Identification of seven loci for static glucokinesis and dynamic
glucokinesis in mice
Laboratory for Genome Exploration Research Group, RIKEN Genomic Sciences Center (GSC), RIKEN Yokohama Institute, 1-7-22, Suehirocho,
Tsurumi-ku, Kanagawa, 230-0045, Japan
Genome Science Laboratory, RIKEN, 2-1, Hirosawa, Wakoshi, Saitama, 351-0198, Japan
Division of Genomic Information Resource Exploration, Science of Biological Supramolecular Systems, Yokohama City University, Graduate School
of Integrated Science, 1-7-29, Suehirocho, Tsurumi-ku, Kanagawa, 230-0045, Japan
Experimental Animal Research Division, Biogenic Resources Center, RIKEN Tsukuba Institute, 3-1-1 Koyadai, Tsukuba 305-0074, RIKEN Tsukuba
Institute, 3-1-1 Koyadai, Tsukuba 305-0074, Japan
Department of Medicine, Tsukuba University, Tennodai 1-1-1, Tsukuba, Ibaraki, 305-0006, Japan
Received: 4 October 2001 / Accepted: 8 February 2002
Abstract. Non-insulin-dependent diabetes mellitus (NIDDM) is
characterized by a breakdown of glucose homeostasis and is re-
sponsible for serious complications in various organs and vessels.
Most of the genetic factors of NIDDM are yet unknown. Here, we
identified two types of genetic factors that regulate homeostasis of
blood glucose by measuring various pharmacokinetic parameters,
some of which are used in the non-compartment analysis of drug
metabolism in 340 F
progeny from the NIDDM model KK-A
Jcl mouse strain, and in non-diabetic PWK strain. We define
“static glucokinesis” as the regulation of homeostasis that occurs
during glucose deprivation, and “dynamic glucokinesis” as that
during glucose stress; for instance, glucose tolerance test. Quanti-
tative trait locus analysis revealed eight loci involved in the regu-
lation of glucose homeostasis on chromosomes 7 (Nidd1k), 2
(Nidd2k),1(Nidd3k, Nidd4k, and Nidd5k), 11 (Nidd6k),5(Nidd7k)
(named Nidd1k through Nidd7k), and 4 (Bwt1k). Nidd1k, Nidd4k,
and Nidd7k were novel loci associated with NIDDM in mice.
Nidd1k, Nidd2k, Nidd3k, and Nidd4k had linkage to factors char-
acteristic of both static and dynamic glucokinesis. Nidd5k and
Nidd6k showed linkage specific to markers of dynamic glucokine-
sis, and Nidd7k had linkage specific to static glucokinesis. Bwt1k
was linked to obesity. Thus, the genetic factors for static gluco-
kinesis and those for dynamic glucokinesis partially overlapped.
Non-insulin-dependent diabetes mellitus (NIDDM) accounts for
serious secondary sequelae with the major mortality. Although
Calnain 10 gene was detected for the candidate for NIDDM in
human (Horikawa et al. 2000), NIDDM still consists of many
unknown polygenic factors.
In mice, many QTLs were detected by the studies with differ-
ent strains. Diabetic QTLs with NZO(Leiter et al., 1998), KK (Ay)
(Suto et al. 1998), NSY (Ueda et al. 1999), TSOD (Hirayama et al.
1999), C57BL/6 (Kayo et al. 2000), and TallyHo (Kim et al. 2001)
strains have been reported. Leiter et al. (1998) detected three QTLs
progeny mated NZO with NON. Hirayama et al. (1999)
reported three QTLs in (TSOD × C3H/He) F
. Suto and colleagues
(Suto et al. 1998) found one with significant linkage and six sig-
nificant linkage in (KK-A
× C57BL/6J) F
. Recently, Kim et al.
(2001) detected four QTLs using TallyHo strains.
The KK strain is intolerant to glucose without hyperglycemia.
Diabetes of the KK strain is associated with marked insensitivity
of adipose tissue to insulin (Taketomi et al. 1973.) Diabetes and
obesity of KK is moderate, but introduction of the agouti yellow
) for KK increase diabetes markedly (Nishimura 1969;
Dulin and Wyse 1970).
To begin our study, we performed intraperitoneal glucose tol-
erance tests (ipGTTs) by administering 2.5 mg glucose per g body
weight (BW) to KK-A
/Ta Jcl (KK-A
) mice and to the nondia-
betic PWK strain, and we obtained glucose decay curves (Fig. 1).
In the PWK animals, glucose began to disappear rapidly from the
blood by 15 min after injection, and the glucose level had normal-
ized by 30 min after injection. However, hyperglycemia was pro-
longed in the KK-A
Three pharmacokinetic models (the one-, two-, and non-
compartment models) (Carson and Finkelstein 1983; Cobelli et al.
1999; Nuesch 1984) are used to describe the metabolism of various
exogenous molecules. Because we could not determine the number
of compartments from the patterns of the glucose decay curves
(Fig. 1a), we used four parameters for the non-compartment model
(Nuesch 1984) to analyze glucose metabolism in our diabetes
study. Specifically, we evaluated the area under the blood concen-
tration–time curve (AUC), the area under the moments curve
(AUMC), the mean resident time (MRT), and the steady-state
glucose concentration (C
) during ipGTT (Fig. 1b, see Methods).
In addition to these four parameters, blood sugar (i.e., glucose)
levels at 30 min (BS30), 60 min (BS60), and 120 min (BS120) can
be defined as dynamic aspects of drug elimination in pharmaco-
kinetic models (Nuesch 1984). We named the regulation of glu-
cose homeostasis during glucose stress “dynamic glucokinesis”
(Fig. 1b), which we assessed by evaluating the seven previously
mentioned phenotypes. The regulation of blood glucose to prevent
hypoglycemia during fasting also is essential; we defined this type
of regulation as “static glucokinesis” (Fig. 1b). To evaluate static
glucokinesis, we measured the fasting blood glucose level
(FBG)—here, the blood glucose concentration of mice after a 16-
to 20-h fast.
Materials and methods
mice were purchased from Clea Japan (Tokyo,
Japan). PWK was maintained in the Animal Facility of Biogenic Resources
Center, RIKEN Tsukuba Institute. The mice were fed with a standard diet
(CRF-1: Oriental Industries, Japan) and tap water ad libitum at a tempera-
ture of 21°–25°C and a humidity of 50–60%, with a 12-h light period
Since the agouti yellow mutation is strongly associated with obesity
Correspondence to: Y. Hayashizaki; E-mail: firstname.lastname@example.org
Mammalian Genome 13, 293–298 (2002).
© Springer-Verlag New York Inc. 2002
Incorporating Mouse Genome