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Am J Physiol Endocrinol Metab 293: E70-E74, 2007. First published March 13, 2007; doi:10.1152/ajpendo.00259.2006
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Impaired insulin secretion in a mouse model of ataxia telangiectasia

Philip D. Miles,1 Kai Treuner,2 Marc Latronica,2 Jerrold M. Olefsky,1 and Carrolee Barlow2

1Division of Endocrinology and Metabolism, Department of Medicine, University of California San Diego, La Jolla; and 2Laboratory of Genetics, Salk Institute for Biological Studies, La Jolla, California

Submitted 29 May 2006 ; accepted in final form 14 December 2006


   ABSTRACT
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 ABSTRACT
METHODS
 RESULTS
 DISCUSSION
 GRANTS
 REFERENCES
 
Ataxia telangiectasia (A-T) is an autosomal recessive disease caused by mutations in the A-T mutated (ATM) gene. The gene encodes a serine/threonine kinase with important roles in the cellular response to DNA damage, including the activation of cell cycle checkpoints and induction of apoptosis. Although these functions might explain the cancer predisposition of A-T patients, the molecular mechanisms leading to glucose intolerance and diabetes mellitus (DM) are unknown. We have investigated the pathogenesis of DM in a mouse model of A-T. Here we show that young Atm-deficient mice show normal fasting glucose levels and normal insulin sensitivity. However, oral glucose tolerance testing revealed delayed insulin secretion and resulting transient hyperglycemia. Aged Atm–/– mice show a pronounced increase in blood glucose levels and a decrease in insulin and C-peptide levels. Our findings support a role for ATM in metabolic function and point toward impaired insulin secretion as the primary cause of DM in A-T.

Atm–/– mice; diabetes mellitus

ATAXIA TELANGIECTASIA (A-T) is an autosomal recessive disease caused by loss of function of the protein kinase A-T mutated (ATM). A-T is characterized by progressive cerebellar ataxia, cancer predisposition, and immune system deficiencies (8). In addition, A-T patients show abnormalities in glucose homeostasis and frank diabetes mellitus (DM) develops in nearly 25% of A-T patients who survive to age 30 (3, 6, 7, 18). Atm-deficient mice display several phenotypes consistent with the human disease, including predisposition to cancer, growth retardation, cell proliferation defects, and infertility. However, it is currently unknown whether Atm–/– mice show evidence of glucose intolerance seen in A-T patients.

A variety of genetic diseases exhibit an increased incidence of DM, e.g., Down's syndrome, Turner syndrome, and Friedreich's ataxia (2, 11, 12). Type 1 diabetes is caused by the autoimmune destruction of beta-cells in the pancreas, leading to hypoinsulinemia and hyperglycemia, whereas type 2 diabetes is generally believed to be a polygenic disorder affecting insulin secretion and/or insulin action. Insulin resistance is often present before the development of overt diabetes, and the abnormality in insulin secretion occurs later. The elucidation of the pathophysiology of DM in ATM is limited to a few case reports. One set of studies revealed insulin resistance in A-T patients based on a blunted hypoglycemic response to exogenous insulin (3, 18). In contrast, one case study demonstrated a loss of the first phase of insulin response to intravenous glucose, showing that A-T patients display signs of pancreatic beta-cell dysfunction (6). It is clear from these studies that the precise mechanism underlying the human pathophysiology of A-T patients remains controversial.

The gene mutated in A-T, ATM, encodes a predominantly nuclear protein that functions as a serine/threonine kinase. Biochemical evidence for the role of ATM in insulin signaling came from the observation that ATM enhances the phosphorylation of the eukaryotic initiation factor-4E-binding protein 1/phosphorylated heat-acid stable protein-1 in response to insulin stimulation (22). It is well established that normal insulin function is critical to normal growth, e.g., the insulin-IGF signaling system is important for promoting somatic growth during development. Interestingly, one of the characteristic phenotypes in A-T is growth retardation. It is conceivable that impaired or altered insulin signaling in the absence of ATM is responsible for the growth retardation.

Here we report that Atm–/– mice show abnormalities in glucose-stimulated insulin secretion. Atm–/– mice exhibit normal insulin sensitivity but display transient hyperglycemia during an oral glucose tolerance test (OGTT). The insulin secretory defect appears to progress with age, leading to a hyperglycemic and hypoinsulinemic phenotype.


   METHODS
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 METHODS
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Generation and maintenance of mice. All animal procedures were performed according to protocols approved by the Salk Institute for Biological Studies animal care and use committees and the animal subjects committee of the University of California, San Diego. Atm–/– mice (129S6/SvEvTac) were generated and maintained as described (4). Genotyping was performed from tail biopsies as described (4). Mice were housed under controlled light (12:12 h) and temperature conditions and had free access to food and water.

OGTT. One group of wild-type and Atm–/– mice underwent OGTT at 12 wk of age to assess metabolic alterations. Animals were fasted for 5 h. A basal blood sample (150 µl) was collected from the tip of the tail (time t = 0 min) by nicking the tail tip with a scalpel blade, gently stripping the tail, and collecting the blood in a heparinized capillary tube. An additional blood sample of 5 µl was collected for immediate determination of blood glucose (B-Glucose Analyzer; HemoCue, Mission Viejo, CA). Mice were then gavaged with dextrose (1.5 g/kg), and additional blood samples were collected at 15, 30, and 60 min. The larger blood samples were spun, and the resultant plasma was frozen for insulin determination. Insulin was measured using a radioimmunoassay kit (Sensitive Rat Insulin Assay; Linco, St. Charles, MO).

Hyperinsulinemic euglycemic clamp. A separate group of wild-type and Atm–/– mice underwent glucose clamp experiments at 12 wk of age to assess insulin sensitivity, as previously described (15). Briefly, surgery was performed to implant two catheters into the right jugular vein. Catheters were tunneled subcutaneously, exteriorized at the back of the neck, and filled with heparinized saline. Four days after surgery, the animal was fasted for 5 h and placed in a restrainer to which it was accustomed. A basal blood sample was collected from the tail tip for immediate glucose determination. The clamp was begun with the infusion of regular human insulin (Novolin R; Novo Nordisk; 4 mU·kg–1·min–1) into one jugular catheter. The insulin infusate was diluted with saline containing 0.1% BSA (Baxter, Glendale, CA). Blood samples of 5 µl were drawn at 10-min intervals for immediate determination of blood glucose levels. Based on these values, exogenous glucose (50% dextrose; Abbott, Chicago, IL) was variably infused into the other jugular catheter to maintain the plasma glucose concentration at ~150 mg/dl. Steady state [stable plasma glucose concentration and exogenous glucose infusion rate (Ginf)] was generally achieved within 90–120 min, at which time a blood sample of 225 µl was collected. The animal was then euthanized. The steady-state Ginf was used as a measure of insulin sensitivity.

Long-term evaluation of Atm–/– mice. In a separate group, wild-type and Atm–/– mice were followed from 6 to 33 wk of age. All of the animals were closely monitored for disease and signs of tumor development. Animals that were severely moribund or found dead were necropsied to determine cause of death. Blood samples were regularly collected via the retro-orbital sinus from nonfasted animals for glucose, insulin, and C-peptide determination. C-peptide was measured using a rat immunoassay kit (Linco).

Statistics. Values presented are means ± SE. Statistical analysis was performed using a two-way ANOVA for unbalanced data (SAS, SAS Institute, Cary, NC). Significance was assumed at P < 0.05.


   RESULTS
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 METHODS
 RESULTS
DISCUSSION
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Atm–/– mice show normal insulin sensitivity. Atm–/– mice were infertile and apparently healthy at birth. The control group was composed of wild-type littermates of the homozygous deficient mice. By ~12 wk of age, Atm–/– mice begin to develop T-cell lymphomas (TCLs), leading to death between 3 and 6 mo of age (4). As a result, we studied mice at 12 wk of age, which were confirmed to be tumor free. At this age, Atm–/– mice were significantly smaller than age-matched wild-type mice, and females in general tended to be smaller than male animals (Fig. 1A). The disparity of male and female mice regarding body weight and percentage of body fat and muscle mass required a stratified analysis according to sex.


Figure 1
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  		Fig. 1. Insulin sensitivity of ataxia telangiectasia mutated (Atm)–/– mice. The bar charts show the body weight (A), basal glucose (B), and glucose infusion rate (Ginf; C) of male and female mice at 3 mo of age. Significant differences are indicated (P < 0.05).

 
The basal glucose concentrations of wild-type and Atm–/– mice were similar at 12 wk of age (Fig. 1B). Between the sexes, it was evident that female mice displayed a significantly lower basal glucose level than their male counterparts. The small size of the mice at 12 wk of age precluded the use of tritiated glucose to measure glucose turnover during the glucose clamp studies (15). Consequently, relative insulin sensitivity was reported as the steady-state Ginf achieved by the end of the hyperinsulinemic euglycemic clamp. Overall, body insulin sensitivity is directly proportional to the Ginf necessary to maintain euglycemia. The analysis revealed no difference between wild-type and Atm–/– mice or between male and female mice, indicating that all groups analyzed were equally insulin sensitive (Fig. 1C).

Atm–/– mice are glucose intolerant. Next we wanted to determine whether wild-type and Atm–/– mice show differences in glucose tolerance as measured by OGTT. After the animals were fasted for 5 h, dextrose was administered and blood samples were collected to determine blood glucose concentration and plasma insulin levels. Interestingly, male and female mice responded differently to the OGTT when tested at 12 wk of age. The excursions in glucose and insulin were similar in male wild-type and Atm–/– mice, except that the glucose concentration of Atm–/– mice was significantly higher after 15 min (Fig. 2, A and B).


Figure 2
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  		Fig. 2. Transient hyperglycemia in Atm–/– mice. The graphs show blood glucose (A and C) and plasma insulin concentrations (B and D) of male (A and B) and female (C and D) mice during oral glucose tolerance test at 3 mo of age. The error bars represent the SE of the mean. *Significant differences between Atm–/– and wild-type animals (P < 0.05).

 
In female mice, however, the excursion in glucose concentration was markedly greater in Atm–/– mice compared with wild-type mice (Fig. 2C). Furthermore, the insulin concentration in Atm–/– mice peaked at 30 min compared with 15 min in wild-type mice (Fig. 2D). Taken together, these results indicate that insulin secretion following a glucose bolus is delayed in Atm–/– mice and that this delay is more prominent in female mice.

Atm–/– mice develop DM with age. A separate group of mice, ranging in age from 6 to 33 wk, were studied over time to follow the progression of impaired insulin secretion. This long-term study was complicated by the fact that Atm–/– mice develop aggressive TCLs. Virtually all Atm–/– mice succumb to aggressive TCLs, ultimately leading to death (4, 21). The ongoing loss of animals to TCLs precluded performing OGTTs on predetermined groups. Instead, postprandial plasma glucose, insulin, and C-peptide levels were measured at 3-wk intervals as a basic measure of beta-cell function (Fig. 3). In male and female wild-type mice, the blood glucose concentration gradually rose with age (Fig. 3, A and C), while the plasma insulin concentration remained relatively constant (Fig. 3, B and D). In contrast, Atm–/– mice became overtly diabetic during the same period. The blood glucose concentration of Atm–/– mice was initially similar to that of wild-type mice; however, it became significantly higher in male Atm–/– mice by 27 wk of age (Fig. 3A) and in female Atm–/– mice by 21 wk of age (Fig. 3C). The insulin levels of Atm–/– mice were initially similar to those of wild-type mice; however, they became significantly lower in male Atm–/– mice by 27 wk of age (Fig. 3B) and in female Atm–/– mice by 27 wk of age (Fig. 3D).


Figure 3
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  		Fig. 3. Hyperglycemia and hypoinsulinemia in Atm–/– mice. The graphs show nonfasting blood glucose (A and C) and plasma insulin concentrations (B and D) of male (A and B) and female (C and D) mice from 6 to 33 mo of age. The error bars represent the SE of the mean.

 
Based on the decline in insulin levels, we pooled plasma samples from 6–21 and 24–33 wk of age because of limited plasma volumes and analyzed C-peptide levels. Consistent with the decreasing insulin levels, male and female Atm–/– mice showed a decline in C-peptide levels after 21 wk of age, whereas levels remained constant in wild-type mice (Table 1). Taken together, these results show that loss of ATM results in deteriorating insulin and C-peptide levels in the mice over time, which is indicative of beta-cell dysfunction.


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  		Table 1. C-peptide levels in wild type and Atm–/–mice

 

   DISCUSSION
TOP
 ABSTRACT
 METHODS
 RESULTS
 DISCUSSION
GRANTS
 REFERENCES
 
Insulin sensitivity of Atm–/– mice. In this study, we have used Atm–/– mice to investigate the symptoms of glucose intolerance seen in A-T patients. The mechanisms leading to the development of DM in A-T are unknown. Our studies demonstrate normal basal glucose levels and insulin sensitivity in Atm–/– mice, as measured by the hyperinsulinemic euglycemic clamp at 12 wk of age (Fig. 1). However, OGTT revealed that Atm–/– mice display a delay in glucose-stimulated insulin secretion, leading to transient hyperglycemia (Fig. 2). It appears that male Atm–/– mice secrete less insulin, with insulin levels remaining constant for a longer period of time, whereas female Atm–/– mice exhibit a delayed peak of insulin secretion and a failure to lower blood glucose levels.

It is well established that glucose oxidation in the pancreatic beta-cell induces closure of ATP-sensitive K+ channels and consequent calcium entry via voltage-sensitive L-type calcium channels (16). It is plausible that the ATM kinase is part of an intracellular signaling pathway in the beta-cell, which results in insulin secretion. It has been shown that mice deficient in genes of the insulin receptor substrate (IRS) family 1–4 have varying degrees of insulin resistance. Interestingly, IRS-2–/– mice develop diabetes, because inactivation of IRS-2 not only causes insulin resistance, but also impairs insulin secretion in the beta-cell (20). It was recently shown that ATM regulates the transcriptional activity of cAMP response element binding protein (CREB) in response to DNA damage and oxidative stress (19). CREB is activated in response to a variety of stimuli, including cAMP, Ca2+, UV light, hypoxia, and growth factors (13, 14). CREB also plays a role in mediating beta-cell survival via induction of the IRS-2 (10). It is tempting to speculate that at least one of the mechanisms through which ATM participates in intracellular signaling involves CREB activation and expression of a variety of genes such as IRS-2. However, activation of CREB following insulin stimulation was normal in Atm–/– mice, and we were unable to detect any differences in insulin receptor and GLUT4 expression in liver, muscle, or adipose tissues (data not shown).

Insulin secretory decline increases with age in Atm–/– mice. Glucose intolerance is a risk factor for the development of DM. Atm–/– mice develop DM as evidenced by a rise in glucose concentration in both male and female Atm–/– mice, which most likely resulted from a reduction in postprandial insulin secretion (Fig. 3). Consequently, the delayed insulin secretion seen at 12 wk of age appears to have progressed to impaired insulin secretion by ~27 wk of age. This decline in insulin and C-peptide levels with age is indicative of beta-cell dysfunction, possibly caused by autoimmune destruction or cell death/apoptosis of the islets. However, autoimmune destruction appears unlikely, since A-T patients and Atm–/– mice are immunocompromised (4, 8). In addition, we find no evidence of beta-cell apoptosis by caspase-3 and terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling staining in wild-type or Atm–/– mice at a young age (data not shown). However, we currently cannot exclude the possibility of islet cell autoimmunity and concurrent reduction in beta-cell mass in Atm–/– mice at older ages. It will be of interest to study insulin and glucose levels in Atm–/– mice at more than 40 wk of age to determine whether increased glucose and decreased insulin levels are exacerbated with time. However, due to thymic lymphoma development of Atm–/– mice, we were limited in the number of available mice at an old age. It would be possible to extend these studies by analyzing double mutant mice, e.g., Atm–/– Rag2–/–, which have a mean age of death of 12 mo, compared with only 6.4 mo for Atm–/– mice (17). However, this would require a considerable breeding effort to achieve a similar comprehensive study, and these mice are severely immunocompromised, which may be a confounding variable.

Interestingly, it was recently shown that Atm+/– apolipoprotein E (apoE)–/– transgenic mice exhibit highly advanced atherosclerosis, suggesting that ATM deficiency promotes atherogenesis by elevating plasma lipids and increasing the sensitivity to oxidized LDL (23). Since DM is a significant risk factor for cardiovascular disease, this may explain why Atm+/– apoE–/– mice develop the ailment. Furthermore, it is known that transient hyperglycemia is a risk factor for developing metabolic syndrome (1, 9).

Taken together, our studies provide insight into the mechanisms behind the pathogenesis of DM in A-T, which is either caused or at least exacerbated by impaired insulin secretion of beta-cells. Atm–/– mice display an early defect in glucose-stimulated insulin release and later develop hyperglycemia. Therefore, we conclude that impaired insulin secretion causes repetitive transient hyperglycemic conditions in A-T. It is possible that the development of hyperglycemia per se could lead to secondary insulin resistance, since it is well known that high glucose levels impair insulin action through a "glucotoxic" effect. This might aggravate beta-cell dysfunction, eventually leading to a failure of beta-cells and progression of the disease. The fact that reduced insulin secretion in A-T is already evident in young, nonobese mice with normal insulin sensitivity suggests that beta-cell dysfunction or insufficiency is a primary feature of A-T. On this account, it will be interesting to study secretory responses to other secretagogues, such as KCl, arginine, and glucagon-like peptide-1. Investigations in the link between ATM signaling, insulin secretion, and metabolic syndrome will shed further light on possibly common molecular mechanisms behind apparently separate diseases.


   GRANTS
TOP
 ABSTRACT
 METHODS
 RESULTS
 DISCUSSION
 GRANTS
REFERENCES
 
This work was supported by National Institutes of Health (NIH) Grants DK-33651 to J.M. Olefsky and NS-39601, and financial support from the Charles H. and Anna S. Stern Foundation and The V-Foundation for Cancer Research to C. Barlow.

Present address of K. Treuner and C. Barlow: BrainCells, Inc., 10835 Road to the Cure, Suite 150, San Diego, CA 92121.


   ACKNOWLEDGMENTS
 
We are thankful to Oded Singer for advice and for technical expertise.


   FOOTNOTES
 

Address for reprint requests and other correspondence: C. Barlow, BrainCells, Inc., 10835 Road to the Cure, Ste. 150, San Diego, CA 92121 (e-mail: cbarlow{at}braincellsinc.com)

The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.


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