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.     

Psammomys obesus and the albino rat--two different models of nutritional insulin resistance, representing two different types of human populations.

Animal models for insulin resistance and type 2 diabetes are required for the study of the mechanism of these phenomena and for a better understanding of diabetes complications in human populations. Type 2 diabetes is a syndrome that affects 5-10% of the adult population. Hyperinsulinaemia, hypertriglyceridaemia, decreased high-density lipoprotein (HDL) cholesterol levels, obesity and hypertension, all form a cluster of risk factors that increase the risk of coronary artery disease, and are known as insulin resistance syndrome or syndrome X. The gerbil, Psammomys obesus is characterized by primary insulin resistance and is a well-defined model for dietary induced type 2 diabetes. Weanling Psammomys and Albino rats were held individually for several weeks on high energy (HE) and low energy (LE) diets in order to determine the development of metabolic changes leading to diabetes. Feeding Psammomys on HE diet resulted in hyperglycaemia (303 +/- 40 mg/dl), hyperinsulinaemia (194 +/- 31 microU/ml) and a moderate elevation in body weight, obesity and plasma triglycerides. Albino rats on HE diet demonstrated an elevation in plasma insulin (30 +/- 4 microU/ml), hypertriglyceridaemia (170 +/- 11 mg/dl), an elevation in body weight and obesity, but maintained normoglycaemia (98 +/- 6 mg/dl). Psammomys represent a model that is similar to human populations, with primary insulin resistance expressed in young age, which leads to a high percentage of adult type 2 diabetes. Examples for such populations are the Pima Indians, Australian Aborigines and many other Third World populations. The results indicate that the metabolism of Psammomys is well adapted towards life in a low energy environment, where Psammomys takes advantage of its capacity for a constant accumulation of adipose tissue that will serve for maintenance and breeding in periods of scarcity. This metabolism known as 'thrifty metabolism', is compromised at a high nutrient intake.     

Génétique du syndrome métabolique

Metabolic syndrome (MetS) is a common phenotype, affecting about 24 % of the US population. It is associated with an increased risk for type 2 diabetes and cardiovascular disease. Although there is no universally accepted definition for MetS, affected individuals commonly have a cluster of features, including abdominal obesity, hypertension, dyslipidemia, and dysglycemia. Recently, there has been extensive interest in potential genetic contributions to MetS. At present, no single gene or cluster of genes has been consistently replicated for MetS among different populations, likely due to the complex interplay between gene and environment necessary for expression of this phenotype. We review recent studies regarding the genetic contributions to MetS.     

Intergenerational effect of an adverse intrauterine environment on perturbation of glucose metabolism.

Human epidemiological and animal studies have revealed the late consequences of malnutrition during gestation and early life on the health of the offspring. These studies have highlighted the inverse relationship between birth weight and the incidence of insulin resistance and type 2 diabetes later in life. The aim of this paper is to review the different means of achieving foetal malnutrition and its consequences even for a next generation, in animal models and to identify key area for further research. We address the impact of two models of maternal malnutrition (protein restriction and caloric restriction) as well as the impact of maternal diabetes, the three maternal conditions leading to perturbed foetal nutritional environment. Particular emphasis is given to the endocrine pancreas and the insulin sensitive tissues. More specifically, alterations of the foetal nutritional environment perturb the development of the endocrine pancreas and target the ss cell mass at birth. Some adaptations later in life may take place but stress situations such as pregnancy and ageing precipitate the animals to glucose intolerance and insulin resistance. Even the next generation features alterations in the development of the endocrine pancreas. Some mechanisms by which the foetal ss cell mass is altered are approached in this review and specific attention is paid to the amino acid profile. The preventive role of taurine is discussed.     

Association between shift work and risk of type 2 diabetes mellitus: a systematic review and dose-response meta-analysis of observational studies

ABSTRACT

To evaluate the association between shift work and risk of type 2 diabetes mellitus, we searched PubMed, EMBASE and Web of Science from their inception to June 8, 2019. Observational studies examining the relationship between shift work and type 2 diabetes were included. Subgroup analyses were conducted to explore whether specific characteristics would affect the relationship. A dose-response relationship was estimated by using generalized least squares trend regression. Finally, twelve cohort studies and nine cross-sectional studies were included (inter-rater agreement, k = 0.96). The result of meta-analysis indicated that shift work was associated with an increased risk of type 2 diabetes (relative risk = 1.10, 95% confidence interval = 1.05–1.14). Subgroup analyses demonstrated that female shift workers have increased risk of type 2 diabetes while male not observed, health care workers showed the highest risk compared with civil servants and manual workers, and night shift and rotating shift were associated with an increased risk of type 2 diabetes. Dose-response meta-analysis based on three cohorts among female workers indicated that there might be a positive association between duration of shift work and the risk of type 2 diabetes. In conclusion, shift work is positively associated with an increased risk of type 2 diabetes. Among female workers, with the years of exposure to shift work prolonged, the risk of type 2 diabetes might increase accordingly. In the future, more studies are needed to confirm the results of dose-response analysis.     

The role of iron in type 2 diabetes in humans

The role of micronutrients in the etiology of type 2 diabetes is not well established. Several lines of evidence suggest that iron play may a role in the pathogenesis of type 2 diabetes. Iron is a strong pro-oxidant and high body iron levels are associated with increased level of oxidative stress that may elevate the risk of type 2 diabetes. Several epidemiological studies have reported a positive association between high body iron stores, as measured by circulating ferritin level, and the risk of type 2 diabetes and of other insulin resistant states such as the metabolic syndrome, gestational diabetes and polycystic ovarian syndrome. In addition, increased dietary intake of iron, especially that of heme iron, is associated with risk of type 2 diabetes in apparently healthy populations. Results from studies that have evaluated the association between genetic mutations related to iron metabolism have been inconsistent. Further, several clinical trials have suggested that phlebotomy induced reduction in body iron levels may improve insulin sensitivity in humans. However, no interventional studies have yet directly evaluated the effect of reducing iron intake or body iron levels on the risk of developing type 2 diabetes. Such studies are required to prove the causal relationship between moderate iron overload and diabetes risk.     

The influence of leptin on early life programming of obesity

Epidemiological evidence together with experimental models shows a direct relationship between fetal and early postnatal growth patterns and an increased risk of adult metabolic disease. Maternal health and nutrition are key determinants in influencing infant growth but the precise molecular mechanisms underlying this relationship are unclear, although it is evident that there are critical time windows when these effects are important. Animal models show mechanistic parallels with human populations and highlight that the early environment represents a therapeutic window for protection from obesity and metabolic disease. The observation that developmental programming can be reversed has been demonstrated in studies in which both maternal and neonatal leptin treatment prevents the induction of the adverse metabolic phenotype. Given that orally administered peptides are absorbed intact by the new born, the prospect of providing supplemental leptin either as drops or in milk deserves serious consideration as a means of reducing or reversing the obesity and type 2 diabetes epidemic.     

Association of gestational diabetes mellitus and low-density lipoprotein (LDL) particle size

A predominance of small, dense low-density lipoproteins (LDL) is characteristic of the dyslipidemic state seen in type 2 diabetes. However, no study has investigated the association in gestational diabetes mellitus (GDM), which is pathophysiologically similar to type 2 diabetes. We hypothesized that LDL particle size is reduced in GDM cases compared with controls. Gradient gel electrophoresis was used to characterize LDL subclass phenotypes in non-fasting intrapartum plasma from 105 GDM cases and 96 controls. All participants were free of pre-existing diabetes or hypertension. The authors used logistic regression to estimate odds ratios (OR) and 95 % confidence intervals (CI) adjusted for confounders. Women with this phenotype had a significant 4.9-fold (95 % CI: 1.1-23.2) increased risk of GDM compared with those with the large, buoyant phenotype. The magnitude of this association was attenuated when plasma triglyceride and other confounders were included in the model (OR=4.2, 95 % CI: 0.5-39.5). Mean LDL particle size in GDM cases was smaller compared with controls (270.1 vs. 272.7A, p=0.003). The OR of GDM risk was 1.8 (95 % CI: 0.9-3.3) for every 10-A reduction in LDL particle size. Large prospective studies are needed to evaluate the association between smaller LDL particle size in early pregnancy with subsequent GDM risk.     

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.     

Consumption of Meals Prepared at Home and Risk of Type 2 Diabetes: An Analysis of Two Prospective Cohort Studies

BackgroundThere has been a trend towards increased dining out in many countries. Consuming food prepared out of the home has been linked to poor diet quality, weight gain, and diabetes risk, but whether having meals prepared at home (MPAH) is associated with risk of type 2 diabetes (T2D) remains unknown.ConclusionsIn two large prospective cohort studies, frequent consumption of MPAH is associated with a lower risk of developing T2D, and this association is partly attributable to less weight gain linked with this dining behavior.     

Peroxisome proliferator-activated receptor-gamma agonists in atherosclerosis: current evidence and future directions

PURPOSE OF REVIEW: The prevalence of type 2 diabetes globally is reaching epidemic proportions. Type 2 diabetes is strongly associated with increased risk of cardiovascular disease. Atherosclerosis is thought to arise as a result of a chronic inflammatory process within the arterial wall. Insulin resistance is central to the pathogenesis of type 2 diabetes and may contribute to atherogenesis, either directly or through associated risk factors. The peroxisome proliferator-activated receptor-gamma agonists, the thiazolidinediones, pioglitazone and rosiglitazone, are insulin sensitizing agents, that are licensed for the management of hyperglycaemia. Growing evidence supports an array of additional effects of thiazolidinedione therapy, both immunomodulatory and antiinflammatory, which may attenuate atherogenesis in type 2 diabetes. RECENT FINDINGS: Studies have shown that thiazolidinedione therapy may lead to risk factor modulation in type 2 diabetes. Thiazolidinediones treatment has been shown to reduce blood pressure, modify the atherogenic lipid profile associated with type 2 diabetes, reduce microalbuminuria and ameliorate the prothrombotic diathesis. Further evidence suggests that thiazolidinediones therapy inhibits the inflammatory processes which may be involved in atherosclerotic plaque initiation, propagation and destabilization. SUMMARY: Modification of insulin resistance by thiazolidinedione therapy in type 2 diabetes and the range of pleiotropic effects may not only impact on incident type 2 diabetes, but also on associated cardiovascular disease. Numerous large clinical endpoint studies are under way to investigate these issues.     

Nongenomic memory of foetal history in chronic diseases development

Foetal growth from conception to birth is a complex process predetermined by the genetic configuration of the foetus, the availability of nutrients and oxygen to the foetus, maternal nutrition and various growth factors and hormones of maternal, foetal and placental origin. Maintenance of the optimal foetal environment is the key factor of the future quality of life. Such conditions like inadequate nutrition and oxygen supply, infection, hypertension, gestational diabetes or drug abuse by the mother, expose the foetus to nonphysiological environment. In conditions of severe intrauterine deprivation, there is a potential loss of structural units within the developing organ systems affecting their functionality and efficiency. Extensive human epidemiologic and animal model data indicate that during critical periods of prenatal and postnatal mammalian development, nutrition and other environmental stimuli influence developmental pathways and thereby induce permanent changes in metabolism and chronic disease susceptibility. The studies reviewed in this article show how environmental factors influence a diverse array of molecular mechanisms and consequently alter disease risk including diseases such as metabolic syndrome and cardiovascular diseases, insulin resistance and diabetes mellitus, neuropsychiatric disorders, osteoporosis, asthma and immune system diseases.     

Assessment of the association between GSTM1 null genotype and risk of type 2 diabetes

Many studies have investigated the association between Glutathione S-Transferase M1 (GSTM1) null genotype and risk of diabetes mellitus, but the impact of GSTM1 null genotype on diabetes mellitus is unclear owing to the obvious inconsistence among those studies. This study aimed to quantify the strength of association between GSTM1 null genotype and risk of diabetes mellitus. We searched the PubMed, Embase and Wangfang databases for studies relating the association between GSTM1 null genotype and risk of diabetes mellitus. We estimated summary odds ratio (OR) with their 95 % confidence interval (95 % CI) to assess the association. Subgroup analyses were performed by type of diabetes and ethnicity. 10 case–control studies with 7, 054 subjects were included into this meta-analysis. Meta-analysis of total 10 studies showed GSTM1 null genotype was associated increased risk of diabetes mellitus (OR = 1.59, 95 % CI 1.14–2.22, P = 0.007). Subgroup analyses by type of diabetes mellitus suggested GSTM1 null genotype was associated increased risk of type 2 diabetes (OR = 1.90, 95 % CI 1.37–2.64, P < 0.001), but was not associated with risk of type 1 diabetes (OR = 0.84, 95 % CI 0.66–1.07, P = 0.153). Subgroup analysis by ethnicity further identified the obvious association between GSTM1 null genotype and increased risk of type 2 diabetes. The cumulative meta-analyses showed a trend of obvious association between GSTM1 null genotype and risk of type 2 diabetes as information accumulated. No evidence of publication bias was observed. Thus, evidence from current meta-analysis suggests an association between GSTM1 null genotype and risk of type 2 diabetes.     

Babies born small for gestational age: insulin sensitivity and growth hormone treatment

Epidemiological studies have identified an association between size at birth and adult risk for type 2 diabetes mellitus and cardiovascular disease. In contemporary populations, children who are relatively small at birth and show rapid infancy weight gain are at greatest risk for the development of childhood obesity, increased visceral fat and insulin resistance: possible early markers of adult disease risk. Individuals presenting to growth clinics with short stature and a history of low birthweight will not have shown post-natal catch-up growth and may be a very heterogeneous group. Nevertheless, there are some data to suggest that as a group they are insulin resistant with decreased lean mass. Growth hormone treatment leads to reversible worsening of the insulin resistance, and short-term data do not indicate an increased risk for type 2 diabetes. However, further long-term follow-up is required, and particular care should be taken in monitoring children with a strong family history of type 2 diabetes and those from ethnic groups in which there is a high background prevalence of the disease.     

Recent progress in the use of genetics to understand links between type 2 diabetes and related metabolic traits

Genome-wide association studies have identified genetic variants associated with increased risk of type 2 diabetes. The aim of this review is to highlight some of the insights into the mechanism underlying type 2 diabetes provided by genetic association studies.     

HDL revisited: new opportunities for managing dyslipoproteinaemia and cardiovascular disease

Low concentrations of high-density lipoprotein (HDL) cholesterol constitute a risk factor for coronary heart disease (CHD). There is increasing evidence that increasing HDL-cholesterol levels reduces cardiovascular risk. The phenotype of low HDL cholesterol with or without elevated triglycerides is common and it is characteristic of patients with central obesity, insulin resistance, hypertension and type 2 diabetes mellitus; conditions associated with increased cardiovascular risk and are part of the rubric of the metabolic syndrome. Epidemiological, experimental and clinical trial evidence suggests that there is a good rationale for raising HDL-cholesterol in these and other high-risk patients. The protective effect of HDL-cholesterol against atherosclerosis and cardiovascular disease is mediated by both enhanced reverse cholesterol transport (RCT) and by direct anti-atherosclerotic mechanisms. Recent studies have elucidated mechanisms whereby HDL acts to reduce cardiovascular risk, supporting the rationale for targeting of HDL with lipid-modifying therapy. Ongoing investigation of mechanisms by which HDL acts to reduce the risk of atherosclerosis will provide opportunities for the development of new therapeutic strategies to decrease the risk of atherosclerosis.     

The TNF-alpha -308G/A polymorphism is associated with type 2 diabetes mellitus: an updated meta-analysis

The tumor necrosis factor (TNF)-alpha -308G/A polymorphism has long been suspected of being a gene variant that is associated with type 2 diabetes, but studies have reported conflicting outcomes. An updated meta-analysis was performed to investigate whether the TNF-alpha -308A variant is associated with an increased risk of type 2 diabetes. Statistical analyses were performed using Revman 5.0 and STATA 10.0 software. A total of 38 case–control studies in 38 articles were included. Statistical analyses of the results suggested that the TNF-alpha -308G/A polymorphism was associated with an increased risk of type 2 diabetes mellitus (OR = 1.21, 95 % CI 1.06–1.37, P = 0.003) in a dominant model, particularly for Asian carriers of the A mutation (GA+AA), who were shown to have a 39 % increased risk of type 2 diabetes (OR = 1.39, 95 % CI 1.11–1.74, P = 0.004) compared with wild-type (GG) subjects. However, no significant difference in diabetes risk was found between the mutant and wild-type genotypes in Caucasian subjects (OR = 1.08, 95 % CI 0.98–1.18, P = 0.12). This meta-analysis indicates that the TNF-alpha -308A variant could be a risk factor for the development of type 2 diabetes, particularly in Asian subjects. However, this association was not statistically significant in Caucasian subjects. More specified ethnical studies are required to reveal the detailed physiological characteristics of the TNF-alpha -308 G/A polymorphism.     

Serum insulin-like growth factor-I levels and potential risk of type 2 diabetes

The effects of circulating insulin-like growth factor (IGF)-I on increasing insulin sensitivity are well recognized. IGF-I may have a further important role in maintaining beta-cell mass, and lower IGF-I activity could explain links between small size at birth and risk of type 2 diabetes in short, obese adults. In the representative Avon Longitudinal Study of Pregnancy and Childhood birth cohort, whereas insulin sensitivity is related to early postnatal weight gain, insulin secretion is related to IGF-I level and statural growth. Adult studies suggest that lower IGF-I levels at baseline predict increased risk for developing impaired glucose tolerance and type 2 diabetes. A common genetic polymorphism in the IGF1 gene could influence size at birth, postnatal growth and type 2 diabetes risk, but results of studies have been inconsistent. Extrapolation of these data to short children born small for gestational age is complex. Some have evidence of IGF-I and insulin resistance, suggesting inherent defects in IGF-I signalling. These children have poor growth responses to growth hormone (GH) therapy and perhaps the highest type 2 diabetes risk. Where these metabolic abnormalities are less severe, responses to GH therapy are good and diabetes risk may then depend on other genetic factors, indicated by a family history of diabetes or origin from ethnic groups with high diabetes prevalence.     

Type 2 diabetes mellitus as risk factor for colorectal cancer

Colorectal cancer occurs more frequently in patients with type 2 diabetes mellitus. The hyperinsulinemia-hypothesis suggests that elevated levels of insulin and free IGF-1 promote proliferation of colon cells and lead to a survival benefit of transformed cells, ultimately resulting in colorectal cancer. In patients with type 2 diabetes mellitus, epidemiological studies show an increased risk for colorectal cancer and an even higher risk if patients are treated with sulphonylureas or insulin. Moreover, tumour progression at hyperinsulinemia is more rapid and tumour-associated mortality is increased. Colorectal cancer can be avoided by screening. Recommendations for colorectal cancer screening should employ the recent epidemiologic evidence. All patients with type 2 diabetes mellitus should be recommended to undergo colonoscopy before starting insulin therapy, and screening intervals should not exceed 5 years. For this concept, a review of the evidence is presented, and a screening algorithm for colorectal cancer in patients with type 2 diabetes mellitus is proposed.