Research article
Dietary carbohydrate dictates development of Type 2 diabetes in the Nile rat,☆☆

https://doi.org/10.1016/j.jnutbio.2013.06.004Get rights and content

Abstract

Amount and type of dietary carbohydrate (CHO), as well as the CHO:fat ratio, are thought to be critical for both the rate of development and severity of Type 2 diabetes mellitus. Thus, these nutritional considerations were examined in the previously described “spontaneous” model of diabetes and metabolic syndrome, the Nile rat. Weanling male Nile rats (n=92) were fed semipurified diets, modifying glycemic index and load by changing the amount of fiber or altering the CHO:fat ratio. Random and fasting blood glucose and body weight were assessed, and diabetes was characterized in terms of blood glucose, relevant plasma and liver parameters, food and water intake and terminal organ weights. Nile rats fed with hiCHO became more hyperglycemic than rats fed with modCHO (P<.05), while loCHO and hiCHO+hiFiber rats remained essentially normoglycemic. Liver lipid and glycogen accumulation was associated with severe hyperlipemia in diabetic rats, analogous to metabolic syndrome in humans. Advanced diabetes was linked to liver and kidney damage and elevated blood urea nitrogen with weight loss. Dispersing dietary CHO by fiber or replacing it by moderate fat (reducing the glycemic index and load) delayed the onset of diabetes but did not prevent signs of insulin resistance. A very low content of dietary CHO (high fat) seemed to prevent even these early indicators of insulin resistance. Thus, the Nile rat represents a novel CHO-sensitive model for study of Type 2 diabetes that reliably follows the course of disease in humans.

Introduction

Type 2 diabetes mellitus (T2DM) and metabolic syndrome (MetS) have become pandemic disorders of global proportions in need of a solution, ideally one based on dietary intervention [1], [2], [3]. Several diet plans have been offered that range from an Atkins-type diet [very low dietary carbohydrate (CHO)] on the one hand to an Ornish-type diet (low fat, high complex CHO) on the other hand, with many recommendations in between [4]. Determining the efficacy of different diet plans would be served well by examining possible nutritional approaches in an appropriate animal model.

One striking epidemiological observation regarding dietary macronutrient composition and T2DM in the US is the marked increase in T2DM prevalence that occurred in the past 25 years when fat intake was reduced in favor of CHO — the “American Paradox” [5]. This suggests that hiCHO is problematic. On the other hand, large cohort studies have found a link between risk for T2DM and total fat intake when saturated fat and trans fat are consumed at the expense of vegetable oils, which decrease risk [6], [7]. An increasing number of recent clinical studies describe beneficial effects of reducing the dietary glycemic load on diabetes and its related conditions [8], [9], [10], [11], [12], [13], [14]. In addition, a critical level of dietary fat and essential fatty acids may be required, especially during growth, to insure pancreatic beta cell development and adequate insulin secretion [15], [16], as well as development and maintenance of muscle membranes to ensure insulin receptor function [17], [18].

To further investigate the relationship between dietary CHO, fat, glycemic index and load, studies were conducted in the Nile rat (NR) (Arvicanthis niloticus), which develops T2DM and all the criteria of MetS when fed laboratory chow [19], [20]. Since the diabetes has previously been modulated by diet, this renders the model particularly attractive for study of the macronutrient impact on the disease process. Accordingly, different intakes of CHO (as %en replacing fat) were evaluated along with the impact of fiber to test the hypothesis that lowering the dietary glycemic index and load would reduce the diabetic burden in this model, as suggested by numerous data, including human studies [10], [13], [14], [21], [22], [23], [24].

Our test diets explored a wide range of caloric densities (2.5 to 6.0 kcal/g) and were specifically designed to separate the diabetogenic and obesity-inducing potential of CHO from that of fat, while protein intake was constant at 17–20%en for all diets. The objective was to focus on two central questions: first, what is the impact of altering the glycemic load (modified by replacing CHO with fat) on diabetes outcome, that is, which macronutrient is more likely to induce diabetes in NRs if consumed in relative abundance — fat or CHO? Second, how does the quality of dietary CHO, modified by altering the glycemic index (increasing the dietary fiber content), influence the diabetes-inducing potential of CHO?

Section snippets

NR background

Diabetes progression in the NR is most sensitively followed by assessment of random blood glucose (RBG). Preliminary experiments revealed that RBG measured at 11 a.m., 1 p.m. or 5p.m. (i.e., at random) in the same rat for several days within the same week provided very similar results (different blood glucose values for each rat were within +/−10 mg/dl of each other). Thus, a rat with elevated glucose repeatedly fell within the same subcategory of clinical diabetes based on three ranges of RBG:

Body and organ weights, energy intake, blood glucose and liver parameters

Fig. 1 and Table 2 compare growth data for the 78 rats fed with hiCHO, modCHO or hiCHO+hiFiber diets from 4 weeks of age. As a group, rats fed with the modCHO diet gained weight more consistently than their hiCHO counterparts and were significantly heavier (10% after 3 weeks of diet challenge). In fact, as diabetes accelerated after 3 weeks, the loss of body fat was considerable for all rats with advanced diabetes in any group, and they experienced terminal weight loss as ketosis developed,

Discussion

Findings from the current experiments extend our understanding of Type 2 diabetes in the NR, making several points relative to the human disease. First, a hiCHO diet was most deleterious for acute induction and progression of T2DM. Second, energy density did not seem to be an issue, per se, in terms of diabetes status. Third, diet composition did not appear to affect caloric intake or growth efficiency, at least not before T2DM was apparent. Finally, insulin resistance was most pronounced in

Conclusion

An important conclusion is that neither the adipose pool size, nor fat intake, nor caloric density of the diet necessarily predict diabetes outcome in NRs, similar to the situation in humans. Dietary CHO content and quality, on the other hand, appear to be sensitive predictors for the development and severity of NR diabetes. The analogy with the human condition renders the growing NR an attractive T2DM model, especially when compared to diet-induced obesity (DIO) mice or other rodent models,

Acknowledgments

The authors thank Karen Lai, Yulia Dushkina, Tegan Polack, Darryn Remillard, Emily Lai, Jeff Hu and Eli Miller for their attentive care of the NR breeding colony, special diet preparation, feeding of rats and technical assistance throughout the study.

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    Authors' contributions: JB, AP and KCH contributed to various aspects of the design and participated in data collection. JB and AP performed statistical analysis. JB interpreted the data and drafted the manuscript. All authors read and approved the final manuscript.

    ☆☆

    Funding sources: The studies were supported by the Foster Biomed Res Lab funds for research and teaching and a grant from the Malaysian Palm Oil Board.

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