Cold climate genes and the prevalence of type 2 diabetes mellitus

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Summary

Type 2 diabetes mellitus (T2D) is approaching epidemic proportions globally. However, some human populations, such as Western-Europeans, have a lower prevalence compared with urban or westernized groups with origins in warmer climates. To explain this conspicuous trend we have developed a hypothesis suggesting that pressure for survival on ancestral Western-Europeans (or on other human populations) in extremely cold climates could lead to selection for a combination of specific genes or alleles, which we have named cold climate genes, promoting adaptation to these condition. The possible molecular basis for the effects of these genes could lead to decreasing susceptibility to T2D. The possible candidates for cold climate genes have been evaluated from three areas: the uncoupling proteins, maternally-transmitted mitochondrial genes, and mitochondrial biogenesis.

Conclusions/significance: The possible existence of cold climate genes can lead to both increased thermogenesis and decreased prevalence of T2D. This may help explain the variations in prevalence of T2D in different ethnic groups. This consideration suggests testable experimental approaches towards prevention and therapies for T2D.

Introduction

Diabetes mellitus is a major public health problem that is approaching epidemic proportions globally [1], [2], [3]. Lifestyle transition in certain ethnic groups has a significant impact on health, in particular the incidence of type 2 diabetes mellitus (T2D). However, some human populations are much more affected by T2D than others. For this reason, the information derived from studies of T2D pathophysiology in different ethnic groups in so far as they can be defined can help us to better understand the relationships among genes, environment and society, that conspire to accelerate morbidity and mortality from T2D.

Variations in different ethnic groups related to diabetes or obesity were recently analyzed by Diamond [1]. He collected and analyzed age-standardized data on the prevalence of T2D. Among the main features he found was the higher prevalence in urban or westernized groups, that had relatively recently separated from their rural or traditional counterparts. The highest prevalence, 37–50%, was among urban or westernized groups of Nauru Islanders in the tropical Pacific, Pima Indians in Arizona and urban Wanigela people in Papua New Guinea. Populations undergoing increases in the incidence of T2D also include the urban or westernized groups of Asian Indians and Chinese, Japanese, Aboriginal Australians, Hispanic Americans and Afro-Americans, compared with their rural or traditional counterparts.

However, a conspicuous exception is the absence of any comparable explosion of T2D among people of European ancestry (although the incidence is increasing in the United States; see also [2], [4]). For this reason, Diamond [1] has put forward the question: “Why is the prevalence of T2D now exploding in most populations, but not in Europeans?”.

Diamond [1] has attempted to explain these differences based on the “thrifty gene hypothesis” of James Neel [5]. Neel postulated that a combination of genes might exist that improves the survival chances of their carriers in situations of long-term starvation. Under these conditions, individuals who could efficiently accumulate extra energy stores and use them most opportunistically would have a survival advantage. In modern environments, thrifty genes would contribute to obesity and T2D. However, Europeans also experienced famines that caused widespread mortality in medieval and Renaissance Europe [1]. To explain this contradiction, that is, the relative lack of T2D in modern European populations, Diamond [1] proposed that before the advent of modern medicine Europeans underwent an epidemic of T2D as a result of the introduction of adequate food supplies. After this unrecorded epidemic there was little selective pressure to maintain the diabetes-prone bearers of the thrifty genotype [1].

Other possibilities are also plausible. For example, Europeans were more physically active and lived predominantly in rural areas before the advent of modern urban societies and medicine. These circumstances considerably decrease the prevalence of T2D [1], [6]. Secondly, as Diamond also notes, T2D usually develops in middle-aged people after offspring are born and an elimination of diabetes-prone bearers would not stop gene inheritance. These factors contradict Diamond’s proposal that bearers of diabetes-prone genes were largely eliminated before the advent of modern history. While diet, economics and lifestyle surely contribute to the emerging epidemic of T2D, we have attempted to find additional explanations for the lower prevalence of T2D among people of European ancestry that would not require a selective pressure against thrifty genes and the resulting undocumented large-scale elimination of adult-onset individuals due to diabetes in their reproductive years. We focused on the possible influence of climate, because ancestral Western-Europeans lived in relatively cold climates, as opposed to such groups as Africans, South Asians and Pacific Islanders.

Section snippets

Cold climate genes hypotheses

Rural and urban areas were considered separately in Diamond’s article [1], since prevalence is known to differ markedly with differences in diet, physical exercise, and other socioeconomic factors. However, overweight and obesity are important classical risk factors for T2D. For this reason, the data from Diamond [1] need additional analysis to avoid possible effects of overweight and negative factors such as possible differences in living conditions and food availability. We can clarify this

Thermogenesis and metabolic rates

To clarify the possible physiological role of CCGs we briefly consider the basic metabolic mechanisms of thermogenesis, divided into two types: obligatory and facultative. Obligatory thermogenesis can be viewed as constitutive heat production independent of ambient temperature. It is well reflected in the so-called basal metabolic rate (BMR) or the less strict but more practical resting energy expenditure (REE), which are measured under conditions that eliminate the energy cost of physical

Molecular basis of heat, reactive species production and T2D onset

The molecular basis of heat production includes several candidates for possible CCGs. The energy needed for basic metabolic and thermogenesis processes contained in food is captured largely in the form of ATP produced in mitochondria, which is then used to sustain practically all vital processes. In mitochondria, electrons are fed into the electron transport chain from reduced substrates (such as NADH or FADH2). As electrons flow down their chemical gradient, complexes of the electron transport

Search of possible CCGs

The search for CCG candidates includes many aspects of human energy balance, from whole body thermogenesis to the coupling efficiency of oxidative phosphorylation. However, at present, little information is available to allow a useful estimation of the genetic contribution connecting thermogenesis and T2D onset. Here, we will focus on CCGs candidates in three areas: the uncoupling proteins, maternally-transmitted mitochondrial genes, and mitochondrial biogenesis (Fig. 1).

Variation in activity

Comparison of CCGs and thrifty genes

The present version of the Neel’s “thrifty” gene hypothesis of T2D [5] is that certain populations may have genes that determine increased energy storage, which in times of famine represent a survival advantage, but in a modern environment result in obesity and T2D [1], [21]. The concept finds support in several mouse mutant obesity–diabetes models [46] and a unique desert rodent model (Psammomys obesus) [47], as well as among high type 2 diabetes susceptibility populations, such as North

CCGs and prevention of T2D

All populations are potentially at higher risk for increased rates of T2D under conditions of rapid dietary change associated with caloric excess and insufficient physical activity [1], [3]. Our analysis derives from the observations that T2D has become a public health problem particularly among developing countries and the epidemic is just beginning in populous countries in Africa, Middle East, South Asia or Central America. However, according to our hypothesis some populations, such as

Acknowledgement

We thank Drs., G. Bell, R. Landau, S. Refetoff, D. Steiner and N. Tamarina for fruitful discussions. This work was supported by grants from National Institutes of Health.

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