Endocrine Journal 2012, 59 (9), 845-847

Note

Effect of metformin on hepatic glucose production in

Japanese patients with type 2 diabetes mellitus
Mitsuyoshi Takahara1), Hideaki Kaneto1), Naoto Katakami1), Munehide Matsuhisa2) and Iichiro Shimomura2)
1)
2)

Department of Metabolic Medicine, Osaka University Graduate School of Medicine, Osaka, Japan
Diabetes Therapeutics and Research Center, Tokushima University, Tokushima, Japan

Abstract. We investigated the effect of metformin on hepatic glucose production and peripheral glucose uptake in Asian
patients with type 2 diabetes mellitus. We recruited ten Japanese patients whose fasting glucose levels remained poorly
controlled under meal-time injection of short-acting insulin. Metformin was added to their insulin therapy, and both
hepatic glucose production and peripheral glucose uptake were assessed before and one week after metformin treatment,
with the use of stable isotope [6,6-2H2] glucose. Metformin was titrated to a maximum dose of 500 mg. As a result, fasting
glucose levels and hepatic glucose production were significantly improved after the metformin treatment (p < 0.01 and
0.02), whereas their peripheral glucose uptake was not significantly changed (p = 0.63). Furthermore, the change of fasting
glucose levels was significantly correlated with that of hepatic glucose production, whose coefficient was 0.76 (p = 0.01).
On the other hand, there was no significant correlation between the change of fasting glucose levels and that of peripheral
glucose uptake (p = 0.43). In conclusion, low dose of metformin significantly reduced hepatic glucose production in
Japanese patients with type 2 diabetes mellitus. The efficacy of metformin on correcting fasting hyperglycemia was
strongly associated with reduced hepatic glucose production, rather than ameliorated peripheral glucose uptake.
Key words: Metformin, Hepatic glucose production, Stable isotope

Metformin is now regarded as the first-line medication for type 2 diabetes mellitus in many clinical
guidelines [1], because of its hypoglycemic effectiveness as well as low price, although its mechanism of
action is not fully understood. The mechanisms so
far revealed are suppression of hepatic glucose production (HGP) and improvement of peripheral glucose uptake (PGU) [2], and the former is recognized
as the main contributor to lowering fasting glucose
levels in Caucasian patients, especially who are obese
and therefore expected to have hepatic insulin resistance. However, no data are available about whether
the efficacy of metformin can be similarly explained
by HGP suppression in Asians, who are less obese but
are reported to be more peripherally insulin resistant
perhaps because of different fat distribution [3]. We
therefore investigated the effect of metformin on HGP
Submitted Feb. 16, 2012; Accepted Apr. 27, 2012 as EJ12-0068
Released online in J-STAGE as advance publication May 23, 2012

Correspondence to: Hideaki Kaneto, M.D., Ph.D., Department

of Metabolic Medicine, Osaka University Graduate School of
Medicine, 2-2 Yamadaoka, Suita, Osaka 565-0871, Japan
E-mail: kaneto@endmet.med.osaka-u.ac.jp
The Japan Endocrine Society

in Japanese patients with type 2 diabetes mellitus.

Patients and Methods

We recruited ten Japanese patients with type 2 diabetes mellitus, whose fasting glucose levels remained
poorly controlled under meal-time injection of shortacting insulin. Their fasting glucose levels remained
higher than bedtime glucose levels, even after insulin
was titrated enough to keep their bedtime glucose levels below 7.8 mmol/L. Metformin was then added to
their insulin therapy, and was titrated to a maximum
dose of 500 mg. The medication was taken once a day,
at bedtime. We assessed HGP and PGU, as well as their
fasting glucose levels, before and one week after metformin treatment. HGP and PGU were evaluated with
the use of [6,6-2H2] glucose. In brief, [6,6-2H2]glucose was infused for 120 minutes (a bolus infusion at
0.3 mg/kg/min for 10 minutes and a subsequent steady
infusion at 0.05 mg/kg/min for 110 minutes), and blood
samples were obtained. Its enrichment in plasma was
analyzed by gas chromatography/mass spectrometry,
after trifluoroacetylation of glucose [4]. We performed

Takahara et al.

846

Table 1 Effect of metformin on hepatic glucose production in Japanese patients with

type 2 diabetes mellitus
Baseline

After Treatment

p value

HGP (mol/kg/min)
PGU (mL/kg/min)

18 (15, 27)
2.4 (2.0, 2.9)

15 (13, 18)
2.4 (2.0, 2.7)

0.02
0.63

FPG (mmol/L)
Insulin (pmol/L)

8.3 (7.1, 9.0)

43 (24, 54)

6.8 (6.5, 7.6)

30 (22, 46)

<0.01
0.18

Data are medians and quartiles. A p value was assessed with the use of Wilcoxon
signed-rank test. HGP, hepatic glucose production; PGU, peripheral glucose uptake;
FPG, fasting plasma glucose.

the current study in accordance with the declaration of

Helsinki, and it was approved by the ethics committee of Osaka University. We obtained written informed
consent from all the recruited patients. Statistical
analyses were performed using IBM SPSS Statistics
Version 19 (SPSS Inc., IL, USA). Data are presented
as medians and quartiles. A p value was assessed with
nonparametric procedures because of the small sample
size and the uncertainty about data distribution.

Results
Six patients were male and four were female. They
were 56 (52, 60) years old, and their body mass index
was 26.7 (22.8, 30.9) kg/m2 (medians and quartiles).
Their waist circumference was 101 (92, 108) cm; eight
of ten had an increased waist circumference, defined as
85 cm in males and 90 cm in females. The baseline
fasting glucose level were 8.3 (7.1, 9.0) mmol/L under
multiple short-acting insulin injection. Triglycerides,
high-density lipoprotein (HDL) cholesterol, low-density lipoprotein (LDL) cholesterol levels were 1.7 (1.4,
2.0) mmol/L, 1.3 (1.0, 1.5) mmol/L, and 3.4 (3.0, 4.1)
mmol/L, respectively.
Fasting glucose levels and HGP were significantly
improved after the metformin treatment (p < 0.01 and
0.02), whereas their PGU was not significantly changed
(p = 0.63) (Table 1). Furthermore, the change of fasting
glucose levels was significantly correlated with that of
HGP, whose coefficient was 0.76 (p = 0.01). On the
other hand, there was no significant correlation between

the change of fasting glucose levels and that of PGU

(p = 0.43). Neither was body mass index significantly
associated with the change of fasting glucose levels,
HGP or PGU (p = 0.24, 0.33, and 0.61, respectively).

Discussion
It was long pointed out that metformin was effective
in Asian patients, even in a low dose [5], but its mechanism remained unknown. Our current study revealed
that efficacy of metformin on correcting fasting hyperglycemia was strongly associated with reduced HGP,
rather than ameliorated PGU, in Japanese patients, as
observed in Caucasians. Given that an impaired HGP
suppression was observed in lean Japanese patients
and was significantly associated with fasting hyperglycemia [4], these findings would support the validity of
metformin therapy in Japanese patients to target at their
underlying pathogeneses. In conclusion, low dose of
metformin significantly reduced hepatic glucose production in Japanese patients with type 2 diabetes mellitus. The efficacy of metformin on correcting fasting
hyperglycemia was strongly associated with reduced
hepatic glucose production, rather than ameliorated
peripheral glucose uptake.

Acknowledgements
There are no conflicts of interests associated with
this manuscript.

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