Impaired Beta-cell Function Research Articles

6429 An Unusual Gene Mutation and Clinical Manifestation of MODY 10

Abstract Disclosure: J. Ambalavanan: None. O. Abdulhussein: None. J. Ferri-Guerra: None. G. Madrigal Loria: None. K. Alkwatli: None. A. Iqbal: None. R.R. Correa: None. Introduction: Maturity-Onset Diabetes of the Young (MODY) is a rare monogenic form of diabetes characterized by impaired beta cell function accounting for < 5% of all people with diabetes. About 14 different subtypes of MODY have been described in the. MODY 10 is an extremely rare form with mutation in the INS (insulin) gene. We present a previously unreported genetic mutation in the INS gene, its clinical course and subsequent management. Case: A 23-year-old female presented to us for consultation regarding new diagnosis of diabetes. She came to medical attention for pre-diabetes at the age of 16 years and was managed with diet control. She was officially diagnosed with diabetes by PCP in October 2022 after onset of polyuria and nocturia, and HbA1c of 8.7%. During initial evaluation, we suspected type 1 diabetes due to her age, low BMI of 17.61 kg/m2 and prescribed a CGM while we awaited extensive antibody evaluation. Within a week she reported average blood sugars in the 200-300 mg/dl range. As a result, she was on insulin glargine 5 units at bedtime. Within 3 months, her HbA1c dropped to 6.5% but she started experiencing frequent symptomatic hypoglycemia at work. At this point we suspected MODY due to age at diagnosis; antibody negative status for GAD-65, IA-2, ZnT8 and insulin; detectable C-peptide 1.7 ng/ml (0.81-3.85); low BMI and good glycemic control and frequent hypoglycemia on insulin. On evaluation of family history, she had a history of diabetes in maternal grandmother, paternal grandfather and paternal great uncle. Her parents did not have diabetes. We stopped glargine and started glipizide XL 2.5mg once daily. She was also referred to our clinical genetics team. On genetic evaluation she was found to have one heterozygous variant of uncertain significance in the INS gene. On further evaluation, this was found to be guanine to adenine substitution at c:139 in exon 2 of the INS gene on chromosome 11:2182063 resulting in a variant protein p.Gly47Ser which is a missense change that occurs when glycine (Gly) is replaced by serine (Ser) at position 47. This mutation has not been previously reported to be pathogenic or benign and has not been reported in significant frequency anywhere based on our literature search. Furthermore, in silico analysis supported that this missense variant had a deleterious effect on the insulin structure/function. Given the rarity of this condition, there are no formal guidelines or consensus regarding the management. During a subsequent follow up visit, we discussed that she fit the diagnosis clinically and suggested possible medications. In the end, we decided to change her from glipizide to sitagliptin 50mg daily as she was continuing to have lows at work. This helped avoid hypoglycemia and maintained time in rage at 98%. Conclusion: We present a patient with rare form of MODY 10 with a new mutation in c139:G>A at exon 2 of INS gene managed with sulfonylurea and eventually DPP4 inhibitor. Presentation: 6/2/2024

12553 Severe Hyperglycemia After Initiation Of Bictegravir Antiretroviral Therapy With Resolution Upon Discontinuation

Abstract Disclosure: S. Hudson: None. J. Aurora: None. K. Grossman: None. L. Kogelman: None. A.G. Pittas: None. Background: Antiretroviral therapy (ART) containing bictegravir (BIC), a second-generation integrase strand transfer inhibitor (INSTI), is a first-line treatment for HIV. There are mixed reports of INSTIs causing adverse metabolic effects, such as weight gain and hyperglycemia. There are cases of BIC causing hyperglycemia and diabetic ketoacidosis (DKA) within weeks to months following initiation; however, this has not been reported in clinical trials (1). It is unclear whether discontinuing BIC resolves hyperglycemia. We report a case of a patient with prediabetes who developed severe hyperglycemia after switching to a BIC-containing ART. The discontinuation of BIC resulted in significant improvement in glycemia, leading to the de-escalation of diabetes pharmacotherapy. Clinical Case: A 36-year-old woman with obesity was diagnosed with HIV during pregnancy, which was complicated by gestational diabetes mellitus. After pregnancy, she had prediabetes. Her initial ART was darunavir/cobicistat/emtricitabine/tenofovir alafenamide. Due to intolerable GI side effects, six years later, she was switched to bictegravir/emtricitabine/tenofovir alafenamide (BIC/FTC/TAF). Laboratory tests four months before starting BIC/FTC/TAF were consistent with prediabetes (HbA1c 6.4%, non-fasting blood glucose of 118 mg/dL). After one month, she was started on metformin when her HbA1c increased to 9.1% with a non-fasting blood glucose of 332 mg/dL. Another month later, HbA1c increased to 12.8% with a non-fasting blood glucose of 685 mg/dL without DKA. She was hospitalized for diabetes management. There were no significant changes in weight, viral load, or CD4 count. A search for secondary causes of hyperglycemia (diabetogenic medications, hypercortisolism, and autoimmune diabetes) was not revealing. She was discharged on metformin and insulin glargine. Her HIV regimen was switched to FTC/TAF and doravirine due to suspicion of BIC-induced hyperglycemia. After five months, she developed symptoms of hypoglycemia, and her estimated HbA1c by continuous glucose monitoring was 6.3%. Insulin glargine was discontinued. While on metformin, HbA1c three months later was 6.3%. Two years later on metformin and linagliptin: HbA1c was 6.1% and beta-cell function did not reveal insulin deficiency or resistance (non-fasting blood glucose 96 mg/dL, insulin 13.5 uIU/mL [RR 2.6-24.9 mIU/mL], C-peptide 3.7 ng/mL [RR 1.1-4.4 ng/mL]). Conclusion: Patients with HIV and a history of obesity and/or dysglycemia who are switched to a BIC-containing ART regimen should be educated and monitored for acute hyperglycemia. This may be due to impaired beta-cell function and/or insulin resistance; however, further research is needed to understand the mechanism. An alternative ART regimen should be considered if hyperglycemia develops. Reference: 1. Nolan NS, et al. Open Forum Infect Dis. 2021;16;8(5): ofab077. Presentation: 6/3/2024

Genetic predisposition to impaired beta-cell function modifies the association between serum pyrethroid levels and the risk of type 2 diabetes: A gene-environment interaction study

Previous studies suggested that pyrethroid exposure was associated with elevated type 2 diabetes (T2D) risk, while it remains uncertain whether genetic predisposition modifies this association. A nested case-control study within the prospective Dongfeng-Tongji cohort comprised 1832 T2D cases, age- (±5 years) and sex-matched controls with qualified genotyping data. Serum pyrethroids were measured by gas chromatography-tandem mass spectrometry. Overall diabetes-related genetic risk score (GRS) or pathway-specific GRS, including unweighted GRSs (uGRS) and weighted GRSs (wGRS), was developed by genetic variants identified in Asian populations. Higher overall diabetes-related GRS and GRS specific to the pathway of impaired beta cell function (Beta-cell GRS) were associated with a higher incident T2D risk. Beta-cell uGRS significantly modified the association of serum permethrin (Pinteraction=0.04) and deltamethrin (Pinteraction=0.01) with T2D. Specifically, for each doubling increase in serum deltamethrin, the odds ratios (ORs) (95 % confidence intervals [CIs]) for T2D were 1.23 (0.98–1.56) and 0.91 (0.77–1.07) in the highest and lowest Beta-cell uGRS group, as well as 1.23 (1.02–1.47) and 0.95 (0.78–1.15) for Beta-cell wGRS group, respectively. When considering jointly, those with the highest deltamethrin levels and highest Beta-cell GRS had a substantially higher T2D risk, compared with the reference group (OR for uGRS: 3.79 [95 % CI: 2.03–7.07], Pinteraction=0.03 and 3.23 [95 % CI: 1.78–5.87], Pinteraction=0.05 for wGRS). Our findings suggested that genetic susceptibility to impaired beta-cell function should be considered for T2D prevention targeting pyrethroid exposure, particularly deltamethrin.

Secreted chemokines reveal diverse inflammatory and degenerative processes in the intervertebral disc of the STZ-HFD mouse model of Type 2 diabetes.

The chronic inflammation present in type 2 diabetes causes many chronic inflammatory comorbidities, including cardiovascular, renal, and neuropathic complications. Type 2 diabetes is also associated with a number of spinal pathologies, including intervertebral disc (IVD) degeneration and chronic neck and back pain. Although confounding factors such as obesity are thought to increase the loads to the musculoskeletal system and subsequent degeneration, studies have shown that even after adjusting age, body mass index, and genetics (e.g. twins), patients with diabetes suffer from disproportionately more IVD degeneration and back pain. Yet the tissue-specific responses of the IVD during diabetes remains relatively unknown. We hypothesize that chronic diabetes fosters a proinflammatory microenvironment within the IVD that accelerates degeneration and increases susceptibility to painful disorders. To test this hypothesis, we evaluated two commonly used mouse models of diabetes - the leptin-receptor deficient mouse (db/db) and the chronic high-fat diet in mice with impaired beta-cell function (STZ-HFD). The db/db is a genetic model that spontaneous develop diabetes through hyperphagia, while the STZ-HFD mouse first exhibits rapid obesity development under HFD and pronounced insulin resistance following streptozotocin administration. Both animal models were allowed to develop sustained diabetes for at least twelve weeks, as defined by elevated hemoglobin A1C, hyperglycemia, and glucose intolerance. Following the twelve-week period, the IVDs were extracted in quantified in several measures including tissue-specific secreted cytokines, viscoelastic mechanical behavior, structural composition, and histopathologic degeneration. Although there were no differences in mechanical function or the overall structure of the IVD, the STZ-HFD IVDs were more degenerated. More notably, the STZ-HFD model shows a significantly higher fold increase for eight cytokines: CXCL2, CCL2, CCL3, CCL4, CCL12 (monocyte/macrophage associated), IL-2, CXCL9 (T-cell associated), and CCL5 (pleiotropic). Correlative network analyses revealed that the expression of cytokines differentially regulated between the db/db and the STZ-HFD models. Moreover, the STZ-HFD contained a fragmented and modular cytokine network, indicating greater complexities in the regulatory network. Taken together, the STZ-HFD model of type 2 diabetes may better recapitulate the complexities of the chronic inflammatory processes in the IVD during diabetes.

Data-driven Cluster Analysis Reveals Increased Risk for Severe Insulin-Deficient Diabetes in Black/African Americans.

Diabetes is a heterogenic disease and distinct clusters have emerged, but the implications for diverse populations have remained understudied. Apply cluster analysis to a diverse diabetes cohort in the U.S. Deep South. Retrospective hierarchical cluster analysis of electronic health records from 89,875 patients diagnosed with diabetes between January 1, 2010, and December 31, 2019, at the Kirklin Clinic of the University of Alabama at Birmingham, an ambulatory referral center. Adult patients with ICD diabetes codes were selected based on available data for 6 established clustering parameters (GAD-autoantibody; HbA1c; BMI; Diagnosis age; HOMA2-B; HOMA2-IR); ∼42% were Black/African American. Diabetes subtypes and their associated characteristics in a diverse adult population based on clustering analysis. We hypothesized that racial background would affect the distribution of subtypes. Outcome and hypothesis were formulated prior to data collection. Diabetes cluster distribution was significantly different in Black/African Americans compared to Whites (P<0.001). Black/African Americans were more likely to have severe insulin deficient diabetes (SIDD) (OR 1.83, CI 1.36-2.45, P<0.001), associated with more serious metabolic perturbations and a higher risk for complications (OR 1.42, 95% CI 1.06-1.90, P=0.020). Surprisingly, Black/African Americans specifically had more severe impairment of beta cell function (HOMA2-B, C-peptide) (P<0.001), while not being more obese or insulin resistant. Racial background greatly influences diabetes cluster distribution and Black/African Americans are more frequently and more severely affected by SIDD. This may further help explain the disparity in outcomes and have implications for treatment choice.

Data-Driven Patient clusters of Type 2 Diabetes May Help to Identify Patients at Risk and Predict Metabolic Surgery Outcomes on Diabetes Remission and NAFLD Pregression

Abstract Background Precision medicine and customized medicine have gained enormous attention in recent years, especially in the treatment of type 2 diabetes (T2D). Different subgroups of diabetes have been identified by research employing data-driven cluster analysis, each with a unique diabetes progression and complication risk (Ahlqvist et al., Lancet Diabetes Endocrinol. 2018). Aims We aimed to apply the proposed cluster analysis to a patent population post metabolic surgery and investigate the association with T2D remission and presence of NAFLD. Methods We retrospectively linked newly defined clusters to metabolic surgery outcomes in 53 T2D patients. Utilizing k-means and hierarchical clustering, three clusters emerged based on glutamate decarboxylase antibodies, age, BMI, HbA1c, and homoeostatic model assessment estimates of β-cell function (HOMA2-B%) and insulin resistance (HOMA2-IR). Intraoperative liver biopsies assessed nonalcoholic fatty liver disease (NAFLD) presence differentiating between simple steatosis (NAFL) and steatohepatitis (NASH). Clinical and biochemical data were collected over two years, focusing on T2D remission and NAFLD improvement. Results Cluster 1, characterized by the lowest BMI, highest NASH rate, impaired beta-cell function, and increased insulin resistance, displayed a favorable response to surgery, indicating robust regeneration of beta-cells. Despite increased insulin production, T2D remission was surprisingly low at 44.0% after one year, in contrast to 75.00% in Cluster 2 and 100.00% in Cluster 3. Metabolic surgery notably reduced insulin resistance and promoted NASH remission, evidenced by a significant reduction in a non-invasive NASH detection score and liver enzyme levels across all three clusters. Conclusion Our findings suggest that patients in Cluster 1 already show a lack of beta-cell compensation being associated with a higher prevalence of NAFLD and poorer diabetic control and therefore especially might benefit from an earlier intervention. Data-driven classification might help to customize treatment plans and identify patients at higher risk of problems at diagnosis.

Challenges and pitfalls of youth-onset type 2 diabetes.

The incidence and prevalence of youth-onset type 2 diabetes mellitus (T2DM) are increasing. The rise in frequency and severity of childhood obesity, inclination to sedentary lifestyle, and epigenetic risks related to prenatal hyperglycemia exposure are important drivers of the youth-onset T2DM epidemic and might as well be responsible for the early onset of diabetes complications. Indeed, youth-onset T2DM has a more extreme metabolic phenotype than adult-onset T2DM, with greater insulin resistance and more rapid deterioration of beta cell function. Therefore, intermediate complications such as microalbuminuria develop in late childhood or early adulthood, while end-stage complications develop in mid-life. Due to the lack of efficacy and safety data, several drugs available for the treatment of adults with T2DM have not been approved in youth, reducing the pharmacological treatment options. In this mini review, we will try to address the present challenges and pitfalls related to youth-onset T2DM and summarize the available interventions to mitigate the risk of microvascular and macrovascular complications.

RFX6 haploinsufficiency predisposes to diabetes through impaired beta cell function

Aims/hypothesisRegulatory factor X 6 (RFX6) is crucial for pancreatic endocrine development and differentiation. The RFX6 variant p.His293LeufsTer7 is significantly enriched in the Finnish population, with almost 1:250 individuals as a carrier. Importantly, the FinnGen study indicates a high predisposition for heterozygous carriers to develop type 2 and gestational diabetes. However, the precise mechanism of this predisposition remains unknown.MethodsTo understand the role of this variant in beta cell development and function, we used CRISPR technology to generate allelic series of pluripotent stem cells. We created two isogenic stem cell models: a human embryonic stem cell model; and a patient-derived stem cell model. Both were differentiated into pancreatic islet lineages (stem-cell-derived islets, SC-islets), followed by implantation in immunocompromised NOD-SCID-Gamma mice.ResultsStem cell models of the homozygous variant RFX6−/− predictably failed to generate insulin-secreting pancreatic beta cells, mirroring the phenotype observed in Mitchell–Riley syndrome. Notably, at the pancreatic endocrine stage, there was an upregulation of precursor markers NEUROG3 and SOX9, accompanied by increased apoptosis. Intriguingly, heterozygous RFX6+/− SC-islets exhibited RFX6 haploinsufficiency (54.2% reduction in protein expression), associated with reduced beta cell maturation markers, altered calcium signalling and impaired insulin secretion (62% and 54% reduction in basal and high glucose conditions, respectively). However, RFX6 haploinsufficiency did not have an impact on beta cell number or insulin content. The reduced insulin secretion persisted after in vivo implantation in mice, aligning with the increased risk of variant carriers to develop diabetes.Conclusions/interpretationOur allelic series isogenic SC-islet models represent a powerful tool to elucidate specific aetiologies of diabetes in humans, enabling the sensitive detection of aberrations in both beta cell development and function. We highlight the critical role of RFX6 in augmenting and maintaining the pancreatic progenitor pool, with an endocrine roadblock and increased cell death upon its loss. We demonstrate that RFX6 haploinsufficiency does not affect beta cell number or insulin content but does impair function, predisposing heterozygous carriers of loss-of-function variants to diabetes.Data availabilityUltra-deep bulk RNA-seq data for pancreatic differentiation stages 3, 5 and 7 of H1 RFX6 genotypes are deposited in the Gene Expression Omnibus database with accession code GSE234289. Original western blot images are deposited at Mendeley (https://data.mendeley.com/datasets/g75drr3mgw/2).Graphical

Gender Specific Effects of Nr4a1 in Obese Mice

A central aspect of type 2 diabetes disease progression is impaired functional β-cell mass. The hyperglycemic and hyperlipidemic environment present in type 2 diabetes corresponds with impaired beta cell function. The orphan nuclear receptor Nr4a1 is critical for fuel utilization in various tissues, however little is known regarding its function in the β-cell. Nr4a1 expression is decreased in the β-cell of rodent models of type 2 diabetes, as well as in primary human islets from type 2 diabetics. Here we demonstrate sex specific effects of β-cell specific Nr4a1 deletion under high fat chow feeding. While female and male βNr4a1−/− mice were no different than wild type controls when fed a standard chow diet, a clear sex dependent difference is observed when fed a high fat diet. While high fat fed male βNr4a1−/− have improved fasting and non-fasting blood glucose levels and no change in glucose tolerance, high fat fed female βNr4a1−/− mice have impaired glucose tolerance as early as one month after beginning high fat feeding. We also found that βNr4a1−/− female mice have decreased β-cell mass and decreased expression in known targets of Nr4a1 regulation including Eno1 and SDHβ. Our data suggest that Nr4a1 is critical for maintenance of beta cell function, and that loss of Nr4a1 under conditions of obesity and overnutrition in females results in impaired beta cell compensation and function. NIH R15DK124835-01A1. This is the full abstract presented at the American Physiology Summit 2024 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.

Interplay Between the American Diabetes Association's ABC Targets for Diabetes, Insulin Resistance Indices, and Dyslipidemia in Indian Type 2 Diabetes Patients.

Background The increasing incidence of type 2 diabetes (T2D) in India underscores the pressing need for effective management strategies. Meeting the American Diabetes Association (ADA) ABC targets for diabetes (glycated hemoglobin (HbA1c), blood pressure, and serum low-density lipoprotein cholesterol (LDL-C)) is crucial for effectively managing T2D, as it reflects the optimal control of key metabolic parameters. Insulin resistance (IR) and impaired beta cell function (BCF) have been found to have a significant impact on glycemic control, lipid metabolism, and hypertension, contributing to the complex cardiovascular risk profile of patients with T2D. This study aimed to explore the association between ABC targets for diabetes, IR, BCF, and dyslipidemia in a cross-sectional cohort of T2D patients. Methods This retrospective study examined data from 681 T2D patients with comorbid hypertension and dyslipidemia. The patients were part of a one-year online lifestyle intervention program for diabetes management at the Freedom from Diabetes Clinic in Pune, India, between January 2021 and December 2022. Baseline data (at the time of enrollment in the program) on medical history and anthropometric and biochemical parameters were retrospectively extracted from medical records and used to assess ABC targets and other clinical parameters. The ABC targets for diabetes include three goals: an HbA1c level of less than 7.0%, a blood pressure level of less than 140/90 mmHg, and an LDL-C level of less than 100 mg/dL. Homeostatic Model Assessment of Insulin Resistance (HOMA-IR), Homeostatic Model Assessment of Beta Cell Function (HOMA-B), and Quantitative Insulin Sensitivity Check Index (QUICKI) were calculated using standard formulas. Results Cross-sectional analysis at baseline showed that 152 (22.3%) participants met all three ABC targets, 306 (45.0%) and 183 (26.8%) participants met two or one targets, respectively, and 40 (5.9%) did not meet any of the ABC targets. Participants meeting all three targets showed significantly lower IR, higher sensitivity (HOMA-IR, median 2.1; QUICKI, median 0.34), higher BCF (HOMA-B, median 62.9), and healthier lipid profiles (mg/dL) (total cholesterol, median 126; triglycerides, median 114; and non-high-density lipoprotein (HDL), median 84) than those who did not meet any of the ABC targets (HOMA-IR, median 3.4; QUICKI, median 0.31; HOMA-B, median 31.7; total cholesterol, median 221; triglycerides, median 187; and non-HDL, median 182) (p < 0.01). A significant association was observed between lower BMI (< 25 kg/m2), lower IR (HOMA-IR <2.5), and meeting all three ABC targets (p < 0.01). No significant association was observed between the duration of diabetes and ABC target status (p > 0.1). Lower IR was identified as a predictor of achievement of all three ABC targets (p < 0.01). Conclusion This study highlights the significance of meeting ABC targets for diabetes in relation to not only a better lipid profile but also lower IR and higher BCF. These preliminary findings provide novel insights into the interplay between IR, BCF, dyslipidemia, and meeting ABC targets in an Indian T2D population. These findings highlight the need for effective diabetes management strategies and improved patient outcomes, considering factors such as BMI and IR indices.

Retatruide' drug trial: A paradigm shift in Type 2 Diabetes management.

Type 2 diabetes mellitus (T2DM) is a chronic medical condition characterised by persistent hyperglycemia caused by insulin resistance and impaired beta cell function. Typically, it occurs in individuals aged 45 and above, but due to the growing prevalence of obesity and sedentary lifestyle, it is increasingly being diagnosed in younger adults and adolescents. A positive family history of T2DM and specific genes such as TCF7L2 and PPARG also play an essential role.[1] Consequently, persistent hyperglycemia in type 2 DM can give rise to a range of microvascular complications such as retinopathy, neuropathy and nephropathy and macrovascular complications such as coronary artery and cerebrovascular diseases. T2DM accounts for 90% of the cases of diabetes, raising concern among the healthcare sector worldwide. In 2017, approximately 462 million individuals were affected by type 2 DM, accounting for 6.28% of the world’s population. By 2030, it is estimated that the global prevalence will rise to 7079 individuals per 100,000.[2] To prevent the complications caused by T2DM, it is essential to prioritize glycemic control. First and foremost, effective dietary control is pivotal. It has been established that obesity in individuals with T2DM is closely associated with insulin resistance and defects in insulin secretions thus managing the calorie intake is mandatory. However, pharmacologic intervention with oral glucose-lowering agents or insulin therapy is necessary when the patient’s blood glucose doesn’t fall within normal limits despite weight reduction, exercise and dietary modifications. The first line pharmacological agent used is Metformin, an oral medication that reduces glucose production in the liver. Additionally, insulin secretagogues such as sulfonylureas and glinides promote insulin release by stimulating beta cells. Thiazolidinediones is another example of an oral agent used to treat diabetes by enhancing glucose uptake by the muscle, liver and adipose tissue.[3] Furthermore, it is crucial to understand that the Incretin effect, responsible for stimulating insulin secretion after meals, is primarily mediated by gut-derived incretin hormones known as glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide-1 (GLP-1). However, patients with type 2 diabetes (T2DM) commonly exhibit defects in this process. To address this issue, in addition to oral medications, injectable drugs such as RA-GLP1 (Semaglutide, Dulaglutide) are administered to emulate the actions of human GLP-1 effectively. These injectable treatments are vital in reducing postprandial hyperglycemia and have become indispensable in managing T2DM. ---Continue

Phenotypic clusters of type 2 diabetes mellitus among North Indians reveal higher levels of insulin deficiency along with insulin resistance

BackgroundType 2 diabetes is now considered a heterogenous disease. Distinct clusters have been identified with patterns varying between Europeans and South Asians as well as between South Indians who have described a novel cluster; Combined Insulin-Resistant and Deficient Diabetes, and individuals from West and East India who have reported that insulin deficiency is the primary driver of heterogeneity. Therefore, North Indian patients may also have a distinct, novel clustering pattern due to unique genetic, epigenetic, and environmental factors. We aim to identify clusters of type 2 diabetes in North Indians and to describe the different characteristics of these clusters. MethodsThe K value for the optimal number of clusters was obtained from two-step clustering. K means clustering was done with this K value using SPSS 29.0 software. Variables used for clustering were age, BMI, HbA1c, HOMA-beta, HOMA-IR, and waist circumference. ResultsFour phenotypically different clusters were identified in 469 individuals with type 2 diabetes. Cluster 1 was severe insulin deficient diabetes (15%), Cluster 2 was severe insulin resistant diabetes (22%), Cluster 3 was moderate obesity-related diabetes (35%), and Cluster 4 was moderate age-related diabetes (27%). Clusters 1 and 2 were similar to earlier studies but in different proportions. Clusters 3 and 4 characteristics were different from earlier studies, with greater impairment in beta cell function and higher HbA1c levels. Significant insulin resistance was noted in all clusters. ConclusionThe phenotypic clusters of type 2 diabetes identified in the present study were characterized by high levels of insulin deficiency along with important contributions from insulin resistance.

Association of Alcohol Consumption with Impaired Beta-Cell Function Independent of Body Mass Index Among Indian Men

Heavy alcohol consumption is linked to the development of type 2 diabetes. Alcohol's effects on the function of cells are not completely known at this time. This investigation looked into the relationships that exist between all of these different characteristics. All of the males who participated in this study were of Indian descent, and their ages ranged anywhere from 25 to 80 years old. Participants were categorized as abstainers, teetotalers, light drinkers (drinking between 0.1 and 20 grams of alcohol per day), moderate drinkers (consuming between 21.0 and 40 grams of alcohol per day), or heavy drinkers (consuming more than 41 grams of alcohol per day). Light drinkers consumed between 0.1 and 20 grams of alcohol per day. Moderate drinkers consumed between 21.0 and 40 kilos of alcohol per day. Heavy drinkers used more than 41 grams of alcohol per day. After that, the participants were separated into two groups: those with a body mass index (BMI) of less than 25 kilograms per square meter and those with a BMI of 25 kilograms per square meter or more. A number of parameters, such as age, smoking status, body mass index (BMI), waist circumference, blood pressure, lipids, and serum uric acid levels, were taken into consideration. In comparison to individuals who refrained from alcohol use, those who drank alcohol had a lower HOMA- score, and this was the case independent of their body mass index. In the group with a BMI of less than 25 \(kg/m^{2}\), both past and current alcohol use were substantially connected with HOMA-IR. However, this association was not seen in the group with a BMI of more than 25 \(kg/m^{2}\). According to the results of multiple research, drinking alcohol is associated with -cell dysfunction in boys of Indian heritage, independent of the BMI of the participants in the studies.

Intra-pancreatic fat is associated with high circulating glucagon and GLP-1 concentrations following whey protein ingestion in overweight women with impaired fasting glucose: A randomised controlled trial

AimIntra-pancreatic fat deposition (IPFD) while hypothesised to impair beta-cell function, its impact on alpha-cells remains unclear. We evaluated the association between IPFD and markers of pancreatic cells function using whey protein. MethodsTwenty overweight women with impaired fasting glucose (IFG) and low or high IPFD (<4.66% vs ≥4.66%) consumed 3 beverage treatments: 0 g (water control), 12.5 g (low-dose) and 50.0 g (high-dose) whey protein, after an overnight fast, in randomised order. Blood glucose, insulin, C-peptide, glucagon, gastric-inhibitory polypeptide (GIP), glucagon-like peptide-1 (GLP-1) and amylin were analysed postprandially over 4 h. Incremental area-under-the-curve (iAUC), incremental maximum concentration (iCmax), and time to maximum concentration (Tmax) for these were compared between IPFD groups using repeated measures linear mixed models, also controlled for age (pcov). ResultsiAUC and iCmax glucose and insulin while similar between the two IPFD groups, high IPFD and ageing contributed to higher postprandial glucagon (iAUC: p = 0.012; pcov = 0.004; iCmax: p = 0.069; pcov = 0.021) and GLP-1 (iAUC: p = 0.006; pcov = 0.064; iCmax: p = 0.011; pcov = 0.122) concentrations. ConclusionIn our cohort, there was no evidence that IPFD impaired protein-induced insulin secretion. Conversely, IPFD may be associated with increased protein-induced glucagon secretion, a novel observation which warrants further investigation into its relevance in the pathogenesis of dysglycaemia and type-2 diabetes.

Post-bariatric hypoglycaemia diagnosed during pregnancy.

There is a scarcity of literature relating to post-bariatric hypoglycaemia (PBH) in pregnancy. Recurrent hyperglycaemia and hypoglycaemia can have significant consequences for both the mother and the developing fetus. We describe a case of a young pregnant woman who was diagnosed with symptomatic PBH in the second trimester of pregnancy using continuous glucose monitoring (CGM) 3 years after Roux-en-Y gastric bypass (RYGB) surgery. Instigating a low glycaemic index and complex carbohydrate diet significantly improved the patient's glycaemic excursions. Given that this condition is likely underdiagnosed as a complication of RYGB surgery, a greater awareness of this complication is needed. Patients should be adequately consented pre-operatively for this relatively frequent late surgical complication to enable patients to identify symptoms of this condition at an early stage and seek medical treatment. PBH is an important diagnosis in patients post-RYGB surgery, particularly in women of childbearing age when consequences of both hyperglycaemia and hypoglycaemia during pregnancy can adversely affect both mother and the fetus. Adverse outcomes of recurrent hypoglycaemia to the fetus can include small for gestational age, intrauterine growth restriction and possible impairment of beta cell function. Providing adequate carbohydrate intake to allow growth of the fetus during pregnancy while also attempting to resolve both hyperglycaemia and hypoglycaemia associated with PBH by reducing the intake of simple carbohydrates and high glycaemic index foods can prove challenging. Patients should be adequately consented for late complications of RYGB surgery such as PBH in order to allow early recognition of symptoms and enable prompt treatment.

Characterization of impaired beta and alpha cell function in response to an oral glucose challenge in cystic fibrosis: a cross-sectional study.

The purpose of the study was to further elucidate the pathophysiology of cystic fibrosis (CF)-related diabetes (CFRD) and potential drivers of hypoglycaemia. Hence, we aimed to describe and compare beta cell function (insulin and proinsulin) and alpha cell function (glucagon) in relation to glucose tolerance in adults with CF and to study whether hypoglycaemia following oral glucose challenge may represent an early sign of islet cell impairment. Adults with CF (≥18 years) were included in a cross-sectional study using an extended (-10, -1, 10, 20, 30, 45, 60, 90, 120, 150, and 180 min) or a standard (-1, 30, 60, and 120 min) oral glucose tolerance test (OGTT). Participants were classified according to glucose tolerance status and hypoglycaemia was defined as 3-hour glucose <3.9 mmol/L in those with normal glucose tolerance (NGT) and early glucose intolerance (EGI). Among 93 participants, 67 underwent an extended OGTT. In addition to worsening in insulin secretion, the progression to CFRD was associated with signs of beta cell stress, as the fasting proinsulin-to-insulin ratio incrementally increased (p-value for trend=0.013). The maximum proinsulin level (pmol/L) was positively associated with the nadir glucagon, as nadir glucagon increased 6.2% (95% confidence interval: 1.4-11.3%) for each unit increase in proinsulin. Those with hypoglycaemia had higher 60-min glucose, 120-min C-peptide, and 180-min glucagon levels (27.8% [11.3-46.7%], 42.9% [5.9-92.85%], and 80.3% [14.9-182.9%], respectively) and unaltered proinsulin-to-insulin ratio compared to those without hypoglycaemia. The maximum proinsulin concentration was positively associated with nadir glucagon during the OGTT, suggesting that beta cell stress is associated with abnormal alpha cell function in adults with CF. In addition, hypoglycaemia seemed to be explained by a temporal mismatch between glucose and insulin levels rather than by an impaired glucagon response.

Reinstating acute-phase insulin release among sedentary adults at high risk for type 2 diabetes with Yoga and Walking based lifestyle modification

BackgroundWe compared the impact of 2 lifestyle modifying physical activities, yoga (YBLM) or walking (WBLM) on impaired beta cell function (IBF) or insulin resistance (IR) in restoring acute phase insulin release (APIR) among prediabetes at high risk for type 2 diabetes (HRDM). MethodMale and female adults (N = 42, 38.1 ± 4.8 years) with abdominal obesity (Male:103 ± 8.1 cm) Female: 92 ± 11.1 cm), randomized into YBLM (n = 20) and WBLM (n = 22), were monitored for the practice of the intervention, 45 min a day/5 days a week for 12 weeks. Blood sample was collected at 0th minute to estimate the level of Fasting Blood Glucose (FBG), Sr. Insulin and lipid profile and at 10th minute (APIR). IBF, IR and sensitivity (IS) reading were checked in HOMA-2 calculator. ResultWilcoxon sign rank t-test denoted an improved APIR among the subjects with IBF (p = 0.008) and not among the subjects with IR (p = 0.332). However, regression analysis yielded an improved APIR among subjects with IBF (F(1,10) = 7.816, p = 0.002) with the management of body weight and lipid profile and IR (F(1,13) = 17.003, p = 0.001) being found influenced with selected lipid components. In all, during the post assessment period, an impressive boost in APIR was manifested among people shifted to Normoglycemia (n = 14, 35.9%). ConclusionIntriguingly, we postulate the potential role of YBLM over WBLM in the management of lipid profile and body weight on accelerating APIR either through improved Beta cell compensation or by sensitizing skeletal muscles regulating IR, helping improve glucose tolerance resulting in either remission or management of prediabetes.

Oxidative Stress in Type 2 Diabetes: Impacts from Pathogenesis to Lifestyle Modifications.

Oxidative stress is a critical factor in the pathogenesis and progression of diabetes and its associated complications. The imbalance between reactive oxygen species (ROS) production and the body's antioxidant defence mechanisms leads to cellular damage and dysfunction. In diabetes, chronic hyperglycaemia and mitochondrial dysfunction contribute to increased ROS production, further exacerbating oxidative stress. This oxidative burden adversely affects various aspects of diabetes, including impaired beta-cell function and insulin resistance, leading to disrupted glucose regulation. Additionally, oxidative stress-induced damage to blood vessels and impaired endothelial function contribute to the development of diabetic vascular complications such as retinopathy, nephropathy, and cardiovascular diseases. Moreover, organs and tissues throughout the body, including the kidneys, nerves, and eyes, are vulnerable to oxidative stress, resulting in diabetic nephropathy, neuropathy, and retinopathy. Strategies to mitigate oxidative stress in diabetes include antioxidant therapy, lifestyle modifications, and effective management of hyperglycaemia. However, further research is necessary to comprehensively understand the underlying mechanisms of oxidative stress in diabetes and to evaluate the efficacy of antioxidant interventions in preventing and treating diabetic complications. By addressing oxidative stress, it might be possible to alleviate the burden of diabetes and improve patient outcomes.

784-P: Characteristics of People with Young-Onset T2D in the SURPASS Program

Young-onset T2D, defined as diagnosed before age 40, is increasing around the world. Recent data suggest a faster deterioration in beta-cell function and earlier development of complications in this population, compared to later-onset T2D. This post-hoc analysis evaluated the baseline characteristics of people with young-onset vs later-onset T2D in the SURPASS clinical trial program. Baseline demographics and clinical characteristics were compared in participants with young-onset vs later-onset T2D from the SURPASS-1, -2, -3, and -5 clinical trials (N=4267). Analyses were performed by study. Across the SURPASS program, which included participants at various stages of T2D management, participants with young-onset T2D were younger, had longer duration of diabetes, worse glycemic control, higher mean body weight and BMI, and a worse lipid profile at baseline vs patients with later-onset T2D. Data from SURPASS-1 and SURPASS-2 also showed participants with young-onset T2D had greater insulin resistance (HOMA2-IR) at baseline. Despite their younger age at baseline, participants with young-onset T2D in the SURPASS program had an overall worse health status as compared to patients with later-onset T2D. Early intervention in young-onset T2D may be important to optimize long-term outcomes. Disclosure R.J.Galindo: Consultant; Novo Nordisk, Eli Lilly and Company, Sanofi, Pfizer Inc., Bayer Inc., WW (Weight Watchers), Research Support; Novo Nordisk, Eli Lilly and Company, Dexcom, Inc. P.Zeitler: Consultant; Eli Lilly and Company, Boehringer Ingelheim Inc., Johnson &amp; Johnson. M.J.Davies: Advisory Panel; Lilly, Boehringer-Ingelheim, Novo Nordisk, Sanofi, Lexicon Pharmaceuticals, Inc., Pfizer Inc., Medtronic, ShouTi Pharma Inc., Consultant; Lilly, Boehringer-Ingelheim, Novo Nordisk, Sanofi, Research Support; AstraZeneca, Novo Nordisk, Sanofi-Aventis U.S., Boehringer-Ingelheim, Janssen Pharmaceuticals, Inc., Speaker's Bureau; Lilly, Boehringer-Ingelheim, Novo Nordisk, AstraZeneca, Napp Pharmaceuticals Limited, Novartis, Sanofi. C.Lee: Employee; Eli Lilly and Company, Stock/Shareholder; Eli Lilly and Company. V.Thieu: None. C.Nicolay: Employee; Eli Lilly and Company. S.Allen: None. B.Bergman: Employee; Eli Lilly and Company, Stock/Shareholder; Eli Lilly and Company. Funding Eli Lilly and Company

213-LB: Impact of Alpha- and Beta-Cell Dysfunction on the Longitudinal Progression to Type 2 Diabetes

T2D results from glucotoxicity-driven impairment of insulin secretion which limits compensation for increased insulin demand. Increased demand results from insulin resistance and elevated hepatic glucose production (HGP). Increased HGP can result either from insulin resistance or alpha-cell dysregulation leading to hyperglucagonemia. Objectives: To investigate with a mathematical model whether increased HGP and progression to T2D could result from impaired glucagon secretion in addition to insulin resistance. Toward this end, we developed a realistic model of beta-cell growth, death and function and interfaced it with a previously validated model of glucose-insulin-glucagon dynamics. Methods: A previously published model of longitudinal progression to T2D over years was extended to include glucagon dynamics. The beta cell mass/function equation was parametrized by interfacing with results from a previously published paper on modeling isoglycemic, intravenous glucose infusion tests to obtain snapshots of the metabolic state. The range of parameters observed in the cohort studied cover the gamut from normal, insulin sensitive to normal, insulin resistant to T2D patients, and was used to calibrate the model. The influence of insulin resistance and impaired glucagon secretion as they develop over time was included in the combined model to see how they impact the balance between enhanced and impaired beta-cell function and mass. Results and Conclusion: When only insulin sensitivity was allowed to decrease, the normal subjects did not transition to T2D. This was because the glucose levels were not elevated sufficiently to upset the balance between enhancement and impairment and lead to a catastrophic decline in insulin secretion. Including time-dependent impairment of glucagon suppression, in addition to declining insulin sensitivity, was sufficient to lead to the significant imbalance required to progress to T2D diabetes. Thus, both appear to be required. Disclosure V. Subramanian: None. A. Sherman: None. Funding National Institute of Diabetes and Digestive and Kidney Diseases (DK131328)