
our subjects and may have contributed to a decrease in net
utilizable energy intake. Other potential mechanisms of
weight loss are only speculative. Studies have shown that
only 26% of ingested D-tag is absorbed in the distal small
bowel of pigs [14], leading to its low net energy content. It
has been proposed that the osmotic effect of malabsorbed
D-tag speeds its transit time through the gastrointestinal tract
and that this may impair the absorption of other macronutrients [15]. The digestibility of sucrose after oral D-tag
was reduced by 7.6% in pig small intestine [16].
A progressive and marked rise in HDL cholesterol was
observed following dietary supplementation with D-tag. The
hypothesis that daily tagatose would raise HDL cholesterol
was accepted. The low-baseline HDL cholesterol in our
population is seen commonly in obese patients with type 2
DM and has been shown to be a major risk factor for
coronary heart disease (CHD) [17-20]. An aggregate
analysis of 4 large epidemiologic studies found that for
each 1-mg/dL increase in HDL cholesterol, one would
expect a 2% decrease in CHD risk in men and a 3% decrease
in CHD risk in women [21]. Reductions in body weight
likely contributed to the improvement in HDL cholesterol in
this study. Kaplan et al showed that energy restriction for 3
months in obese patients with type 2 DM leading to a 3-kg
weight loss was associated with a 5.5-mg/dL increase in
HDL cholesterol [22]. Wing et al [23] found a more modest
2.5-mg/dL increase in HDL cholesterol in obese type 2 DM
patients only in those with weight loss exceeding 6.9 kg,
following 1 year of energy restriction and increased exercise.
Our subjects did not change their amount of physical activity
or alcohol intake, and none discontinued cigarettes, all
parameters known to affect HDL cholesterol. It is unknown
whether the small amounts of D-tag that enter into the
circulation, although known to be extensively metabolized
in the liver, affect hepatic synthesis of HDL cholesterol.
No changes in LDL cholesterol or triglycerides were
seen, and the hypothesis that these parameters would be
reduced is rejected.
Interpreting the beneficial effects of D-tag on weight and
HDL cholesterol is made difficult by the inherent limitations
of a small, nonplacebo-controlled study. Adjustments of
medications having metabolic effects by outside physicians
during the study period also led to subsequent lipid and
weight measurements being excluded from data analysis.
There is no evidence in this study of a D-tagassociated
deterioration of diabetic control.
Among the 5 subjects who received 12 months of D-tag
and had no oral diabetes medications added during the study,
a nonsignificant 1% decrease in GlyHb was seen. The
hypothesis that daily tagatose would lead to a reduction in
GlyHb is rejected. Oral administration of D-tag has
previously been shown to blunt hyperglycemia significantly
following oral glucose in a dose-dependent manner in

805

subjects with type 2 DM, with doses as low as 10 g being

efficacious [3]. Subjects in this study received 15 g of D-tag
with meals for 12 months. The 1.1% increase in GlyHb that
occurred during the 2-month run-in period demonstrates that
study subjects were in a state of deteriorating glycemic
control when they started D-tag. This may help explain why
a significant decline in GlyHb was not seen during the
study period. A larger, placebo-controlled study is needed to
determine whether D-tag use in type 2 DM patients improves
glycemic control, and if so, to what degree better glycemic
control correlates with weight loss. A recent study in
hypercholesterolemic mice showed that equivalent substitution of D-tag when compared with sucrose as dietary
carbohydrate led to less obesity, hyperglycemia, hyperlipidemia, and atherosclerosis [24].
The 15 g of D-tag given with meals led to adverse
gastrointestinal effects in 10 of 12 of the subjects initially
enrolled into the trial. These symptoms were mostly transient
and mild in severity. In 2 subjects, the effects were poorly
tolerated and led to withdrawal from the study within 1
week. Poorly absorbed D-tag is thought to osmotically draw
water into the colon, thereby softening the stool. The
transient nature of most of the adverse gastrointestinal effects
in our subjects may be due to adaptation to D-tag by colonic
bacteria. Sprague-Dawley rats adapted to D-tag for 28 days
were found to have progressively less frequent soft stools
over time [25]. Pigs fed D-tag over a 15-day period were
found to harbor a significantly greater number of D-tag
degrading colonic bacteria compared with pigs fed a control
diet [15]. Future studies investigating the metabolic benefits
of D-tag would benefit from an adaptation period using lower
and more graded doses of D-tag to help minimize early,
adverse gastrointestinal effects.
In conclusion, this pilot study found that daily ingestion
of D-tag with food in subjects with type 2 diabetes leads to
weight loss and improvements in HDL cholesterol. These
beneficial effects need to be confirmed in larger, placebocontrolled studies that are currently underway. The rise in
HDL cholesterol appears to be disproportionate to the degree
of weight loss observed during the study. No adverse effects
on glycemic control or other biochemical parameters were
seen. If beneficial effects of D-tag on weight and HDL
cholesterol are confirmed in patients with type 2 DM,
treatment with D-tag could help reduce cardiovascular
disease in this high-risk population.

Acknowledgment
We would like to thank Maryland Industrial Partnerships,
Glenn L. Martin Institute of Technology, University of
Maryland, College Park, and Spherix Incorporated (Beltsville, Md) for their financial support of this study. We are
most grateful to Debra Ostrowski for her expert technical
assistance and to Alan Shuldiner for his critical review of
the manuscript.

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T.W. Donner et al. / Nutrition Research 30 (2010) 801806

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