Defining the molecular nexus of cancer, type 2 diabetes and cardiovascular disease

The metabolic syndrome is characterized by a state of metabolic dysfunction resulting in the development of several chronic diseases that are potentially deadly. These metabolic deregulations are complex and intertwined and it has been observed that many of the mechanisms and pathways responsible for diseases characterizing the metabolic syndrome such as type 2 diabetes and cardiovascular disease are linked with cancer development as well. Identification of molecular pathways common to these diverse diseases may prove to be a critical factor in disease prevention and development of potential targets for therapeutic treatments. This review focuses on several molecular pathways, including AMPK, PPARs and FASN that interconnect cancer development, type 2 diabetes and cardiovascular disease. AMPK, PPARs and FASN are crucial regulators involved in the maintenance of key metabolic processes necessary for proper homeostasis. It is critical to recognize and identify common pathways deregulated in interrelated diseases as it may provide further information and a much more global picture in regards to disease development and prevention. Thus, this review focuses on three key metabolic regulators, AMPK, PPARs and FASN, that may potentially serve as therapeutic targets.     

The ribotype theory on the origin of life

The ribotype is defined as the ribonucleoprotein system of any cell. The theory substitutes the genotype-phenotype duality with the trinity genotype-ribotype-phenotype, and proposes that life on earth originated with the ancestors of today's ribotypes.The first three chapters describe separate models on precellular evolution, the evolution of protocells and the nature of the cell respectively, and the unity of the theory comes from the fact that they form a consistent and interdependent whole.The core of the theory is the ribotype hypothesis, of which two formulations are given. The restricted version is based on a link between ribotypes and ribosome biogenesis, and provides an explanation for the difference between 70S and 80S ribosomes. The general version describes a link between ribotypes and cell-types and explains why prokaryotes have 70S ribosomes, eukaryotes 80S ribosomes and endosymbionts a type of ribosomes similar to the bacterial ones.If the creation hypothesis, panspermia and spontaneous generation are set aside, all alternative models of the origin of life belong to two schemes which are referred to as the genotype and the phenotype theories. It is shown that these theories rely on some discontinuity between past and present biological principles because of the need to break their inherent chicken-and-egg paradoxes, while the ribotype theory does not. Its hypotheses, free and arbitrary as they are or appear to be, have been built exclusively on properties and processes for which solid evidence exists, and the continuity between past and present biological laws is assumed as a corollary. Finally, it is shown that falsification tests are possible, and some of them are expected in the relatively near future.     

Geographical distribution and the origin of life: The development of early nineteenth-century British explanations

Conclusions By the 1840s and 1850s biogeographical theory had polarized into two opposing views — both of which had their origins in the sixteenth or seventeenth centuries. At issue in this polarization was the question of God's involvement with His creation. At one end of the spectrum were Sclater, Agassiz, Kirby, and others who saw a neatly designed world in which geographical distributions were planned and executed by the hand of God at creation. For most of these naturalists, organisms were created en masse within the regions they now occupy. Disjunct distributions were proof to them that God had indeed created species in situ as many individuals. These naturalists hoped to reveal God's biogeographical plan by discovering His regions of creation. They had hoped to demonstrate a neatly devised set of regions of creation which might be applicable to all creatures, but in attempting to do so, they arrived at conflicting sets of delineations — thus helping to undermine their conceptions of nature in which design (both idealist and utilitarian) played an important part.⁹³ At the other end of the biogeographical spectrum were the theoretical ideas of Prichard and Lyell, who viewed a more remote God — one who allowed His creation to be shaped and modified by secondary laws. Lyell in particular wished to leave considerations of design aside, hoping to demonstrate that the shape of the present creation is due to natural laws. Prichard and Lyell saw God's role in the creation of species (and distributions) as being extremely limited. In fact, the regions of creation seen today are in actuality only natural artifacts produced by migrations and barriers. They saw distributions being in constant flux, as was the rest of nature.Those supporting the views of Prichard and Lyell spent a great deal of effort in attempting to remove a major obstacle in their paths — disjunct distributions. If disjunct distributions were indeed the products of separate creative acts, as Sclater and others claimed, then the arguments of Prichard and Lyell would be negated. For if the creation of a species was shown to be the product of multiple creations, then what was the need of migrations and dispersal mechanisms? Also at stake, of course, was the concept of species based upon generation. Darwin was well aware that if the supernatural implications of disjunct distributions could not be refuted, then his evolutionary system — founded upon a species concept based on descent — would be in peril.⁹⁴ A further barrier to the acceptance of the Prichard/Lyell view was the fact that those sympathetic to a nonsupernatural explanation of disjunct distributions could not agree upon a natural explanation for those anomalies, and an internal debate between naturalists within this group raged for decades.⁹⁵ By 1859 a biogeographical stalemate had occurred. Sclater and others, supporting their static view of nature, continued to look for regions of creation, pointing to disjunct distributions in support of their arguments, while those favorable to the views of Prichard and Lyell continued to search for natural explanations for such biogeographical anomalies.The key needed to resolve the biogeographical debate was a credible theory for species origins. By 1858 there were essentially three options for British naturalists: supernatural creation, Lamarckian transmutation, or natural creation. A few British naturalists grasped at these straws, but most workers preferred the option of remaining silent until a more viable explanation for the origin and distribution of species could be advanced.⁹⁶ And not until the publication of Darwin's theory did that explanation become available.     

Malnutrition in early life and risk of type 2 diabetes: Theoretical framework and epidemiological evidence

There exist numerous experimental and epidemiological data indicating that malnutrition in early development may influence the risk of developing metabolic disorders in adult life, including type 2 diabetes mellitus (T2DM). Epidemiological evidence for such a relationship was mostly obtained in quasi-experimental studies (natural experiments) carried out on the populations of different countries. These studies revealed that exposure to famine in prenatal and/or early postnatal development is associated with increased risk of developing type 2 diabetes in adult life. Epigenetic regulation of gene activity is considered to be the main mechanism linking starvation in early life and increased risk of type 2 diabetes in adulthood. It is believed that exposure to famine during pregnancy may induce persistent epigenetic variations that are thought to have some adaptive value in the early postnatal development but that also lay grounds for metabolic disorders, including type 2 diabetes, in later life. The present review consolidates and discusses the data indicating the possibility of early developmental programming of type 2 diabetes obtained in the course of quasi-experimental studies.     

A theory of the origin of life

Life on Earth is essentially nucleic acids (NAs) influencing peptide synthesis such that NA replication is favored. It is proposed that the ability to synthesize polypeptides evolved gradually — one peptide bond at a time. The proposed evolution of the peptide synthesis apparatus begins with a transfer NA (tNA) which catalyzes the transfer of activated amino acids to accessible amino groups in its environment. The resulting capped molecules (with single amino acid caps) in turn favor NA replication. The proposed evolution of the peptide synthesis apparatus from the tNA onward is characterized by a progressive increase in the number of amino acids per cap: two tNAs jointly produce a dipeptide cap, three tNAs jointly produce a tripeptide cap, etc. Messenger NAs evolve because they can specify the composition and sequence order of the peptide caps. Lastly, ribosomal NAs evolve. The origin, expansion, and standardization of the genetic code are discussed. It is proposed that the present triplet code evolved by a process of codon length refinement, and that originally codons of varying lengths were allowable, as were unassigned bases between codons. An environmental supply of activated compounds for early evolving entities is proposed. An environmental NA replication process via single template-directed bond formation events is proposed. An environmental retention and redistribution process is proposed to have acted as a functional substitute for the cell wall and cell division of early evolving entities.     

Effects of high-fat diet exposure during fetal life on type 2 diabetes development in the progeny

Nutrition during fetal life is a critical factor contributing to diabetes development in adulthood. The aim of our study was to verify: 1) whether a high-fat (HF) diet in young adult mice induces alterations in beta-cell mass, proliferation, neogenesis, and apoptosis, as well as insulin sensitivity and secretion; 2) whether these alterations may be reversible after HF diet suspension; 3) the effects in a first (F1) and second generation (F2) of mice without direct exposure to a HF diet after birth. Type 2 diabetes developed in adult mice on a HF diet, in F1 mice that were HF diet-exposed during fetal or neonatal life, and in F2 mice whose mothers were HF diet-exposed during their fetal life. beta-cell mass, replication, and neogenesis were high in HF diet-exposed mice and decreased after diet suspension. beta-cell mass and replication remained high in F1 mice and decreased in F2 mice whose mothers were exposed to a HF diet. beta-cell neogenesis was present in adult mice on a HF diet and in F1 mice that were HF diet-exposed during fetal and/or neonatal life. We conclude that a HF diet during fetal life, particularly if combined with the same insult during the suckling period, can induce the type 2 diabetes phenotype, which can be directly transmitted to the progeny even in the absence of additional dietary insults.     

Comparison of prognosis for men with type 2 diabetes mellitus and men with cardiovascular disease

Background

People with type 2 diabetes mellitus are at high risk for cardiovascular disease. In some studies, the mortality rate among people with this condition has been equivalent to that among people with cardiovascular disease. We compared cardiovascular mortality between incident cases of diabetes and cardiovascular disease.

Methods

The study population was part of a random sample of 4376 men from Quebec, Canada, aged 35 to 64 years, who did not have cardiovascular disease in 1974 and who were followed until 1998. Three groups of incident cases were identified: diabetes without cardiovascular disease, first cardiovascular event (myocardial infarction, unstable angina or stroke) without diabetes, and both cardiovascular disease and diabetes. These cases were age-matched to a control group without diabetes or cardiovascular disease.

Results

During the 24-year follow-up period, new diabetes without cardiovascular disease was documented in 137 men. A first cardiovascular event without diabetes was documented in 527 men. Relative to the 627 controls, men with 1 of the 2 diseases of interest had higher cardiovascular mortality (age-adjusted relative risk [RR] 3.11, 95% confidence interval [CI] 1.96–4.92) for those with diabetes and 4.46 (95% CI 3.15–6.30) for those with cardiovascular disease). However, within the first 5 years after diagnosis, men with cardiovascular disease had higher cardiovascular mortality than men with diabetes (age-adjusted RR 2.03, 95% CI 1.01–4.08).

Interpretation

Men with isolated type 2 diabetes and men with isolated cardiovascular disease had similar cardiovascular mortality rates several years after initial diagnosis of either condition. These findings reinforce the need to prevent and optimally manage diabetes and cardiovascular disease.In 1971, type 2 diabetes mellitus was already considered an epidemic, affecting more than 170 million people worldwide.¹ In 2001, it was estimated that diabetes prevalence would increase by nearly 50% by the year 2010.¹ Epidemiologic studies performed in randomly sampled populations and initiated in the 1970s and 1980s have shown that diabetes increases the risk of all-cause death, as well as death due to cardiovascular disease and coronary artery disease.^2–23 In some studies,^12–17 but not all studies,^18–23 coronary or cardiovascular mortality among people with type 2 diabetes without previous cardiovascular disease was equivalent to that of people without diabetes who had had a first myocardial infarction or first cardiovascular event. Thus, there is controversy as to whether diabetes alone confers a risk of cardiovascular mortality similar to that associated with having had a first coronary or cardiovascular event. The differences in findings among various studies may be attributable to several factors such as age, sex, duration of diabetes and cardiovascular disease, ethnicity, cardiovascular risk factors and therapies. Furthermore, most studies used prevalent cases without considering the duration of cardiovascular disease or diabetes and did not exclude high-risk patients who had angina or intermittent claudication before the diagnoses of diabetes and cardiovascular disease.The rationale for undertaking the present study was the need for more information about the cardiovascular prognosis of men with type 2 diabetes relative to men with cardiovascular disease. We used incident instead of prevalent cases, without prior angina and without intermittent claudication. We speculated that the adverse prognosis associated with a diagnosis of diabetes would be similar to the prognosis associated with a diagnosis of cardiovascular disease over the long term but would be less similar over the short term. We formulated 2 hypotheses: first, that within the first few years after diagnosis, the risk of a fatal cardiovascular event would be higher among men with a first cardiovascular event and no diabetes than among men with type 2 diabetes and no cardiovascular disease; and second, that over the longer term, the risk of death within these 2 clinical subsets would tend toward equivalence.     

Epidemiological evidence for the role of physical activity in reducing risk of type 2 diabetes and cardiovascular disease.

Epidemiological studies suggest that physically active individuals have a 30-50% lower risk of developing type 2 diabetes than do sedentary persons and that physical activity confers a similar risk reduction for coronary heart disease. Risk reductions are observed with as little as 30 min of moderate-intensity activity per day. Protective mechanisms of physical activity include the regulation of body weight; the reduction of insulin resistance, hypertension, atherogenic dyslipidemia, and inflammation; and the enhancement of insulin sensitivity, glycemic control, and fibrinolytic and endothelial function. Public health initiatives promoting moderate increases in physical activity may offer the best balance between efficacy and feasibility to improve metabolic and cardiovascular health in largely sedentary populations.     

Relationship of metabolic risk factors and development of cardiovascular disease and diabetes

The prevalence of obesity and diabetes has reached pandemic proportions. Obesity, particularly in association with high waist circumference and high BMI, is an independent risk factor for coronary heart disease (CHD) and diabetes. Several large studies have shown that marginal (5 lb) to moderate (11 to 22 lb) weight gain in adulthood (age 20 to 50 years) increases the risk of chronic disease and negatively affects CHD risk status. The metabolic syndrome, a clustering of cardiovascular and metabolic risk factors that includes abdominal obesity, is increasing among adults and children and is strongly associated with the development of diabetes and CHD. Recent evidence suggests that elevated liver enzymes, an indicator of non-alcoholic fatty liver disease, may comprise an additional component of the metabolic syndrome and may serve as a surrogate marker for type 2 diabetes, particularly if used in conjunction with C-reactive protein.     

Cardiovascular disease in diabetes mellitus type 2: a potential role for novel cardiovascular risk factors

A major consequence of diabetes mellitus type 2 is the accelerated development of atherosclerosis. Assessment of conventional risk factors such as plasma lipids, lipoproteins and hypertension only partly account for the excessive risk of developing cardiovascular disease in this population. Increasing evidence has emerged suggesting that conditions associated with diabetes mellitus type 2, such as insulin resistance, hyperinsulinemia and hyperglycemia, may also play a significant role in regulating 'novel' cardiovascular risk factors. These factors and their potential roles in the development of atherosclerosis and cardiovascular events are discussed in this review.     

Iron-sulphur proteins: Their possible place in the origin of life and the development of early metabolic systems

A review is made of certain features of the biology and chemistry of the iron-sulphur proteins which suggests that these proteins may be descended from an ancestral form or form swhich arose very early in the development of biological metabolic systems (the origin of life). If this hypothesis is correct it would suggest that this class of proteins developed during the epoch in which the Earth's atmosphere was reducing in nature and that the relative facility with which the active site of certain contemporary iron-sulphur proteins is experimentally reconstituted may have played a part in their evolutionary development.     

Pre- and early postnatal nongenetic determinants of type 2 diabetes

Epidemiological studies have revealed strong and internationally reproducible links between early growth restriction and subsequent risk of developing type 2 diabetes and the metabolic syndrome (glucose intolerance, hypertension and hypertriglyceridaemia). This effect can exist independently of genetic factors. There is also direct evidence that poor maternal nutrition and maternal smoking cause both a reduction in birthweight and subsequent loss of glucose tolerance. High rates of growth in childhood may add to these effects. The 'thrifty phenotype' hypothesis attempts to explain these associations in terms of an altered programming of growth and metabolism that aids survival both pre- and postnatally. Type 2 diabetes is envisaged as a consequence of a clash of this programming with adult obesity. Tests of this hypothesis in animal models have shown that both the metabolic syndrome and type 2 diabetes can result from early growth restriction in rats consequent upon rat dams being fed a reduced protein, isocaloric diet (in which the protein is replaced by an equal quantity of nonprotein energy). A variety of other models of early growth restriction in rats lead to a similar phenotype. Several structural and gene expression changes have been shown in many tissues, including pancreas, liver, kidney, muscle and adipose tissue. Changes in gene expression include those concerned with hormone receptors, signalling and glycolytic enzymes. Many important questions remain for future research.     

The role of melatonin in the treatment of type 2 diabetes mellitus and Alzheimer's disease

In type 2 diabetes mellitus (T2DM) and its related disorders like obesity, the abnormal protein processing, oxidative stress and proinflammatory cytokines will drive the activation of inflammatory pathways, leading to low-grade chronic inflammation and insulin resistance (IR) in the periphery and impaired neuronal insulin signaling in the brain. Studies have shown that such inflammation and impaired insulin signaling contribute to the development of Alzheimer''s disease (AD). Therefore, new therapeutic strategies are needed for the treatment of T2DM and T2DM-linked AD. Melatonin is primarily known for its circadian role which conveys message of darkness and induces night-state physiological functions. Besides rhythm-related effects, melatonin has anti-inflammatory and antioxidant properties. Melatonin levels are downregulated in metabolic disorders with IR, and activation of melatonin signaling delays disease progression. The aim of this Review is to highlight the therapeutic potentials of melatonin in preventing the acceleration of AD in T2DM individuals through its therapeutic mechanisms, including antioxidative effects, anti-inflammatory effects, restoring mitochondrial function and insulin sensitivity.