Type 2 diabetes across generations: from pathophysiology to prevention and management

Novel insights in the interplay between inflammation and metabolic diseases: A role for the pathogen sensing kinase PKR

Strategies of anti-cytokine monoclonal antibody development: immunoassay of IL-10 and IL-5 in clinical samples.

Regulatory roles of CARD9-BCL10-Rac1 (CBR) signalome in islet β-cell function in health and metabolic stress: Is there room for MALT1?

Type 2 diabetes mellitus (T2DM) in children and adolescents is becoming an increasingly important public health concern throughout the world (1–17). Because of the relatively recent recognition of the problem in this age group, many children with new onset T2DM may be misclassified as having T1DM. Conversely, as the population becomes heavier, overweight adolescents with autoimmune diabetes may be misdiagnosed as having T2DM. T2DM is often associated with risk factors for cardiovascular disease that may already be present at the time of diagnosis, making normalization of blood glucose levels and diagnosis and treatment of hypertension and dyslipidemia important (18). T2DM occurs when insulin secretion is inadequate to meet the increased demand posed by insulin resistance (19). Thus, T2DM is commonly associated with other features of the insulin resistance syndrome [hyperlipidemia, hypertension, acanthosis nigricans, ovarian hyperandrogenism, non-alcoholic fatty liver disease (NAFLD)] (20). Insulin secretion depends on disease status and duration, and can vary from delayed but markedly elevated in response to a glucose challenge, to absolutely diminished (19). Adults with symptoms have 50% reduction at the time of diagnosis, and may become insulin dependent within a few years (21). T2DM occurs: in youth most often during the second decade of life, with a mean age of diagnosis of ∼13.5 years. This coincides with the peak of physiologic pubertal insulin resistance, which may lead to onset of overt diabetes in previously compensated adolescents. in all races, but at a much greater prevalence in those of non-white European descent, e.g. those of black African descent, native North American, Hispanic (especially Mexican)-American, Asian, South Asian (Indian Peninsula), and Native Pacific islanders. The SEARCH for Diabetes in Youth population-based study found the proportion of physician diagnosed T2DM among 10–19-year-olds to vary greatly by ethnicity in the US: 6% for non-Hispanic whites, 22% for Hispanics, 33% for blacks, 40% for Asians/Pacific Islanders, and 76% for Native Americans (8). In Hong Kong > 90% of young onset diabetes is T2DM (10), in Taiwan 50% (11) and nearly 60% in Japan (Ogawa et al. personal communication). in > 75% of cases in youth in the USA there is a first or second-degree relative with T2DM. in youth in the USA and Europe with body mass index (BMI) above 85th percentile for age and sex. In Japan, however, ∼30% of T2DM are not obese (17), in Asian Indian urban children, half of those with T2DM had normal weight (< 120% ideal for height) (12), and half of Taiwanese children with T2DM were not obese (11). in some asymptomatic individuals in high-risk populations during medical, school, or sports examinations (22,23). in the presence of ketosis/ketoacidosis, one third or more of newly diagnosed patients (24). This presentation is responsible for misclassification of T2DM patients as T1DM. occasionally with severe dehydration (hyperosmolar hyperglycemic coma, hypokalemia) at presentation, which can be fatal (24,25) with a sex ratio (male:female) that varies from 1: 4–1:6 in native North Americans to 1:1 in Asians and Libyan Arabs without associated HLA specificities. without associated islet cell autoimmunity (see autoimmunity T2DM). The pathophysiology of autoimmune 'T2DM' is unclear. It most likely represents autoimmune T1DM in overweight or obese individuals with underlying insulin resistance. It has been postulated that obesity and insulin resistance may promote an inflammatory response to antigen exposure caused by apoptosis of beta cells (26). Youth and adults in US and Europe who are clinically diagnosed with T2DM are found to have T1DM-associated auto-antibodies in 15–40% of cases, including many who are not receiving insulin one year after diagnosis (27–30). Antibody positive young adult individuals with the T2DM phenotype are significantly less overweight and younger than antibody negative patients (21, 27). Hemoglobin (HbA1c) concentrations are significantly higher in young adults with T2DM who are antibody positive compared with those who are antibody negative (27). ß-cell function is significantly less in antibody positive individuals, the most dramatic difference being reported in younger adult patients (25–34 years), resulting in more rapid development of insulin dependence, usually by 3 years duration (27, 30). The presence of islet cell antibodies (ICA) and glutamic acid decarboxylase antibodies in adults with clinically typical T2DM has been referred to as latent autoimmune diabetes of adults (27, 31). Neither the autoimmunity nor the diabetes is latent, however (26). Atypical diabetes mellitus (ADM) occurs throughout childhood, but rarely begins past age 40. It has only been described in young people of African descent. There is a strong family history in multiple generations with an autosomal dominant pattern of inheritance, but an abnormal sex ratio (M : F = 1 : 3). ADM is not associated with HLA specificities and islet autoimmunity does not occur. Ketosis or ketoacidosis is typical at onset. Insulin secretion is present but diminished and without long-term deterioration of function. Interestingly, insulin is often not required for survival after treatment of acute metabolic deterioration, although diabetes control may be poor and ketoacidosis may recur without insulin, e.g. with illness or pregnancy. ADM is not associated with obesity beyond that in the general population and it is not associated with insulin resistance. Monogenic diabetes (formerly referred to as maturity onset diabetes of the young or MODY) For more in depth information see the ISPAD Clinical Consensus Guidelines for Monogenic Diabetes (34). Identified in families with multigenerational diabetes; including asymptomatic individuals identified through testing of family members. Monogenic diabetes is not associated with obesity beyond that in the general population and it is not associated with insulin resistance The clinician is obliged to weigh the evidence in each individual patient to distinguish between T1DM and T2DM. The reasons for this conundrum are: with increasing obesity in childhood, as many as 15–25% of newly diagnosed T1DM (or monogenic diabetes) patients may be obese. the significant number of pediatric patients with T2DM demonstrating ketonuria or ketoacidosis at diagnosis (2). T2DM is common in the general adult population, with a random family history of ∼15% or greater in minority populations, reducing the specificity of a positive family history. positive family history for T2DM is increased for patients with T1DM as much as threefold over the non-diabetic population and T1DM is more frequent in relatives of patients with T2DM (35, 36). There is considerable overlap in insulin or C-peptide measurements between T1DM, T2DM and MODY at onset of diabetes and over the first year or so. This overlap is due to the recovery phase of autoimmune-mediated T1DM (the honeymoon) and degree of glucotoxicity/lipotoxicity impairing insulin secretion at the time of testing in both T1DM and T2DM. In addition the insulin resistance of obesity raises residual C-peptide levels in obese adolescents with T1DM. Such measurements are thus relatively valueless in the acute phase. [The role of C peptide may be more helpful in established diabetes as persistent elevation of C-peptide above the level of normal would be unusual in T1DM after 12–24 months.] The criteria and classification of diabetes are presented in greater detail in the ISPAD Clinical Practice Consensus Guidelines: Definition, Epidemiology, Diagnosis and Classification of Diabetes (37) Diagnostic criteria for diabetes are based on BG measurements and the presence or absence of symptoms (E) (38,39). Three ways to diagnose diabetes are possible and each, in the absence of unequivocal hyperglycemia, must be confirmed, on a subsequent day, by any one of the three methods given below. Diabetes is diagnosed when: A fasting plasma glucose (FPG) is ≥ 7.0 mmol/l (126 mg/dl) or The post challenge plasma glucose is > 11.1 mmol/l (200 mg.dl) performed as described by the World Health Organization (39), using a glucose load containing the equivalent of 75 g anhydrous glucose dissolved in water. or Symptoms of diabetes and a casual plasma glucose ≥ 200 mg/dl (11.1 mmol/L). Casual is defined as any time of day without regard to time since last meal. The classic symptoms of diabetes include polyuria, polydipsia, and unexplained weight loss. Diabetes in children, including T2DM, usually presents with characteristic symptoms such as polyuria, polydipsia, blurring of vision, and weight loss, in association with glycosuria and, in some cases, ketonuria. In its most severe form, ketoacidosis or hyperglycemic hyperosmolar state may develop and lead to stupor, coma, and in absence of effective treatment, death. The diagnosis is usually confirmed quickly in symptomatic individuals by measurement of a marked elevation of the blood glucose level. In this situation, if ketones are present in the blood or urine, treatment is urgent. Waiting another day to confirm the hyperglycemia may be dangerous in allowing ketoacidosis or hyperosmolarity to evolve. In the absence of symptoms or presence of mild symptoms of diabetes, hyperglycemia detected incidentally or under conditions of acute infective, traumatic, circulatory, or other stress may be transitory and should not in itself be regarded as diagnostic of diabetes. The diagnosis of diabetes, in the absence of symptoms, should not be based on a single plasma glucose concentration. Diagnosis may require continued observation with fasting and/or 2-h postprandial BG levels and/or an oral glucose tolerance test (OGTT). An OGTT should not be performed if diabetes can be diagnosed using fasting, random, or postprandial criteria, as excessive hyperglycemia can result using a fasting OGTT in these circumstances. (E). If doubt remains, periodic re-testing should be undertaken until the diagnosis is established or refuted. There are individuals whose glucose levels do not meet the criteria for diabetes, but are too high to be considered normal. Impaired glucose tolerance (IGT) and impaired fasting glycaemia (IFG) are intermediate stages in the natural history of disordered carbohydrate metabolism between normal glucose homeostasis and diabetes (E). IFG and IGT are not interchangeable and represent different abnormalities of glucose regulation. IFG is a measure of disturbed carbohydrate metabolism in the basal state, while IGT is a dynamic measure of carbohydrate intolerance after a standardized glucose load. Patients with IFG and/or IGT are now referred to as having 'pre-diabetes', indicating the relatively high risk for development of diabetes in these patients (38). IFG and IGT may be associated with the metabolic syndrome (MS), which includes obesity (especially abdominal or visceral obesity), dyslipidemia of the high-triglyceride and/or low-high density lipoprotein type, and hypertension. Individuals who meet the criteria for IGT or IFG may be euglycemic in their daily lives as shown by normal or near-normal glycated hemoglobin levels, and those with IGT may manifest hyperglycemia only when challenged with an OGTT. FPG < 5.6 mmol/L (100 mg/dL)= normal fasting glucose. FPG 5.6–6.9 mmol/L (100–125 mg/dL)= IFG. FPG ≥ 7.0 mmol/L (126 mg/dL)= provisional diagnosis of diabetes (the diagnosis must be confirmed, as described above under 'Diagnostic criteria for type 2 diabetes'). The corresponding categories for IGT when the OGTT is used are as follows: 2-h postload glucose < 7.8 mmol/l (140 mg/dl)= normal glucose tolerance. 2-h postload glucose 7.8–11.1 mmol/l (140–199 mg/ dl)= IGT. 2-h postload glucose > 11.1 mmol/l (200 mg/dl)= provisional diagnosis of diabetes (the diagnosis must be confirmed with additional testing, as described above). After the diagnosis of diabetes is established, autoantibody testing should be considered when diagnosing and treating T2DM. Diabetes autoantibody testing should be considered in all pediatric patients with the clinical diagnosis of T2DM because of the high frequency of islet cell autoimmunity in otherwise "typical" T2DM. Antibodies will indicate an earlier need for insulin as well as the need to monitor for thyroid autoimmunity and to consider other autoimmune disorders associated with T1DM. (E) Diabetes autoantibody testing also should be considered in overweight/obese children > 13 years of age with a clinical picture of T1DM (weight loss, ketosis/ketoacidosis), some of whom may have T2DM (E) Insulin resistance is an impaired response to the physiologic effects of insulin, including effects on glucose, lipid, and protein metabolism, and on vascular endothelial function. Insulin resistance occurs in most tissues including liver, muscle, and fat tissue and is influenced by sex, age, race/ethnicity, stage of sexual maturation, and total adiposity. While visceral adiposity is important in insulin resistance in adults, the specific contribution of visceral adiposity to insulin resistance in the pediatric population remains uncertain. Several events in development may be associated with increased risk for the insulin resistance syndrome. These include premature adrenarche in girls (pubic hair appearing before the age of 8 years) and being born small for gestational age. Girls with a history of premature adrenarche are at increased risk for ovarian hyperandrogenism and PCOS and thus, insulin resistance (40). Children born small for gestational age are at increased risk for insulin resistance related to decreased intrauterine growth (41) and also at increased risk for premature adrenarche. Diabetes is only one manifestation of the insulin resistance syndrome or the MS (22, 42–50). Other associations include: Obesity: Obesity has deleterious associations with morbidity and cardiovascular risk independent of effects related to insulin resistance and diabetes (51–54). Nephropathy: Albuminuria (either micro- or macro- ) is present at the time of diagnosis in a substantial number of adolescents with T2DM and prevalence increases with duration of diabetes (24). Proteinuria and focal segmental glomerular sclerosis have also been reported in African-American adolescents with severe obesity, in the absence of diabetes (55). Hypertension; Hypertension is estimated to account for 35–75% of diabetes complications, both microvascular and macrovascular (56). Diabetes or impaired glucose tolerance doubles the risk of developing hypertension (57). In addition, there is a possible genetic predisposition to hypertension in T2DM related to the associated angiotensin converting enzyme genotype (58). Hypertension in T2DM is due to volume expansion and increased vascular resistance (59) related to reduced (NO)-mediated vasodilatation and increased activity of the renin-angiotensin system. Dyslipidemia: Hypertriglyceridemia and decreased high-density lipoprotein cholesterol are the hallmarks of T2DM dyslipidemia. Additional findings include elevated very low-density lipoprotein (VLDL), elevated LDL-c, elevated lipoprotein(a), and increased small dense LDL particles. Decreased lipoprotein lipase activity, increased lipoprotein glycation and increased lipoprotein oxidation render the lipoproteins more atherogenic. (60,61) Ovarian hyperandrogenism and premature adrenarche (62): PCOS is being increasingly recognized in adolescents as part of the insulin resistance syndrome. Adolescents with PCOS have ∼40% reduction in insulin-stimulated glucose disposal compared to body composition matched non-hyperandrogenic control subjects (59). Decreasing insulin resistance may improve ovarian function and increase fertility. NAFLD: Hepatic steatosis is present in 25–45% of adolescents with T2DM and more advanced forms of NAFLD, such as non-alcoholic steatohepatitis, are increasingly common and associated with progression to cirrhosis (24, 64). NAFLD now represents the most common cause of cirrhosis in children and the most common reason for liver transplantation in adults in the US. Systemic inflammation: elevated C-reactive protein, inflammatory cytokines and white blood cell counts in obese adolescents have been associated with increased risk for cardiovascular disease in adults (54). Additional health problems related to obesity include Obstructive sleep apnea (OSA) with associated pulmonary hypertension (65), orthopedic problems resulting in diminishing physical activity (66,67), pancreatitis, cholecystitis and pseudotumor cerebri. In adults, there is a strong association between level of hyperglycemia and increased risk of macrovascular disease. Hyperglycemia, dyslipidemia, and hypertension are contributors to the acceleration of atherosclerosis in T2DM, along with oxidative stress, glycation of vascular proteins, and abnormalities of platelet function and coagulation. Defective endothelium dependent vasodilatation is an additional factor accelerating atherosclerosis in T2DM. It is an early sign of increased risk for cardiovascular disease, and predictive of cardiovascular events (68) (B) and occurs in obese children relative to their level of obesity and degree of insulin resistance (69) (B). Co-morbidities characteristic of the insulin resistance syndrome are commonly seen at diagnosis or appear early in the course of T2DM and should be tested for sooner than in T1DM, where these disorders are complications of the diabetes rather than co-morbid conditions (70, 71) (B). A more complete discussion of testing for complications/co-morbidities is presented in the ISPAD Clinical Practice Guidelines for microvascular and macrovascular complications (72). Either micro- or macro-albuminuria, may be present at the time of diagnosis and albuminuria should be evaluated at diagnosis and annually thereafter (55, 72)(E). Likewise, hypertension may be present at, or prior to diagnosis of diabetes and each individual should be evaluated at every visit for hypertension. Dyslipidemia is more common in type 2 diabetes and in family members, (60,61) and should be screened for when metabolic stability is achieved. Evaluation for NAFLD should be done at diagnosis and annually thereafter (24)(E). Inquiries about puberty, menstrual irregularities and obstructive sleep apnea should be made at diagnosis and regularly thereafter (65)(E). Additional information is available in the ISPAD Clinical Practice Guidelines on complications. (72). Dyslipidemia, hypertension and albuminuria are more common in type 2 diabetes compared to type 1 diabetes and may be present at diagnosis and should be assessed after blood glucose control has been optimized. Confirmed hypertension (BP> 95% for age, gender and height) or albuminuria should be treated with an ACE inhibitor or, if not tolerated, an angiotensin receptor blocker (E). Combination therapy may be required if hypertension or albuminuria does not normalize on single agent treatment (E). Side effects are cough, hyperkalemia, headache and impotence (73). In addition, major congenital malformations have been reported with first trimester exposure to ACE inhibitors but not with other antihypertensive agents in non-diabetic women (74). Testing for dyslipidemia should be performed soon after diagnosis when BG control has been achieved and annually thereafter. (60,61) E Goal is LDL-C < 2.6 mmol (100 mg/dl) (68). If LDL-C is borderline (2.6-3.4 mmol;100–129 mg/ dl), or elevated (≥ 3.4 mmol; 130 mg/dl), repeat lipid profile should be performed in 6 months and dietary intervention to decrease total and saturated fat initiated. If LDL-C remains elevated after 3-6 months of attempting to optimize blood glucose control and diet, pharmacotherapy is warranted (72). Statin therapy has been shown to be safe and effective in children as in adults and should be the first pharmacologic intervention (72) although long term safety data are not available. Special attention should be paid to symptoms associated with muscles and connective tissues, as there is an increased risk of rhabdomyolysis The of T2DM in children and adolescents has required that with the of T1DM in children and adolescents the between the treatment of these T1DM is throughout the population to T2DM in North and Europe those with e.g. levels, less less well This has not been described for Asian T2DM. age. T1DM occurs throughout childhood, when is T2DM occurs in when family of families with a with T1DM have family with the disease, while 75% or more of families of the with T2DM have such The of these family to control weight and is with complications in the family and a of and in the treatment In most T1DM, beyond insulin and glucose is only for those individuals who are overweight and In all youth with T2DM, the is on and on glucose and effects of have the of T1DM and blood glucose insulin In in with an that dense increasingly and have to the of T2DM in children and its in of of including hypertension, dyslipidemia, and in the of complications may require more control in insulin T2DM than in T1DM, and attention to as by the Diabetes (21). also the ISPAD Clinical Practice Guidelines for diabetes and family for youth with type 2 diabetes is as important as it is in type 1 diabetes. and for T2DM will on and in insulin therapy and may not be required in T2DM will a greater on dietary and physical activity than is required for T1DM. should be given by with and of the and of youth with T2DM should be in a and age Because the of youth with T2DM are the ISPAD Guidelines for are to the of youth and families with T2DM The family will need to the of treatment of T2DM and to the of the required to T2DM should that the in the diagnosis type 1 type in a minority of patients can be and for the youth and The can be by the of blood glucose metabolism using therapy is to the metabolic of the specific of the of diabetes. is the of treatment of T2DM The family and should the of obesity and T2DM. must have an of the health and of the to an effective should be made in small and with the that these need to be The patient and family should be to monitor the and of and physical in any a and is for The and treatment for T2DM should include a and/or to a with and in of children with is should be to family and should be to all The family should be to dietary with including for weight reduced total and saturated fat increased and increased physical activity specific dietary are given in the ISPAD Guidelines for dietary should include: on and in of these and and for can result in substantial weight and is one of the most important for weight loss. and for the family and for the patient in an age including about dietary and activity related to and activity by of and using for that should be on in one with other activity as a family and should be in a or and not from a or of high density and in the the of and control of positive of or weight reduction in high and for and activity as for of and activity and for and should be for each patient and family that are to family and and should be to all A family or should be identified who is available to in physical activity with the may be to patients and family members. to with the dietary and is important to the of the should include: and an daily is to the of increased at reducing such as the and the time in related may be the most effective activity to be as a This should include daily to be more such as using of or to and to and and (E). for to and physical activity, including increases in daily (E). of blood glucose should be performed of should be and include a of fasting and postprandial glucose have been fasting a and daily post after the are while the within the (E). If the impaired glucose tolerance more frequent testing should be for of acute illness or when symptoms of or patients should more frequent testing and be in with their diabetes for (E). Patients on insulin or need to monitor for asymptomatic (E). should be at a year and if insulin is being used or metabolic control is should be continued in addition to pharmacologic therapy The of pharmacologic therapy is to decrease insulin resistance, increase insulin or to postprandial glucose The first used should be It has the over of reduction in without the risk of weight is decreased or remains and LDL-C and levels decrease during for type 2 diabetes in children and adolescents. of with over 3 months the need to a or insulin or in with a or a inhibitor Patients for should be on the effects of diabetes and oral agents on and oral agent should be used during pregnancy.

Maternal depression and mental health in early childhood: an examination of underlying mechanisms in low-income and middle-income countries

BackgroundSecondhand smoke (SHS) exposure has adverse effects on the cardiovascular system. This study aimed to determine the effects of SHS on the cardiovascular disease biomarkers, namely the metabolic, inflammatory, and oxidative stress markers in healthy adult women.MethodsThis comparative cross-sectional study was conducted among healthy women. The cases included those women exposed to SHS, and the controls included those women not exposed to SHS. SHS exposure was defined as being exposed to SHS for at least 15 min for 2 days per week. Venous blood was taken to measure the metabolic markers (high molecular weight adiponectin, insulin level, insulin resistance, and nonesterified fatty acids), oxidative stress markers (oxidized low density lipoprotein cholesterol and 8-isoprostane), and inflammatory markers (high-sensitivity C-reactive protein and interleukin-6). A hair nicotine analysis was also performed. An analysis of covariance and a simple linear regression analysis were conducted.ResultsThere were 101 women in the SHS exposure group and 91 women in the non-SHS exposure group. The mean (with standard deviation) of the hair nicotine levels was significantly higher in the SHS exposure group when compared to the non-SHS exposure group [0.22 (0.62) vs. 0.04 (0.11) ng/mg; P = 0.009]. No significant differences were observed in the high molecular weight adiponectin, insulin and insulin resistance, nonesterified fatty acids, 8-isoprostane, oxidized low density lipoprotein cholesterol, interleukin-6, and high-sensitivity C-reactive protein between the two groups. The serum high molecular weight adiponectin was negatively associated with the insulin level and insulin resistance in the women exposed to SHS. However, no significant relationships were seen between the high molecular weight adiponectin and nonesterified fatty acids, 8-isoprostane, oxidized low density lipoprotein cholesterol, high-sensitivity C-reactive protein in the SHS group.DiscussionThere were no significant differences in the metabolic, oxidative stress, and inflammatory markers between the SHS exposure and non-SHS exposure healthy women. A low serum level of high molecular weight adiponectin was associated with an increased insulin level and resistance in the women exposed to SHS.

See article in J. Gastroenterol. Hepatol. 2010; 25: 1687–1691.

Determination of glycogen in small tissue samples.

Insulin resistance is a risk marker for non-alcoholic fatty liver disease, and a risk factor for liver disease progression. We assessed temporal trajectories of insulin resistance and β-cell response to serum glucose concentration throughout adulthood and their association with diabetes risk in non-alcoholic fatty liver disease. Three thousand and sixty participants from Coronary Artery Risk Development in Young Adults, a prospective bi-racial cohort of adults age 18-30years at baseline (1985-1986; Y0) who completed up to 5 exams over 25years and had fasting insulin and glucose measurement were included. At Y25 (2010-2011), non-alcoholic fatty liver disease was assessed by noncontrast computed tomography after exclusion of other liver fat causes. Latent mixture modelling identified 25-year trajectories in homeostatic model assessment insulin resistance and β-cell response homeostatic model assessment-β. Three distinct trajectories were identified, separately, for homeostatic model assessment insulin resistance (low-stable [47%]; moderate-increasing [42%]; and high-increasing [12%]) and homeostatic model assessment-β (low-decreasing [16%]; moderate-decreasing [63%]; and high-decreasing [21%]). Y25 non-alcoholic fatty liver disease prevalence was 24.5%. Among non-alcoholic fatty liver disease, high-increasing homeostatic model assessment insulin resistance (referent: low-stable) was associated with greater prevalent (OR 95% CI=8.0, 2.0-31.9) and incident (OR=10.5, 2.6-32.8) diabetes after multivariable adjustment including Y0 or Y25 homeostatic model assessment insulin resistance. In contrast, non-alcoholic fatty liver disease participants with low-decreasing homeostatic model assessment-β (referent: high-decreasing) had the highest odds of prevalent (OR=14.1, 3.9-50.9) and incident (OR=10.3, 2.7-39.3) diabetes. Trajectories of insulin resistance and β-cell response during young and middle adulthood are robustly associated with diabetes risk in non-alcoholic fatty liver disease. Thus, how persons with non-alcoholic fatty liver disease develop resistance to insulin provides important information about risk of diabetes in midlife above and beyond degree of insulin resistance at the time of non-alcoholic fatty liver disease assessment.

"Taylor, Prof. Edwin William, (born 8 June 1929), Louis Block Professor of Molecular Genetics and Cell Biology, University of Chicago, 1984–99, half-time, 1999, now Emeritus (Professor, Department of Biophysics, 1975–99); part-time Research Professor, Department of Cell and Molecular Biology, Northwestern University Medical School, since 2000" published on by Oxford University Press.

IntroductionThe first five years of life is an important developmental period that establishes the foundation for future health and well-being. Mothers play a primary role in providing emotional and physical nourishment during early childhood. This systematic review aims to explore the association between maternal health and child health in the first five years of the child’s life.Materials and methodsAs primary aims, we systematically synthesised published evidence relating to the first five years of life for associations between maternal health exposures (mental, physical and Health-Related Quality of Life (HRQoL) and child health outcomes (physical health, mental health, HRQoL and Health Service Use (HSU) /cost). As a secondary aim, we explored how the above associations vary between disadvantaged and non-disadvantaged populations. The search was limited to studies that published and collected data from 2010 to 2022. The systematic review was specific to countries with similar health systems to Australia. The search was conducted in MEDLINE, CINAHL, APA PsycINFO, GLOBAL HEALTH, and EMBASE databases. The quality of the included studies was assessed by The Effective Public Health Practice Project (EPHPP) tool.ResultsThirteen articles were included in the final synthesis from the identified 9439 articles in the primary search. Six (46%) explored the association between maternal mental health and child’s physical health, two (15%) explored maternal and child’s physical health, one (8%) explored maternal and child’s mental health, one (8%) explored maternal physical health and child’s HRQoL, and three (23%) explored maternal mental health and child’s HSU. We found an association between maternal health and child health (physical and mental) and HSU outcomes but no association between maternal health and child’s overall HRQoL. The results for disadvantaged communities did not show any difference from the general population.Discussion and conclusionOur review findings show that maternal health influences the child’s health in the first five years. However, the current evidence is limited, and the findings were primarily related to a specific maternal or child’s health condition. There was no evidence of associations of child health outcomes in healthy mothers. There is an extensive research gap investigating maternal health exposures and child outcomes in quality of life and overall health.

Broader Focus Required to Understand the Effects of the Perinatal Environment on Child Neurodevelopment: Response to Bell and Chimata.

Gestational obesity, defined as obesity during pregnancy or a pre-pregnancy BMI ≥30, is a growing global health challenge with profound implications for both maternal and offspring health. This narrative review synthesizes current evidence on the mechanistic pathways by which maternal obesity affects pregnancy outcomes and intergenerational health trajectories. For mothers, gestational obesity increases the risk of gestational diabetes, hypertensive disorders, cesarean delivery, and postpartum weight retention. Offspring exposed to maternal obesity face higher risks of obesity, metabolic syndrome, cardiovascular disease, and neurodevelopmental disorders, many of which persist across the lifespan. The underlying mechanisms include metabolic dysregulation, insulin resistance, chronic inflammation, oxidative stress, and alterations in placental function. Epigenetic modifications, such as DNA methylation, histone changes, and non-coding RNA expression, play central roles in fetal programming, while maternal gut dysbiosis and alterations in breast milk microbiota further shape infant health outcomes. Importantly, maternal obesity not only influences pregnancy and early life but also perpetuates an intergenerational cycle of obesity and related comorbidities. Preventive strategies targeting preconception and prenatal health, combined with interventions to optimize lactation and maternal diet, may mitigate long-term risks. Future research should prioritize longitudinal and mechanistic studies to refine interventions aimed at disrupting the transmission of obesity-related disease across generations.

Does PCOS have developmental origins?

Diabetes in Socioeconomically Vulnerable Populations.