Articles |
From Departments of Biochemistry and Comparative Biosciences (T.R., K.L.S., A.D.A.) and Biodynamics Laboratory (C.D.,G.D.C.), University of Wisconsin-Madison, Madison, WI 53706.
Correspondence to Alan D. Attie, PhD, Department of Biochemistry, University of WisconsinMadison, 420 Henry Mall, Madison, WI 53706-1569. E-mail attie{at}biochem.wisc.edu
| Abstract |
|---|
|
|
|---|
Key Words: diabetes genomes insulin resistance
| Introduction |
|---|
|
|
|---|
People's susceptibility to insulin resistance and NIDDM appears to result from an interplay between genetic and dietary factors.68 The Pima Indians provide a dramatic example.9,10 The population in Mexico that consumes the traditional high-carbohydrate, low-fat diet has a very low incidence of NIDDM. In striking contrast, the population living in Arizona consumes a high-fat diet and has an incidence of NIDDM of about 65%, among the highest in the world. Thus, in this population, there appears to be a unique combination of susceptibility alleles that interact with diet to produce insulin resistance and NIDDM.
Studies in rats1113 and mice14,15 also reveal that genetic and dietary factors play a role in insulin resistance. Certain strains are more susceptible to diet-induced insulin resistance.13,14 However, apart from the four recognized gene loci that are involved in causing obesity (and, indirectly, insulin resistance) and the agouti locus,1620 specific insulin resistance genes have not yet been identified in rodent models. Paralleling human genetic studies, gene mapping in rodent models suggests that multiple gene loci interact to influence the susceptibility to insulin resistance.2123
Extensive clinical genetic studies in humans have assessed the potential role of insulin signaling and glucose metabolism genes in NIDDM.5,6,24,25 In small numbers of patients, polymorphisms at candidate loci such as the GLUT2 glucose transporter,26 insulin,27,28 and the insulin receptor29 have been found.5 However, these are extremely rare alleles relative to the high incidence of NIDDM. In addition, it appears more likely that these alleles interact with particular alleles at other loci, and perhaps environmental factors, to produce the full-blown NIDDM syndrome.29 Additional genes need to be identified before a more complete understanding of these gene-gene interactions can be achieved.
Our laboratory has been using the BTBR mouse strain for chemical mutagenesis studies. This strain shows normal insulin responsiveness even when shifted to a moderately high-fat diet. In preparation for genetic mapping, we crossed BTBR mice with C57BL/6J (B6) mice, since our studies had shown that the B6 strain also exhibited no insulin resistance or hyperinsulinemia when shifted to a 15% fat diet. We were surprised to discover that the male offspring from the BTBRxB6 cross showed severe insulin resistance (without hyperinsulinemia) on the basal diet and severe hyperinsulinemia on the high-fat diet. Since this phenotype is not present in either parental strain, it results from unique interactions between alleles in the BTBR and B6 genomes.
In this report, we describe the phenotype of a new model of insulin resistance. The animals represent a valuable new model for the complex genetics of insulin resistance and for studying the relationship between dietary lipid and hyperinsulinemia.
| Methods |
|---|
|
|
|---|
C57BL/6J mice were obtained from the Jackson Laboratory. All animals were housed under controlled temperature (24°C) and lighting (12 hours light: 0600 to 1800; 12 hours dark: 1800 to 0600) with free access to food and water. All procedures were approved by the Institutional Animal Care and Use Committee at the University of Wisconsin-Madison.
Mouse diets were obtained from Harlan Teklad. The basal diet (Formulab chow, 5008) consisted of 6.5% fat and 23.5% protein (by weight), and the experimental diet (TD 94059) consisted of diet 5015 supplemented with cocoa butter to achieve a fat content of 15%. Each diet was supplemented with a vitamin and mineral mixture (Harlan Teklad).
After weaning, the animals were fed the basal diet until 6 weeks of age. Thereafter, the control group continued on the same diet, while the experimental group was switched to the 15% fat diet. Both groups were kept on the diets for 4 weeks and were immediately studied. Daily food consumption was determined for 3 weeks by weighing the food and correcting for the amount not eaten, including spillage.
Food was withdrawn from the mice at 0800 hours on the day of the experiments. The animals were weighed, and between 1200 and 1400 hours, they were anesthetized with an intraperitoneal injection of sodium pentobarbital (50 mg/kg body weight). The order of anesthetization was randomized so that the mean time of tissue sampling did not vary among the groups. Blood was sampled via the retroorbital sinus for determination of glucose, insulin, free fatty acid, triacylglycerol, and cholesterol. Right and left soleus and extensor digitorum longus (EDL) were dissected out. The following visceral fat pads were removed from the abdominal cavity and weighed: gonadal/ovarian, consisting of the adipose tissue associated with the reproductive organs; perirenal, consisting of the adipose tissue associated with the kidneys; retroperitoneal, consisting of the adipose tissue associated with the dorsal wall of the peritoneal cavity; and omental-mesenteric, consisting of the adipose tissue associated with the digestive organs.
Metabolic Analyses
Plasma glucose was measured by the glucose oxidase method (Sigma
Diagnostics). Total cholesterol and
triacylglycerol were quantified by the use of
cholesterol esterase and cholesterol oxidase
reactions and lipase, respectively, using kits from Sigma
Diagnostics. Plasma insulin was analyzed by a
radioimmunoassay from Linco. Free fatty acid levels were determined
using the acyl-CoA synthetase and acyl-CoA oxidase method (Wako
Chemicals USA).
Muscle Incubations
Muscles were incubated at 35°C in a temperature-controlled,
shaking water bath in 3 mL of pregassed Krebs-Henseleit bicarbonate
buffer (KHB)33 supplemented with 0.1% bovine
serum albumin (BSA), 8 mmol/L glucose, and 32
mmol/L mannitol with or without insulin, as specified in the
text. The gas concentrations in the 25-mL Erlenmeyer flasks were 95%
O2, 5% CO2, except in
experiments involving hypoxia, where the gas phase was 95%
N2, 5%
CO2.34 The incubation time
at 35°C was 30 minutes except in experiments involving
hypoxia. In experiments involving stimulation of glucose
transport by hypoxia, all muscles (ie, hypoxic and control
oxygenated muscles) were incubated for 45 minutes. After
the initial incubation period, all muscles were washed for 10 minutes
at 30°C in oxygenated medium to remove glucose before
assay of glucose transport activity. The medium (3 mL/flask) consisted
of KHB containing BSA and 40 mmol/L mannitol. The gas phase
in the flasks was 95% O2, 5%
CO2. If insulin was present during the
initial incubation, it was also added to the wash step.
Determination of Glucose Transport Activity
Glucose transport activity was measured with the
nonmetabolizable glucose analog, 2-deoxyglucose
(2-DG).35 Muscles were incubated for 15 minutes
at 30°C in 2 mL of oxygenated KHB supplemented with
1 mmol/L
2-deoxy-D-[1,2-3H]glucose (1.7
mCi/mmol) and 39 mmol/L
[U-14C]mannitol (8.5 µCi/mmol). If insulin
was present during the 35°C incubation, it was also included in
the transport assay. The gas phase in the flasks consisted of 95%
O2, 5% CO2. Uptake of 2-DG
into muscles under basal and stimulated conditions is linear over the
time period assayed. Furthermore, at stimulated rates of uptake, more
than 98% of the intracellular 2-DG is
phosphorylated.36 At the
conclusion of this incubation period, muscles were rapidly blotted onto
filter paper, trimmed, and quick-frozen between aluminum clamps cooled
to the temperature of liquid N2. Muscles were
stored at -70°C until use and subsequently weighed and processed by
homogenization in 0.3 mol/L perchloric acid
at 4°C. The homogenate was centrifuged, and
aliquots of the supernatant were used for determination of glucose
transport activity by quantitating the 3H and
14C radioactivity in a liquid scintillation
counter.
Oral Glucose Tolerance Tests
Food was withdrawn for 4 hours (0800 to 1200 hours), followed by
a baseline (0 minute) blood sample collected from the retroorbital
sinus, and glucose (1 g glucose/kg body weight) was administrated by
oral gavage. Blood was sampled at 15, 30, and 90 minutes for
measurements of plasma glucose and insulin concentrations.
Statistical Analysis
All values are reported as the mean±SD of indicated samples and
number of experiments. Comparison of different treatments was evaluated
by the Student's t test (two-tailed). One-way ANOVA was
used when comparisons were made among three groups. The Tukey-Kramer
Multiple Comparison post hoc test was used to locate the source of
significant variance.
| Results |
|---|
|
|
|---|
|
|
The diet-induced hyperinsulinemia in the (BTBRxB6)F1 mice could be a consequence of outbreeding of the BTBR mice and the loss of homozygosity of particular BTBR alleles. Accordingly, BTBR mice were bred with A/J and with C3H/HeJ mice, strains that also do not show diet-induced hyperinsulinemia under the conditions used in these experiments. (BTBRxA/J)F1 mice and (BTBRxC3H/HeJ)F1 mice showed a phenotype that was indistinguishable from any of the parental strains, a result indicating that the diet-induced hyperinsulinemia in the (BTBRxB6)F1 mice is not simply a consequence of loss of homozygosity of BTBR alleles.
Oral Glucose Tolerance
The fasting insulin values suggested a diet-induced insulin
resistance in (BTBRxB6)F1 males. Therefore, we
performed oral glucose tolerance tests on
(BTBRxB6)F1 males that were fed either the
baseline diet or the 15% fat diet. In addition, because of the sex
difference in the F1s, we also evaluated females
on the 15% fat diet.
(BTBRxB6)F1 males on the 15% fat diet had
moderate fasting hyperglycemia compared to the other two groups (Fig 3
; P<.001 versus females on
the 15% fat diet; P<.05 versus males on the baseline
diet). The blood glucose of the fat-fed males was significantly
different from that of both other groups at each time point
(P<.01 versus females; P<.05 versus males on
the baseline diet). In addition, the blood glucose levels of the males
on the baseline diet was significantly higher than that of females at
15 and 30 minutes (P<.05). In response to the oral glucose
challenge, the F1 males on the 15% fat diet
showed delayed glucose clearance and pronounced
hyperinsulinemia: Peak insulin levels were fourfold
higher in the fat-fed males than in males on the baseline diet (Fig 3
).
In addition, the males on the baseline diets showed significantly
higher (P<.01 by ANOVA) insulin levels than did the fat-fed
females at 15 and 30 minutes after the glucose load (Fig 3
).
|
Body Weight and Fat Distribution
Obesity is strongly associated with insulin resistance. It was
therefore important to determine whether the
hyperinsulinemia in the
(BTBRxB6)F1 male mice might be a consequence of
obesity. The 15% fat diet led to a larger increase in visceral fat
mass in male than in female F1s (Table 1
). In the male mice, insulin levels
correlated with visceral fat content (Fig 4
). However, although the high-fat diet
produced more visceral fat in the female mice, there was not a
commensurate increase in fasting insulin levels (Fig 4
).
|
|
The 15% fat diet has a higher caloric density than the baseline diet.
The fat composition of a diet can affect feeding behavior by changing
the palatability of the food. Accordingly, we monitored food intake.
Food consumption was determined by weighing the food daily, adjusting
for spillage, over three weeks. The daily food consumption was
determined for 3 weeks by weighing the food and subtracting the amount
not eaten, including spillage. On the basal diet, the caloric intake
was 20.1 calories/day, and on the 15% fat diet, it was 23.2
calories/day. The visceral fat mass of the mice on the 15% fat diet
was increased relative to that of mice on the baseline diet in both
female and male mice (Table 1
). Nevertheless, only the males became
hyperinsulinemic on the 15% fat diet (Fig 4
). In
addition, males on the baseline diet were insulin-resistant in
muscle. Therefore, the hyperinsulinemia and the
insulin resistance cannot be attributable solely to the increase in
visceral fat.
Plasma Lipids
Insulin resistance is often associated with increases in plasma
triglycerides and sometimes elevated free fatty acid
levels. Serum triglyceride was elevated by approximately
40% in the males that received either diet, compared to the females.
Free fatty acid levels were unaffected by diet and did not differ
between male and female mice. In both females and males that were fed
the high-fat diet, plasma cholesterol increased twofold and
1.7-fold, respectively, compared to animals that were given regular
chow (Table 2
). Apolipoprotein B levels
were not significantly affected by the diet in either group.
|
Basal and Insulin-Stimulated Glucose Transport Activity in
Skeletal Muscle
Skeletal muscle is the major site for insulin-mediated whole-body
glucose disposal; hence, this tissue is an important contributor to the
maintenance of glucose homeostasis. Accordingly, we measured
the uptake of 2-deoxyglucose in soleus and EDL muscles in the absence
(basal) and presence of 20,000 µU/ml insulin and 150 µU/ml insulin
(insert) in F1 mice on the 15% fat diet (Figs 5A
and 5B
).
|
There was a dramatic sex difference in insulin-stimulated glucose
uptake in the (BTBRxB6)F1 mice. In female
(BTBRxB6)F1 mice on either diet, there was no
evidence of insulin resistance in muscle. In female mice eating regular
chow (Fig 5A
) or a 15% fat diet (Fig 5B
), maximal (20,000 µU/ml) and
physiological (150 µU/ml) insulin concentrations
stimulated 2-deoxyglucose transport approximately 3.5-fold and 2.5-fold
respectively, in the soleus muscle. The EDL muscle was similarly
responsive.
In striking contrast to the females, both muscles from male
(BTBRxB6)F1 mice were profoundly insulin
resistant, even on the basal diet. 2-Deoxyglucose transport
activity was not stimulated by insulin in the soleus (150 or 20,000
µU/ml insulin) or the EDL (20,000 µU/ml insulin), regardless of
diet (Figs 5A
and 5B
). Thus, in this animal model, it appears that the
degree of insulin resistance does not predict insulin levels. Placing
the animals on a moderately high-fat diet induced
hyperinsulinemia but did not exacerbate the
impaired insulin-stimulated glucose transport.
Since the (BTBRxB6)F1 animals on the baseline
diet were insulin resistant without being
hyperinsulinemic, it was conceivable that the parental
strains might also show the same phenotype. Therefore, it
became important to assess the insulin responsiveness of the parental
strains. In both strains, insulin stimulated 2-deoxyglucose transport
in soleus and EDL muscles (Figs 6A
and 6B
). Muscle tissue from males and females was equally responsive to
insulin. Hence, the parental strains are not insulin resistant;
therefore, the insulin resistant phenotype of the
(BTBRxB6)F1 animals is a consequence of a
synergistic combination of BTBR and B6 alleles.
|
Basal and Hypoxia-Stimulated Glucose Transport Activity in
Skeletal Muscles in Mice on Fat Diet
Hypoxia stimulates glucose transport through the GLUT4
transporter by an insulin-independent pathway.34
Consequently, the measurement of hypoxia-induced glucose
transport allowed us to determine whether the impairment in
insulin-stimulated glucose transport in the
(BTBRxB6)F1 mice was specific to the
insulin-stimulated pathway. Hypoxia treatment of soleus and EDL
muscles stimulated the 2-deoxyglucose transport activity twofold to
threefold (Fig 7
). In contrast to insulin
stimulation, the degree of stimulation by hypoxia was the same
in male and female mice, a finding indicating that the impaired glucose
transport was specific for an insulin-sensitive step.
|
| Discussion |
|---|
|
|
|---|
Prior studies in mice and rats have shown that some strains develop insulin resistance in response to a high-fat diet. Many of these studies used diets that are extremely high in fat for rodents even though they are only moderately high relative to normal human diets. In addition, some of the diets include cholic acid to enhance fat absorption. A potential drawback of cholic acid is that it induces inflammatory responses in mice; therefore, the induction of inflammation-related genes such as cytokines might complicate the interpretation of experiments aimed at investigating insulin responsiveness.37 In the present studies, we chose to use a moderately high-fat diet without cholate to increase the likelihood of discovering major gene effects without inducing inflammatory responses.
It is surprising to note that despite severe insulin resistance, the hybrid mice had normal insulin levels on the basal diet. In contrast, after 4 weeks on the 15% fat diet, the same animals developed significant hyperinsulinemia even though their level of insulin resistance appeared to be the same. The glucose transport studies were carried out in muscle because it is responsible for the majority of insulin-stimulated glucose clearance. Our studies cannot rule out the possibility that other tissues, such as adipose tissue, might, in the presence of muscle insulin resistance, make a larger contribution to overall glucose clearance, thus preventing hyperinsulinemia. However, the glucose tolerance tests seem to argue against such a compensatory effect because whole-animal glucose tolerance is impaired in the hybrid animals.
The effect of lipids on insulin secretion has been explained in several ways. Fatty acids have been suggested to directly influence insulin secretion.38,39 Perhaps a more important mechanism is through the well-studied effect of fatty acids on hepatic gluconeogenesis. Studies of lipolysis-induced insulin release suggest that it is an indirect consequence of fatty acid stimulation of gluconeogenesis,40,41 a result of the potent inhibitory effect of acetyl-CoA on pyruvate dehydrogenase and activation of pyruvate carboxylase.42 In the (BTBRxB6)F1 mice, the normal amount of insulin is probably just barely enough to keep pace with the rate of glucose production. A lipid load in the diet might tip the balance by inducing excess glucose production, leading to a large induction in insulin secretion.
In our studies of oral glucose tolerance, muscle glucose transport, and diet-induced hyperinsulinemia, there was a difference between male and female (BTBRxB6)F1s: Only males showed impaired glucose tolerance, insulin resistance, and diet-induced hyperinsulinemia. Sexual dimorphism in the expression of diabetic phenotypes has been well studied by Leiter and co-workers. The balance of estrogenic and androgenic hormones influences hepatic glucose output.43,44 Thus, alterations in the effective concentrations of estrogen or testosterone can interact with diabetes-susceptibility genes to exacerbate or counteract a diabetes phenotype. The sulfation of dehydroepiandrosterone (DHEA), an androgen prehormone, effectively reduces the androgen level. This sulfation reaction, catalyzed by DHEA sulfotransferase, is suppressed at puberty in lean male mice. The retention of its activity in lean female mice effectively inactivates androgens in females. In animals expressing certain diabetogenic alleles, such as db and ob, the failure of the females to induce the sulfation of DHEA makes them susceptible to hyperglycemia and insulin resistance.45 In contrast, when females retain the ability to catalyze the sulfation of DHEA, as in the fat/fat mouse, they are protected from the diabesity phenotype. It would appear that the genes contributing to the diabetes phenotypes in the (BTBRxB6)F1s do not suppress females' ability to inactivate androgens as is the case in certain strains of mice carrying the db or ob mutation.
Diabetes mellitus is currently more prevalent than at other times in recorded history. In addition, diabetes is far more common in populations that consume high-calorie, high-fat diets and have a relatively sedentary lifestyle. It has been argued that the high prevalence of diabetes is a consequence of the selection in favor of diabetes traits, which would be beneficial under other circumstances.46 For example, there might be a potential benefit of having a blunted insulin response in times of nutritional deprivation. Indeed, animal experiments suggest that diabetic animals are better able to withstand starvation than are normal animals.47 Thus, a blunted insulin response may have been selected during times of nutritional deprivation and exists as a pathological state in times of nutritional abundance.46
Given the many effects of insulin and the complexity of the insulin signaling system, one would predict that many gene loci might have alleles that influence the response to insulin. In addition, different types of nutritional adversity might interact with genes in a unique fashion to produce particular insulin-resistant syndromes.
The genetics of insulin resistance and diabetes mellitus is complex. With only a few rare exceptions, single gene loci have not yet been identified with particular diabetes alleles that act independently to produce the clinical disease with complete penetrance. Rather, the genetic data suggest that multiple genes are involved and that they interact with one another and with environmental factors.5 This inference is supported by the recent creation of an animal model of NIDDM in which one allele of the insulin receptor and of IRS-1 were disrupted by homologous recombination.48
Rodent models of insulin resistance and NIDDM also involve the interactions multiple gene loci. For example, a recent analysis of the Goto-Kakiazaki rat, a model of NIDDM, suggests that different loci contribute to different components of the diabetes phenotype.21,22 Thus, three loci influence glucose tolerance while another locus contributes to body weight. Within the three loci influencing glucose tolerance, one affects postprandial but not fasting hyperglycemia and the other two affect both.
Genetic evidence supports the notion that insulin resistance and diet-induced glucose changes are independent phenomena. Surwit et al49 showed that genetic differences between B6 and A/J strains in insulin resistance and hyperglycemia in response to a high-fat/high-carbohydrate diet did not cosegregate among recombinant inbred BxA strains, a result suggesting that different gene loci contribute to these distinct phenotypes. It is interesting to note that on the higher level of fat used in the latter studies (36%), the B6 strain developed hyperinsulinemia; there appears to be a lipid threshold in the B6 strain (somewhere between 15% and 36%) before this strain becomes hyperinsulinemic.
Genetic synergism has been described for insulin-dependent diabetes mellitus in the nonobese diabetic (NOD) mouse. In this mouse strain, several loci have been estimated to be necessary for the expression of the diabetes phenotype.50 An NOD-derived major histocompatiblity (MHC) haplotype is required; however, different combinations of non-MHC alleles can interact to produce the diabetic phenotype. Epistatic interactions have also been described for susceptibility to various kinds of cancer, indicating that certain cancer susceptibility genes can go undetected if they are not expressed in conjunction with alleles at loci that interact to influence the cancer phenotype.5153
The insulin-resistance phenotype of the (BTBRxB6)F1 mice appears to result from the combination of alleles from these two parental strains rather than from loss of homozygosity of their alleles. This model can therefore be used for gene-mapping studies to identify gene loci that interact to produce insulin resistance.
| Acknowledgments |
|---|
Received April 4, 1997; accepted June 10, 1997.
| References |
|---|
|
|
|---|
2. Reaven GM. Role of insulin resistance in the pathophysiology of non-insulin dependent diabetes mellitus. Diabetes-Metabolism Reviews. 1993;9:5S12S.
3. Haffner SM, Miettinen H, Gaskill SP, Stern MP. Decreased insulin secretion and increased insulin resistance are independently related to the 7-year risk of NIDDM in Mexican-Americans. Diabetes. 1995;44:13861391.[Abstract]
4. Lillioja S, Mott DM, Aqwadzki JK, Young AA, Abbott WGH, Knowler WC, Bennett PH, Moll P, Bogardus C. In vivo insulin action is familial characteristic in nondiabetic Pima Indians. Diabetes. 1987;36:13291335.[Abstract]
5. Kahn CR, Vicent D, Doria A. Genetics of non-insulin-dependent (type-II) diabetes mellitus. Annu Rev Med. 1996;47:509531.[Medline] [Order article via Infotrieve]
6. Elbein SC, Maxwell TM, Schumacher MC. Insulin and glucose levels and prevalence of glucose intolerance in pedigrees with multiple diabetic siblings. Diabetes. 1991;40:10241032.[Abstract]
7. Stern MP, Gonzalez C, Mitchell BD, Villalpando E, Haffner SM, Hazuda HP. Genetic and environmental determinants of type II diabetes in Mexico City and San Antonio. Diabetes. 1992;41:48492.[Abstract]
8. Mitchell BD, Kammerer CM, Hixson JE, Atwood LD, Hackleman S, Blangero J, Haffner SM, Stern MP, MacCluer JW. Evidence for a major gene affecting postchallenge insulin levels in Mexican-Americans. Diabetes. 1995;44:2849.[Abstract]
9. Hanson RL, Elston RC, Pettitt DJ, Bennett PH, Knowler WC. Segregation analysis of non-insulin-dependent diabetes mellitus in Pima Indians: evidence for a major-gene effect. Am J Hum Genet. 1995;57:160170.[Medline] [Order article via Infotrieve]
10. Knowler WC, Saad MF, Pettitt DJ, Nelson RG, Bennett PH. Determinants of diabetes mellitus in the Pima Indians. Diabetes Care. 1993;16:216227.[Abstract]
11.
Pedersen O, Kahn CR, Flier JS, Kahn BB. High fat
feeding causes insulin resistance and a marked decrease in the
expression of glucose transporters (Glut 4) in fat cells of rats.
Endocrinology. 1991;129:771777.
12.
Kahn BB, Pederson O. Suppression of GLUT4 expression in
skeletal muscle or rats that are obese from high fat feeding but not
from high carbohydrate feeding or genetic obesity.
Endocrinology. 1993;132:1322.
13. Storlien LH, Pan DA, Kriketos AD, Baur LA. High fat diet-induced insulin resistance: lessons and implications from animal studies. [Review]. Ann N Y Acad Sci. 1993;683:8290.[Medline] [Order article via Infotrieve]
14. Surwit RS, Kuhn CM, Cochrane C, McCubbin JA, Feinglos MN. Diet-induced type II diabetes in C57BL/6J mice. Diabetes. 1988;37:11631167.[Abstract]
15. Zierath JB, Houseknecht KL, Gnudi L, Kahn BB. High-fat feeding impairs insulin-stimulated GLUT4 recruitment via an early insulin-signaling defect. Diabetes. 1997;46:215223.[Abstract]
16. Naggert JK, Fricker LD, Varlamov O, Nishina PM, Rouille Y, Stener DF, Carroll RJ, Paigen BJ, Leiter EH. Hyperproinsulinaemia in obese fat/fat mice associated with a carboxypeptidase E mutation which reduces enzyme activity. Nature Genetics. 1995;10:135141.[Medline] [Order article via Infotrieve]
17. Lee GH, Proenca R, Montez JM, Carroll KM, Darvishzadeh JG, Lee JI, Friedman JM. Abnormal splicing of the leptin receptor in diabetic mice. Nature. 1996;379:632635.[Medline] [Order article via Infotrieve]
18. Zhang Y, Proenca R, Maffe IM, Barone M, Leopold L, Friedman JM. Positional cloning of the mouse obese gene and its human homologue. Nature. 1994;372:425432.[Medline] [Order article via Infotrieve]
19. Bultman SJ, Michaud EJ, Woychik RP. Molecular characterization of the mouse agouti locus. Cell. 1992;71:11951204.[Medline] [Order article via Infotrieve]
20.
Miller MW, Duhl DM, Vrieling H, Cordes SP, Ollmann MM,
Winkes BM. Cloning of the mouse agouti gene predicts a secreted protein
ubiquitously expressed in mice carrying the lethal yellow mutation.
Genes & Development. 1993;7:454467.
21. Gauguier D, Froguel P, Parent V, Bernard C, Bihoreau MT, Portha B, James MR, Penicaud L, Lathrop M, Ktorza A. Chromosomal mapping of genetic loci associated with non-insulin dependent diabetes in the GK rat. Nature Genetics. 1996;12:3843.[Medline] [Order article via Infotrieve]
22. Galli J, Li LS, Glaser A, Ostenson CG, Jiao H, Fakharai-Rad H, Jacob HJ, Lander ES, Luthman H. Genetic analysis of non-insulin dependent diabetes mellitus in the GK rat. Nature Genetics. 1996;12:3137.[Medline] [Order article via Infotrieve]
23. Reaven GM. Insulin resistance, hyperinsulinemia, hypertriglyceridemia, and hypertension: parallels between human disease and rodent models. [Review]. Diabetes Care. 1991;14:195202.[Abstract]
24. Elbein SC, Chiu KC, Hoffman MD, Mayorga RA, Bragg KL, Leppert MF. Linkage analysis of 19 candidate regions for insulin resistance in familial NIDDM. Diabetes. 1995;44:12591265.[Abstract]
25. Elbein SC, Bragg KL, Hoffman MD, Mayorga RA, Leppert MF. Linkage studies of NIDDM with 23 chromosome 11 markers in a sample of whites of northern European descent. Diabetes. 1996;45:370375.[Abstract]
26.
Mueckler M, Kruse M, Strube M, Riggs AC, Chiu KC,
Permutt MA. A mutation in the Glut2 glucose transporter gene of a
diabetic patient abolishes transport activity. J Biol
Chem. 1994;269:1776517777.
27. Steiner DF, Tager HS, Chan SJ, Nanjo K, Sanke T, Rubenstein AH. Lessons learned from molecular biology of insulin-gene mutations. Diabetes Care. 1990;13:600109.[Abstract]
28. Given BD, Mako ME, Tager HS, Baldwin D, Markese J, Rubenstein AH, Olefsky J, Kobayashi M, Kolterman O, Poucher R. Diabetes due to secretion of an abnormal insulin. N Engl J Med. 1980;302:129135.[Abstract]
29.
Yoshimasa Y, Seino S, Whittaker J, Kakehi T, Kosaki A,
Kuzuya H, Imura H, Bell GI, Steiner DF. Insulin-resistant
diabetes due to a point mutation that prevents insulin proreceptor
processing. Science. 1988;240:784787.
30.
Shedlovsky A, King TR, Dove WF. Saturation germ line
mutagenesis of the murine t region including a lethal
allele at the quaking locus. Proc Natl Acad Sci U S A.. 1988;85:180184.
31.
McDonald JD, Bode VC, Dove WF, Shedlovsky A.
Pahhph-5: a mouse mutant deficient in
phenylalanine hydroxylase. Proc Natl Acad Sci U S A.. 1990;87:19651967.
32. Artzt K, Hamburger L, Flaherty L. H-39, a histocompatibility locus closely linked to the T/t complex. Immunogenetics. 1977;5:477480.
33. Krebs HA, Henseleit K. Untersuchungen über die Harnstoffbildung im Tierkorper. Hoppe-Seyler's Z Physiol Chem. 1932;210:3336.
34. Cartee GD, Douen AG, Ramlal T, Klip A, Holloszy JO. Stimulation of glucose transport in skeletal muscle by hypoxia. J Appl Physiol. 1991;76:15931600.
35.
Young DA, Uhl JJ, G.D. C, Holloszy JO. Activation of
glucose transport in muscle by prolonged exposure to insulin.
J Biol Chem. 1986;261:1604916053.
36.
Gulve EA, Ren JM, Marshall BA, Gao J, Hansen PA, J.O.
H, Mueckler M. Glucose transport activity in skeletal muscles from
transgenic mice overexpressing GLUT1. J Biol Chem. 1994;269:1836618370.
37.
Berliner JA, Navab M, Fogelman AM, Frank JS, Demer LL,
Edwards PA, Watson AD, Lusis AJ. Atherosclerosis: basic
mechanisms: oxidation, inflammation, and genetics.
Circulation. 1995;91:24882496.
38. Crespin SR, Greenough WB, Steinberg D. Stimulation of insulin secretion by long-chain free fatty acids. J Clin Invest. 1973;52:19791984.
39. Boden G, Chen X, Rosner J, Barton M. Effects of a 48-h fat infusion on insulin secretion and glucose utilization. Diabetes. 1995;44:12391242.[Abstract]
40. Rebrin K, Steil GM, Getty L, Bergman RN. Free fatty acid as a link in the regulation of hepatic glucose output by peripheral insulin. Diabetes. 1995;44:10381045.[Abstract]
41. Fanelli C, Calderone S, Epifano L, Vincenzo A, Modarelli F, Pampanelli S, Perriello G, Feo P, Brunetti P, Gerich JE, Bolli GB. Demonstration of a critical role for free fatty acids in mediating counerregulatory stimulation of gluconeogenesis and suppression of glucose utilization in humans. J Clin Invest. 1993;92:16171622.
42. Sugden MC, Orfali KA, Holness MJ. The pyruvate dehydrogenase complex: Nutrient control and the pathogenesis of insulin resistance. J Nutr. 1995;125.
43.
Leiter EH, Chapman HD, Coleman DL. The influence of
genetic background on the expression of mutations at the diabetes locus
in the mouse. V. Interaction between the db gene and hepatic
sex steroid sulfotransferases correlates with gender-dependent
susceptibility to hyperglycemia. Endocrinology. 1989;124:912922.
44. Leiter EH, Chapman HD, Falany CN. Synergism of obesity genes with hepatic steroid sulfotransferases to mediate diabetes in mice. Diabetes. 1991;40:13601363.[Abstract]
45. Leiter EH, Chapman HD. Obesity-induced diabetes (diabesity) in C57BL/KsJ mice produces aberrant trans-regulation of sex steroid sulfotransferase genes. J Clin Invest. 1994;93:20072013.
46. Wendorf M, Goldfine ID. Archaeology of NIDDM. Excavation of the "thrifty" genotype. Diabetes. 1991;40:16611665.
47. Coleman DL. Obesity genes: beneficial effects in heterozygous mice. Science. 1989;203:663665.
48. Bruning JC, Winnay J, Weir SB, Taylor SI, Accili D, Kahn CR. Development of a novel polygenic model of NIDDM in mice heterozygous for IR and IRS-1 null alleles. Cell. 1997;88:561572.[Medline] [Order article via Infotrieve]
49. Surwit RS, Selditn MF, Kuhn CM, Cochrane C, Feinglos MN. Control of expression of insulin resistance and hyperglycemia by different genetic factors in diabeteic C57BL/6J mice. Diabetes. 1991;40:8287.[Abstract]
50. McAleer MA, Reifsnyder P, Palmer SM, Prochazka M, Love JM, Copeman JB, Powell EE, Rodrigues NR, Prins JB, Serreze DV, DeLarato NH, Wicker LS, Peterson LB, Schork NJ, Todd JA, Leiter EH. Crosses of NOD mice with the related NON strain - A polygenic model for IDDM. Diabetes. 1995;44:11861195.[Abstract]
51. Dietrich WF, Lander ES, Smith JS, Moser AR, Gould KA, Luongo C, Borenstein N, Dove W. Genetic identification of Mom-1, a major modifier locus affecting Min-induced intestinal neoplasia in the mouse. Cell. 1993;75:631639.[Medline] [Order article via Infotrieve]
52. Wezel T, Stassen APM, Moen CJA, Hart AAM, Valk MA, Demant P. Gene interaction and single gene effects in colon tumour susceptibility in mice. Nature Genetics. 1996;14:468470.[Medline] [Order article via Infotrieve]
53. Fijneman RJA, Vries SS, Jansen RC, Demant P. Complex interactions of new quantitative trait loci, Sluc1, Sluc2, Sluc3, and Sluc4, that influence the susceptibility to lung cancer in the mouse. Nature Genetics. 1996;14:465467[Medline] [Order article via Infotrieve]
This article has been cited by other articles:
![]() |
J. B. Flowers, M. E. Rabaglia, K. L. Schueler, M. T. Flowers, H. Lan, M. P. Keller, J. M. Ntambi, and A. D. Attie Loss of Stearoyl-CoA Desaturase-1 Improves Insulin Sensitivity in Lean Mice but Worsens Diabetes in Leptin-Deficient Obese Mice Diabetes, May 1, 2007; 56(5): 1228 - 1239. [Abstract] [Full Text] [PDF] |
||||
![]() |
J. B. Flowers, A. T. Oler, S. T. Nadler, Y. Choi, K. L. Schueler, B. S. Yandell, C. M. Kendziorski, and A. D. Attie Abdominal obesity in BTBR male mice is associated with peripheral but not hepatic insulin resistance Am J Physiol Endocrinol Metab, March 1, 2007; 292(3): E936 - E945. [Abstract] [Full Text] [PDF] |
||||
![]() |
S. M. Clee and A. D. Attie The Genetic Landscape of Type 2 Diabetes in Mice Endocr. Rev., February 1, 2007; 28(1): 48 - 83. [Abstract] [Full Text] [PDF] |
||||
![]() |
M. E. Rabaglia, M. P. Gray-Keller, B. L. Frey, M. R. Shortreed, L. M. Smith, and A. D. Attie {alpha}-Ketoisocaproate-induced hypersecretion of insulin by islets from diabetes-susceptible mice Am J Physiol Endocrinol Metab, August 1, 2005; 289(2): E218 - E224. [Abstract] [Full Text] [PDF] |
||||
![]() |
R. C. Davis, E. E. Schadt, A. C.L. Cervino, M. Peterfy, and A. J. Lusis Ultrafine Mapping of SNPs From Mouse Strains C57BL/6J, DBA/2J, and C57BLKS/J for Loci Contributing to Diabetes and Atherosclerosis Susceptibility Diabetes, April 1, 2005; 54(4): 1191 - 1199. [Abstract] [Full Text] [PDF] |
||||
![]() |
A. H. Minn, H. Lan, M. E. Rabaglia, D. M. Harlan, B. A. Peculis, A. D. Attie, and A. Shalev Increased Insulin Translation from an Insulin Splice-Variant Overexpressed in Diabetes, Obesity, and Insulin Resistance Mol. Endocrinol., March 1, 2005; 19(3): 794 - 803. [Abstract] [Full Text] [PDF] |
||||
![]() |
H. J. Goren, R. N. Kulkarni, and C. R. Kahn Glucose Homeostasis and Tissue Transcript Content of Insulin Signaling Intermediates in Four Inbred Strains of Mice: C57BL/6, C57BLKS/6, DBA/2, and 129X1 Endocrinology, July 1, 2004; 145(7): 3307 - 3323. [Abstract] [Full Text] [PDF] |
||||
![]() |
E. H. Leiter and P. C. Reifsnyder Differential Levels of Diabetogenic Stress in Two New Mouse Models of Obesity and Type 2 Diabetes Diabetes, February 1, 2004; 53(90001): S4 - 11. [Abstract] [Full Text] |
||||
![]() |
J. P. Stoehr, J. E. Byers, S. M. Clee, H. Lan, I. V. Boronenkov, K. L. Schueler, B. S. Yandell, and A. D. Attie Identification of Major Quantitative Trait Loci Controlling Body Weight Variation in ob/ob Mice Diabetes, January 1, 2004; 53(1): 245 - 249. [Abstract] [Full Text] [PDF] |
||||
![]() |
M. Rossmeisl, J. S. Rim, R. A. Koza, and L. P. Kozak Variation in Type 2 Diabetes-Related Traits in Mouse Strains Susceptible to Diet-Induced Obesity Diabetes, August 1, 2003; 52(8): 1958 - 1966. [Abstract] [Full Text] [PDF] |
||||
![]() |
H. Lan, J. P. Stoehr, S. T. Nadler, K. L. Schueler, B. S. Yandell, and A. D. Attie Dimension Reduction for Mapping mRNA Abundance as Quantitative Traits Genetics, August 1, 2003; 164(4): 1607 - 1614. [Abstract] [Full Text] [PDF] |
||||
![]() |
H. Lan, M. E. Rabaglia, J. P. Stoehr, S. T. Nadler, K. L. Schueler, F. Zou, B. S. Yandell, and A. D. Attie Gene Expression Profiles of Nondiabetic and Diabetic Obese Mice Suggest a Role of Hepatic Lipogenic Capacity in Diabetes Susceptibility Diabetes, March 1, 2003; 52(3): 688 - 700. [Abstract] [Full Text] [PDF] |
||||
![]() |
M. Kobayashi, T. Ohno, A. Tsuji, M. Nishimura, and F. Horio Combinations of Nondiabetic Parental Genomes Elicit Impaired Glucose Tolerance in Mouse SMXA Recombinant Inbred Strains Diabetes, January 1, 2003; 52(1): 180 - 186. [Abstract] [Full Text] [PDF] |
||||
![]() |
P. C. Reifsnyder and E. H. Leiter Deconstructing and Reconstructing Obesity-Induced Diabetes (Diabesity) in Mice Diabetes, March 1, 2002; 51(3): 825 - 832. [Abstract] [Full Text] [PDF] |
||||
![]() |
S. T. Nadler, J. P. Stoehr, M. E. Rabaglia, K. L. Schueler, M. J. Birnbaum, and A. D. Attie Normal Akt/PKB with reduced PI3K activation in insulin-resistant mice Am J Physiol Endocrinol Metab, December 1, 2001; 281(6): E1249 - E1254. [Abstract] [Full Text] [PDF] |
||||
![]() |
C. L. Dumke, J. S. Rhodes, T. Garland Jr, E. Maslowski, J. G. Swallow, A. C. Wetter, and G. D. Cartee Genetic selection of mice for high voluntary wheel running: effect on skeletal muscle glucose uptake J Appl Physiol, September 1, 2001; 91(3): 1289 - 1297. [Abstract] [Full Text] [PDF] |
||||
![]() |
S. T. Nadler, J. P. Stoehr, K. L. Schueler, G. Tanimoto, B. S. Yandell, and A. D. Attie The expression of adipogenic genes is decreased in obesity and diabetes mellitus PNAS, October 10, 2000; 97(21): 11371 - 11376. [Abstract] [Full Text] [PDF] |
||||
![]() |
P. C. Reifsnyder, G. Churchill, and E. H. Leiter Maternal Environment and Genotype Interact to Establish Diabesity in Mice Genome Res., October 1, 2000; 10(10): 1568 - 1578. [Abstract] [Full Text] |
||||
![]() |
J. C. Escolà-Gil, J. Julve, A. Marzal-Casacuberta, J. Ordóñez-Llanos, F. González-Sastre, and F. Blanco-Vaca Expression of human apolipoprotein A-II in apolipoprotein E-deficient mice induces features of familial combined hyperlipidemia J. Lipid Res., August 1, 2000; 41(8): 1328 - 1338. [Abstract] [Full Text] |
||||
![]() |
I. Murray, P. J. Havel, A. D. Sniderman, and K. Cianflone Reduced Body Weight, Adipose Tissue, and Leptin Levels Despite Increased Energy Intake in Female Mice Lacking Acylation-Stimulating Protein Endocrinology, March 1, 2000; 141(3): 1041 - 1049. [Abstract] [Full Text] [PDF] |
||||
![]() |
I. Murray, A. D. Sniderman, P. J. Havel, and K. Cianflone Acylation Stimulating Protein (ASP) Deficiency Alters Postprandial and Adipose Tissue Metabolism in Male Mice J. Biol. Chem., December 17, 1999; 274(51): 36219 - 36225. [Abstract] [Full Text] [PDF] |
||||
![]() |
W. W. Winder and D. G. Hardie AMP-activated protein kinase, a metabolic master switch: possible roles in Type 2 diabetes Am J Physiol Endocrinol Metab, July 1, 1999; 277(1): E1 - E10. [Abstract] [Full Text] [PDF] |
||||
| |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
|
ATVB Home | Subscriptions | Archives | Feedback | Authors | Help | AHA Journals Home | Search Copyright © 1997 American Heart Association, Inc. All rights reserved. Unauthorized use prohibited. |