Impaired Glycemic Control Research Articles

Modulation of Oxidative Stress and Glycemic Control in Diabetic Wistar Rats: The Therapeutic Potential of Theobroma cacao and Camellia sinensis Diets.

Background Diabetes mellitus is a complex metabolic disorder characterized by oxidative stress and impaired glycemic control. This study investigates the therapeutic potential of Theobroma cacao and Camellia sinensis diets in diabetic Wistar rats and assesses their impact on oxidative stress markers and blood glucose levels. Methods In this experiment, eight groups of six male Wistar rats (n = 12.5%), aged 8 to 12 weeks, were carefully set up to see how different treatments for diabetes and oxidative stress affected the two conditions. The random selection process was implemented to minimize any potential bias and ensure that the results of the study would be representative of the general population of Wistar rats. The groups were as follows: a nondiabetic control group (NDC) served as the baseline, while diabetes was induced in the alloxan monohydrate group (150 mg/kg). Another group was given the standard drug metformin (M, 100 mg/kg), and two control groups that did not have diabetes were given extracts of Theobroma cacao (TC, 340 mg/kg) and Camellia sinensis (CS, 200 mg/kg). Three groups of diabetic rats were given a mix of these treatments. Theobroma cacao and Camellia sinensis extracts were given at set doses (TC, 340 mg/kg; CS, 200 mg/kg), along with 150 mg/kg of a drug that causes diabetes.Over a 21-day period, oxidative stress parameters such as glutathione (GSH), malondialdehyde (MDA), superoxide dismutase (SOD), and glutathione reductase (GSHrd) levels, and blood glucose were carefully measured to check for signs of oxidative stress and diabetes progression Results Considerable differences in GSH levels were noted across the groups, with the highest GSH concentration found in the group treated with the inducing drug, while the lowest GSH levels were observed in the diabetic group that was administered both Theobroma cacao and Camellia sinensis (p < 0.001). MDA levels also varied, with the diabetic group treated with Theobroma cacao having the highest MDA concentration (3.54 ± 0.29 μmol/L) and the nondiabetic control group treated with Camellia sinensis exhibiting the lowest MDA levels (1.66 ± 0.08 μmol/L; p < 0.001). SOD activity was highest in the standard drug group and lowest in the diabetic group treated with Theobroma cacao. GSH activity was notably higher in the diabetic groups that received dietary interventions (p < 0.001). Blood glucose levels showed diverse responses, with the standard drug group experiencing a substantial reduction, while the inducing drug group exhibited a consistent increase. Conclusion The study highlights the significant impact of dietary interventions with Theobroma cacao and Camellia sinensis on oxidative stress markers and blood glucose regulation in diabetic Wistar rats. These findings suggest a potential role for these dietary components in mitigating oxidative stress and improving glycemic control in diabetes, although further research is warranted to elucidate the underlying mechanisms and clinical implications.

Associations of Sedentary Behavior and Screen Time with Human Gut Microbiome Composition and Diversity.

Human gut microbiome richness, diversity, and composition are associated with physical activity and impaired glycemic control; however, the associations with sedentary behavior and screen time are not as well-established. This study evaluated associations of sedentary behavior and screen time with the alpha diversity and composition of the human gut microbiome in adults with and without impaired glycemic control. Sedentary behavior and screen time data were collected via survey from 47 adults (38% with impaired glycemic control). Microbiome composition and alpha diversity were determined in fecal microbial DNA. Sedentary behavior was negatively associated with the number of observed operational taxonomic units (OTUs), Chao 1 Index, and Fisher's Alpha Index. These associations were slightly attenuated but remained significant when controlling for covariates. Screen time was negatively associated with the number of observed OTUs, Shannon Index, and Fisher's Alpha Index; however, only the association with observed OTUs was independent of all covariates. Our findings suggest sedentary behavior and screen time may be significant influencers of compositional changes in human gut microbiota. This may be a potential mechanism linking sedentary behavior and screen time to an increased risk of type 2 diabetes.

Type 2 Diabetes: Platelets and Long-Term Metabolic Control as Estimated from Glycosylated Haemoglobin (HbA1c).

In type 2 diabetes, platelets are likely affected by impaired long-term glycaemic control, but such pathophysiological links are poorly understood. This study thus compares platelet reactivity (i.e. agonist-evoked platelet reactions) in vitro with glycosylated haemoglobin (HbA1c), a measure commonly used for monitoring long-term metabolic control of type 2 diabetes. Elders with type 2 diabetes (n = 35) were divided according to HbA1c into groups (HbA1c-low and high) consisting of 17 and 18 subjects, respectively. For estimating mitochondria disintegration, a flow cytometer determined mitochondrial transmembrane potentials after whole blood agonist stimulation. The activating agents used were α-thrombin (10 μM) and collagen (0.15 μg/mL). The same apparatus analysed the fibrinogen receptor activity, lysosomal exocytosis (surface lysosomal-associated membrane protein 1), and platelet procoagulant characteristics (membrane-attached annexin V) after stimulation. In type 2 diabetes, after in vitro agonist stimulation, platelet mitochondria injury was higher in the HbA1c-high group. The fibrinogen receptor, lysosomal secretion, and the creation of procoagulant platelets proved to be uninfluenced by HbA1c.

Glycemic Control Is Associated with Histological Findings of Nonalcoholic Fatty Liver Disease.

Poor lifestyle habits may worsen nonalcoholic fatty liver disease (NAFLD), with progression to nonalcoholic steatohepatitis (NASH) and cirrhosis. This study investigated the association between glycemic control status and hepatic histological findings to elucidate the effect of glycemic control on NAFLD. This observational study included 331 patients diagnosed with NAFLD by liver biopsy. Effects of the glycemic control status on histological findings of NAFLD were evaluated by comparing the following four glycemic status groups defined by the glycosylated hemoglobin (HbA1c) level at the time of NAFLD diagnosis: ≤5.4%, 5.5%-6.4%, 6.5%-7.4%, and ≥7.5%. Compared with the lowest HbA1c group (≤5.4%), the higher HbA1c groups (5.5%-6.4%, 6.5%-7.4%, and ≥7.5%) were associated with advanced liver fibrosis and high NAFLD activity score (NAS). On multivariate analysis, an HbA1c level of 6.5%- 7.4% group was significantly associated with advanced fibrosis compared with the lowest HbA1c group after adjusting for age, sex, hemoglobin, alanine aminotransferase, and creatinine levels. When further controlling for body mass index and uric acid, total cholesterol, and triglyceride levels, the higher HbA1c groups were significantly associated with advanced fibrosis compared with the lowest HbA1c group. On the other hand, compared with the lowest HbA1c group, the higher HbA1c groups were also associated with a high NAS in both multivariate analyses. Glycemic control is associated with NAFLD exacerbation, with even a mild deterioration in glycemic control, especially a HbA1c level of 6.5%-7.4%, contributing to NAFLD progression.

Renal tubule-specific Atgl deletion links kidney lipid metabolism to glucagon-like peptide 1 and insulin secretion independent of renal inflammation or lipotoxicity

ObjectiveLipotoxic injury from renal lipid accumulation in obesity and type 2 diabetes (T2D) is implicated in associated kidney damage. However, models examining effects of renal ectopic lipid accumulation independent of obesity or T2D are lacking. We generated renal tubule-specific adipose triglyceride lipase knockout (RT-SAKO) mice to determine if this targeted triacylglycerol (TAG) over-storage affects glycemic control and kidney health. MethodsMale and female RT-SAKO mice and their control littermates were tested for changes in glycemic control at 10–12 and 16–18 weeks of age. Markers of kidney health and blood lipid and hormone concentrations were analyzed. Kidney and blood lysophosphatidic acid (LPA) levels were measured, and a role for LPA in mediating impaired glycemic control was evaluated using the LPA receptor 1/3 inhibitor Ki-16425. ResultsAll groups remained insulin sensitive, but 16- to 18-week-old male RT-SAKO mice became glucose intolerant, without developing kidney inflammation or fibrosis. Rather, these mice displayed lower circulating insulin and glucagon-like peptide 1 (GLP-1) levels. Impaired first-phase glucose-stimulated insulin secretion was detected and restored by Exendin-4. Kidney and blood LPA levels were elevated in older male but not female RT-SAKO mice, associated with increased kidney diacylglycerol kinase epsilon. Inhibition of LPA-mediated signaling restored serum GLP-1 levels, first-phase insulin secretion, and glucose tolerance. ConclusionsTAG over-storage alone is insufficient to cause renal tubule lipotoxicity. This work is the first to show that endogenously derived LPA modulates GLP-1 levels in vivo, demonstrating a new mechanism of kidney-gut-pancreas crosstalk to regulate insulin secretion and glucose homeostasis.

Analysis of association between new-onset type 2 diabetes mellitus and pancreatic cancer: retrospective research

Introduction. Pancreatic cancer is characterized by an extremely unsatisfactory prognosis, despite the development of technologies for the treatment of this pathology. In more than 80 % of patients at the time of the initial request for medical care, the disease is represented by a locally advanced or metastatic stage. Currently used methods of treatment of this nosology are most effective at the early stages of the disease. The absence of characteristic clinical, instrumental and laboratory symptoms, as well as organizational measures for the early detection of this neoplasia creates certain difficulties for effective treatment. Type 2 diabetes is probably one of the risk factors for the development of pancreatic cancer. Epidemiological studies have shown that newly diagnosed type 2 diabetes is associated with a 1.5–2.0-fold increased risk of developing pancreatic cancer in patients over 50 years of age. Insulin resistance and its associated hyperglycemia, hyperinsulinemia, and inflammation are thought to be the main mechanisms contributing to the development of diabetes-related pancreatic cancer. New-onset type 2 diabetes mellitus may be a preclinical sign of pancreatic cancer, and patients with newly diagnosed diabetes may constitute a population in which pancreatic cancer can be detected at an early stage, that will significantly improve the results of treatment.&#x0D; Objective. To analyze the relationship between new-onset type 2 diabetes mellitus and the development of pancreatic cancer.&#x0D; Material and methods. A retrospective analysis of the medical records of patients with a confirmed diagnosis of pancreatic cancer, who were treated at the Academician A.M. Granov Russian Scientific Center of Radiology and Surgical Technologies from 2019 to 2022, was carried out. As a source of information, data from medical records of inpatient and outpatient treatment cards were used. In total, the data of 203 persons were studied: morphologically confirmed pancreatic ductal adenocarcinoma was diagnosed in 172 patients (group I), in 31 patients pancreatic tumors had a different histological structure: acinar carcinoma, neuroendocrine tumors (group II). Group I excluded 8 patients without diabetes mellitus who were taking medications, which affect the blood glucose levels. The frequency of occurrence of type 2 diabetes mellitus in the groups was analyzed and then the statistical significance was assessed using the calculation of Fisher's exact test. Group I was analyzed by sex and age, then patients from group I aged 50–75 years were divided into 3 subgroups depending on the glycemic profile: 1) patients with long-term type 2 diabetes mellitus (anamnesis more than 3 years); 2) patients with new-onset type 2 diabetes mellitus (anamnesis less than 3 years); 3) patients without disorders of glucose metabolism. In the subgroup of patients with a long history of type 2 diabetes mellitus, the fact of disease decompensation was additionally assessed.&#x0D; Results. Type 2 diabetes mellitus was more common in patients with pancreatic ductal adenocarcinoma (p 0.01, Fisher's exact test p = 0.0012) than in other pancreatic neoplasms. The age of patients in group I ranged from 36 to 81 years. The average age of men was 61 ± 8.5 years. The average age of women was 58.9 ± 8.2 years. Among patients of group I aged 50–75 years, new-onset type 2 diabetes mellitus occurred in 78 (68.4 %) persons, type 2 diabetes mellitus with an anamnesis of more than 3 years was detected in 19 (16.6 %) patients, normal metabolism of glucose was observed in 17 (14 %) patients. Of 19 patients with a long anamnesis of type 2 diabetes mellitus (more than 3 years), decompensation in the form of impaired glycemic control was observed in 12 (63.2 %) patients before the diagnosis of pancreatic cancer, in 7 (36.8 %) patients no signs of decompensation of the course of type 2 diabetes mellitus were registered.&#x0D; Conclusions. New-onset type 2 diabetes mellitus occurred in 78 (64.4 %) patients over 50 years of age with pancreatic ductal adenocarcinoma. The data obtained indicate the feasibility of conducting studies to identify patients aged 50–70 years with newly diagnosed type 2 diabetes in the risk group for the development of pancreatic cancer and examine this contingent at the stage of primary health care. Further retrospective as well as prospective multicenter studies on the association between newly diagnosed type 2 diabetes mellitus and the risk of developing pancreatic cancer are required.

Abstract A009: Association between unstable diabetes mellitus and risk of pancreatic cancer

Abstract Worsening of hyperglycemia in people with pre-existing diabetes mellitus may be an indicator of undiagnosed pancreatic cancer. However, there is limited evidence from longitudinal studies regarding the association between deterioration of diabetes and pancreatic cancer in people with previously stable diabetes. The size of the association between deterioration of diabetes and pancreatic cancer, and how the association changes over time, needs further investigation. A population-based matched cohort study was conducted within Australian women with stable diabetes mellitus. Unstable diabetes, the exposure of interest, was defined as change in the type of antidiabetic medication or addition of another antidiabetic medication after at least 24 months of stable antidiabetic medication use. The date of exposure was defined as the index date. Each woman with unstable diabetes was matched to 4 women with stable diabetes by birth year (±1 year) at the index date. Flexible parametric survival models were used to estimate hazard ratios (HR) (overall and at different times) and 95% confidence intervals (CI), and absolute risk in both groups at different time points. We identified 134,954 women with unstable diabetes; these were matched to women who had not developed unstable diabetes at the index date. The mean age of the cohort was 68 years. Over a median follow-up period of 2.8 years, 1,315 pancreatic cancer cases were diagnosed. Overall, women who experienced deterioration in glycemic control had a 2.5-fold increased risk of developing pancreatic cancer (HR 2.55; 95% CI 2.29 – 2.85). The risk was very high during the initial few months [HRs at 3 months (5.76; 95% CI 4.72 – 7.04), 6 months (4.56; 95% CI 3.81 – 5.46), and 12 months (3.33; 95% CI 2.86 – 3.89)]. The risk then progressively declined with time. Worsening of glycemic control in those with previously stable diabetes may be an early clinical manifestation of pancreatic cancer. Further research is warranted to differentiate this pancreatic cancer-associated deterioration of glycemic control from other causes. The longer-term (3-7 years) weaker association between pancreatic cancer and deterioration of glycemic control suggests that poorly controlled hyperglycemia is a predisposing factor for pancreatic cancer. Citation Format: Sitwat Ali, Michael Coory, Peter Donovan, Renhua Na, Nirmala Pandeya, Sallie-Anne Pearson, Katrina Spilsbury, Louise Stewart, Bridie Thompson, Karen Tuesley, Mary Waterhouse, Penelope Webb, Susan Jordan, Rachel Neale. Association between unstable diabetes mellitus and risk of pancreatic cancer [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Pancreatic Cancer; 2023 Sep 27-30; Boston, Massachusetts. Philadelphia (PA): AACR; Cancer Res 2024;84(2 Suppl):Abstract nr A009.

The effect of bodyweight exercise on 24-h glycemic responses determined by continuous glucose monitoring in healthy inactive adults: a randomized crossover study

Vigorous intermittent exercise can improve indices of glycemia in the 24 h postexercise period in apparently healthy individuals. We examined the effect of a single session of bodyweight exercise (BWE) on glycemic responses using continuous glucose monitoring (CGM) under controlled dietary conditions. Healthy inactive adults (n = 27; 8 males, 19 females; age: 23 ± 3 years) completed 2 virtually supervised trials spaced ~ 1 week apart in a randomized, crossover manner. The trials involved an 11-min BWE protocol that consisted of 5 × 1-min bouts performed at a self-selected pace interspersed with 1-min active recovery periods or a non-exercise sitting control period (CON). Mean heart rate during the BWE protocol was 147 ± 14 beats per min (75% of age-predicted maximum). Mean 24 h glucose after BWE and CON was not different (5.0 ± 0.4 vs 5.0 ± 0.5 mM respectively; p = 0.39). There were also no differences between conditions for measures of glycemic variability or the postprandial glucose responses after ingestion of a 75 g glucose drink or lunch, dinner, and breakfast meals. This study demonstrates the feasibility of conducting a remotely supervised BWE intervention using CGM under free-living conditions. Future studies should investigate the effect of repeated sessions of BWE training or responses in people with impaired glycemic control.

THU279 Long duration Of CFTR Modulators Consistently Improve Glucose Metabolism Parameters In Patients With Cystic Fibrosis

Abstract Disclosure: A. Cohen: None. A. Mass: None. D. Zangen: None. M. Cohen-Cymberknoh: None. Background: Impaired glycemic control and consequently Cystic fibrosis Related Diabetes (CFRD) due to gradual pancreatic β-cell dysfunction is a common complication (upto 50% in adults) in patients with cystic fibrosis (CF.) The novel use of CFTR modulators (CFTRm), improve pulmonary function and reduce disease exacerbations. Data regarding the long-term effect of CFTRm on glycemic control is limited. In this observational-retrospective study, we evaluate the effect of CFTRm on the classical pathophysiological deterioration in glucose tolerance in patients with CF. Methods and Results: 15 patients with CF (ages 13-37) treated with CFTRm were followed by routine Oral Glucose Tolerance Test (OGTT). OGTT Results of Pre and 3-81 months (mean 28) post initiation of CFTRm therapy were compared and also classified to 4 classic categories: normal glucose tolerance (NGT), indeterminate (INDET), impaired glucose tolerance (IGT) and diabetes (CFRD). The end point of OGTT at 120 minutes significantly improved post CFTRm therapy being 159.7 (80-419.4) compared to 130.4 (54-286) pre-CFTRm (p = 0.047). Regarding the categories sub-classification of patients: Two patients with CFRD improved after CFTRm therapy to NGT or INDET. 2 with INDET pre-therapy improved to NGT post therapy.Of 3 patients with IGT, 2 improved to NGT or INDET and 1 worsened to CFRD. Out of the 6 patients who had NGT pre CFTRm therapy, 4 remained NGT, one worsened to INDET, and one became CFRD. Conclusions: This is the first and largest study so far demonstrating consistent significant improvement in glycemic control in CFRD after CFTRm treatment of at least 3 months duration. Treatment seems to delay and possibly reverse the deterioration in glycemic control that is typical to the natural history of patients with cystic fibrosis. Larger studies are indicated but awareness to the current findings may prevent hypoglycemic events while staying on a fixed insulin dose while on CFTRm therapy. Presentation: Thursday, June 15, 2023

Deterioration of glycemic control in youth-onset type 2 diabetes: What are the early and late predictors?

Deterioration of glycemic control in youth-onset type 2 diabetes: What are the early and late predictors?

Current treatment status of IgA nephropathy in Japan: a questionnaire survey

BackgroundIn 2020, the Committee of Clinical Practical Guideline for IgA Nephropathy (IgAN) revised the clinical practice guidelines. Herein, we conducted a questionnaire survey to assess the potential discrepancies between clinical practice guidelines and real-world practice in Japan.MethodsA web-based survey of members of the Japanese Society of Nephrology was conducted between November 15 and December 28, 2021.ResultsA total of 217 members (internal physicians: 203, pediatricians: 14) responded to the questionnaire. Of these respondents, 94.0% answered that the clinical practice guidelines were referred to “always” or “often.” Approximately 66.4% respondents answered that histological grade (H-Grade) derived from the “Clinical Guidelines for IgA nephropathy in Japan, 3rd version” and the “Oxford classification” were used for pathological classification. Moreover, 73.7% respondents answered that the risk grade (R-grade) derived from the “Clinical Guidelines for IgA nephropathy in Japan, 3rd version” was referred to for risk stratification. The prescription rate of renin–angiotensin system blockers increased based on urinary protein levels (> 1.0 g/day: 88.6%, 0.5–1.0 g/day: 71.0%, < 0.5 g/day: 25.0%). Similarly, the prescription rate of corticosteroids increased according to proteinuria levels (> 1.0 g/day: 77.8%, 0.5–1.0 g/day: 52.8%, < 0.5 g/day: 11.9%). The respondents emphasized on hematuria when using corticosteroids. In cases of hematuria, the indication rate for corticosteroids was higher than in those without hematuria, even if the urinary protein level was 1 g/gCr or less. Few severe infectious diseases or serious deterioration in glycemic control were reported during corticosteroid use.ConclusionOur questionnaire survey revealed real-world aspects of IgAN treatment in Japan.

Lipids, Blood Pressure, and Diabetes Mellitus on Risk of Cardiovascular Diseases in East Asians: A Mendelian Randomization Study

Elevated blood pressure, dyslipidemia, and impaired glycemic control are well-established cardiovascular risk factors in Europeans, but there are comparatively few studies focused on East Asian populations. This study evaluated the potential causal relations between traditional cardiovascular risk factors and disease risk in East Asians through a 2-sample Mendelian randomization approach. We collected summary statistics for blood pressure parameters, lipid subsets, and type 2 diabetes mellitus liability from large genome-wide association study meta-analyses conducted in East Asians and Europeans. These were paired with summary statistics for ischemic heart disease (IHD), ischemic stroke (IS), peripheral vascular disease, heart failure (HF) and atrial fibrillation (AF). We performed univariable Mendelian randomization analyses for each exposure-outcome pair, followed by multivariable analyses for the available lipid subsets. The genetically predicted risk factors associated with IHD and AF were similar between East Asians and Europeans. However, in East Asians only genetically predicted elevated blood pressure was significantly associated with IS (odds ratio 1.05, 95% confidence interval 1.04 to 1.06, p<0.0001) and HF (odds ratio 1.05, 95% confidence interval 1.04 to 1.06, p<0.0001), whereas nearly all genetically predicted risk factors were significantly associated with IS and HF in Europeans. In conclusion, this study provides supportive evidence for similar causal relations between traditional cardiovascular risk factors and IHD and AF in both East Asian and European ancestry populations. However, the identified risk factors for IS and HF differed between East Asians and Europeans, potentially highlighting distinct disease etiologies between these populations.

E4orf1 improves adipose tissue-specific metabolic risk factors and indicators of cognition function in a mouse model of Alzheimer’s disease

ObjectiveObesity, impaired glycemic control, and hepatic steatosis often coexist and are risk factors for developing dementia, and Alzheimer’s disease (AD). We hypothesized that a therapeutic agent that improves glycemic control and steatosis may attenuate obesity-associated progression of dementia. We previously identified that adenoviral protein E4orf1 improves glycemic control and reduces hepatic steatosis despite obesity in mice. Here, we determined if this metabolic improvement by E4orf1 will ameliorate cognitive decline in a transgenic mouse model of AD.MethodsFourteen- to twenty-month-old APP/PS1/E4orf1 and APP/PS1 (control) mice were fed a high-fat diet. Cognition was determined by Morris Water Maze (MWM). Systemic glycemic control and metabolic signaling changes in adipose tissue, liver, and brain were determined.ResultsCompared to control, E4orf1 expression significantly improved glucose clearance, reduced endogenous insulin requirement and lowered body-fat, enhanced glucose and lipid metabolism in adipose tissue, and reduced de novo lipogenesis in the liver. In the brain, E4orf1 mice displayed significantly greater expression of genes involved in neurogenesis and amyloid-beta degradation and performed better in MWM testing.ConclusionThis study opens-up the possibility of addressing glycemic control and steatosis for attenuating obesity-related cognitive decline. It also underscores the potential of E4orf1 for the purpose, which needs further investigations.

Effects of Activities that Calm the Mental State on Caregiver HbA1c Levels

Background: Caregivers have a significantly higher incidence of cardiovascular disease compared to non-caregivers. While stress is an important risk factor for impaired glycemic control, no study has examined variations in HbA1c levels in caregivers. This study aimed to examine whether performing acts that calm the mental state of caregivers improve their HbA1c levels.

1163-P: The Arrival of a New Sibling May Be Associated with a Deterioration in Glycemic Control for Children with Type 1 Diabetes

Introduction: Caring for young children with Type 1 diabetes comes with significant burden for parents. We hypothesised that pregnancy and the arrival of a new sibling may be associated with a deterioration in control of type 1 diabetes for older siblings with type 1 diabetes. Research Design and Methods: We identified young children currently under the care of the John Hunter Children's Hospital Paediatric Diabetes team who had welcomed a younger sibling since their diagnosis using our prospective Paediatric Diabetes database. We reviewed the HbA1c pre and post the arrival of a new sibling. Results: 38 children (20 male) had become older siblings since diagnosis of type 1 diabetes. 5 children were excluded as no data were available prior to pregnancy. Mean age of children at diagnosis was 3.5 years. Mean age at arrival of sibling was 6years with mean duration of diabetes at that time of 3.4 years. 15 of eligible participants were using insulin pump therapy. Mean HbA1c during pregnancy was 51mmol/mol (6.8%) compared to 54mmol/mol (7.1%) following delivery (p&amp;lt;0.05). 67% of children had HbA1c &amp;lt;53mmol/mol (7%) during pregnancy compared to 53% following delivery. Conclusion: The arrival of a new sibling was associated with a significant increase in HbA1c. This may be due to the high care burden of type 1 diabetes on parents which cannot be met when also attempting to attend to the needs of a newborn. Programs to assist new parents may help children with young siblings to continue to meet glycaemic targets. Despite the young age of the cohort of children prior to delivery of a new sibling, 67% were able to meet the ADA glycaemic target of &amp;lt;7%. This indicates that the goals of intensive management of diabetes are achievable even in the toddler, preschool and early primary school years. Disclosure P.E.Lopez: None. B.R.King: None. C.E.Smart: None. A.Sinclair: None. M.Neylan: None. R.Seckold: None. M.A.Paterson: None.

1348-P: Glycemic Control Is Associated with the Histological Severity of Nonalcoholic Fatty Liver Disease

Background: Diabetes mellitus (DM) is a major risk for progression of nonalcoholic steatohepatitis (NASH) from nonalcoholic fatty liver (NAFL). Although DM influences on the pathophysiology of NASH, the impact of glycemic control status on the histological severity of NASH is unclear. Methods: We conducted an observational study of 331 patients (140 men and 191 women) diagnosed with nonalcoholic fatty liver disease (NAFLD) by liver biopsy. Impact of glycemic control status on histological severity of NAFLD was evaluated by comparison of the four divided groups, based on the hemoglobin A1c (HbA1c) levels: HbA1c ≤5.4%; 5.5-6.4%; 6.5-7.4%; and ≥7.5%, at the time of liver biopsy. The histological severity of NAFLD was determined by fibrosis staging; stage 0-4, and NAS score; 0-8 points. The advanced liver fibrosis and the high NAS score were defined as stage 3-4 and 5-8 points, respectively. Results: Higher HbA1c groups (5.5-6.4%; 6.5-7.4%; and ≥7.5%) were associated with advanced fibrosis compared to the lowest HbA1c group. In the multivariate analysis, the HbA1c 6.5-7.4% group was significantly associated with advanced fibrosis compared to the lowest HbA1c group after adjusting for age, sex, hemoglobin, alanine aminotransferase, and creatinine levels. When further controlling for body mass index, as well as uric acid, total cholesterol, and triglyceride levels, HbA1c 5.5-6.4%, 6.5-7.4%, ≥7.5% groups were significantly associated with advanced fibrosis compared to the lowest HbA1c group. These HbA1c groups (5.5-6.4%; 6.5-7.4%; and ≥7.5%) were also associated with higher NAFLD activity scores, these associations remained significant in the multivariate analysis. Conclusions: The glycemic control status is strongly associated with the histological severity of NAFLD, even with mild deterioration in glycemic control. Therefore, adequate glycemic control in NAFLD patients might be important in improving NAFLD activity and preventing progression to NASH. Disclosure T.Miyake: None. Y.Hiasa: None. S.Furukawa: Speaker's Bureau; Kowa Company, Ltd., Ono Pharmaceutical Co., Ltd., Sanofi, Novo Nordisk, Eli Lilly Japan K.K. B.Matsuura: None. O.Yoshida: None. M.Miyazaki: None. A.Shiomi: None. S.Kanzaki: None. H.Nakaguchi: None. M.Abe: None.

91-LB: COVALENT-111, a Phase 1/2 Trial of BMF-219, a Covalent Menin Inhibitor, in Patients with Type 2 Diabetes Mellitus—Preliminary Results

Type 2 Diabetes Mellitus (T2DM) is characterized by impaired glycemic control caused by insulin resistance and progressive beta cell failure. Menin, a scaffold protein, drives beta cell proliferation when inhibited. We have reported BMF-219, an oral covalent menin inhibitor, elicits durable glycemic control following a short treatment in a ZDF Rat model. COVALENT-111, a randomized, double-blind, placebo-controlled study is evaluating BMF-219 in healthy adults and adults with T2DM diagnosed ≤15 yrs (NCT05731544). Here we report initial results from the first cohort of T2DM patients treated with BMF-219. Patients with poor glycemic control (HbA1C ≥7%) on their current antidiabetic regimen were enrolled. Twelve patients were randomized 5:1 (10 BMF-219, 2 placebo) to receive 100 mg QD for 4 weeks while continuing their existing treatment. BMF-219 was well tolerated; no subjects discontinued treatment or exited the trial during the 4-week treatment and all subjects continue in follow-up to assess durability of the treatment effect. There were no dose reductions, SAEs, or severe AEs. All TRAEs were mild and observed in 3 of 12 subjects. No subjects showed symptomatic hypoglycemia. These data demonstrate preliminary proof of concept for the novel disease-modifying effect of BMF-219 in T2DM. Enrollment is ongoing at higher doses; additional follow-up data will be presented. Disclosure J. E. Rodriguez: None. A. Abitbol: Advisory Panel; Abbott Diabetes, Lilly Diabetes, Dexcom, Inc., Novo Nordisk Canada Inc., Janssen Pharmaceuticals, Inc., Research Support; Abbott Diabetes, Lilly Diabetes, Zucara Therapeutics, Novo Nordisk Canada Inc., Moderna, Inc., Senseonics, Speaker's Bureau; Boehringer Ingelheim (Canada) Ltd., Lilly Diabetes, Amgen Canada, Dexcom, Inc., Novo Nordisk Canada Inc., HLS Therapeutics Inc., Janssen Pharmaceuticals, Inc., Merck &amp; Co., Inc., Sanofi. F. Abuzgaya: None. C. Perez: None. S. Mourya: Employee; Biomea Fusion, Inc. B. Munneke: Employee; Biomea Fusion, Inc., Corvus Pharmaceuticals. S. W. Morris: Employee; Biomea Fusion, Inc. T. Butler: Board Member; Biomea Fusion, Inc., Employee; Biomea Fusion, Inc., Stock/Shareholder; Biomea Fusion, Inc. Funding Not applicable

600-P: Higher Hydration Status Is Indicative of Better Glucose Tolerance

Introduction: Water intake is an important dietary behavior to replace high-caloric beverages and to enhance metabolic health. Type 2 diabetes is a metabolic disorder that has been shown to be more prevalent in Hispanics, a population shown to consume relatively less water compared to non-Hispanic Whites. The underlying cause of type 2 diabetes is insulin resistance, characterized by hyperglycemia and impaired glycemic control. However, whether a relationship exists between dehydration and the development of diabetes remains to be elucidated. Purpose: To evaluate if hydration status indicates glucose tolerance among a dominant Mexican American population. Methods: Sixty-one participants without diabetes (Age: 26.5 ± 9.1 years; BMI: 27.5 ± 6.0 kg/m2) participated in the study. Fasting blood glucose level was determined, and a 2-hour glucose tolerance test was performed following the ingestion of a 75g glucose drink. Blood glucose concentration levels were determined at 15−, 30−, 60−, 90−, and 120-minute time intervals post ingestion and glucose area under the curve was analyzed as well. Blood works were performed to determine blood urea nitrogen (BUN) and creatinine concentrations. Hydration status was estimated using the ratio of BUN to creatinine values. Results: Hydration status measured by BUN/Creatinine was positively associated with glucose intolerance measured at 15−, 30−, 60−, and 90-minute post glucose load and by glucose area under the curve (r=0.33; r=0.43; r=0.37; r=0.27; and r=0.41 respectively; p&amp;lt;0.05). Conclusion: Adequate fluid consumption should be encouraged for glycemic control, especially among people with high diabetes risks. Disclosure J.Apaflo: None. J.Labadah: None. G.Narvaez: None. V.M.Rocha: None. A.Mossayebi: None. S.Bajpeyi: None.

844-P: Lanifibranor Improves Markers of Cardiometabolic Health in Patients with NASH and Type 2 Diabetes, Correlated with Responses in Adiponectin Levels

Background: Lanifibranor, a pan-PPAR agonist, has shown efficacy on liver histology and metabolic-immune markers of NASH in the phase 2b NATIVE study. PPAR signaling is involved in common pathways of NASH and type 2 diabetes (T2D). Adiponectin (ADP) is a pleiotropic adipokine which improves insulin resistance (IR), lipid metabolism, inflammation and fibrosis; low ADP levels are associated with risk for cardiovascular disease and NASH. Methods: NATIVE evaluated lanifibranor 800 and 1200 mg/d versus placebo in 247 patients with non-cirrhotic NASH for 24 weeks treatment. Of these 103 had T2D, 144 did not have T2D of whom 47 had prediabetes defined by fasting glucose levels (FGL) between 5.6 - 6.9 mmol/l. ADP serum levels, metabolic-immune and hepatic markers (glycemic control, IR, lipids, systemic inflammation) were measured at baseline (BL) and end of treatment (EOT). In each subgroup, we evaluated ADP at BL, ADP fold-change at EOT, and correlation between ADP change and response of markers. Results: ADP levels were lower in patients with T2D compared to those with pre-DM or normal glycemic control (NGC) (mean 4.6, 5.5, and 5.6 ug/ml, respectively). More patients with T2D had ADP below 5 mg/ml compared to pre-DM or NGC (65% vs 62/54%). In lanifibranor-treated group, ADP folds were similar in the 3 groups, with mean 4.3 fold increase by EOT, versus no increase in the placebo-treated group. In the pooled lanifibranor arms, increase in ADP correlated with improvements in glycemic control, IR, lipid metabolism, and systemic inflammation, consistently in the 3 groups, with higher improvements in patients with T2D and prediabetes compared to the NGC group. Conclusion: The pan-PPAR agonist lanifibranor significantly improves ADP levels and this improvement correlated with markers of cardiometabolic health in patients with T2D and prediabetes. Lanifibranor improves cardiovascular risk profile in patients with impaired glycemic control and NASH. Disclosure L.H.Griffel: Employee; Inventiva Pharma. S.Francque: None. M.F.Abdelmalek: Advisory Panel; Intercept Pharmaceuticals, Inc., Madrigal Pharmaceuticals, Inc., Inventiva Pharma, Novo Nordisk, Merck &amp; Co., Inc., Sonic Incytes, NGM Biopharmaceuticals, Consultant; Hanmi Pharm. Co., Ltd., Research Support; Intercept Pharmaceuticals, Inc., Madrigal Pharmaceuticals, Inc., Hanmi Pharm. Co., Ltd., Boehringer Ingelheim Inc., Gilead Sciences, Inc., Inventiva Pharma, Novo Nordisk, Poxel SA, DURECT Corporation, Enyo Pharma, Enanta, Genentech, Inc., Celgene, NGM Biopharmaceuticals, TARGET PharmaSolutions, Inc., Allergan. P.Huot-marchand: Employee; Inventiva Pharma. L.Dzen: Employee; Inventiva Pharma. M.Baudin: Employee; Inventiva Pharma. J.L.Junien: Consultant; Inventiva Pharma. P.Broqua: None. M.P.Cooreman: Employee; Inventiva Pharma.

Shift Work and Metabolic Syndrome Updates: A Systematic Review

AbstractShift work can cause circadian cycles disturbances and misaligns the endogenous rhythms. The physiological variables are driven by the circadian system and, its misalignment, can impair the metabolic functions. Thus, the main objective of this study was to evaluate the metabolic alterations as a result of shift work and night work reported in articles published in the last 5 years, using the eligibility criteria both gender and indexed articles in English language. In order to execute this work, we perform a systematic review according to PRISMA guidelines and searched about Chronobiology Disorders and Night Work, both related to metabolism, in Medline, Lilacs, ScienceDirect and Cochrane. Cross-sectional, cohort and experimental studies with low risk of bias were included. We found a total of 132 articles, and, after the selection process, 16 articles remained to be analyzed. It was observed that shift work can cause circadian misalignment and, consequently, some metabolic parameters alterations such as an impaired glycemic control and insulin functioning, cortisol phase release, cholesterol fractions imbalance, changes in morphological indexes and melatonin secretion. There are some limitations, such as heterogenicity in used databases and the 5 years restriction period, because the effects of sleep disturbance may have been reported earlier. In conclusion, we suggest that shift work interferes with the sleep-wake cycle and eating patterns, which cause crucial physiological alterations that, together, can lead to metabolic syndrome.