Metabolic programming of insulin action and secretion

Type 2 diabetes (T2D), also known as non-insulin dependent diabetes mellitus, arises as a consequence of peripheral insulin resistance in combination with an inability of pancreatic islet β-cells to secrete adequate amounts of insulin. It is widely recognized that the current environment (e.g. an unhealthy diet and sedentary lifestyle) contributes to this process. In recent years, however, the role of the early environment, particularly nutrition, has emerged as an important factor capable of influencing health and disease risk of an individual, including risk of T2D. The impact of early environment on glucose metabolism has been extensively studied. Compelling evidence from epidemiological studies and animal models suggests that early nutrition can affect insulin action as a mediator of glucose homeostasis in peripheral tissues and as an important regulator of appetite and body weight. The early environment can also affect β-cell mass and function, and hence insulin secretion. The molecular mechanisms underlying the relationship between a suboptimal early environment and impaired insulin action and secretion is thought to include epigenetic modifications of the foetal genome, oxidative stress and mitochondrial dysfunction.     

Consequences of fetal exposure to maternal diabetes in offspring

CONTEXT: Type 2 diabetes is the result of both genetic and environmental factors. Fetal exposure to maternal diabetes is associated with a higher risk of abnormal glucose homeostasis in offspring beyond that attributable to genetic factors, and therefore, may participate in the excess of maternal transmission of type 2 diabetes. Evidence acquisition: A MEDLINE search covered the period from 1960-2005. EVIDENCE SYNTHESIS: Human studies performed in children and adolescents suggest that offspring who had been exposed to maternal diabetes during fetal life exhibit higher prevalence of impaired glucose tolerance and markers of insulin resistance. Recent studies that directly measured insulin sensitivity and insulin secretion have shown an insulin secretory defect even in the absence of impaired glucose tolerance in adult offspring. In animal models, exposure to a hyperglycemic intrauterine environment also led to the impairment of glucose tolerance in the adult offspring. These metabolic abnormalities were transmitted to the next generations, suggesting that in utero exposure to maternal diabetes has an epigenetic impact. At the cellular level, some findings suggest an impaired pancreatic beta-cell mass and function. Several mechanisms such as defects in pancreatic angiogenesis and innervation, or modification of parental imprinting, may be implicated, acting either independently or in combination. CONCLUSION: Thus, fetal exposure to maternal diabetes may contribute to the worldwide diabetes epidemic. Public health interventions targeting high-risk populations should focus on long-term follow-up of subjects who have been exposed in utero to a diabetic environment and on a better glycemic control during pregnancy.     

Potential role of E4orf1 protein in aging-associated impairment in glycemic control

Aging constitutes a major risk factor for the development of type-2 diabetes (T2D) where glucose tolerance declines with age, resulting in a high prevalence of T2D and impaired glucose tolerance in the elderly population. Currently more than half of the 20 million U.S. adults with T2D are above the age of 60, and the largest increase in T2D prevalence is expected in the elderly. Obesity is a causative factor for T2D associated insulin resistance and hyperglycemia. Furthermore, the aging process is accelerated by hyperglycemia and effective treatment options are limited for the vulnerable aging population. One of the mechanisms contributing to aging associated hyperglycemia is resistance to insulin-mediated glucose disposal. Chronic hyperglycemia also accelerates aging by increasing pro-inflammatory milieu leading to impaired immune function. Although currently available anti-diabetic agents improve glycemic control, they have potential serious side effects in some cases. Therefore, additional and better drugs are urgently needed for treatment of insulin resistance and aging associated health risk factors. This review presents the novel use of a microbial protein, E4orf1 as a potential anti-diabetic agent, which functions independent of insulin and obesity, highlighting the role of unique sources for future drug development.     

Effects of infant birthweight and maternal body mass index in pregnancy on components of the insulin resistance syndrome in China

BACKGROUND: Reduced birthweight is associated with increased risk for the insulin resistance syndrome. Part of this risk is hypothesized to originate from undernutrition in utero. The prevalence of the insulin resistance syndrome increases in countries that undergo the transition from chronic malnutrition to adequate nutrition, when postnatal nutrition improves more rapidly than prenatal nutrition. OBJECTIVE: To determine whether the components of the insulin resistance syndrome are associated with reduced fetal growth and maternal undernutrition. DESIGN: A nonconcurrent, prospective study of men and women whose mothers' heights and weights were recorded during pregnancy. SETTING: Beijing, China. PARTICIPANTS: 627 men and women (mean age, 45 years) whose mothers' obstetric records were preserved. MEASUREMENTS: Adult offspring's blood pressure, plasma glucose levels, insulin levels, and lipid concentrations during an oral glucose tolerance test. The main explanatory measurements were mothers' body mass index during pregnancy and offspring's birthweight and adult size. RESULTS: After adjustment for sex and current body mass index, low birthweight was associated with elevated plasma glucose levels, insulin levels, triglyceride concentrations, and blood pressure. For every 1-kg increase in birthweight, systolic blood pressure decreased by 2.9 mm Hg (95% CI, 0.3 to 5.4 mm Hg) and the 2-hour plasma glucose level decreased by 5.1% (CI, 0.7% to 9.3%). Low maternal body mass index in early and late pregnancy was associated with elevated levels of plasma glucose, insulin, and triglycerides in adult offspring but was not associated with elevated blood pressure. CONCLUSIONS: Risk for the insulin resistance syndrome may be partially established through low maternal body mass before pregnancy and consequent fetal undernutrition. This risk is independent of that associated with adult obesity. In developing countries such as China, improved nutrition in girls and young women may offer long-term benefits to offspring.     

Maternal/Fetal Determinants of Insulin Resistance in Women During Pregnancy and in Offspring Over Life

Insulin resistance is a component of the pathophysiology of both type 2 diabetes and gestational diabetes mellitus (GDM), but is also characteristic of normal glycemic physiology during pregnancy. In recent years, many studies have tried to understand determinants of insulin resistance in normal pregnancy and GDM, revealing that the placenta is capable of secreting many cytokines and hormones, classically considered as adipokines. More specifically, it appears that leptin and TNFα could be implicated in gestational insulin resistance and GDM pathophysiology. In addition, the maternal metabolic milieu was also identified as a key determinant of later insulin resistance in offspring, a phenomenon often described as ‘fetal programming’. This article reviews the established risk factors and the more novel suspected biomarkers involved in maternal insulin resistance during pregnancy as well as the maternal and early life determinants of insulin resistance in offspring later in their life. We are also highlighting recent reports of the potential mechanisms involved in ‘programming’ of insulin resistance such as epigenetic modulation.     

Perinatal growth failure: the road to obesity,insulin resistance and cardiovascular disease in adults

A continuum of increasing risk of adulthood diseases, such as cardiovascular disease, type 2 diabetes and hypertension, with decreasing size at birth is now well-reported and a number of different hypotheses have been proposed. Birthweight links with disease risk markers such as insulin resistance are apparent from childhood, particularly when low birthweight is followed by rapid postnatal weight gain and childhood obesity. Such growth patterns follow fetal growth restraint, associated with maternal-uterine factors such as primiparity, smoking, maternal genes or variations in maternal diet. The fetal metabolic and hormonal responses to intrauterine growth restraint and to rapid postnatal growth are likely to be key to the early pathogenesis of adulthood disease. Thrifty fetal genotypes may enhance these adaptations and improve perinatal survival but predispose to adulthood disease. Their historical selection could explain high prevalences of type 2 diabetes in some ethnic groups, and their identification could allow targeting of potential interventions.     

The metabolic syndrome and endothelial dysfunction: Common highway to type 2 diabetes and CVD?

Due to global lifestyle changes, obesity (the main driver of type 2 diabetes [T2D] and cardiovascular disease [CVD]) is reaching pandemic proportions. The metabolic syndrome, which is regarded as a prediabetic state, is characterized by a concurrence of interrelated cardiovascular risk factors, including abdominal obesity, insulin resistance, hypertension, dyslipidemia, and glucose intolerance. Endothelial dysfunction (ED) is common in the metabolic syndrome and is associated with increased risk for T2D and CVD. This review focuses on the mechanisms linking ED to the metabolic syndrome, T2D, and CVD, and the possible therapies that may improve ED and reduce T2D and CVD risk.     

Type 2 diabetes in children

The emerging epidemic of type 2 diabetes (T2DM) in young people reflects increasing rates of obesity and parallels the increasing frequency of T2DM in adults. As in adults, T2DM in children is part of the insulin resistance syndrome that includes hyperandrogenism seen as premature adrenarche and polycystic ovary syndrome, hypertension, dyslipidemia, and other atherosclerosis risk factors. Recent studies in children document risk factors for T2DM, and associated cardiovascular risk factors, including obesity, family history, diabetic gestation, and underweight or overweight for gestational age. Genetically determined insulin resistance or limited β-cell reserve has been demonstrated in high-risk individuals, including first-degree relatives of girls with premature adrenarche. This genetic background, considered advantageous in a feast-and-famine existence (the thrifty genotype), is rendered detrimental with abundant food and physical inactivity, a lifestyle demonstrated to be typical of families of children with T2DM. The increasing incidence of T2DM in children and adolescents threatens to become a major public health problem. Risk factors for cardiovascular disease, hypertension, hyperlipidemia, and microalbuminuria are present at diagnosis of T2DM in Native American adolescents, indicating that insulin resistance has been present for some time before the diagnosis of diabetes was made. Case finding is likely to be beneficial in high-risk youths. Treatment is the same as that of adults. The only data on use of oral hypoglycemic agents in children have been with metformin. Community and governmental efforts to educate all children and their parents about the need for physical activity and dietary modification are essential to control this epidemic.     

Innovative biomarkers for predicting type 2 diabetes mellitus: relevance to dietary management of frailty in older adults

Type 2 diabetes mellitus (T2DM) increases in prevalence in the elderly. There is evidence for significant muscle loss and accelerated cognitive impairment in older adults with T2DM; these comorbidities are critical features of frailty. In the early stages of T2DM, insulin sensitivity can be improved by a “healthy” diet. Management of insulin resistance by diet in people over 65 years of age should be carefully re-evaluated because of the risk for falling due to hypoglycaemia. To date, an optimal dietary programme for older adults with insulin resistance and T2DM has not been described. The use of biomarkers to identify those at risk for T2DM will enable clinicians to offer early dietary advice that will delay onset of disease and of frailty. Here we have used an in silico literature search for putative novel biomarkers of T2DM risk and frailty. We suggest that plasma bilirubin, plasma, urinary DPP4-positive microparticles and plasma pigment epithelium-derived factor merit further investigation as predictive biomarkers for T2DM and frailty risk in older adults. Bilirubin is screened routinely in clinical practice. Measurement of specific microparticle frequency in urine is less invasive than a blood sample so is a good choice for biomonitoring. Future studies should investigate whether early dietary changes, such as increased intake of whey protein and micronutrients that improve muscle function and insulin sensitivity, affect biomarkers and can reduce the longer term complication of frailty in people at risk for T2DM.     

'Sensing' the link between type 1 and type 2 diabetes

Obesity-associated insulin resistance is a core element of metabolic syndrome and type 2 diabetes (T2D). Notably, insulin resistance is also a feature of type 1 diabetes (T1D), where findings in the non-obese diabetic mouse model have implicated transient receptor potential vanilloid-1 (TRPV1+) sensory neurons in local islet inflammation and glucose metabolism. Here, we briefly review the role of TRPV1 in non-obese diabetic (NOD) T1D pathogenesis, highlighting commonalities that suggest TRPV1 may contribute to obesity and T2D as well. With the recently discovered importance of adipose infiltrating lymphocytes in the metabolic disturbances of obesity and T2D, sensory innervation of fat may thus play an analogous role to sensory neurons in the islet--modulating neuroendocrine homeostasis and inflammation. In such a scenario, TRPV1+ sensory nerves would provide the pathoaetiological link connecting the shared metabolic and immunologic features of type 1 diabetes and T2D.     

Turning the tide: type 2 diabetes trends in offspring of mothers with gestational diabetes mellitus

In this review, the thesis is presented that maternal hyperglycemia produces an overnourished, fat fetus. If the fetus has a predisposition for type 2 diabetes, then the fat deposition in the fetus is predominantly in the fetal visceral cavity. Visceral fat deposition is the origin of insulin resistance. The fat fetus begins life with its pancreatic output of insulin compromised. Thus, the stage is set for developing type 2 diabetes in its lifetime. This review supports the hypothesis that normalization of maternal nutrition and fucose will decrease the risk of type 2 diabetes.     

Metabolic acidosis-induced insulin resistance and cardiovascular risk

Microalbuminuria has been conclusively established as an independent cardiovascular risk factor, and there is evidence of an association between insulin resistance and microalbuminuria, the former preceding the latter in prospective studies. It has been demonstrated that even the slightest degree of metabolic acidosis produces insulin resistance in healthy humans. Many recent epidemiological studies link metabolic acidosis indicators with insulin resistance and systemic hypertension. The strongly acidogenic diet consumed in developed countries produces a lifetime acidotic state, exacerbated by excess body weight and aging, which may result in insulin resistance, metabolic syndrome, and type 2 diabetes, contributing to cardiovascular risk, along with genetic causes, lack of physical exercise, and other factors. Elevated fruits and vegetables consumption has been associated with lower diabetes incidence. Diseases featuring severe atheromatosis and elevated cardiovascular risk, such as diabetes mellitus and chronic kidney failure, are typically characterized by a chronic state of metabolic acidosis. Diabetic patients consume particularly acidogenic diets, and deficiency of insulin action generates ketone bodies, creating a baseline state of metabolic acidosis worsened by inadequate metabolic control, which creates a vicious circle by inducing insulin resistance. Even very slight levels of chronic kidney insufficiency are associated with increased cardiovascular risk, which may be explained at least in part by deficient acid excretory capacity of the kidney and consequent metabolic acidosis-induced insulin resistance.     

Current controversies in the mechanisms and treatment of gestational diabetes

Gestational diabetes mellitus (GDM) is a heterogeneous entity, including carbohydrate intolerance of variable severity with onset or first recognition during pregnancy. Insulin resistance and a-cell dysfunction are thought to be major determinants of its development. Its pathomechanism in many ways resembles that of type 2 diabetes. There is an evolving body of evidence from the last decade presenting similarities between gestational diabetes and the metabolic (insulin resistance) syndrome. These new observations suggest that GDM might be an early manifestation of the metabolic syndrome. The desired treatment target of GDM is normoglycemia. It can be reached by dietary treatment; however, if it fails, maternal glycemic monitoring or combined fetalmaternal monitoring, or even insulin (if required) can help reach it. Multiple daily insulin regimens are becoming more widely accepted for the treatment of GDM. Insulin analogues, however, need some more evidence to support their usefulness and safety during pregnancy. The screening for GDM, the reclassification, regular care, and follow-up of these women after pregnancy are of the utmost importance to delay or prevent not only type 2 diabetes but cardiovascular complications as well.     

Plasma ghrelin and resistin concentrations are suppressed in infants of insulin-dependent diabetic mothers

This study aimed to investigate 1) the effect of maternal diabetes mellitus on ghrelin, resistin, leptin, and insulin in term newborns; 2) the interrelationship of these metabolic hormones in the early postnatal period; and 3) the association of the hormones with anthropometric parameters at birth. A total of 120 term newborns were prospectively enrolled and categorized into three groups: 40 were infants of nondiabetic mothers (group N), 42 were infants born to mothers with gestational diabetes on low energy dietary treatment (group D), and 38 were infants born to mothers with preexisting or severe gestational diabetes who required exogenous insulin for stabilization of blood sugar during pregnancy (group I). Plasma ghrelin and resistin were significantly lower in group I than in either group N or group D infants (P < 0.048). Plasma ghrelin and subscapular skinfold thickness were significantly higher in female than in male infants [plasma ghrelin: median (interquartile range), 3.8 (3.0-4.8) vs. 3.0 (2.4-4.0) ng/ml in females and males, respectively; P = 0.003; subscapular skinfold thickness: 4.9 (4.2-5.6) vs. 4.6 (3.9-5.2) mm; P = 0.03]. In group N, plasma ghrelin was significantly, but negatively, associated with birth weight (r = -0.31; P = 0.05) and body length (r = -0.33; P = 0.04), whereas in group I, plasma ghrelin was negatively correlated with plasma resistin (r = -0.37; P = 0.02). Plasma ghrelin and resistin are suppressed in infants of insulin-dependent diabetic mothers, suggesting that the metabolic hormonal system is probably operational in fetal and early postnatal life. A low circulating ghrelin concentration may be advantageous to these infants, because a reduction in appetite may prevent excessive weight gain postnatally and counterbalances the in utero anabolic effect of hyperinsulinism in poorly controlled diabetic mothers. The suppressive effect of insulin on resistin may partially explain the excess accumulation of adipose tissue in infants of diabetic mothers by reducing the inhibitory effect of resistin on adipogenesis. Female infants have significantly higher plasma ghrelin levels than male infants, suggesting that sexual dimorphism exists in utero. This study has also shown an association between some of the metabolic hormones in specific groups of infants and thus suggests that these hormones could have interacted in utero to regulate growth and fat storage during this critical period.     

Cardiovascular risk in double diabetes mellitus--when two worlds collide

Historically, clinical management of patients with type 1 diabetes mellitus (T1DM) has been focused on glycaemic control, which is sometimes achieved at the expense of weight gain on intensive insulin regimes. Although HbA(1c) level is an important contributor to increased macrovascular risk, several prospective studies have concluded that factors related to obesity, metabolic syndrome and insulin resistance are more important than HbA(1c) for the prediction of cardiovascular risk, especially for coronary heart disease events. 'Double diabetes mellitus' describes a combination of T1DM with characteristics associated with type 2 diabetes mellitus, including central adiposity and exacerbation of insulin resistance. In lean patients with T1DM, portal insulinopaenia might actually confer cardioprotective effects via changes in hepatic lipid profiles (mainly increased HDL cholesterol levels) and a reduction in hepatic steatosis. In patients with double diabetes mellitus, this situation is reversed and atherothrombotic pathophysiology is potentially accelerated by the combination of chronic hyperglycaemia and abnormal lipid partitioning. The prevalence of double diabetes mellitus is increasing in parallel with the societal trend of increased adiposity. This Review discusses how to identify patients susceptible to double diabetes mellitus and suggests alterations to their clinical management that might reduce their risk of future premature coronary disease.     

Modulation of β-cell function: a translational journey from the bench to the bedside

Both decreased insulin secretion and action contribute to the pathogenesis of type 2 diabetes (T2D) in humans. The insulin receptor and insulin signalling proteins are present in the rodent and human β-cell and modulate cell growth and function. Insulin receptors and insulin signalling proteins in β-cells are critical for compensatory islet growth in response to insulin resistance. Rodents with tissue-specific knockout of the insulin receptor in the β-cell (βIRKO) show reduced first-phase glucose-stimulated insulin secretion (GSIS) and with aging develop glucose intolerance and diabetes, phenotypically similar to the process seen in human T2D. Expression of multiple insulin signalling proteins is reduced in islets of patients with T2D. Insulin potentiates GSIS in isolated human β-cells. Recent studies in humans in vivo show that pre-exposure to insulin increases GSIS, and this effect is diminished in persons with insulin resistance or T2D. β-Cell function correlates to whole-body insulin sensitivity. Together, these findings suggest that pancreatic β-cell dysfunction could be caused by a defect in insulin signalling within β-cell, and β-cell insulin resistance may lead to a loss of β-cell function and/or mass, contributing to the pathophysiology of T2D.     

The metabolic triad of non-alcoholic fatty liver disease,visceral adiposity and type 2 diabetes: Implications for treatment

Non-alcoholic fatty liver disease (NAFLD) is associated with visceral obesity, insulin resistance, type 2 diabetes (T2D) and has been often considered as the hepatic expression of the metabolic syndrome (MetS). Epidemiological studies highlight a bidirectional relationship of NAFLD with T2D in which NAFLD increases the risk of incident T2D and T2D increases the risk of severe non-alcoholic steatohepatitis (NASH) and liver fibrosis. Regarding the molecular determinants of NAFLD, we specifically focused in this review on adipocyte dysfunction as a key molecular link between visceral adipose tissue, MetS and NAFLD. Notably, the subcutaneous white adipose tissue expandability appears a critical adaptive buffering mechanism to prevent lipotoxicity and its related metabolic complications, such as NAFLD and T2D. There is a clinical challenge to consider therapeutic strategies targeting the metabolic dysfunction common to NASH and T2D pathogenesis. Strategies that promote significant and sustained weight loss (~10% of total body weight) such as metabolic and bariatric surgery or incretin-based therapies (GLP-1 receptor agonists or dual GLP-1/GIP or GLP-1/glucagon receptor co-agonists) are among the most efficient ones. In addition, insulin sensitizers such as PPARγ (pioglitazone) and pan-PPARs agonists (lanifibranor) have shown some beneficial effects on both NASH and liver fibrosis. Since NASH is a complex and multifactorial disease, it is conceivable that targeting different pathways, not only insulin resistance but also inflammation and fibrotic processes, is required to achieve NASH resolution.     

Exercise attenuates the premature cardiovascular aging effects of type 2 diabetes mellitus

Type 2 diabetes mellitus (T2D) is an example of a disease process that results in decrements in function additional to those imposed by the inexorable 'primary aging' process. These decrements due to disease, rather than primary aging, can be termed 'secondary aging', and include the premature development (as early as adolescence) of asymptomatic preclinical cardiovascular abnormalities (e.g. endothelial dysfunction, arterial stiffness, diastolic dysfunction), as well as impaired exercise performance. These abnormalities are important, as they are associated with greater cardiovascular morbidity and mortality in people with and without T2D. A better understanding of the pathophysiology of secondary cardiovascular aging in people with T2D is warranted, and an evaluation of the benefits of existing treatments for these abnormalities is useful (e.g. exercise training). The focus of this review is to discuss the data relevant to the following key postulates: (a) T2D causes premature cardiovascular aging; (b) in contrast to primary cardiovascular aging, the premature cardiovascular aging of T2D may be modifiable with exercise. The exercise-focused perspective for this review is appropriate because impairments in exercise performance are markers of premature cardiovascular aging in T2D, and also because exercise training shows promise to attenuate some aspects of cardiovascular aging during the preclinical stage.     

Effects of physical exercise on memory in type 2 diabetes: a brief review

Metabolic Brain Disease - Type 2 diabetes (T2D) is a metabolic disorder that can lead to memory impairment. T2D main features are insulin resistance and hyperglycemia. Physical exercise is a...