ORIGINAL ARTICLE

Yacon supplementation reduces serum free fatty acids and tumornecrosis factor alpha concentrations in patients with type 2diabetes

Hiroaki Satoh • Akihiro Kudoh • Koji Hasegawa •

Hiroyuki Hirai • Tsuyoshi Watanabe

Received: 28 May 2013 / Accepted: 28 October 2013

� The Japan Diabetes Society 2013

Abstract Yacon is a perennial plant originating from

South America that forms [20 large subterranean tubers

weighing from 100 to 500 g. These tubers have become

popular in Japan and contain beta-1, 2-oligofructans as the

main saccharides. Preliminary work in animals revealed

yacon feeding ameliorates diabetes by reducing blood

glucose. We therefore examined whether yacon feeding

modulates glucose metabolism in patients with type 2

diabetes. We conducted a single-center, open-label, ran-

domized controlled trial to investigate the effect of yacon

on patients with type 2 diabetes. Fifty-eight patients with

type 2 diabetes were selected from the medical outpatients

department. There had been no changes in their diet or

medications during the 3 months before the study com-

menced. After ethical clearance, written informed consent

was obtained. Patients were randomly assigned to two

groups: group 1 received an intake level of 100 g yacon/

day, and group 2 received an intake level of 100 g aroid/

day (control). Fasting glucose, insulin, glycated albumin,

and adiponectin concentrations at baseline did not differ

significantly between groups; after 5 months, concentra-

tions did not change significantly in either group. Inter-

estingly, after 5 months of yacon consumption, tumor

necrosis factor alpha (TNF-a) and free fatty acid (FFA)

concentrations decreased significantly by 10.3 % and

9.8 % (p \ 0.01), respectively; neither changed signifi-

cantly in the aroid group. In conclusion, the results suggest

longer-term yacon supplementation may improve insulin

resistance by reducing FFA and TNF-a in patients with

type 2 diabetes.

Keywords Yacon � TNF-a � Free fatty acids � Type

2 diabetes

Abbreviations

TNF-a Tumor necrosis factor alpha

FFAs Free fatty acids

LMW Low molecular weight

MMW Middle molecular weight

HMW High molecular weight

FOS b-1, 2-fructooligosaccharides

RLP-C Remnant-like particle cholesterol

IRS-1 Insulin receptor substrate 1

Introduction

Insulin resistance and obesity are key features of metabolic

syndrome and type 2 diabetes [1]. One potential mecha-

nism involves the production of hormones, or adipocyto-

kines, by adipose tissue. Plasma concentrations of many

adipocytokines, such as leptin, tumor necrosis factor alpha

(TNF-a), free fatty acids (FFAs), and resistin, are posi-

tively associated with insulin resistance, whereas adipo-

nectin is negatively associated with insulin resistance [2,

3]. In addition, circulating adiponectin exists predomi-

nantly as low molecular weight (LMW) trimers, middle

molecular weight (MMW) hexamers, and high molecular

weight (HMW) complexes believed to possess different

biological activities [4]. HMW adiponectin is believed to

be more closely associated with insulin sensitivity and

considered to be a relatively more metabolically active

H. Satoh (&) � A. Kudoh � K. Hasegawa � H. Hirai �T. Watanabe

Department of Nephrology, Hypertension, Diabetology,

Endocrinology, and Metabolism, Fukushima Medical University,

1 Hikarigaoka, Fukushima City, Fukushima 960-1295, Japan

e-mail: hiroakis-tky@umin.ac.jp

123

Diabetol Int

DOI 10.1007/s13340-013-0150-y

form than LMW and MMW adiponectin. As LMW and

MMW adiponectin—but not HMW adiponectin—enter

cerebrospinal fluid from the circulation, LMW and MMW

adiponectin activate adenosine monophosphate (AMP)-

activated protein kinase via its receptor, AdipoR1, in the

hypothalamus; this stimulates food intake and decreases

energy expenditure [5]. Furthermore, hypoadiponectinemia

is associated with an increased incidence of metabolic

syndrome, diabetes, and vascular disease [6].

Many interventions are thought to improve insulin

resistance and might also affect insulin secretion. The

Diabetes Prevention Program, a multicenter, randomized

controlled trial, examined the effects of two active inter-

ventions to prevent or delay type 2 diabetes mellitus in

people at high risk of the disease; results showed that the

risk of developing type 2 diabetes was reduced by 58 %

and 31 % in intensive lifestyle-change and metformin-

treated groups, respectively, compared with the placebo-

treated group [7]. Intensive lifestyle intervention was more

effective than metformin in slowing progression to diabe-

tes, partly because lifestyle modification improves insulin

sensitivity to a greater extent [8]. Thus, dietary interven-

tions are an effective tool for preventing and treating

insulin resistance and type 2 diabetes [7].

Yacon (Smallanthus sonchifolius, Asteraceae) is a

perennial plant originating from South American that

forms a clump of [20 large subterranean tubers weighing

100–500 g [9]. In recent decades, yacon has gained

increasing popularity both in Japan and worldwide for its

caloric value. Yacon tubers store their carbohydrates in the

form of b-1, 2-fructooligosaccharides (FOS) [9]. FOS are

able to resist the hydrolysis of enzymes of the upper part of

the gastrointestinal tract. Thus, despite their sweet flavor,

yacon tubers contain fewer calories than might be expected

[9]. Yacon tubers have been traditionally recommended for

people with diabetes and various digestive diseases [10–

12]. Recently, yacon syrup, which is extracted from yacon

tubers and concentrated, was shown to improve insulin

resistance and reduce body weight in obese individuals

[12]. These studies raise the interesting possibility that

yacon consumption has beneficial effects toward treatment

of obesity-related insulin resistance and type 2 diabetes.

We thus investigated the effect of yacon tuber feeding over

5 months in patients with type 2 diabetes through a ran-

domized controlled intervention study.

Participants and methods

Plant material

Yacon root and aroid were obtained from the 2007 harvest

of a field in Tenei Village, Fukushima Prefecture, Japan.

Yacon root contains 54 kcal/100 g and 8 % (w/w) FOS,

whereas aroid contains 70 kcal/100 g and small amounts of

FOS.

Participant eligibility

We conducted a single-center, open-label, randomized

controlled trial to investigate the effect of yacon on patients

with type 2 diabetes. Patients aged 21–80 years with type 2

diabetes were recruited from the Department of Internal

Medicine, Fukushima Medical University, from October to

November 2007. Exclusion criteria were type-1-diabetes-

related antibodies, elevated serum creatinine ([2.0 and

[1.5 mg/dl in male and female participants, respectively),

liver enzyme concentrations exceeding two times the upper

limit of normal (ULN), severe coronary artery disease

(myocardial infarction within the past 6 months or active

angina), stage 3 or 4 heart failure, pregnancy or lack of

approved contraception, untreated proliferative diabetic

retinopathy, any life-threatening conditions, and con-

sumption of more than two alcoholic drinks per day within

the 3 months before enrollment. The study was approved

by the Fukushima Medical University Institutional Review

Board.

Study design

This study was undertaken in the Department of Internal

Medicine, Fukushima Medical University from November

2007 to March 2008. Fifty-eight patients with type 2

diabetes were selected from the medical outpatients

department. After ethical approval, written informed con-

sent was obtained from all participants prior to the start of

the study. Participants were studied for a 5-month period

after being randomly assigned to two groups: group 1

N=30Assigned to yacon group

N=28Assigned to aroid group

N=58T2DM eligible to randomization

N=29Completed trial

N=27Completed trial

N=1Dropped out

N=1Dropped out

Fig. 1 Patient randomization. T2DM type 2 diabetes

H. Satoh et al.

123

received 100 g yacon/day; group 2 received 100 g aroid/

day. All patients were instructed to exclude food products

containing large amounts of FOS, such as onions and

leeks, from their diet. No participant changed their phar-

macotherapy 3 months prior to or throughout the study.

Anthropometric parameters

Anthropometric parameters were obtained by trained per-

sonnel. Body weight was measured with a digital balance

scale when participants were fasting, had an empty bladder,

and were minimally clothed. Height was measured with a

tape measure under the same conditions with the partici-

pant standing.

Data acquisition

During the screening visit, baseline laboratory data,

blood pressure, and body mass index (BMI) were

determined for each participant. BMI was calculated as

weight (kg) divided by height (m) squared. Blood

samples were obtained between 8:00 and 10:00 a.m.

after overnight fasting to measure blood glucose and

lipids using standard laboratory techniques. Insulin

resistance was determined by the homeostatic model

assessment–estimated insulin resistance (HOMA-IR)

and calculated as the product of fasting plasma glucose

(mg/dl) and insulin concentration (lU/ml) divided by

405 [13]. Remnant-like particle cholesterol (RLP-C);

TNF-a; resistin; total adiponectin; and HMW, MMW,

and LMW adiponectin were analyzed by a private lab-

oratory (SRL Laboratory, Tokyo). Briefly, all but RLP-

C was measured using commercially available enzyme-

Table 1 Participant baseline clinical and biochemical results

Aroid group

(n = 27)

Yacon group

(n = 29)

P value

Age (years) 65.6 ± 1.6 66.9 ± 1.3 0.535

Gender (M/F) 13/13 16/13

Body weight (kg) 63.8 ± 3.3 62.2 ± 2.3 0.792

BMI (kg/m2) 24.5 ± 1.3 24.6 ± 0.7 0.950

Blood pressure (mmHg)

Systolic 134.8 ± 3.2 136.8 ± 3.7 0.281

Diastolic 80.2 ± 2.2 74.7 ± 2.2 0.062

Serum glucose and insulin

Fasting glucose

(mg/dl)

129.3 ± 5.8 124.2 ± 3.5 0.440

Fasting insulin

(lU/ml)

11.57 ± 3.12 8.47 ± 1.19 0.337

Fasting proinsulin

(pmol/ml)

7.01 ± 0.95 7.26 ± 0.89 0.852

Proinsulin/insulin

(mol ratio)

0.151 ± 0.0018 0.168 ± 0.0015 0.455

Glycated albumin

(%)

18.84 ± 0.71 19.06 ± 0.54 0.800

Serum lipids

Total cholesterol

(mg/dl)

196.6 ± 6.2 189.7 ± 4.9 0.384

Triglycerides

(mg/dl)

110.5 ± 10.4 107.2 ± 10.2 0.820

HDL-C (mg/dl) 56.2 ± 3.8 53.8 ± 2.3 0.593

LDL-C (mg/dl) 110.4 ± 5.5 112.0 ± 4.7 0.778

RLP-C (mg/dl) 4.77 ± 0.77 3.77 ± 0.28 0.221

FFAs (mEq/L) 0.480 ± 0.040 0.578 ± 0.038 0.083

Adipokine

Leptin (ng/ml) 11.43 ± 1.40 9.10 ± 1.40 0.457

TNF-a (ng/ml) 1.56 ± 0.13 1.39 ± 0.08 0.267

Resistin (ng/ml) 7.67 ± 0.58 8.66 ± 0.93 0.386

Adiponectin (lg/

ml)

11.73 ± 1.56 10.14 ± 1.52 0.472

HMW (lg/ml) 6.85 ± 1.21 5.97 ± 1.24 0.613

MMW (lg/ml) 1.85 ± 0.16 1.83 ± 0.23 0.930

LMW (lg/ml) 3.02 ± 0.31 2.34 ± 0.11 0.036

Inflammatory marker

hs-CRP (ng/ml) 2591.9 ± 1848.1 1050.8 ± 288.6 0.438

Values are means ± standard deviation. There were no significant

differences between groups (p [ 0.05)

BMI body mass index, HDL-C high-density-lipoprotein cholesterol,

LDL low-density lipoprotein cholesterol, RLP-C remnant-like particle

cholesterol, FFAs free fatty acids, TNF-a , HMW high molecular

weight, MMW middle molecular weight, LMW low molecular weight,

hs-CRP C reactive protein

Table 2 Participant treatments at baseline

Aroid group

(n = 27)

Yacon group

(n = 29)

Glucose-lowering drugs 20 (76.9) 24 (82.8)

Sulfonylurea [no. (%)] 9 (34.6) 14 (48.3)

Metformin [no. (%)] 10 (38.5) 5 (17.2)

Pioglitazone [no. (%)] 12 (46.2) 14 (48.3)

a-GI [no. (%)] 8 (30.8) 11 (37.9)

Glinide [no. (%)] 8 (30.8) 4 (13.8)

Insulin [no. (%)] 3 (11.5) 0 (0)

Cholesterol-lowering drugs

Statin [no. (%)] 11 (62.1) 18 (42.3)

Other lipid-drug [no.

(%)]

0 (0.0) 0 (0.0)

Blood pressure-lowering drugs

ARB 9 (34.6) 15 (51.7)

ACE inhibitor 2 (7.7) 4 (13.8)

Ca channel blocker

[no. (%)]

7 (26.9) 9 (31.0)

Diuretics 2(7.7) 1 (3.4)

a-blocker 1 (3.8) 0 (0.0)

b-blocker 0 (0.0) 2 (6.9)

ACE angiotensin-converting enzyme, ARB angiotensin receptor

blocker, a-GI alpha glycosidase inhibitor, Ca calcium channel

Yacon reduces FFA and TNF-a

123

linked immunosorbent assay (ELISA) kits (R&D Sys-

tem). Blood pressure was measured twice with a mer-

cury sphygmomanometer. Each patient was reviewed at

least every 3 months; general health, compliance with

medications, laboratory data, blood pressure, and diet

and excise status were checked at each visit. The lab-

oratory parameters, blood pressure, and BMI of each

participant were reexamined 1, 3, and 5 months after

enrollment. The average laboratory values for the

observation period were calculated from data obtained

at each visit.

Statistical analysis

Data are presented as means ± standard deviation (SD).

Baseline data of each group were compared using the

Mann–Whitney U or v2 test. Changes from baseline within

each group were assessed by paired t test or Wilcoxon

0

20

40

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Yacon

Aroid

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Yacon

Aroid

Blo

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ress

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(mm

Hg)

Yacon

Aroid

Bod

y w

eigh

t (k

g)

Yacon

Aroid

(Month)0 1 3 5

(Month)0 1 3 5

(Month)0 1 3 5

a

b

c

Fig. 2 Time courses of body weight (a), body mass index (BMI) (b),

and blood pressure (c) during the 5-month follow-up in the yacon

(open circle) and control (closed square) groups. Data are expressed

the mean ± standard deviation

Yacon

Aroid

Gly

cate

d al

bum

in (

%)

Yacon

Aroid

HO

MA

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Yacon

Aroid

Fas

ting

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gluc

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(mg/

dL)

(Month)0 1 3 5

(Month)0 1 3 5

(Month)0 1 3 5

0102030405060708090

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0

2

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18

20

22

0.0

0.5

1.0

1.5

2.0

2.5

3.0

3.5

4.0

a

b

c

Fig. 3 Time courses of fasting plasma glucose (a), glycated albumin

(b), and homeostatic model assessment–estimated insulin resistance

(HOMA-IR) (c) during the 5-month follow-up in the yacon (open

circle) and control (closed square) groups. Data are expressed the

mean ± standard deviation

H. Satoh et al.

123

single-rank test, where appropriate. Two-factor repeated-

measurements analysis of variance (ANOVA) followed by

a post hoc test was used to compare the time-course curves

of body weight, BMI, blood pressure, fasting plasma glu-

cose, glycated albumin, HOMA-IR, low-density-lipopro-

tein cholesterol (LDL-C), triglyceride, high-density-

lipoprotein cholesterol (HDL-C), RLP-C, high-sensitivity

CRP (hs-CRP), leptin, resistin, FFAs, TNF-a, and adipo-

nectin during follow-up. Changes from baseline in FFAs

and TNF-a between groups during follow-up were assessed

by paired t test. All statistical tests were two sided, with a

significance level of 5 %.

Results

From October through November 2007, we recruited 58

type 2 diabetic patients from the Department of Internal

Medicine, Fukushima Medical University to participate in

an open-label randomized controlled study during a

5-months period. Fifty-eight participants were randomly

divided into two groups. One participant dropped out of

each group. Among the control group, one participant

withdrew because of poor compliance. One participant in

the yacon group was lost to follow-up (Fig. 1). Therefore,

56 patients (29 and 27 in the yacon and control groups,

respectively) completed the study (Fig. 1). Daily con-

sumption of 100 g yacon or aroid was well tolerated by all

patients without adverse effects such as diarrhea, severe

abdominal distention, flatulence, or nausea. Table 1 sum-

marizes patient baseline characteristics of both groups.

Glucose and insulin metabolism, lipid profile, and adipo-

kines did not differ significantly between groups at base-

line. As shown in Table 2, baseline antidiabetic,

antihypertensive, and antilipidemic therapy did not differ

between groups. During the 5-month follow-up period, all

participants maintained the daily dosages of antidiabetic,

antihypertensive, and antilipidemic therapy.

During the 5-month follow-up period, body weight

(Fig. 2a), BMI (Fig. 2b), and blood pressure (Fig. 2c) did

Yacon

AroidYacon

Aroid

Tri

glyc

erid

e (m

g/dL

)

cLD

L-C

(m

g/dL

)

(Month)0 1 3 5

(Month)0 1 3 5

0

10

20

30

40

50

6070

80

90

100

110

120

130

140

0102030405060708090

100110120130140150

0.0

1.0

2.0

3.0

4.0

5.0

6.0

7.0

8.0

9.0

10.0

RP

L-C

(m

g/dL

)

Yacon

Aroid

(Month)0 1 3 5

HD

L-C

(m

g/dL

)

Yacon

Aroid

(Month)0 1 3 5

*

*

0

10

20

30

40

50

60

70

80

a b

c d

Fig. 4 Time courses of low-density-lipoprotein cholesterol (LDL-C)

(a), triglycerides (b), high-density-lipoprotein cholesterol (HDL-C)

(c), and remnant-like particle cholesterol (RLP-C) (d) during the

5-month follow-up in the yacon (open circle) and control (closed

square) groups. Data are expressed the mean ± standard deviation.

*p \ 0.01 compared with baseline data

Yacon reduces FFA and TNF-a

123

not change significantly in either group compared with

baseline values.

Glucose and insulin metabolism, including fasting

plasma glucose (Fig. 3a), glycated albumin (Fig. 3b), and

HOMA-IR (Fig. 3c), did not change significantly in either

group compared with baseline values. On the other hand,

HDL-C (Fig. 4c) increased significantly in both groups

5 months after commencement of the treatment. Mean-

while, LDL-C (Fig. 4a), triglycerides (Fig. 4b), and RLP-C

(Fig. 4c) did not change significantly in either group during

the follow-up period.

Levels of hs-CRP (Fig. 5a), leptin (Fig. 5b), and res-

istin (Fig. 5c) were not significantly different between

groups during the follow-up period. However, both of

FFA (Fig. 5d) and TNF-a (Fig. 5e) levels decreased

significantly in the yacon group 5 months after com-

mencement of treatment by 10.3 % and 9.8 %

(p \ 0.01), respectively. Furthermore, FFA change from

baseline (Fig. 6a) was significantly decreased, by 28 %

(p \ 0.05), in the yacon compared with control group at

5 months after commencement of treatment, whereas

baseline TNF-a change (Fig. 6b) was not significantly

different between groups. On the other hand, total

(Fig. 7a), HMW (Fig. 7b), MMW (Fig. 7c), and LMW

(Fig. 7d) adiponectin did not change significantly in

either group.

0.01.02.03.04.05.06.07.08.09.0

10.011.012.013.014.015.0

0.0 1.0 2.0 3.0 4.0 5.0 6.0 7.0 8.0 9.0

10.0 11.0 12.0 13.0 14.0 15.0

Yacon

Aroid

Res

isti

n (n

g/m

L)

Yacon

Aroid

(Month)0 1 3 5

(Month)0 1 3 5

Lep

tin

(ng/

mL

)Yacon

Aroid

(Month)0 1 3 5

0

500

1,000

1,500

2,000

2,500

3,000

3,500

4,000

4,500

5,000

hs-C

RP

(ng

/mL

)

a b

c

FF

A (

mE

q/L

)

Yacon

Aroid

Yacon

Aroid

TN

F-α

(pg/

mL

)

*

*

(Month)0 1 3 5

(Month)0 1 3 5

0.000.050.100.150.200.250.300.350.400.450.500.550.600.650.700.750.80

0.00.10.20.30.40.50.60.70.80.91.01.11.21.31.41.51.61.71.8

d

e

Fig. 5 Time courses of high-sensitivity C reactive protein (hs-CRP)

(a), leptin (b), resistin (c), free fatty acids (FFAs) (d), and tumor

necrosis factor alpha (TNF-a) (e) during the 5-month follow-up in the

yacon (open circle) and control (closed square) groups. Data are

expressed as mean ± standard deviation. *p \ 0.01, compared with

baseline data

H. Satoh et al.

123

Discussion

Study results revealed that 5 months of yacon supple-

mentation did not significantly alter fasting plasma glucose

concentration and insulin sensitivity. However, supple-

mentation for 5 months reduced TNF-a and FFA concen-

trations compared with baseline levels. Furthermore, the

change from baseline in FFAs was significantly decreased

compared with the control group 5 months after treatment

commencement, whereas change from baseline in TNF-awas not significant between groups during the follow-up

period. However, it was previously reported that yacon

syrup improves insulin resistance and reduces body weight

in obese individuals [12]; differences in participant char-

acteristics between studies may explain these inconsisten-

cies. Patients in the previous report [12] were not diabetic

and had severe obesity (BMI 34 vs. 24.5 kg/m2) and insulin

resistance (HOMA-IR 6.30 vs. 2.59) compared with our

patients.

Elevated plasma FFA concentrations are typically cor-

related with obesity and decreased target-tissue insulin

sensitivity in humans [14]. Evidence suggests oversupply-

ing FFAs causes intracellular accumulation of FFA-derived

metabolic products [15], which can activate the serine/

threonine-kinase stress-activated protein kinase or JNK,

IKKb, and PKCh [15, 16], all of which can phosphorylate

insulin-receptor-substrate 1 (IRS-1) on serine residues.

Consequently, this impairs IRS-1 activation via tyrosine

phosphorylation, leading to a reduction in insulin-receptor-

mediated signaling and subsequent insulin resistance. Lipid

infusion and high fat feeding also impair PI3-kinase, Akt,

and PKCk/n activation in muscle [17]. Moreover, defects

in muscle PI3-kinase and PKCk/n activity has been

observed in obese and diabetic individuals [18]. As these

effects are fully reversed after removing FFAs from the

medium, FFA treatment does not produce nonspecific,

toxic effects.

The proinflammatory cytokine, TNF-a, is another

important contributor to the development of insulin resis-

tance [19]. TNF-a concentrations are elevated in adipose

tissue of various rodent obesity models as well as in obese

humans [19]. However, a genetic defect in TNF-a signaling

significantly improved insulin-receptor signaling capacity

and insulin sensitivity in dietary-induced and genetically

obese mice [20]. It is well documented that exposing 3T3-

L1 adipocytes to TNF-a for 3–4 days causes insulin

resistance [21] and that a large decrease in GLUT4 content

plays a major role in the decrease in insulin-stimulated

glucose transport [22, 23]. Moreover, long-term exposure

to TNF-a was reported to cause insulin resistance and

decrease insulin receptor and IRS-1 tyrosine phosphoryla-

tion in response to a maximal insulin stimulus in Fao

hepatoma cells [24] and L6 myocytes [25]. These reports

suggest long-term exposure to TNF-a directly causes

insulin resistance. Conversely, we previously demonstrated

that short-term exposure to TNF-a does not affect insulin-

stimulated glucose uptake in 3T3-L1 adipocytes but does

decrease adiponectin secretion. In the study reported here,

yacon supplementation for 5 months did not significantly

improve glucose or insulin metabolism despite significant

incremental reductions in TNF-a concentrations. These

findings raise the possibility that longer-term yacon sup-

plementation may improve glucose and insulin metabo-

lism. This study shows for the first time that yacon

supplementation significantly reduces serum TNF-a and

FFAs concentrations.

FOS, which are soluble, nondigestible carbohydrates,

effectively increase stool bulk. FOS are classified as pre-

biotics because they are fermented by the microflora in the

**p < 0.05

-30.0%

-20.0%

-10.0%

0.0%

10.0%

20.0%

30.0%

YaconAroid

(Month)1

FFA

YaconAroid

3

YaconAroid

5

-25.0%

-20.0%

-15.0%

-10.0%

-5.0%

0.0%

YaconAroid

(Month)

1

TNF-

YaconAroid

3YaconAroid

5

**

Δ

Δ α

a

b

Fig. 6 Changes (D) from baseline in free fatty acids (FFAs) (a) and

tumor necrosis factor alpha (TNF-a) (b) during the 5-month follow-

up in the yacon (open columns) and control (closed columns) groups.

Data are expressed the mean ± standard deviation. **p \ 0.05

compared with aroid group

Yacon reduces FFA and TNF-a

123

large intestine, leading to modulation in the composition of

the natural ecosystem. Yacon FOS are reported to have the

potential to be fermented by bifidobacteria and lactobacilli,

making yacon root a novel source of prebiotics [26]. Pro-

biotics are foods that contain microorganisms that modulate

intestinal microbiota and aid gastrointestinal tract func-

tioning and thus possibly prevent disease occurrence.

Meanwhile, prebiotics are food containing substances

resistant to enzymatic breakdown and stimulate prolifera-

tion or activity of certain bacteria in the intestinal micro-

biota, thus acting as selective substrate in the colon. Foods

that contain both probiotics and prebiotics are called syn-

biotics [27]. Within this context, fermented foods contain-

ing probiotics and prebiotics can be important dietary

components because of their nutritional characteristics and

ability to reduce the risk of chronic diseases [28]. Cani et al.

[29] showed that changes in intestinal microbiota induced

by an antibiotic treatment improved inflammation, oxida-

tive stress, and macrophage infiltration markers in mice fed

a high-fat diet. Those authors also showed increased insulin

signaling activation after intestinal microbiota modulation

in antibiotic-treated mice on the high-fat diet. In addition,

they also showed marked augmentation of Zo-1 (also

known as Tjp1) messenger RNA (mRNA), encoding zonula

occludens 1, an important intestinal barrier protein, which

correlated with diminished intestinal permeability and

reducing circulating lipopolysaccharide levels. There is also

some evidence suggesting the effect of TNF-a on gut-bar-

rier integrity. In Cao-2 cell cultures, TNF-a reduced trans-

epithelial resistance and ZO-1 protein expression via the

nuclear factor kappa B (NFkB)-dependent pathway [30].

The effect of TNF-a on NFkB activation increased myosin

light-chain kinase expression and activity, which subse-

quently leads to disorganization of tight-junction proteins at

the intestinal barrier [31]. The role of the inflammatory

pathway appears to be critical in the regulation of gut-bar-

rier function. It has also been reported that yacon can pre-

vent enteric infection by improving the immunological

intestinal barrier [32]. Increased levels of circulating bac-

teria or bacterial products, which are derived from micro-

biota, have been associated with insulin resistance [33]. In a

dietary supplementation study, daily intake levels of yacon

were calculated with respect to the amount of FOS. Yacon

tuber contains *12.5 % of FOS [9]. In our study, the group

treated with 100 g/day yacon completed the study with no

adverse events.

In conclusion, results of this study show that yacon

supplementation for 5 months significantly reduces TNF-a

0.0

0.5

1.0

1.5

2.0

2.5

3.0

0.0

0.5

1.0

1.5

2.0

2.5

3.0

3.5

4.0

Yacon

Aroid

LM

W a

dipo

nect

in (

g/m

L)

Yacon

Aroid

MM

W a

dipo

nect

in (

g/m

L)

(Month)0 1 3 5

(Month)0 1 3 5

Yacon

Aroid

HM

W a

dipo

nect

in (

g/m

L)

(Month)0 1 3 5

Tot

al a

dipo

nect

in (

g/m

L)

Yacon

Aroid

(Month)0 1 3 5

0.0

1.0

2.0

3.0

4.0

5.0

6.0

7.0

8.0

9.0

10.0

0.0 1.0 2.0 3.0 4.0 5.0 6.0 7.0 8.0 9.0

10.0 11.0 12.0 13.0 14.0 15.0

μ μ

μ μ

a b

c d

Fig. 7 Time courses of total adiponectin (a), high molecular weight

(HMW) (b), middle molecular weight (MMW) (c), and low molecular

weight (LMW) (d) adiponectin during the 5-month follow-up in the

yacon (open circle) and control (closed square) groups. Data are

expressed the mean ± standard deviation

H. Satoh et al.

123

and FFA concentrations but does not significantly alter

glucose and insulin metabolism. These results raise the

possibility that longer-term yacon supplementation may

improve insulin resistance.

Acknowledgments This work was supported in part by a Grant-

in-Aid for Challenging Exploratory Research (H.S.) and a Grant-in-

Aid for Scientific Research (H.S.) from the Ministry of Education,

Culture, Sports, Science, and Technology of Japan. We thank the

Fukushima prefectural government for kindly providing the yacon

tubers and aroid, and Atsuko Hashimoto and Hiroko Ohashi for

their excellent technical assistance. HS and TW designed the

research; HS, AK, KH, and HH conducted the research; HS and AK

analyzed the data; HS and TW wrote the paper, HS had primary

responsibility for final content. All authors read and approved the

final manuscript.

Conflict of interest The authors declare that they have no conflict

of interest.

References

1. Rask-Madsen C, Kahn CR. Tissue-specific insulin signaling,

metabolic syndrome, and cardiovascular disease. Arterioscler

Thromb Vasc Biol. 2012;32:2052–9.

2. Satoh H, Nguyen MT, Trujillo M, Imamura T, Usui I, Scherer PE,

Olefsky JM. Adenovirus-mediated adiponectin expression aug-

ments skeletal muscle insulin sensitivity in male wistar rats.

Diabetes. 2005;54:1304–13.

3. Satoh H, Nguyen MTA, Miles PDG, Imamura T, Usui I, Olefsky

JM. Adenovirus-mediated chronic ‘‘hyper-resistinemia’’ leads to

in vivo insulin resistance in normal rats. J Clin Invest.

2004;114:224–31.

4. Pajvani UB, Du X, Combs TP, Berg AH, Rajala MW, Schulthess

T, Engel J, Brownlee M, Scherer PE. Structure-function studies

of the adipocyte-secreted hormone acrp30/adiponectin. Implica-

tions fpr metabolic regulation and bioactivity. J Biol Chem.

2003;278:9073–85.

5. Kubota N, Yano W, Kubota T, Yamauchi T, Itoh S, Kumagai H,

Kozono H, Takamoto I, Okamoto S, Shiuchi T, Suzuki R, Satoh

H, Tsuchida A, Moroi M, Sugi K, Noda T, Ebinuma H, Ueta Y,

Kondo T, Araki E, Ezaki O, Nagai R, Tobe K, Terauchi Y, Ueki

K, Minokoshi Y, Kadowaki T. Adiponectin stimulates amp-

activated protein kinase in the hypothalamus and increases food

intake. Cell Metab. 2007;6:55–68.

6. Machii N, Satoh H, Kudoh A, Watanabe T. Resistin exacerbates

insulin resistance under the condition of low adiponectin in 3t3-l1

adipocytes. J Diabetes Metab. 2012;3:230.

7. Knowler WC, Barrett-Connor E, Fowler SE, Hamman RF, La-

chin JM, Walker EA, Nathan DM. Reduction in the incidence of

type 2 diabetes with lifestyle intervention or metformin. N Engl J

Med. 2002;346:393–403.

8. Kitabchi AE, Temprosa M, Knowler WC, Kahn SE, Fowler SE,

Haffner SM, Andres R, Saudek C, Edelstein SL, Arakaki R,

Murphy MB, Shamoon H. Role of insulin secretion and sensi-

tivity in the evolution of type 2 diabetes in the diabetes preven-

tion program: effects of lifestyle intervention and metformin.

Diabetes. 2005;54:2404–14.

9. Valentova K, Ulrichova J. Smallanthus sonchifolius and lepidium

meyenii - prospective andean crops for the prevention of chronic

diseases. Biomed Pap Med Fac Univ Palacky Olomouc Czech

Repub. 2003;147:119–30.

10. Yan X, Suzuki M, Ohnishi-Kameyama M, Sada Y, Nakanishi T,

Nagata T. Extraction and identification of antioxidants in the

roots of yacon (smallanthus sonchifolius). J Agric Food Chem.

1999;47:4711–3.

11. Geyer M, Manrique I, Degen L, Beglinger C. Effect of yacon

(smallanthus sonchifolius) on colonic transit time in healthy

volunteers. Digestion. 2008;78:30–3.

12. Genta S, Cabrera W, Habib N, Pons J, Carillo IM, Grau A,

Sanchez S. Yacon syrup: beneficial effects on obesity and insulin

resistance in humans. Clin Nutr. 2009;28:182–7.

13. Matthews DR, Hosker JP, Rudenski AS, Naylor BA, Treacher

DF, Turner RC. Homeostasis model assessment: insulin resis-

tance and beta-cell function from fasting plasma glucose and

insulin concentrations in man. Diabetologia. 1985;28:412–9.

14. Boden G. Role of fatty acids in the pathogenesis of insulin

resistance and niddm. Diabetes. 1997;46:3–10.

15. Yu C, Chen Y, Cline GW, Zhang D, Zong H, Wang Y, Bergeron

R, Kim JK, Cushman SW, Cooney GJ, Atcheson B, White MF,

Kraegen EW, Shulman GI. Mechanism by which fatty acids

inhibit insulin activation of insulin receptor substrate-1 (irs-1)-

associated phosphatidylinositol 3-kinase activity in muscle. J Biol

Chem. 2002;277:50230–6.

16. Hirosumi J, Tuncman G, Chang L, Gorgun CZ, Uysal KT, Maeda

K, Karin M, Hotamisligil GS. A central role for jnk in obesity and

insulin resistance. Nature. 2002;420:333–6.

17. Tremblay F, Lavigne C, Jacques H, Marette A. Defective insulin-

induced glut4 translocation in skeletal muscle of high fat-fed rats

is associated with alterations in both akt/protein kinase b and

atypical protein kinase c (zeta/lambda) activities. Diabetes.

2001;50:1901–10.

18. Kim YB, Kotani K, Ciaraldi TP, Henry RR, Kahn BB. Insulin-

stimulated protein kinase c lambda/zeta activity is reduced in

skeletal muscle of humans with obesity and type 2 diabetes:

reversal with weight reduction. Diabetes. 2003;52:1935–42.

19. Peraldi P, Spiegelman B. Tnf-alpha and insulin resistance: sum-

mary and future prospects. Mol Cell Biochem. 1998;182:169–75.

20. Uysal KT, Wiesbrock SM, Marino MW, Hotamisligil GS. Pro-

tection from obesity-induced insulin resistance in mice lacking

tnf-alpha function. Nature. 1997;389:610–4.

21. Hotamisligil GS, Murray DL, Choy LN, Spiegelman BM. Tumor

necrosis factor alpha inhibits signaling from the insulin receptor.

Proc Natl Acad Sci USA. 1994;91:4854–8.

22. Stephens JM, Pekala PH. Transcriptional repression of the glut4

and c/ebp genes in 3t3-l1 adipocytes by tumor necrosis factor-

alpha. J Biol Chem. 1991;266:21839–45.

23. Hotamisligil GS, Shargill NS, Spiegelman BM. Adipose

expression of tumor necrosis factor-alpha: direct role in obesity-

linked insulin resistance. Science. 1993;259:87–91.

24. Feinstein R, Kanety H, Papa MZ, Lunenfeld B, Karasik A. Tumor

necrosis factor-alpha suppresses insulin-induced tyrosine phos-

phorylation of insulin receptor and its substrates. J Biol Chem.

1993;268:26055–8.

25. Begum N, Ragolia L. Effect of tumor necrosis factor-alpha on

insulin action in cultured rat skeletal muscle cells. Endocrinol-

ogy. 1996;137:2441–6.

26. Pedreschi R, Campos D, Noratto G, Chirinos R, Cisneros-

Zevallos L. Andean yacon root (smallanthus sonchifolius poepp.

Endl) fructooligosaccharides as a potential novel source of pre-

biotics. J Agric Food Chem. 2003;51:5278–84.

27. Bengmark S, Martindale R. Prebiotics and synbiotics in clinical

medicine. Nutr Clin Pract. 2005;20:244–61.

28. Cavallini DC, Suzuki JY, Abdalla DS, Vendramini RC, Pauly-

Silveira ND, Roselino MN, Pinto RA, Rossi EA. Influence of a

probiotic soy product on fecal microbiota and its association with

cardiovascular risk factors in an animal model. Lipids Health Dis.

2011;10:126.

Yacon reduces FFA and TNF-a

123

29. Cani PD, Bibiloni R, Knauf C, Waget A, Neyrinck AM, Delzenne

NM, Burcelin R. Changes in gut microbiota control metabolic

endotoxemia-induced inflammation in high-fat diet-induced

obesity and diabetes in mice. Diabetes. 2008;57:1470–81.

30. Ma TY, Iwamoto GK, Hoa NT, Akotia V, Pedram A, Boivin MA,

Said HM. Tnf-alpha-induced increase in intestinal epithelial tight

junction permeability requires nf-kappa b activation. Am J

Physiol Gastrointest Liver Physiol. 2004;286:G367–76.

31. Ye D, Ma I, Ma TY. Molecular mechanism of tumor necrosis

factor-alpha modulation of intestinal epithelial tight junction

barrier. Am J Physiol Gastrointest Liver Physiol.

2006;290:G496–504.

32. Velez E, Castillo N, Meson O, Grau A, Bibas Bonet ME, Per-

digon G. Study of the effect exerted by fructo-oligosaccharides

from yacon (smallanthus sonchifolius) root flour in an intestinal

infection model with salmonella typhimurium. Br J Nutr.

2013;109:1971–9.

33. Burcelin R, Garidou L, Pomie C. Immuno-microbiota cross and

talk: the new paradigm of metabolic diseases. Semin Immunol.

2012;24:67–74.

H. Satoh et al.

123