Changes In Glucose Homeostasis Research Articles

Finerenone protects against progression of kidney and cardiovascular damage in a model of type 1 diabetes through modulation of proinflammatory and osteogenic factors

The non-steroidal mineralocorticoid receptor antagonist (MRA) finerenone (FIN) improves kidney and cardiovascular outcomes in patients with chronic kidney disease (CKD) in type 2 diabetes (T2D). We explored the effect of FIN in a novel model of type 1 diabetic Munich Wistar Frömter (MWF) rat (D) induced by injection of streptozotocin (15 mg/kg) and additional exposure to a high-fat/high-sucrose diet. Oral treatment with FIN (10 mg/kg/day in rat chow) in diabetic animals (D-FIN) was compared to a group of D rats receiving no treatment and a group of non-diabetic untreated MWF rats (C) (n = 7–10 animals per group). After 6 weeks, D and D-FIN exhibited significantly elevated blood glucose levels (271.7 ± 67.1 mg/dl and 266.3 ± 46.8 mg/dl) as compared to C (110.3 ± 4.4 mg/dl; p < 0.05). D showed a 10-fold increase of kidney damage markers Kim-1 and Ngal which was significantly suppressed in D-FIN. Blood pressure, pulse wave velocity (PWV) and arterial collagen deposition were lower in D-FIN, associated to an improvement in endothelial function due to a reduction in pro-contractile prostaglandins, as well as reactive oxygen species (ROS) and inflammatory cytokines (IL-1, IL-6, TNFα and TGFβ) in perivascular and perirenal adipose tissue (PVAT and PRAT, respectively). In addition, FIN restored the imbalance observed in CKD between the procalcifying BMP-2 and the nephroprotective BMP-7 in plasma, kidney, PVAT, and PRAT. Our data show that treatment with FIN improves kidney and vascular damage in a new rat model of DKD with T1D associated with a reduction in inflammation, fibrosis and osteogenic factors independently from changes in glucose homeostasis.

An Okinawan-Based Nordic Diet Leads to Profound Effects on Gut Microbiota and Plasma Metabolites Linked to Glucose and Lipid Metabolism.

Dietary interventions modify gut microbiota and clinical outcomes. Weight reduction and improved glucose and lipid homeostasis were observed after adopting an Okinawan-based Nordic diet (O-BN) in individuals with type 2 diabetes. The aim of the present study was to explore changes in metabolomics and gut microbiota during O-BN and correlate changes with clinical outcomes. A total of 30 patients (17 women), aged 57.5 ± 8.2 years, diabetes duration 10.4 ± 7.6 years, 90% over-weight, were included. Participants were provided an O-BN for 12 weeks. Before and after intervention, and 16 weeks afterwards, anthropometry and clinical data were estimated and questionnaires were collected, as well as samples of blood and stool. Plasma metabolomics were determined by gas- (GC-MS) or liquid- (LC-MS) chromatography-based mass spectrometry and fecal microbiota determination was based on 16S rRNA amplicons from regions V1-V2. During the intervention, weight (6.8%), waist circumference (6.1%), and levels of glucose, HbA1c, insulin, triglycerides, and cholesterol were decreased. Of 602 metabolites, 323 were changed for any or both periods; 199 (101 lipids) metabolites were decreased while 58 (43 lipids) metabolites were increased during the intervention. Changes in glucose homeostasis were linked to changes in, e.g., 1,5-anhydroglucitol, thyroxine, and chiro-inositol. Changes of microbe beta diversity correlated positively with food components and negatively with IL-18 (p = 0.045). Abundance differences at phylum and genus levels were found. Abundances of Actinobacteria, Bacteroidetes, Firmicutes, and Verrucomicrobia correlated with anthropometry, HbA1c, lipids, inflammation, and food. Changes in metabolites and microbiota were reversed after the intervention. The O-BN-induced changes in metabolomics and gut microbiota correspond to clinical outcomes of reduced weight and inflammation and improved glucose and lipid metabolism.

Mouse Models with SGLT2 Mutations: Toward Understanding the Role of SGLT2 beyond Glucose Reabsorption.

The sodium-glucose cotransporter 2 (SGLT2) mainly carries out glucose reabsorption in the kidney. Familial renal glycosuria, which is a mutation of SGLT2, is known to excrete glucose in the urine, but blood glucose levels are almost normal. Therefore, SGLT2 inhibitors are attracting attention as a new therapeutic drug for diabetes, which is increasing worldwide. In fact, SGLT2 inhibitors not only suppress hyperglycemia but also reduce renal, heart, and cardiovascular diseases. However, whether long-term SGLT2 inhibition is completely harmless requires further investigation. In this context, mice with mutations in SGLT2 have been generated and detailed studies are being conducted, e.g., the SGLT2-/- mouse, Sweet Pee mouse, Jimbee mouse, and SAMP10-ΔSglt2 mouse. Biological changes associated with SGLT2 mutations have been reported in these model mice, suggesting that SGLT2 is not only responsible for sugar reabsorption but is also related to other functions, such as bone metabolism, longevity, and cognitive functions. In this review, we present the characteristics of these mutant mice. Moreover, because the relationship between diabetes and Alzheimer's disease has been discussed, we examined the relationship between changes in glucose homeostasis and the amyloid precursor protein in SGLT2 mutant mice.

Fine particulate matter (PM2.5)-induced pulmonary oxidative stress contributes to increases in glucose intolerance and insulin resistance in a mouse model of circadian dyssynchrony

Results of human and animal studies independently suggest that either ambient fine particulate matter (PM2.5) air pollution exposure or a disturbed circadian rhythm (circadian dyssynchrony) are important contributing factors to the rapidly evolving type-2-diabetes (T2D) epidemic. The objective of this study is to investigate whether circadian dyssynchrony increases the susceptibility to PM2.5 and how PM2.5 affects metabolic health in circadian dyssynchrony. We examined systemic and organ-specific changes in glucose homeostasis and insulin sensitivity in mice maintained on a regular (12/12 h light/dark) or disrupted (18/6 h light/dark, light-induced circadian dyssynchrony, LICD) light cycle exposed to air or concentrated PM2.5 (CAP, 6 h/day, 30 days). Exposures during Zeitgeber ZT3–9 or ZT11–17 (Zeitgeber in circadian time, ZT0 = begin of light cycle) tested for time-of-day PM2.5 sensitivity (chronotoxicity). Mice transgenic for lung-specific overexpression of extracellular superoxide dismutase (ecSOD-Tg) were used to assess the contribution of CAP-induced pulmonary oxidative stress. Both, CAP exposure from ZT3–9 or ZT11–17, decreased glucose tolerance and insulin sensitivity in male mice with LICD, but not in female mice or in mice kept on a regular light cycle. Although changes in glucose homeostasis in CAP-exposed male mice with LICD were not associated with obesity, they were accompanied by white adipose tissue (WAT) inflammation, impaired insulin signaling in skeletal muscle and liver, and systemic and pulmonary oxidative stress. Preventing CAP-induced oxidative stress in the lungs mitigated the CAP-induced decrease in glucose tolerance and insulin sensitivity in LICD. Our results demonstrate that circadian dyssynchrony is a novel susceptibility state for PM2.5 and suggest that PM2.5 by inducing pulmonary oxidative stress increases glucose intolerance and insulin resistance in circadian dyssynchrony.

The Correlation between Diabetes Mellitus and Neurodegenerative Diseases.

Today there is no longer any doubt that diabetes mellitus is associated with cognitive impairment and neurodegenerative diseases. The two most common forms of diabetes mellitus are type 1 and type 2. Type 1 diabetes mellitus is characterized by an absolute insulin deficiency that is associated with a large number of metabolic changes. This type of diabetes requires insulin therapy. Without insulin, this disease is fatal. The far more common form of diabetes mellitus nowadays is type 2 diabetes mellitus. It is characterized by insulin resistance. For a number of years drugs have been available that can be used to treat this form of diabetes in a multimodal manner. These therapy options can not only improve metabolic control, but also prevent cardiovascular events. Different cognitive alterations associated with diabetes mellitus can be distinguished. On the one hand, the change in glucose homeostasis itself leads to cognitive alterations, i.e. blood sugar levels that are too high or acutely too low are regularly associated with significant impairments in mental performance, including loss of consciousness. But not only the momentary blood sugar levels, but also long-term changes in glucose metabolism might lead to neurodegeneration and even dementia in a way that has not yet been fully understood. Insulin or insulin-like molecules have important effects in the central nervous system. In the last decades, it has been shown that insulin receptors themselves are expressed in many regions of the brain and e.g. regulate food intake and memory formation in humans and in animal models. In the animal model, disturbances in insulin signal transduction influence the development of pathologies typical of Alzheimer's disease (AD). In humans, central insulin resistance is at least part of the formal pathogenesis of AD. Vascular changes (macroangiopathy) in patients with diabetes mellitus often lead to cerebral insults, microangiopathies and vascular dementia.

Ethanol exposure alters Alzheimer's-related pathology, behavior, and metabolism in APP/PS1 mice

Epidemiological studies identified alcohol use disorder (AUD) as a risk factor for Alzheimer's disease (AD), yet there is conflicting evidence on how alcohol use promotes AD pathology. In this study, a 10-week moderate two-bottle choice drinking paradigm was used to identify how chronic ethanol exposure alters amyloid-β (Aβ)-related pathology, metabolism, and behavior. Ethanol-exposed APPswe/PSEN1dE9 (APP/PS1) mice showed increased brain atrophy and an increased number of amyloid plaques. Further analysis revealed that ethanol exposure led to a shift in the distribution of plaque size in the cortex and hippocampus. Ethanol-exposed mice developed a greater number of smaller plaques, potentially setting the stage for increased plaque proliferation in later life. Ethanol drinking APP/PS1 mice also exhibited deficits in nest building, a metric of self-care, as well as increased locomotor activity and central zone exploration in an open field test. Ethanol exposure also led to a diurnal shift in feeding behavior which was associated with changes in glucose homeostasis and glucose intolerance. Complementary in vivo microdialysis experiments were used to measure how acute ethanol directly modulates Aβ in the hippocampal interstitial fluid (ISF). Acute ethanol transiently increased hippocampal ISF glucose levels, suggesting that ethanol directly affects cerebral metabolism. Acute ethanol also selectively increased ISF Aβ40, but not ISF Aβ42, levels during withdrawal. Lastly, chronic ethanol drinking increased N-methyl-d-aspartate receptor (NMDAR) and decreased γ-aminobutyric acid type-A receptor (GABAAR) mRNA levels, indicating a potential hyperexcitable shift in the brain's excitatory/inhibitory (E/I) balance. Collectively, these experiments suggest that ethanol may increase Aβ deposition by disrupting metabolism and the brain's E/I balance. Furthermore, this study provides evidence that a moderate drinking paradigm culminates in an interaction between alcohol use and AD-related phenotypes with a potentiation of AD-related pathology, behavioral dysfunction, and metabolic impairment.

Impact of biliopancreatic diversion with duodenal switch on glucose homeostasis and gut hormones and their correlations with appetite

Biliopancreatic diversion with duodenal switch (BPD/DS) results in lifelong changes in gastrointestinal physiology with unclear associations with appetite perception. To explore mixed meal-induced changes in glucose homeostasis and gut hormones and their correlations with appetite perception. University hospital. Of 28 patients studied preoperatively (age: 38.4 ± 11.3 years; body mass index [BMI]: 56.5 ± 5.1 kg/m2; 14 women), 19 (68%) returned for postoperative follow-up. Plasma was sampled for 180 minutes during a 260-kcal standardized mixed meal. Concentrations of leptin, glucose, insulin, triglycerides, active acyl-ghrelin, motilin, total glucose-dependent insulinotropic polypeptide (GIP), active glucagon-like peptide 1 (GLP-1), and total peptide YY (PYY) were measured. Subjective appetite sensations were scored. BPD/DS resulted in 66.1% ± 23.3% excess BMI loss. Leptin was halved. Glucose and insulin levels were reduced, blunting a preoperative peak at 30 minutes, giving a lower homeostasis model assessment for insulin resistance (HOMA-IR; 13.9 versus 4.8). In contrast, reduced ghrelin and motilin concentrations were accompanied by pronounced peaks 20-30 minutes prior to meal responses. GIP was reduced, whereas GLP-1 and PYY responses were markedly increased, with an early postprandial peak (P < .05, for all). HOMA-IR correlated with insulin (r = .72) and GIP (r = .57). Postoperatively, satiety correlated with GLP-1 (r = .56), whereas the gastric motility index correlated with the desire to eat (r = .60), percentage excess BMI loss (r = -.55), and percentage total weight loss (r = -.49). Delta insulin, GLP-1, and leptin correlated positively with percentage total weight loss (r = .51, r = .48, and r = .58, respectively). BPD/DS reduces leptin, HOMA-IR, and GIP while markedly increasing GLP-1 and PYY. This study marks the magnitude change in GLP-1 with additional effects of PYY as important factors for weight loss.

ISPAD Clinical Practice Consensus Guidelines 2022: Ramadan and other religious fasting by young people with diabetes.

Fasting is advised, with variable rules, in healthy adults and adolescents in different religions. A common purpose of fasting in these religions is to gain self-restraint, arouse spiritual consciousness, and better understand the plight of the poor and hungry. In this section, general rules and religious guidance on observing and breaking fasting in different religions are given, with emphasis on potential effects on health and glycemic outcomes in children and adolescents with T1D who choose to fast. Ramadan fasting is one of the five pillars of Islam and is obligatory for all healthy adult and adolescent Muslims from the time of completing puberty.1 As per the Islamic rules and guidance from Sunnah (the way of prophet Mohamed), an individual becomes subject to Shari'a rulings that apply when specific features of puberty are attained. Approximately 1.9 billion Muslims celebrate the ninth month of the Hijri (lunar) calendar notable for Ramadan fasting all over the world.2 The Epidemiology of Diabetes and Ramadan (EPIDIAR), a population-based study conducted in 13 countries and involving almost 13,000 adults with diabetes, showed that 78.7% of individuals with type 2 diabetes (T2D) and 42.8% of those with T1D fast for at least for 15 days during Ramadan. Saudi Arabia had the maximum number of individuals with T1D who chose to fast.3 The duration of fasting during Ramadan varies based on geographical location and season but is mandated to be between dawn and dusk. During this period, people who fast abstain from eating, drinking, use of oral medications, and smoking. There are no restrictions on food or fluid intake between dusk and dawn.1, 4 Fasting during Ramadan is not intended to bring excessive difficulty or cause any adverse effect to the individual. Islam has allowed many categories of people to be exempted from fasting; for example, menstruating, pregnant or breastfeeding women, prepubertal children, the elderly, individuals with any acute or chronic illness in whom fasting would be detrimental to health, individuals with an intellectual disability, or individuals who are traveling.1 These principles formed the basis of all the consensus statements by several groups.5-7 The provisions of al-Fitr (i.e., Not to observe the fast) in Ramadan apply if there is any sickness, according to the Almighty saying: “Whoever of you is sick or on a journey, and some of the other days, and on those who support him, ransom poor food.”1 Therefore, if a person fasts and experiences harm or serious hardship while fasting, he/she may be committing a sin.4 Various beliefs exist regarding diabetes management practices during Ramadan. In a study of fasting during Ramadan that included 800 individuals with diabetes, 67% indicated that pricking the skin to measure BGLs breaks the fast.8 Such a belief might endanger individuals with diabetes and predispose them to acute complications. Medical counseling and liaison with Islamic scholars can help correct wrong interpretation as well as understanding and ensure safer fasting. Although some experts would consider fasting, particularly during Ramadan, a practice at high risk for metabolic deterioration, recent studies have demonstrated that individuals with T1D can fast safely during Ramadan, provided they comply with the fasting-focused management plan and are under close professional supervision.6, 9 The Eastern Christian Orthodox Church is the second-largest Christian church, with ~300 million members.10 Orthodox Fasting (OF) is a basic and traditional component of the religion, practiced by a large proportion of the Orthodox population.11 OF includes three main fasting periods: 40 days prior to Christmas, 48 days prior to Easter, 14 days prior to Assumption, along with the fasting period prior to the feast of the Holy Apostles (lasting from 0 to 30 days depending on Easter feast), three other daily feasts (January 5, August 29, September 14), as well as every Wednesday and Friday. Individuals 18–59 years old are expected to fast during these periods. OF is a kind of periodical diet which recommends abstaining from meat, dairy products and eggs for about 180 days annually, and also abstaining from fish for 155 days. The diet during periods of fasting is characterized by increased consumption of cereals, legumes, fruits, vegetables, nuts and seafood. For this reason, it may be considered as a vegetarian dietary pattern, where fasting and non-fasting periods alternate, sharing common features with the classical Mediterranean Diet.11, 12 Studies on OF followers conducted in three different countries (Greece, United States, and Egypt), reported low total energy intake, low fat (total, saturated and trans), low animal and high vegetable protein intake, high complex carbohydrate and fiber intake, high vitamin C, folate and magnesium intake, low calcium and vitamin D intake during different fasting periods.13, 14 The OF meal plan tends to be high in carbohydrate content. Thus, it is advisable for people with T1D to choose carbohydrates with a low glycemic index, and consume them in combination with fiber, proteins (legumes, seafood) or fats (olive oil). Rye, barley, oats, brown rice, quinoa or amaranth are also suitable.15 Although data on the effect of OF diet on metabolic health are heterogenous, a potential benefit on lipid profile has been suggested, whereas there are no data on the effects on cardiovascular and musculoskeletal outcomes. Negative aspects of OF, primarily attributed to dietary limitations of specific vitamins (D and B12) and minerals (calcium and iron), should not be ignored, and relevant guidance might be provided to people following OF by health care professionals.13 Yom Kippur fasting is a major fast and the holiest day in the Jewish religion and calendar.16 It is obligatory for all healthy adult and adolescent Jews from the age of 13 years in males and 12 years in females. All observant and most non-observant Jews practice this 25 h long fasting. It starts at dusk (end of the ninth of Tishrei—first month of the Jewish lunar year) and ends on the following day (10th of Tishrei) at sunset.16 The activity during this fast involves mostly prayer and soul searching within synagogues. Jewish law includes five other days of fasting between dawn and dusk, and these are mostly practiced only by observant Jews. During fasting, Jews abstain from eating, drinking, and smoking. Fasting is not intended to cause any adverse effect to the individual.17 Jewish law allows many categories of people to be exempted from fasting; for example, prepubertal children, women in and around delivery days, individuals with illnesses in whom fasting may be detrimental to health, and individuals with an intellectual disability.17 Jewish law defines an intermediate state where people who need to break their fast due to health reasons can intermittently eat small portions of 30 g in line with a scheduled time plan.16 Various approaches for diabetes management during fasting have been used. Initially, prior to the era of glucometers and CGM, people with diabetes were exempt from fasting. In the last two decades, several studies showed that insulin dose adjustments and close monitoring may enable safe fasting for individuals with T1D.18-21 Jewish law indicates that specific medical counseling and liaison with Jewish legal scholars should facilitate and help to ensure safer fasting for the individual.19-21 Fasting is also common in other religions in the world. It is well known that followers of Hinduism, Buddhism and Jainism believe that the act of fasting would result in the spiritual transformation of the individual or community. In Hinduism, different forms of fasting are frequently practised throughout the year. Fasting is not considered an obligation, but a spiritual and moral act, the aim being to purify the body and mind to acquire self-restraint and divine grace. There are different forms of fasting which vary according to personal, family and community beliefs, which may be strict and difficult to follow, or relatively easy and readily amenable to modifications. The fasting period can be for a single day, weekly (on specific day/s throughout the year), bi-monthly (Pradosha—13th day of every fortnight of the Hindu calendar), monthly (Ekadashi—11th day of the Hindu lunar month, and Purnima—the full moon day). Longer fasting periods may last 9 days and are followed once or twice a year (Navratras), or of 1-month duration (Kartik month). Variability exists according to timing, duration and type of food intake, including no food and water intake, only water allowed; fruit and milk allowed, and broken rice or millets allowed.22 In Buddhism, while fasting is generally practiced by monks, lay people may fast voluntarily as part of a personal spiritual observance. Buddhist Lent is the fast and feast observed for three lunar months every year during the rainy season, when Buddhists fast for a 12-h period, from noon to midnight, followed by feasting for 12 h from midnight to noon.23 Some devout lay Buddhists also follow the rule during special days of religious observance when one must not eat after the noon meal. The duration of fasting can vary from three (sanzhai) to 6 days (liuzhai).24 In the first half of the first, fifth, and ninth months, a continuous long fast (changzhai) is also observed. Fasting is similarly prevalent in Jainism, observed during festivals, holy days, birthdays and anniversaries. There are several types of fasts, varying from 24–36 h to several days and months. Paryushan is the main festival during the monsoons, which usually lasts eight or 10 days, respectively, in the Swetambara and Digambara Jain tradition (the two main sects of Jainism).25 Digambar Jains usually will not consume food and/or water (boiled) more than once in a day; while Shwetambar Jains drink only boiled water during their fast days. Many Jains observe a type of fasting by abstaining from food and water after sunset. Varshitap (year-long fast) is a type of fasting in Jainism where devotees fast for 13 months and 13 days, in which they fast completely on alternate days and eat a limited diet between sunrise and sunset on the other days. The Bahais fast for 19 days in the month of Ala (March), when no food or water is consumed from sunrise to sunset by persons 15–70 years old. In Taoism, fasting is observed in the form of “Bigu,” where grains are avoided. Many reviews, consensus statements, and expert opinions detailing the principles of diabetes care during fasting (especially during Ramadan) have been published.5-7, 26-28 A comprehensive guide has been developed by the International Islamic Fiqh Academy, along with the Islamic organization of health sciences, after a thorough literature review of possible risks to people with diabetes associated with Ramadan fasting. Among defined risk stratification groups, T1D is considered to be a very high-risk group.29, 30 However, this document is not specific to young people with diabetes, and overall studies on religious fasting in this population are limited.31 A survey by Elbarbary et al. highlighted variations among physicians, from 16 predominantly Muslim countries, in the management of children and adolescents with T1D. There are substantial variations in the perceptions, beliefs, general management, and the practice of insulin therapy in this age group during fasting.32 The survey also highlighted limitations related to relying on data on the safety and metabolic impact of fasting based on studies conducted in adults with T2D.32 Furthermore, there is minimal literature on fasting-related issues in religions other than Islam. In many diabetes centers managing Muslim populations, healthcare professionals agree that adolescents can fast if they have reasonable glycemic control, good hypoglycemia awareness, and the willingness to frequently monitor their BGLs during fasting.33 A recent survey indicated that almost 80% of physicians looking after children and adolescents with diabetes would allow them to fast if they wished.32 Pre-fasting assessment and education are vital to ensure the suitability and safety of fasting in young people with diabetes. Many diabetes units run special education sessions prior to the month of Ramadan to ensure safe fasting. The lack of pre-fasting assessment and proper diabetes education are major obstacles for safe fasting in people with T1D.32, 34 Eid et al. showed that an educational program consisting of weekly sessions before and during Ramadan, enabled people with diabetes to fast safely, with a reduced number of hypoglycemic events per month.35 A systematic review showed that Ramadan-focused diabetes education in T2D resulted in a substantial reduction of hypoglycemia and improvement in HbA1c.36 Structured education has also been associated with a 61% decrease in DKA risk in adults with T1D.37 The dose adjustment for normal eating (DAFNE) education program highlights the importance of flexible dosing, carbohydrate counting and matching insulin to carbohydrate intake.38 This, together with rtCGM or isCGM, can help people with uncomplicated T1D to safely fast during Ramadan.39, 40 In a study from Kuwait, people with T1D using CGM and provided with DAFNE training had a reduced incidence of hypoglycemia during Ramadan compared with the pre-Ramadan period. No episodes of severe hypoglycemia, DKA, acute kidney injury, or hospitalization occurred during Ramadan, including no evidence of increased glucose variability.39, 40 Other studies demonstrated that individuals with T1D who received Ramadan-focused education showed more willingness to fast, since they were more capable of managing their diabetes, and they had better glycemic outcomes and fewer complications.41, 42 Qualitative studies suggest that structured Ramadan-focused education needs to be developed and implemented in clinic practice.38, 41, 43 The DAR practical guidelines 2021 also suggested that individuals with diabetes wishing to fast and receiving pre-Ramadan assessment and education, should fast for a few days during the 2 months preceding Ramadan.9 In summary, wider implementation of fasting-focused education for both individuals with T1D and T2D, especially those on insulin therapy, is of paramount importance. Based on the growing number of technologies that support diabetes care, telemedicine has been proposed as an important solution to meet the need of expanding care for the benefit of people with diabetes, while improving efficiency and containing costs.44 During the COVID-19 pandemic, telemedicine and telemonitoring have shifted from an aspirational goal to a de facto standard of care for diabetes management.45 Limited studies have investigated the role of telemedicine in the management of diabetes during Ramadan or other religious fasting, especially in adolescents with T1D. In 2020 and 2021, the Holy Month of Ramadan coincided with the COVID-19 pandemic and lockdown. Limited access to healthcare and the continuous need for diabetes assessment and consultation before and during Ramadan highlighted the urgent need for digital health solutions in diabetes care. The DAR Global Survey on 1483 Muslim participants with T1D showed that 26.8% of those aged <18 years and 73.2% of those aged ≥18 years fasted during Ramadan during the 2020 COVID pandemic.46 When comparing the short-term benefits of a telemonitoring-supplemented focused diabetes education with education alone in individuals with T2D who fasted during Ramadan, frequency of hypoglycemia was lower in the telemonitored group.47 Similarly, the “Making Ramadan Fasting A Safer Experience (MRFAST)” study showed reduced episodes of hypoglycemia and greater reduction in HbA1c in participants with T2D assigned to the telemonitoring group compared to the control group.48 Participants viewed telemedicine as a more convenient alternative, although technological barriers remain a concern. A prospective study assessed the role of a 24-h Helpline Service for people with diabetes during Ramadan and supported its key role in promoting safe fasting and reducing unnecessary hospital visits and admissions.49 More than half of the 927 calls were queries related to glucose monitoring data and insulin dose adjustment in T1D. Overall, telemonitoring offers an attractive option for managing diabetes during Ramadan and other religious fasting, but further data in adolescents with diabetes are needed.50 In healthy individuals, during fasting circulating BGLs tend to fall leading to decreased insulin secretion. In addition, levels of glucagon and catecholamines rise, stimulating glycogenolysis and gluconeogenesis.51 In the early hours of fasting, glycogenolysis meets the glucose requirements of the body. This is followed by gluconeogenesis, and later ketogenesis, if the duration of fasting is prolonged. Similar responses, albeit to a lesser extent, occur during the intermittent fasting that occurs during Ramadan. In people with T1D, hypoglycemia that occurs during fasting may not elicit an adequate glucagon response.52, 53 In addition, individuals with autonomic neuropathy can have defective epinephrine secretion to counteract hypoglycemia.54 In individuals with T1D fasting during Ramadan or other religious observances, abnormalities in the counter-regulatory hormones (glucagon, cortisol and catecholamines) may also be present due to disruption of the normal circadian rhythms and the sleep-wake cycle. In addition, there is risk of hypoglycemia associated with exogenous insulin treatment during fasting with changes in meal timing.53 Several studies have focused on the changes in glucose homeostasis during Ramadan fasting. In a study in young adults without diabetes55 using CGM 1- to 2 weeks before, in the middle and 4 to 6 weeks after Ramadan, an increase in the hyperglycemic area above 140 mg/dl was noted after Ramadan, compared with both before and during Ramadan, along with increased glucose variability.55 However, limited data are available on the safety and metabolic effects of fasting in children and adolescents with T1D.3 In a study assessing the impact of Ramadan fasting on resting metabolic rate (RMR), activity, and total energy expenditure (TEE), fasting was associated with reduced physical activity and reduced RMR, without an overall reduction in TEE. Ramadan differs from both prolonged and short-term starvation, as the former decreases RMR, whereas short-term starvation may increase RMR, and this has been attributed to a rise in norepinephrine concentrations.56 Many adolescents with T1D prefer to fast to feel equal to their peers without diabetes.57 Fasting may boost their self-esteem and make them happier as they feel “mature and capable” in fulfilling their religious obligations. However, considering the risk of acute metabolic complications in individuals with T1D, they are often advised not to fast.5-7, 26, 28, 58 Despite the fact that having diabetes grants an exemption from fasting, a large number of youth with diabetes are passionate about Ramadan, and undergo fasting based on social and cultural reasons and a religious sense of fulfillment.3, 57 Young people with diabetes may often fast without the knowledge or approval of their physicians.59 Predictably, there is a general fear among persons with T1D and their health-care providers about the use of insulin therapy during the fast, due to the increased risk of hypoglycemia.60 Hypoglycemia during the daytime is the most disliked complication as its treatment entails the intake of carbohydrate and therefore leads to breaking the fast prematurely. The interruption of fasting may induce a sense of guilt and failure.61 Data indicate that the majority of Muslim adolescents and older children with T1D are able to fast during Ramadan, with a high proportion of them encouraged by their parents to do so.61 Their expectations of developing complications are realistic, but they underestimate the deterioration in glycemic control during the month. It is reassuring that the majority agree to break their fast should complications arise, which makes fasting safer for them. The DEAR program (Diabetes Education and medication Adjustment in Ramadan) aimed to optimize glycemic control prior to Ramadan, and provide risk assessment, preparation, monitoring and intervention pre-, during and post-Ramadan.62 The program was also initiated to focus on covering the relevant religious and medical aspects through engaging a religious leader and Muslim healthcare professional team. The study highlighted that deficiencies in knowledge among healthcare professionals regarding Ramadan fasting can lead to people with diabetes choosing not to inform their healthcare team that they will fast, particularly in Muslim minority countries.62 Depending on where the adolescents live, they often attend school for the whole day, and partake in after-school activities, including sports, during Ramadan, even though they experience sleep disturbances and changes to routines, with late-breaking of the fast and waking early to have the pre-dawn Suhoor. For adolescents with T1D, fasting adds more challenges, especially for those living in Muslim minority societies, where there may not be adjustments made to school and sports schedules, particularly when the hours of fasting are longer (summers). The psychological effects of fasting during Ramadan can vary. Both healthy individuals and people with diabetes can experience opposing psychological outcomes for different reasons, including the changes that accompany the practice of fasting.63 Further research is needed to assess the psychological effects of fasting during Ramadan in adults as well as adolescents with T1D or T2D. Potential risks associated with fasting are hyperglycemia, hypoglycemia, DKA, thrombotic episodes, and dehydration.5-7 Although most of the available data are based on adult studies, an individualized approach, close monitoring of BGLs and weekly follow-up with the medical team is the best approach to prevent acute complications in both adults and young people with diabetes.64 Data on the impact of Ramadan fasting on glycemic outcomes are based on few small studies with inconsistent results. Some studies in children with diabetes demonstrated a significant improvement in fructosamine levels, whereas others showed no changes, or even an increase in HbA1c levels.57, 61, 65-68 Some studies3, 68 have shown that Ramadan fasting in individuals with T1D might predispose to acute complications, although this has not been confirmed by others. Overall, fasting can be considered a safe practice if people with diabetes monitor BGLs frequently and break the fast when hypoglycemia or marked hyperglycemia occur18, 58, 64, 69, 70 Besides, Ramadan fasting has been found safe when pre-fasting medical assessment, focused education, appropriately adjusted insulin regimens, diet control, and management of daily activities have been implemented in individuals with stable diabetes control and no comorbidities57, 68, 70 Studies have shown that adolescents are able to fast for several days during the Ramadan month,71, 72 but unplanned fasting may predispose to hypoglycemia and hyperglycemia with or without ketosis.28, 59 Hypoglycemia is a major complication of fasting. The EPIDIAR study of 1070 adults with T1D reported that fasting during Ramadan increased the risk of severe hypoglycemia by 7.5-fold. During Ramadan, 2% of people with diabetes experienced at least one episode of severe hypoglycemia requiring hospitalization.3 In a pediatric study symptomatic hypoglycemia resulted in breaking the fast on 15% of the days.72 In addition, CGM data have shown wide BGL fluctuations during fasting and eating hours and episodes of unreported hypoglycemia.72 The frequency and duration of hypoglycemia, hyperglycemia, and severe hyperglycemia were significantly higher in adolescents with T1D who had pre-Ramadan suboptimal than those with good glycemic control.73 In a retrospective study of 50 children and adolescents with T1D (age 12.7 ± 2.1 years), those with HbA1c >8.5% had more frequent episodes of hypoglycemia than those with HbA1c ≤8.5%.74 Hypoglycemia has been typically encountered during the hours preceding Iftar.75 Young adults with suboptimal management of T1D experienced wide fluctuations in glucose levels between the fasting and eating hours, with a greater tendency toward hyperglycemia.76 Monitoring BGLs during fasting is essential to predict, prevent, and treat hypoglycemia. It is of paramount importance that BGL is checked if any symptoms suggestive of hypoglycemia are experienced, so that the fast is interrupted promptly. However, some young people may not be willing to break their fast, particularly if hypoglycemia occurs close to sunset (time to end the fast for the day), and this may predispose them to a severe hypoglycemia. A study of 33 children with T1D in Bangladesh showed that only 3 out of 13 children broke their fasting following onset of symptoms of hypoglycemia.77 However, in another study61 most children and adolescents were willing to terminate their fasting when hypoglycemia occurred, regardless of the time of the day. Education might persuade young people with diabetes to break the fast when hypoglycemia occurs. Fasting increases glucagon levels and accelerates lipolysis and ketosis. These pathophysiological changes, in conjunction with fasting itself, may lead to metabolic decompensation in people with diabetes. Episodes of DKA have been reported during Ramadan fasting.78, 79 Detection of euglycemic ketosis during fasting requires evaluation of acid–base state, blood glucose and ketone values (ideally blood ketone measurements, if available) to differentiate DKA from ketosis due to prolonged fasting.80 See ISPAD 2022 Consensus Guidelines Chapter 12 on Sick Day Management in Diabetes for further details on ketosis monitoring. Knowledge of insulin action, interpreting glucose values and adjusting insulin doses for Iftar and Suhoor meals, is a prerequisite for safe Ramadan fasting. Based on clinical experience, different recommendations on how to adjust the type, dose, and timing of insulin in adults have been suggested.69, 81, 82 However, clear evidence-based guidelines on insulin adjustment for adolescents with T1D are lacking. Current recommendations for people on multiple daily injections (MDI) include a reduction of the total daily dose (TDD) of insulin to 70%–85% of the pre-fasting TDD27, 82 or 60%–70% of the pre-fasting dose of basal insulin.7 For people on continuous subcutaneous insulin (CSII), a reduction of the basal rate of insulin infusion by 20%–40% in the last 3–4 h of fasting is recommended.7 The South Asian Guidelines for Management of Endocrine Disorders in Ramadan recommend reducing basal insulin by 10%–20% during the fast days.79, 80 However, these recommendations are not based on data from large cohort studies or randomized controlled studies. Some studies have not shown a reduction in frequency of hypoglycemia with reduction of basal insulin in MDI and CSII regimens, although this has not been confirmed by all studies.83, 84 A suggested guide for adjustment of insulin dosages is given in Figure 1. Management of diabetes during fasting should be discussed on an individual basis, depending on access to different insulins and technology. Once fasting has started, insulin dosing should be regularly adjusted based on the results of glucose monitoring. Frequent BGL measurement is essential. MDI and CSII are the preferred regimens in young people with T1D during Ramadan.85 In some regions, treatment with two or three daily injections with NPH and short-acting insulin may be used. Use of premixed insulin regimens require fixed intake of carbohydrates at set times and is not advised. Insulin analogs have been safe for the management of well-controlled young people with diabetes during a fasting period of 17–19 h. A significant decline in glucose levels, with periods of hypoglycemia, is seen mostly near the end of the fasting period, although no episodes of severe hypoglycemia have been reported.7, 57, 65, 69, 72, 86, 87 It is recommended that during Ramadan, the pre-Ramadan basal insulin dose should be reduced by 20%, when given in the evening.5, 27, 57, 68-71, 87 When taken at Iftar, a further reduction may be needed—up to 40% of the pre-Ramadan basal dose.7, 88 Further individualized adjustment of the dose needs to be considered. Based on the pharmacodynamic profile of NPH, there is a considerable risk of mid-day hypoglycemia and end-of-the-day hyperglycemia. Reduction of the dose is needed to prevent hypoglycemia, at the possible expense of higher BGLs at the end of the day. In most studies, the pre-Iftar and pre-Suhoor rapid-acting insulin doses are equal to the pre-Ramadan lunch and dinner doses, respectively. In some reports, the pre-dawn dose is reduced by 25%–50%,7 depending on the carbohydrate content of the meal and the pre-meal BGL. In an adult study, the use of rapid-acting insulin analogs was associated with fewer hypoglycemic events and an improvement in postprandial glycemia compared with regular insulin.89 Higher BGLs may require an additional dose of insulin administered as a correction dose, which is usually based on the pre-Ramadan correction factor. Two daily injections of NPH and regular insulin allow less flexibility in lifestyle and nutrition with more risk of hyperglycemia and hypoglycemia; therefore, their use is strongly discouraged. Owing to the NPH peak effect, dose adjustment for a 12–16 h period of fasting is more challenging.84 Children on a twice-daily insulin regimen are much more prone to experience hyperglycemia with/without ketones than those on a basal-bolus regimen.84 Using twice-daily insulin regimens during Ramadan requires more dose adjustments, taking the usual morning dose before the sunset meal and only sho

The Effects of Exercise Training on Glucose Homeostasis and Muscle Metabolism in Type 1 Diabetic Female Mice.

Although exercise training is an important recommendation for the management of type 1 diabetes (T1D), most of the available research studies predominantly focus on male subjects. Given the importance of sex as a biological variable, additional studies are required to improve the knowledge gap regarding sex differences in T1D research. Therefore, the purpose of this study was to examine the role of exercise training in mediating changes in glucose homeostasis and skeletal muscle metabolism in T1D female mice. Female mice were injected with streptozotocin (STZ) to induce T1D. Two weeks after STZ injection, control (CON) and STZ mice were exercise trained on a treadmill for 4 weeks. Aerobic exercise training failed to improve glucose tolerance, prevent the decrease in body weight and adipose tissue mass, or attenuate muscle atrophy in T1D female mice. However, insulin sensitivity was improved in T1D female mice after exercise training. Aerobic exercise training maintained skeletal muscle triglyceride content but did not prevent depletion of skeletal muscle or liver glycogen in T1D mice. Gene expression analysis suggested that T1D resulted in decreased glucose transport, decreased ketone body oxidation, and increased fatty acid metabolism in the skeletal muscle, which was not altered by exercise training. These data demonstrate that 4 weeks of aerobic exercise training of a moderate intensity is insufficient to counteract the negative effects of T1D in female mice, but does lead to an improvement in insulin sensitivity.

Frequent Cannabis Smoking and Association with Prediabetes and Diabetes in Early Adulthood

Background: Cannabis use in young adulthood has been linked with increased risk of prediabetes later in life. However, many previous studies have only used fasting blood samples to determine risk for type 2 diabetes (T2D), which may not detect early changes in glucose homeostasis. The objective of this study was to determine the association between cannabis use and risk for prediabetes and T2D in young adults using several measures of glucose homeostasis, including an oral glucose tolerance test (OGTT). Methods: The Meta-CHEM study is a subset (N=84) of overweight and obese young adults aged 22–25 years from the Children&amp;#x27;s Health Study (CHS). Participants underwent a single clinical visit which included a 2-hour OGTT and questionnaire about cannabis smoking habits in the past year. Participants were classified as non-smokers, light cannabis smokers (smoke &amp;#x3c;once a week), and heavy cannabis smokers (smoke &amp;#x3e;once a week). Those smoking more than one cigarette in the past week were excluded from the study. Participants were classified as having prediabetes or T2D if they had a HbA1c &amp;#x3e;5.6%, fasting glucose &amp;#x3e;99 mg/dL, and/or 2-hour OGTT glucose &amp;#x3e;139 mg/dL. Logistic regression was used to assess the associations between cannabis smoking habits and metabolic outcomes after adjusting for age, sex, education, body mass index, Hispanic ethnicity, physical activity, and alcohol consumption. Results: 52 (62%) participants were non-diabetic, 28 (33%) had pre-diabetes, and 4 (0.05%) had T2D. 25 (30%) participants were nonsmokers, 47 (56%) were light cannabis smokers, and 12 (14%) were heavy cannabis smokers. The odds of having prediabetes or T2D was 7.3 times higher among heavy smokers (95% CI: 0.94, 7.7), and 1.5 times higher among light smokers (CI: 0.43, 6.0) than nonsmokers (P-value for trend = 0.03). Conclusion: Cannabis use in overweight and obese young adults was significantly associated with risk of having prediabetes or T2D.

Measures of glucose homeostasis during and after duodenal exclusion using a duodenal-jejunal bypass liner in a normoglycemic, nonobese canine model.

Discovering the role duodenal exclusion plays in weight loss and resolution of type 2 diabetes (T2D) may help refine the surgical and nonsurgical treatment of obesity and T2D. To assess changes in glucose homeostasis due to duodenal exclusion using a duodenal-jejunal bypass liner (DJBL) in a nonobese canine model. Academic laboratory setting. An intravenous glucose tolerance test (IVGTT), and a mixed-meal tolerance test (MMTT) at baseline, 1, and 6 weeks post DJBL implantation (I1 and I6, respectively), and 1 and 6 weeks post DJBL removal (R1 and R6, respectively) were done in canines (n = 7) fed a normal chow diet. Placement of the DJBL induced weight loss that was maintained until 4 weeks post removal (R4), despite normal food intake. Total bile acids (TBA) and glucagon-like peptide-1 (GLP-1) during the MMTT were significantly increased at I1 and were associated with increased lactate and free fatty acids. Hypoglycemia counter-regulation was blunted during the IVGTT at I1 and I6, returning to baseline at R1. While there were no changes to insulin sensitivity during the experiment, glucose tolerance was significantly increased following the removal of the DJBL at R1. These data show that in a normoglycemic, nonobese canine model, duodenal exclusion induces energy intake-independent weight loss and negative metabolic effects that are reversed following re-exposure of the small intestine to nutrients.

1312-P: Impaired Beta-Cell Function in Older Patients Corresponds to Changes in Salience Network Connectivity

The salience network (anterior cingulate cortex (ACC) —insula) plays an important role in regulating attention and memory in the context of decision making and has also been shown to be highly responsive to changes in peripheral glucose levels. Increased age is also associated with changes in glucose homeostasis and the salience network. To investigate these relationships, 40 healthy, cognitively normal, non-diabetic subjects (20 Young (age mean 28±1 years, BMI 28.1 ±1.1 kg/m2, HbA1c 5.3±0.1%) and 20 Old (age mean of 73±2 years, BMI 26.9±0.9 kg/m2, HbA1c 5.5±0.1%)) underwent an OGTT, resting state functional connectivity (FC) MRI brain scanning, and cognitive assessments (Cambridge Neuropsychological Test Automated Battery) . Despite similar BMI, HbA1C, and fasting glucose levels, older individuals had lower disposition index (young: 9±2, old: 3.3±0.4, p=0.005) indicating impaired β-cell function. There were no differences in measures of insulin sensitivity (HOMA-IR (p=0.38) or Matsuda index (p=0.70) . A seed-based analysis using a predefined cubic voxel in the ACC showed differences in FC between the ACC and the left insula (Main Effect by group, P&amp;lt;0.001) with lower connectivity values in Old compared to Young subjects. This connectivity value also correlated with errors on the Paired Associate Learning task, which tests attention and memory (r=-0.5, P=0.001) . Moreover, the connectivity values correlated with the disposition index in older subjects (r=0.49, P=0.03) but not younger subjects (P=0.9) . Thus, in our cohort of healthy, cognitively normal older subjects, impairments in beta-cell function are associated with altered functional connectivity within the salience network. These findings highlight the need for future investigations to determine whether mild age-related changes in glycemic control contribute to neurocognitive changes in older patients. Disclosure J.Deajon-jackson: None. C.Lacadie: None. C.Watt: None. D.Scheinost: None. J.J.Hwang: None. Funding Claude D. Pepper Older Americans Independence Center at Yale School of Medicine (P30AG021342)

FINERENONE PREVENTS RENAL AND VASCULAR DAMAGE IN A NOVEL MODEL OF TYPE 1 DIABETES MELLITUS

The non-steroidal mineralocorticoid receptor antagonist (MRA), finerenone (FIN) improves renal and cardiovascular outcomes in patients with chronic kidney disease (CKD) in type 2 diabetes (T2D). We explored the effects of FIN in a novel model of CKD in type 1 diabetes (T1D).We employed the Munich Wistar Frömter (MWF) rat model of non-diabetic CKD with mild hypertension and albuminuria to generate a novel model of CKD with T1D. This was achieved by an intra-peritoneal injection of streptozotocin (15 mg/kg) and additional exposure to a high-fat/high-sucrose diet. Oral treatment with FIN (10 mg/kg/day in rat chow) in diabetic animals (MWF-DKD-FIN) was compared to a group of diabetic rats receiving no treatment (MWF-DKD-Control) and a group of non-diabetic untreated MWF rats (MWF). Dietary exposure with or without pharmacological treatment was maintained for 6 weeks (n = 7-10 animals per group).After 6 weeks, MWF-DKD-Control and MWF-DKD-FIN exhibited significantly elevated blood glucose levels (271.7 ± 67.1 mg/dl and 266.3 ± 46.8 mg/dl) as compared to MWF (110.3 ± 4.4 mg/dl; p < 0.05). MWF-DKD-Control showed a 10-fold higher expression of renal damage markers Kim-1 and Ngal compared to MWF. This upregulation was significantly suppressed in MWF-DKD-FIN. FIN treatment resulted in a significant reduction of blood pressure and pulse wave velocity compared to MWF-DKD-Control (p < 0.05). Vascular function studies showed an improvement in endothelial function in MWF-DKD-FIN compared to MWF-DKD-Control due to a reduction in pro-contractile prostaglandins, oxidative stress, and inflammatory cytokines (including IL-1, IL-6, TNFalpha and TGFbeta). FIN induced no changes in blood glucose levels, glucose tolerance or the increase in HOMA index compared to MWF-DKD-Control.Our data show that treatment with FIN improves renal and vascular damage in a new rat model of CKD with T1D. These beneficial effects associated with a reduction in inflammation and oxidative stress and was independent from changes in glucose homeostasis.

Adaptive Changes in Glucose Homeostasis and Islet Function During Pregnancy: A Targeted Metabolomics Study in Mice.

ObjectivePregnancy is a dynamic state involving multiple metabolic adaptions in various tissues including the endocrine pancreas. However, a detailed characterization of the maternal islet metabolome in relation to islet function and the ambient circulating metabolome during pregnancy has not been established.MethodsA timed-pregnancy mouse model was studied, and age-matched non-pregnant mice were used as controls. Targeted metabolomics was applied to fasting plasma and purified islets during each trimester of pregnancy. Glucose homeostasis and islet function was assessed. Bioinformatic analyses were performed to reveal the metabolic adaptive changes in plasma and islets, and to identify key metabolic pathways associated with pregnancy.ResultsFasting glucose and insulin were found to be significantly lower in pregnant mice compared to non-pregnant controls, throughout the gestational period. Additionally, pregnant mice had superior glucose excursions and greater insulin response to an oral glucose tolerance test. Interestingly, both alpha and beta cell proliferation were significantly enhanced in early to mid-pregnancy, leading to significantly increased islet size seen in mid to late gestation. When comparing the plasma metabolome of pregnant and non-pregnant mice, phospholipid and fatty acid metabolism pathways were found to be upregulated throughout pregnancy, whereas amino acid metabolism initially decreased in early through mid pregnancy, but then increased in late pregnancy. Conversely, in islets, amino acid metabolism was consistently enriched throughout pregnancy, with glycerophospholid and fatty acid metabolism was only upregulated in late pregnancy. Specific amino acids (glutamate, valine) and lipids (acyl-alkyl-PC, diacyl-PC, and sphingomyelin) were found to be significantly differentially expressed in islets of the pregnant mice compared to controls, which was possibly linked to enhanced insulin secretion and islet proliferation.ConclusionBeta cell proliferation and function are elevated during pregnancy, and this is coupled to the enrichment of islet metabolites and metabolic pathways primarily associated with amino acid and glycerophospholipid metabolism. This study provides insight into metabolic adaptive changes in glucose homeostasis and islet function seen during pregnancy, which will provide a molecular rationale to further explore the regulation of maternal metabolism to avoid the onset of pregnancy disorders, including gestational diabetes.

Abstract #1183049: Hypertension (HTN) and Diabetes (DM) Improvement During Osilodrostat Therapy in Patients with Cushing’s Disease (CD): Analyses from the Phase III LINC 3 study

CD is a deleterious hypercortisolism disorder. Alleviating the burden of CD-associated comorbidities, including HTN and DM, is a key treatment goal. Osilodrostat, a potent oral 11β-hydroxylase inhibitor, normalized urinary free cortisol (UFC) and improved clinical signs and symptoms in CD patients (pts) in the Phase III LINC 3 study (NCT02180217). We describe blood pressure (BP) and glucose homeostasis changes in pts with baseline (BL) HTN and DM.

Plasma concentrations of lipophilic persistent organic pollutants and glucose homeostasis in youth populations

BackgroundExposure to lipophilic persistent organic pollutants (POPs) is ubiquitous. POPs are metabolic disrupting chemicals and are potentially diabetogenic. MethodsUsing a multi-cohort study including overweight adolescents from the Study of Latino Adolescents at Risk (SOLAR, N = 301, 2001–2012) and young adults from the Southern California Children's Health Study (CHS, N = 135, 2014–2018), we examined associations of POPs and risk factors for type 2 diabetes. SOLAR participants underwent annual visits for a median of 2.2 years and CHS participants performed a single visit, during which a 2-h oral glucose tolerance test was performed. Linear mixed models were used to examine associations between plasma concentrations of POPs [4,4′-dichlorodiphenyldichloroethylene (4,4′-DDE), hexachlorobenzene (HCB), PCBs-153, 138, 118, 180 and PBDEs-154, 153, 100, 85, 47] and changes in glucose homeostasis across age and pubertal stage. ResultsIn SOLAR, exposure to HCB, PCB-118, and PBDE-153 was associated with dysregulated glucose metabolism. For example, each two-fold increase in HCB was associated with approximately 2 mg/dL higher glucose concentrations at 30 min (p = 0.001), 45 min (p = 0.0006), and 60 min (p = 0.03) post glucose challenge. Compared to individuals with low levels of PCB-118, individuals with high levels exhibited a 4.7 mg/dL (p = 0.02) higher glucose concentration at 15 min and a 3.6 mg/dL (p = 0.01) higher glucose concentration at 30 min. The effects observed with exposure to organochlorine compounds were independent of pubertal stages. PBDE-153 was associated with the development of dysregulated glucose metabolism beginning in late puberty. At Tanner stage 4, exposure to PBDE-153 was associated with a 12.7 mg/dL higher 60-min glucose concentration (p = 0.009) and a 16.1 mg*dl−1*hr−1 higher glucose AUC (p = 0.01). These associations persisted at Tanner 5. In CHS, PBDE-153 and total PBDE were associated with similar increases in glucose concentrations. ConclusionOur results suggest that childhood exposure to lipophilic POPs is associated with dysregulated glucose metabolism.

Abstract 010: Longitudinal Impact Of Glucose Homeostasis On Cardiac Structure And Function: Results From The Echocardiographic Study Of Latinos- 2 (echo-sol-2)

Introduction: We assessed whether a longitudinal association between change in glucose homeostasis and change in cardiac structure and function was present. Methods: Data from ECHO-SOL baseline and visit 2 exams were used including 1643 Hispanic/Latino participants aged 45-74 years with serial echocardiograms obtained on average 4.3 (2.8-6.7) years apart. Glucose hoemostasis was evaluated through fasting plasma glucose levels (FGP), 2 hour oral glucose tolerance test (OGTT) and hemoglobin A1C (A1C) . Glucose homeostasis was categorized as: normal glucose tolerance (NGT) (FPG&lt;100 mg/dL, 2hr OGTT &lt;140 mg/dL, or A1C &lt;5.7%), prediabetes (PDM) (FPG 100–125 mg/dL, or 2h OGTT 140–199 mg/dL, or A1C 5.7–6.4%); among those with self-report of diabetes or currently taking diabetes medicine: controlled diabetes (CDM) (A1C&lt;7), and uncontrolled diabetes (UDM) (A1C&gt;7). Linear regression models were used to examine associations between change in glucose homeostasis [worsening (NGT to PDM, NGT to DM, PDM to DM, CDM to UDM) vs unchanged] with changes in left ventricular mass (LVM), relative wall thickness (RWT), ejection fraction (EF), global longitudinal strain (GLS) and E’ velocity. All analyses were weighted to account for the complex survey design. Results: At baseline (mean age 56.4 years ±0.35; 45.4% male), glucose regulation was as follows: NGT (29.1%), PDM (51.8%), CDM (9.2%) and UDM (9.9%). At visit 2, glucose downregulation was as follows: NGT to PDM (55.9%), NGT to DM (13.4%), PDM to DM (27.4%), CDM to UCDM (33.5%). Among those with worsening glucose homeostasis the average age was 55.2 ±0.50 years, 45.7% were male, FPG was 99.4±0.90mg/dL . Change from NGT to PDM compared to remaining at NGT was associated with increase LVM (b=4.0 ±0.9, p&lt;0.001), worsening in GLS (b=0.6 ±0.1, p&lt;0.001) and decrease in E’ velocity (b=-1.1 ±0.1, p&lt;0.001). Neither change from NGT to DM nor from PDM to DM was associated with significant changes in cardiac structure and function. Change from CDM to UDM was associated with increase in RWT (b=0.1 ±0.0, p&lt;0.05), compared to those with unchanged CDM. Worsening glucose homeostasis from any group was not associated with changes in EF. Conclusions: Early stages of worsening glucose homeostasis were associated with cardiac structural and functional changes. Identification of those at risk of developing prediabetes may provide opportunities to prevent future cardiac dysfunction.

Virus Elimination by Direct-Acting Antiviral Agents Impacts Glucose Homeostasis in Chronic Hepatitis C Patients.

Background and AimsChronic hepatitis C virus (HCV) infection is associated with dysregulation of glucose homeostasis, including insulin resistance (IR) and type 2 diabetes. However, independent risk factors associated with IR in chronic HCV-infected patients have not been detailly elucidated. Previous data regarding the impact of HCV elimination by direct-acting antiviral agents (DAAs) on glucose homeostasis is insufficient and controversial. This study aimed to analyze the independent factors associated with IR and to evaluate the changes in glucose homeostasis in chronic HCV-infected patients treated with DAAs therapies.MethodsWe screened 704 patients with chronic HCV infection who underwent treatment with interferon-free DAAs. Patients’ baseline characteristics, biochemical and virological data were collected. The outcome measurements were their IR and β-cell function assessed by the homeostasis model assessment (HOMA) method at baseline and 12-weeks post-treatment.ResultsHigh IR (HOMA-IR ≥ 2.5) was observed in 35.1% of the patients. Multivariable logistic regression analysis revealed that body mass index (BMI) >25 kg/m2, treatment experience, elevated baseline levels of alanine aminotransferase (ALT) and triglyceride, as well as Fibrosis-4 score >3.25 were independently associated with high IR. In patients who achieved sustained virological response (SVR), no significant change in mean HOMA-IR was observed from baseline to 12-weeks post-treatment (2.74 ± 2.78 to 2.54 ± 2.20, p = 0.128). We observed a significant improvement in β-cell secretion stress from 121.0 ± 110.1 to 107.6 ± 93.0 (p = 0.015). Subgroup analysis revealed that SVR was associated with a significant reduction in mean HOMA-IR in patients with baseline HOMA-IR ≥ 2.5 (5.31 ± 3.39 to 3.68 ± 2.57, p < 0.001), HCV genotype 1 (3.05 ± 3.11 to 2.62 ± 2.05, p = 0.027), and treatment experience (4.00 ± 3.37 to 3.01 ± 2.49, p = 0.039).ConclusionsThere were several independent factors associated with IR in patients with chronic HCV infection, including obesity, treatment experience, high serum ALT and triglyceride levels, as well as advanced hepatic fibrosis. After viral elimination by DAAs, we observed a significant reduction in mean HOMA-IR in patients with baseline high IR, HCV genotype 1, and treatment experience.

Prolactin-Induced Adaptation in Glucose Homeostasis in Mouse Pregnancy Is Mediated by the Pancreas and Not in the Forebrain.

Adaptive changes in glucose homeostasis during pregnancy require proliferation of insulin-secreting beta-cells in the pancreas, together with increased sensitivity for glucose-stimulated insulin secretion. Increased concentrations of maternal prolactin/placental lactogen contribute to these changes, but the site of action remains uncertain. Use of Cre-lox technology has generated pancreas-specific prolactin receptor (Prlr) knockouts that demonstrate the development of a gestational diabetic like state. However, many Cre-lines for the pancreas also express Cre in the hypothalamus and prolactin could act centrally to modulate glucose homeostasis. The aim of the current study was to examine the relative contribution of prolactin action in the pancreas and brain to these pregnancy-induced adaptations in glucose regulation. Deletion of prolactin receptor (Prlr) from the pancreas using Pdx-cre or Rip-cre led to impaired glucose tolerance and increased non-fasting blood glucose levels during pregnancy. Prlrl ox/lox /Pdx-Cre mice also had impaired glucose-stimulated insulin secretion and attenuated pregnancy-induced increase in beta-cell fraction. Varying degrees of Prlr recombination in the hypothalamus with these Cre lines left open the possibility that central actions of prolactin could contribute to the pregnancy-induced changes in glucose homeostasis. Targeted deletion of Prlr specifically from the forebrain, including areas of expression induced by Pdx-Cre and Rip-cre, had no effect on pregnancy-induced adaptations in glucose homeostasis. These data emphasize the pancreas as the direct target of prolactin/placental lactogen action in driving adaptive changes in glucose homeostasis during pregnancy.

Fasting blood glucose as a predictor of mortality: Lost in translation

Aging leads to profound changes in glucose homeostasis, weight, and adiposity, which are considered good predictors of health and survival in humans. Direct evidence that these age-associated metabolic alterations are recapitulated in animal models is lacking, impeding progress to develop and test interventions that delay the onset of metabolic dysfunction and promote healthy aging and longevity. We compared longitudinal trajectories, rates of change, and mortality risks of fasting blood glucose, body weight, and fat mass in mice, nonhuman primates, and humans throughout their lifespans and found similar trajectories of body weight and fat in the three species. In contrast, fasting blood glucose decreased late in life in mice but increased over the lifespan of nonhuman primates and humans. Higher glucose was associated with lower mortality in mice but higher mortality in nonhuman primates and humans, providing a cautionary tale for translating age-associated metabolic changes from mice to humans.