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\"Alexandra Butler--daughter of the Pulitzer-Price winning gerontologist Robert Butler and noted social worker and psychotherapist Myrna Lewis--writes of how she cared for her mother during her mother's sudden, brief, and terminal struggle with brain cancer. This memoir examines the strains of caregiving on both the caregiver and the one cared for. Alexandra was 24 when her mother was diagnosed with a glioblastoma, and spent the following months as her mother's primary caregiver, putting her own life on hold during that time. In addition to tracing the course of her mother's tragic illness, Alexandra also examines how the illness affected herself and everyone in her family. Ironically, both Myrna Lewis and Robert Butler were noted gerontologists who championed the concepts of healthy aging--they co-authored the classic work Love and Sex After 60, for example--yet both found their life's themes sorely tested by Lewis's condition. Butler in particular could not handle the illness and left much of the care to Alexandra. Thus the work also examines what happens when a social worker such as Lewis tragically transitions from professional to client\"-- Provided by publisher.

Polycystic ovary syndrome (PCOS) is a metabolic-reproductive-endocrine disorder that, while having a genetic component, is known to have a complex multifactorial etiology. As PCOS is a diagnosis of exclusion, standardized criteria have been developed for its diagnosis. The general consensus is that hyperandrogenism is the primary feature of PCOS and is associated with an array of physiological dysfunctions; excess androgens, for example, have been correlated with cytokine hypersecretion, adipocyte proliferation, and signaling pathway dysregulation. Another key feature of PCOS is insulin resistance, resulting in aberrant glucose and fatty acid metabolism. Additionally, the immune system plays a key role in PCOS. Hyperandrogenism stimulates some immune cells while it inhibits others, thereby disrupting the normal balance of immune cells and creating a state of chronic inflammation. This low-grade inflammation could contribute to infertility since it induces ovarian dysfunction. This dysregulated immune response in PCOS exhibits autoimmunity characteristics that require further investigation. This review paper examines the relationship between androgens and the immune response and how their malfunction contributes to PCOS.

To meet the increased need for food and energy because of the economic shift brought about by the Industrial Revolution in the 19th century, there has been an increase in persistent organic pollutants (POPs), atmospheric emissions and metals in the environment. Several studies have reported a relationship between these pollutants and obesity, and diabetes (type 1, type 2 and gestational). All of the major pollutants are considered to be endocrine disruptors because of their interactions with various transcription factors, receptors and tissues that result in alterations of metabolic function. POPs impact adipogenesis, thereby increasing the prevalence of obesity in exposed individuals. Metals impact glucose regulation by disrupting pancreatic β-cells, causing hyperglycemia and impaired insulin signaling. Additionally, a positive association has been observed between the concentration of endocrine disrupting chemicals (EDCs) in the 12 weeks prior to conception and fasting glucose levels. Here, we evaluate what is currently known regarding the link between environmental pollutants and metabolic disorders. In addition, we indicate where further research is required to improve our understanding of the specific effects of pollutants on these metabolic disorders which would enable implementation of changes to enable their prevention.

Purpose of ReviewTo discuss the current understanding of “β cell identity” and factors underlying altered identity of pancreatic β cells in diabetes, especially in humans.Recent FindingsAltered identity of β cells due to dedifferentiation and/or transdifferentiation has been proposed as a mechanism of loss of β cells in diabetes. In dedifferentiation, β cells do not undergo apoptosis; rather, they lose their identity and function. Dedifferentiation is well characterized by the decrease in expression of key β cell markers such as genes encoding major transcription factors, e.g., MafA, NeuroD1, Nkx6.1, and Foxo1, and an increase in atypical or “disallowed” genes for β cells such as lactate dehydrogenase, monocarboxylate transporter MCT1, or progenitor cell genes (Neurog3, Pax4, or Sox9). Moreover, altered identity of mature β cells in diabetes also involves transdifferentiation of β cells into other islet hormone producing cells. For example, overexpression of α cell specific transcription factor Arx or ablation of Pdx1 resulted in an increase of α cell numbers and a decrease in β cell numbers in rodents. The frequency of α-β double-positive cells was also prominent in human subjects with T2D. These altered identities of β cells likely serve as a compensatory response to enhance function/expand cell numbers and may also camouflage/protect cells from ongoing stress. However, it is equally likely that this may be a reflection of new cell formation as a frank regenerative response to ongoing tissue injury. Physiologically, all these responses are complementary.SummaryIn diabetes, (1) endocrine identity recapitulates the less mature/less-differentiated fetal/neonatal cell type, possibly representing an adaptive mechanism; (2) residual β cells may be altered in their subtype proportions or other molecular features; (3) in humans, “altered identity” is a preferable term to dedifferentiation as their cellular fate (differentiated cells losing identity or progenitors becoming more differentiated) is unclear as yet.

Differentiating between type 1 and type 2 diabetes For people who fit the classic pattern of type 2 diabetes (table 1), and where two glucose test results are in the diabetic range (box 1), no further testing is required for diagnosis, and management should follow current guidelines.1 Follow-up testing of glycated haemoglobin (HbA1c) is useful to assess glycaemia over time and to tailor treatment.1 Table 1 Clinical features at presentation that help to distinguish type 1 and type 2 diabetes Type 1 diabetes Type 2 diabetes Weight loss Yes (though not always, eg, in slow onset type 1)1 Unusual1 Ketonuria Yes (though not always in slow onset type 1)1 No, unless patient has been fasting recently1 Time course for symptoms Weeks or days1 Months to years1 Severity of symptoms (eg, nocturia >3x) Often marked1 Variable, but usually not severe1 Family history Possible family history of autoimmune disease2 and/or insulin dependence at a young age3 Family history present in 30% with onset in adult life4 Age Peak age in pre-school and teenage years, but can present at any age56 Typically after the age of 40, but can present in younger patients56 Box 1 Criteria for the diagnosis of diabetes (all types) as determined by the World Health Organization and the American Diabetes Association17 Fasting plasma glucose (FPG) ≥7.0 mmol/L (126 mg/dL), or 2 hour plasma glucose ≥11.1 mmol/L (200 mg/dL) during an oral glucose tolerance test (OGTT) using a glucose load of 75 g, or HbA1c ≥6.5% (48 mmol/mol), or Random plasma glucose of ≥11.1 mmol/L (200 mg/dL) in a patient with classic symptoms of hyperglycaemia or hyperglycaemic crisis Where a state of hyperglycaemia is uncertain, diagnosis of diabetes requires two abnormal test results from the same sample or in two separate test samples However, the distinction between type 1 and type 2 diabetes is not always clear. While hyperglycaemia in adults is often associated with type 2 diabetes, 40% of type 1 diabetes cases occur in people over 30.8 Indeed, in a retrospective longitudinal study of more than 2000 adults with newly diagnosed type 1 diabetes, the mean age of presentation was 40, mean BMI was 25.3 kg/m2, and mean blood glucose reading was 16.7 mmol/L (300 mg/dL).5 Hence, distinguishing type 1 from type 2 diabetes3 can be particularly difficult in Patients under 40 who are initially treated with insulin but clinically appear to have type 2 diabetes Patients 40 and older with late onset diabetes who require insulin and share characteristics of patients with type 1 diabetes, such as BMI <25 kg/m2.910 The question is whether these patients who might be assumed to have type 2 diabetes actually have early, evolving type 1 diabetes without the typical acute presentation or latent autoimmune diabetes of adulthood (LADA), in which patients have diabetes-specific autoantibodies without a frank requirement for insulin for at least six months after diagnosis.11 In a number of large, clinical and population-based studies, between roughly 4% and 14% of adults who appear to have new onset type 2 diabetes have at least one diabetes-specific autoantibody consistent with LADA12; prevalence is higher (~25%) in those over 40.13 Like type 2 diabetes, the onset of LADA is subclinical and rarely acute.12 Patients with LADA may go on to develop type 1 diabetes, and this risk is higher when multiple diabetes-specific autoantibodies are present (20% with one autoantibody rising to 80% with four autoantibodies present).1415 It is pivotal to identify patients with newly diagnosed type 1 diabetes because of their absolute requirement for insulin therapy.8 Treatment includes extensive teaching and learning for appropriate administration of insulin because insulin therapy has potentially serious side effects, such as iatrogenic hypoglycaemia with increased mortality risk, and weight gain, among others.116 In addition, a diagnosis of type 1 diabetes may have detrimental effects on a patient’s quality of life beyond glucose monitoring and insulin dosing, for example in terms of employment and ability to drive.17 HbA1c is not recommended as a diagnostic test for patients with possible or suspected type 1 diabetes for two reasons. [...]in type 1 diabetes hyperglycaemia can develop rapidly and might not be reflected in the HbA1c level. [...]it can take days for a laboratory to measure HbA1c, but glucose samples are usually tested more rapidly,18 and patients with type 1 diabetes need to begin insulin therapy immediately.

We sought to establish β-cell mass, β-cell apoptosis, and β-cell replication in humans in response to obesity and advanced age. We examined human autopsy pancreas from 167 nondiabetic individuals 20-102 years of age. The effect of obesity on β-cell mass was examined in 53 lean and 61 obese subjects, and the effect of aging was examined in 106 lean subjects. β-Cell mass is increased by ~50% with obesity (from 0.8 to 1.2 g). With advanced aging, the exocrine pancreas undergoes atrophy but β-cell mass is remarkably preserved. There is minimal β-cell replication or apoptosis in lean humans throughout life with no detectable changes with obesity or advanced age. β-Cell mass in human obesity increases by ~50% by an increase in β-cell number, the source of which is unknown. β-Cell mass is well preserved in humans with advanced aging.

Controversy exists regarding the potential regenerative influences of incretin therapy on pancreatic β-cells versus possible adverse pancreatic proliferative effects. Examination of pancreata from age-matched organ donors with type 2 diabetes mellitus (DM) treated by incretin therapy (n = 8) or other therapy (n = 12) and nondiabetic control subjects (n = 14) reveals an ∼40% increased pancreatic mass in DM treated with incretin therapy, with both increased exocrine cell proliferation (P < 0.0001) and dysplasia (increased pancreatic intraepithelial neoplasia, P < 0.01). Pancreata in DM treated with incretin therapy were notable for α-cell hyperplasia and glucagon-expressing microadenomas (3 of 8) and a neuroendocrine tumor. β-Cell mass was reduced by ∼60% in those with DM, yet a sixfold increase was observed in incretin-treated subjects, although DM persisted. Endocrine cells costaining for insulin and glucagon were increased in DM compared with non-DM control subjects (P < 0.05) and markedly further increased by incretin therapy (P < 0.05). In conclusion, incretin therapy in humans resulted in a marked expansion of the exocrine and endocrine pancreatic compartments, the former being accompanied by increased proliferation and dysplasia and the latter by α-cell hyperplasia with the potential for evolution into neuroendocrine tumors.

Polycystic ovary syndrome (PCOS) is the most common endocrine-metabolic disease in females of reproductive age, affecting 4–20% of pre-menopausal women worldwide. MicroRNAs (miRNAs) are endogenous, single-stranded, non-coding, regulatory ribonucleic acid molecules found in eukaryotic cells. Abnormal miRNA expression has been associated with several diseases and could possibly explain their underlying pathophysiology. MiRNAs have been extensively studied for their potential diagnostic, prognostic, and therapeutic uses in many diseases, such as type 2 diabetes, obesity, cardiovascular disease, PCOS, and endometriosis. In women with PCOS, miRNAs were found to be abnormally expressed in theca cells, follicular fluid, granulosa cells, peripheral blood leukocytes, serum, and adipose tissue when compared to those without PCOS, making miRNAs a useful potential biomarker for the disease. Key pathways involved in PCOS, such as folliculogenesis, steroidogenesis, and cellular adhesion, are regulated by miRNA. This also highlights their importance as potential prognostic markers. In addition, recent evidence suggests a role for miRNAs in regulating the circadian rhythm (CR). CR is crucial for regulating reproduction through the various functions of the hypothalamic-pituitary-gonadal (HPG) axis and the ovaries. A disordered CR affects reproductive outcomes by inducing insulin resistance, oxidative stress, and systemic inflammation. Moreover, miRNAs were demonstrated to interact with lncRNA and circRNAs, which are thought to play a role in the pathogenesis of PCOS. This review discusses what is currently understood about miRNAs in PCOS, the cellular pathways involved, and their potential role as biomarkers and therapeutic targets.

Ferroptosis is a recently identified form of cell death characterized by iron accumulation and lipid peroxidation. Unlike apoptosis, necrosis, and autophagy, ferroptosis operates through a distinct molecular pathway. Curcumin, derived from turmeric rhizomes, is a natural compound with diverse therapeutic benefits, including neuroprotective, anti-metabolic syndrome, anti-inflammatory, and anti-cancer properties. Growing evidence suggests that curcumin possesses both pro-oxidant and antioxidant properties, which can vary depending on the cell type. In this review, we explore the relationship between the effects of curcumin and the molecular mechanisms underlying the ferroptosis signaling pathway, drawing from current in vivo and in vitro research. Curcumin has been found to induce ferroptosis in cancer cells while acting as an inhibitor of ferroptosis in tissue injuries. Notably, curcumin treatment leads to alterations in key ferroptosis markers, underscoring its significant impact on this process. Nonetheless, further research focused on elucidating this important attribute of turmeric is crucial for advancing disease treatment.

The islet in type 2 diabetes (T2D) is characterized by amyloid deposits derived from islet amyloid polypeptide (IAPP), a protein co-expressed with insulin by β-cells. In common with amyloidogenic proteins implicated in neurodegeneration, human IAPP (hIAPP) forms membrane permeant toxic oligomers implicated in misfolded protein stress. Here, we establish that hIAPP misfolded protein stress activates HIF1α/PFKFB3 signaling, this increases glycolysis disengaged from oxidative phosphorylation with mitochondrial fragmentation and perinuclear clustering, considered a protective posture against increased cytosolic Ca 2+ characteristic of toxic oligomer stress. In contrast to tissues with the capacity to regenerate, β-cells in adult humans are minimally replicative, and therefore fail to execute the second pro-regenerative phase of the HIF1α/PFKFB3 injury pathway. Instead, β-cells in T2D remain trapped in the pro-survival first phase of the HIF1α injury repair response with metabolism and the mitochondrial network adapted to slow the rate of cell attrition at the expense of β-cell function. Type 2 diabetes is associated with islet amyloid deposits derived from islet amyloid polypeptide (IAPP) expressed by β-cells. Here the authors show that IAPP misfolded protein stress induces the hypoxia inducible factor 1 alpha injury repair pathway and activates survival metabolic changes mediated by PFKFB3.