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Disclosure: S. Poon: None. K. Nash: None. Y. Choi: None. L. Li: None. P. Prasad: None. D. Raalte: Other; Self; consulting relationships with Boehringer Ingelheim, Eli Lilly, Merck and Sanofi, and receives research operating funding from AstraZeneca, Boehringer Ingelheim-Eli Lilly Diabetes Alliance, MSD. A. Karihaloo: Employee; Self; Novo Nordisk. A. Sawyer: None. P. Bjornstad: Advisory Board Member; Self; AstraZeneca, Bayer, Lilly, Boehringer Ingelheim, Novo Nordisk, and XORTX. Other; Self; PB reports serving or having served as a consultant for AstraZeneca, Bayer, Bristol-Myers Squibb, Boehringer Ingelheim, Eli Lilly, LG Chemistry, Sanofi, Novo Nordisk, and Horizon Pharma. Background: Apparent diffusion coefficient (ADC) by magnetic resonance imaging (MRI) provides information about the microstructure and cellular organization of the kidney, and has been linked with kidney function decline in adults with chronic kidney disease. However, it is unclear whether alterations in tissue architecture or cellular density are also present in young persons with type 1 and 2 diabetes. Accordingly, the objective of this analysis was to determine early changes in ADC among young persons with and without diabetes. Materials and Method: Kidney MRIs were performed in 37 lean controls (age: 18±6 years, 54% female, eGFR: 106±19 ml/min/1.73m2), 28 participants with youth-onset T1D (age: 20±4 years, 50% female, diabetes duration: 9±6 years, HbA1c: 8.3±1.3%, eGFR: 110±19 ml/min/1.73m2) and 30 participants with youth-onset T2D (age: 17±4 years, 62% female, diabetes duration: 2±2 years, HbA1c: 7.4±2.2%, eGFR: 127±24 ml/min/1.73m2). All scans were performed on 3T whole-body scanners. A single reader at The NorthShore University HealthSystem analyzed all images while blinded to participants’ clinical information. Lower values of cortical ADC on diffusion-weighted MRI may indicate increased cellular density and are often used to estimate fibrosis. Estimated GFR (eGFR) were calculated by Full Age Spectrum serum creatinine equation. We performed multivariable linear regression models adjusted for age and sex. Results: Compared to lean controls (age and sex-adjusted means ± standard errors (SE): (1722±22 × 10−6 mm2/s), young persons with T1D (1636±28 × 10−6 mm2/s, p=0.02) and T2D (1612±27 × 10−6 mm2/s, p=0.002) exhibited lower cortical ADC. Despite younger age and shorter diabetes duration, young persons with T2D had numerically lower cortical ADC compared to those with T1D, although the difference did not reach statistical significance. Higher age and male sex were associated with lower cortical ADC (β±SE: −7.5±2.8 x 10−6 mm2/s per 1 year of age, p=0.009; β±SE: −71.1±28.5 x 10−6 mm2/s per 1 year for male sex, p=0.008) in multivariable models. Lower eGFR was associated with lower cortical ADC (β±SE: 2.3±0.8 x 10−6 mm2/s per 1 ml/min/1.73m2 increment eGFR, p=0.005). HbA1c and urine albumin-to-creatinine ratio did not associate significantly with cortical ADC in multivariable models. Conclusion: Young persons with diabetes exhibit lower cortical ADC compared to healthy lean controls, suggesting alternations in microstructure and cellular density and potentially early signs of fibrosis. Additionally, despite shorter duration of disease and younger age, participants with T2D had the lowest cortical ADC values among the 3 groups. Further research is needed to investigate the role of cortical ADC in predicting kidney function decline in young individuals with diabetes, as well as molecular determinants of the alterations in microstructure and cellular density. Presentation: Friday, June 16, 2023

Disclosure: C. Muralidharan: None. F.H. huang: None. S.C. May: None. J. Enriquez: None. J.B. Nelson: None. E. Wang: None. A. Chakraborthy: None. K.T. Figatner: None. S.N. Navitskaya: None. S.A. Tersey: None. R.G. Mirmira: None. In type 1 diabetes (T1D), the immune system destroys the insulin-secreting β-cells. This autoimmune attack may be triggered by the β-cells themselves when they encounter viral infections or changes in gut microbiome or diet, years before clinical diagnosis of T1D. In response to these stressors, four kinases (PERK, PKR, GCN2, and HRI) activate the integrated stress response (ISR), which temporarily halts protein translation to promote cellular survival. However, if prolonged, the ISR can render β-cells dysfunctional. Therefore, we hypothesized that inhibiting the ISR under chronic inflammatory stress would suppress β-cell autoimmunity and reduce T1D risk. To test this, we pre-treated human islets with ISR inhibitors (ISRIB or a novel inhibitor of PERK, HC-PERKi) and then exposed them to proinflammatory cytokines (50 IU/mL IL-1β + 1000 IU/mL IFNγ) for 24h. As expected, cytokine treatment blocked protein translation, as revealed by polyribosomal profiling. Consistent with this, we saw reduced total protein synthesis (50% decrease) by puromycin incorporation assay. These effects were partially reversed by pretreating with ISR inhibitors. To determine if ISR inhibition delays or prevents diabetes development, we treated female pre-diabetic non-obese diabetic (NOD) mice with vehicle or HC-PERKi for four weeks (6-10 weeks of age). Compared to controls, NOD mice that received HC-PERKi showed a significant delay in diabetes development. Single cell RNA-sequencing analysis of the pancreatic islets revealed alterations in pathways involved in antigen processing and presentation in the β-cell clusters of HC-PERKi islets. Consistent with this observation, spatial proteomics analysis of the pancreatic β-cell area of HC-PERKi islets revealed a striking upregulation of programmed death-ligand 1 (PD-L1), an immune checkpoint regulator that suppresses adaptive T-cell immunity. Notably, there was no change in transcript levels of PD-L1, suggesting that PD-L1 levels are post-translationally regulated. Collectively, our studies show that inhibition of the ISR activates general protein synthesis, reduces immunogenicity via increased β-cell PD-L1 levels, and decreases T1D risk. Whereas the ISR is an adaptive response, our work emphasizes how the ISR could become maladaptive under chronic inflammation and promote β-cell autoimmunity. Presentation: Friday, June 16, 2023

Disclosure: S. Ahmed: None. L. Medina Mora: None. A. Sanchez Ruiz: None. L. Poretsky: None. Background: SGLT2 inhibitors have a rare but increasingly reported risk of euglycemic diabetic ketoacidosis. Hyperglycemic diabetic ketoacidosis is not an expected risk of SGLT-2 inhibitors. Clinical Case: 52-year-old male with history of type 2 Diabetes presented with progressive weakness, shortness of breath, nausea and vomiting worsening over 48 hours. He reported increased polydipsia and polyuria. Patient was found to have a blood glucose of 685 mg/dL associated with an anion gap of 28 mm/L and bicarbonate level of 6 mm/L. Beta hydroxybutyrate level was >8.0 mmoL/L. He was diagnosed with hyperglycemic diabetic ketoacidosis, given intravenous isotonic fluid and started on an insulin drip. The anion gap closed and he was successfully transitioned off the insulin drip to a basal bolus regimen of insulin. The patient improved quickly without any complication. The patient was never on insulin therapy prior to admission. No obvious source of infection was discovered to precipitate the event. The patient had a 7-year history of diabetes and was only managed on oral medications at home. He was previously on Janumet 50-1000mg twice a day and changed to only dapagliflozin 10mg 9 months prior to the current episode. He never experienced ketoacidosis or hyperosmolar hyperglycemic state. Hemoglobin A1c was found to be 8.0%. He reported that his A1c levels were always less than 8%. Autoimmune workup for type 1 Diabetes was done. C-peptide level was found to be 1.5ng/mL. Patient appeared to have an adequate insulin level despite the recent event of diabetic ketoacidosis. Patient was discharged on 10 units of Glargine® at bedtime and 3 units of Lispro® before meals. He was given glucometer teaching with an appointment for endocrine follow up. During follow up Glutamic Acid decarboxylase, Islet cell, Insulin and Zinc 8 transporter antibodies have come back negative. Patient is being planned for transition to oral antihyperglycemic agents which will not include an SGLT2 inhibitor. A MODY panel is pending results for further evaluation. Conclusion: Monotherapy of SGLT-2 inhibitors appears to not only have a risk of euglycemic diabetic ketoacidosis but also a risk of hyperglycemic diabetic ketoacidosis in type 2 diabetics. In this case we presented a case of hyperglycemic diabetic ketoacidosis in a type 2 diabetic on therapy with dapagliflozin. Presentation: Thursday, June 15, 2023

Disclosure: A.R. Ankireddypalli: None. A. Moheet: None. Introduction: Cystic fibrosis (CF) has classically been associated with malnutrition and being underweight. Intense emphasis on nutritional augmentation and advancement in medical therapies including recent introduction of CFTR modulators have significantly reduced the prevalence of malnutrition in CF. However, this success has been accompanied by a significant rise in overweight/obesity in CF. Recent studies have reported that one-third of all adult CF patients are overweight or obese. Glucagon like peptide receptor-1 agonists (GLP-1RA) therapy is an effective treatment for type 2 diabetes mellitus (T2DM) and obesity. Current guidelines for CF related diabetes (CFRD), recommend insulin as the mainstay of treatment. However, with increase in prevalence of obesity, there is increased interest in examining the role of incretin-based therapies in CFRD. Gastrointestinal (GI) symptoms like abdominal pain, steatorrhea, gastroparesis are common in CF. Concerns about the potential GI side effects had previously dampened the enthusiasm for these drugs in CF.The objective of this case series is to demonstrate impact on glycemic control and weight, and tolerability of GLP1-RA treatment in obese patients with CFRD and pancreatic insufficiency (PI) after 1 year of therapy. Case 1: A 21-year-old female with CF (delta F508 homozygote) and PI, was diagnosed with CRFD at 15 years. She was initially on lantus 14 units daily with HbA1c of 6.7%. She was started on CFTR modulator therapy and with increase in BMI from 37 to 45 in 1 year with HbA1c of 8.9%. She was started on semaglutide and tolerated the medication well with no GI side effects. 1 year later her BMI reduced to 42 and HbA1c was 8.2%. Case 2: A 62-year-old male with CF (delta F508 heterozygote) and PI, diagnosed with CFRD at age 44 years. He was on lantus 66 units and aspart 1 unit per 5 grams carbohydrate coverage. He was started on CFTR modulator and in 1 year BMI increased from 53 to 57. He was started on semalglutide, which he tolerated well with no GI symptoms. 1 year later his Hba1c improved to 7% with a BMI of 54. Discussion: In this era of CFTR modulator therapy, CF patients are faced with changing metabolic parameters, including weight gain and developing T2DM phenotype with insulin resistance. There is one previous case report of short duration of GLP-1RA use in CFRD. We report > 1 year of clinical experience of GLP-1RA use in 2 patients. GLP-1RA was well tolerated in these patients with improvement in glycemic control and weight loss. GLP-1 RA should be considered in obese, PI patients with CFRD as an add-on therapy to insulin. However, larger studies with long-term follow up are required to study the full impact of GLP-1RA to establish it as a treatment option in CFRD. Presentation: Thursday, June 15, 2023

Disclosure: A. Tandon: None. E. Bhowmik: None. Z. Ali: None. S. Tripathi: None. A. B k: None. V. Bhatia: None. P. Dabadghao: None. S. Sudhanshu: None. Background- Basic carbohydrate counting (BCC) represents a meal-planning approach for people with T1DM, emphasizing on consistency in the timing and amount of carbohydrate intake at each meal. In contrast to advanced carbohydrate counting, it is simpler to learn for people with varied levels of education or numeracy skills. The effect of BCC on glycemic control in children with T1DM using MDI is largely unknown. We aimed to determine whether BCC, compared to routine nutritional education (RNE) of our clinic, would improve glycemic control in these children with typical Indian diets. Methods- This randomized, controlled trial included children, adolescents and young adults with T1DM using MDI. In addition to RNE, the intervention group received BCC education including a personalised diet plan with suggestions for carbohydrate exchanges at each meal based on a 2-week food log prepared by them. The control group received the RNE of our clinic including instructions on healthy food choices, food groups, calorie-free foods, glycemic index, and instructions for special occasions. A retrospective CGM study and HbA1c were performed at baseline and at 12 weeks after the dietary education. The primary outcome was the difference in change in TIR (Time in range; 70-180 mg/dl) from baseline through 12 weeks between the two groups. A questionnaire on acceptability of BCC was administered. Results- Ninety two patients [age 15.7 ± 5.0 years, median (IQR) duration of diabetes 5.9 (5.9) years, baseline HbA1c 8.0 ± 1.5 %] wore the FreeStyle Libre Pro sensor for a median of 14 days. Median (IQR) TIR was 41 (18) %, TBR (Time below range; <70 mg/dl) 14 (13) % and TAR (Time above range; >180 mg/dl) 40.7 ± 20.4 %. Coefficient of variation (% CV) was 49.1±10.3% and 92% had high (>36 %) CV. Multivariate regression showed that older age at onset of diabetes was associated with a higher TIR, TBR and a lower TAR, whereas these glycemic metrics were not influenced by current age, urban vs rural residence, education of mother or socioeconomic status. The use of NPH vs glargine for basal insulin was also associated with higher TBR and %CV but lower TAR. Significant improvement was seen in HbA1c in the BCC group, when compared with their own values during the prior 24 months (baseline [8.2 ± 1.3%], 12 weeks [7.9 ± 1.2%], p = 0.042), but not so in the RNE group (baseline [8.0 ± 1.0%], 12 weeks [8.1 ± 1.0%], p = 0.881). However, no significant differences were observed in the changes in TIR, TBR, TAR, %CV and HbA1c between the two groups after 12 weeks of dietary intervention. Although, acceptability of BCC was high, only half of the participants correctly practiced it at more than 50 percent of their meals. Conclusion- Among our families with T1DM treated with MDI, although BCC had high acceptability, it was not frequently practiced and did not lead to greater improvement in glycemic control as compared to routine nutritional education. Presentation: Saturday, June 17, 2023

Disclosure: M. Shaukat: None. R. Memon: None. M. Mack: None. E. Galarza: None. R. Saeed: None. Diabetic Ketoacidosis (DKA) is a life-threatening complication and, occasionally, the initial presentation of Diabetes Mellitus (DM). DKA can rarely present without elevated blood glucose levels, known as Euglycemic DKA, now typically associated with SGLT-2 inhibitors. Metformin is known to cause lactic acidosis but has not been reliably associated with euglycemic DKA. We present a case of metformin-associated lactic acidosis with renal failure and ketosis mimicking euglycemic DKA. Case: 82-year-old female with a history of DM type 2 on metformin and hypertension presented to the Emergency Department (ED) with complaints of presyncope, vomiting and generalized weakness for two weeks. In the ED, her temp. was 90.3 F and BP was 66/28 mmHg. Her labs revealed a potassium of 5.4mmol/L, bicarbonate 5 mmol/L, Creatinine 3.68 mg/dL (baseline 0.7mg/dL), Anion gap (AG) 45mmol/L, Lactate 25.1 mmol/L and Beta-hydroxybutyrate of 21.4 mg/dL. CT Scan of the chest and abdomen showed a 2 cm liver mass and pancreatitis. She was taken to the ICU and started on antibiotics, IV fluids, and vasopressors. The following day, her lactate was 13.5mg/dL, AG was 37mmol/L and Beta-hydroxybutyrate increased to 53.5mg/dL. Her blood sugars remained between 140-180mg/dL and her hemoglobin A1c was in the prediabetic range at 6.1%. She was thought to be in metformin induced euglycemic diabetic ketoacidosis and was started on an insulin drip with 5% Dextrose and 0.45% Normal Saline. Nephrology was consulted and she underwent hemodialysis for metformin toxicity. She remained on the insulin drip for 48 hours after which she was successfully weaned off. She currently remains off on any antidiabetic medication and is doing well. Discussion: DKA is a life-threatening complication of DM that presents as hyperglycemia, ketonemia, and AGMA. Euglycemic DKA is distinguished by blood glucose levels less than 250mg/dL and is usually seen with pregnancy, fasting states and use of SGLT-2 inhibitors. Previous cases of metformin-associated lactic acidosis (MALA) and concurrent euglycemic DKA have been reported, out of which several patients were concurrently on SGLT-2 inhibitors. After a thorough literature review, we were unable to determine a causal mechanism linking metformin and euglycemic DKA. In the reported cases, we believe that renal failure from various causes precipitated MALA due to decrease metformin clearance, with ketosis caused by starvation and exacerbated by metformin-induced inhibition of hepatic gluconeogenesis, further aggravated by an increase in stress hormones resulting in increased insulin resistance and ultimately leading to the development of the severe ketoacidosis. Even though this phenomenon has previously been referred to as “Metformin-induced euglycemic DKA”, we believe that this is more akin to a mimic, rather than true DKA. Presentation: Thursday, June 15, 2023

Disclosure: E. Ermis: None. T. Nargis: None. A. Kulkarni: None. S. May: None. S.A. Tersey: None. R.G. Mirmira: None. R.M. Anderson: None. Type 1 diabetes (T1D) is an autoimmune disease, characterized in part by islet inflammation and macrophage infiltration leading to β-cell injury and loss. The inflammatory mediator 12/15-lipoxygenase (12/15-LOX) and its lipid product 12-hydroxyeicosatetraenoic acid (12-HETE) have both been implicated in T1D. 12-HETE activates the low affinity receptor leukotriene B4 receptor 2 (LTB4R2, or simply BLT2), which was reported as a low-affinity receptor for 12-HETE, suggesting that BLT2 may play a proinflammatory role. Here, we used both mouse and zebrafish models to probe the roles of BLT2 in macrophage activation and/or recruitment to pancreatic islets during T1D progression. First, we analyzed Blt2 gene expression in a variety of C57BL/6J mouse tissues. We found Blt2 gene expression in bone marrow derived macrophages and peritoneal macrophages, however we found little to no expression in pancreatic islets. Although Blt2-/- mice showed a significantly reduced expression of Blt2, they exhibited overall normal growth and glucose tolerance. To uncover roles for BLT2 in macrophage function, we first interrogated its involvement in the in vitro polarization of proinflammatory macrophages to the M1-like state using LPS and IFN-γ and the M2-like state using IL-4. Under these conditions, we found no differences between Blt2-/- and wildtype macrophages, as assessed by flow cytometry analysis, suggesting that BLT2 does not play a substantial role in macrophage polarization. Next, to query roles for BLT2 in macrophage migration, we employed the transgenic zebrafish line Tg(mpeg:EGFP) in which macrophages are labeled with green fluorescent protein (GFP). Following zebrafish tailfin injury, we quantified macrophage accumulation at the injury at 6 hours post amputation. Inhibitory treatments of zebrafish larvae with either a chemical BLT2 inhibitor (LY255283) or by knockdown of the blt2a gene using an antisense morpholino, both decreased the number of GFP+ macrophages found at the injury site. Moreover, in the latter approach ectopic expression of blt2a mRNA effectively restored the wild-type phenotype. To determine if BLT2 mediates macrophage migration to injured islets, we employed a transgenic zebrafish model of β-cell injury, Tg(ins:NTR), in which metronidazole treatment rapidly induces β-cell injury. We treated the Tg(mpeg: GFP); Tg(ins: NTR) zebrafish with metronidazole and monitored macrophage migration into injured islets. We observed a significant decrease in macrophage migration towards injured β-cells in blt2a-knockdown zebrafish. Collectively, these results show that BLT2 plays a role in macrophage migration associated with tissue injury, including the islet β cell as seen in T1D. Presentation: Saturday, June 17, 2023

Disclosure: I.I. Spiliotis: None. L. Anguelova: None. F. Kavvoura: None. K. Owen: None. Diabetes is a multi-hormone disorder involving both insufficient insulin secretion and aberrant glucagon secretion. MODY (Maturity Onset Diabetes of the Young) is a subgroup of diabetes which is caused by mutations in specific genes including HNF1A (MODY3) and HNF4A (MODY1). Most MODY3 or MODY1 patients are managed in the UK with the sulfonylurea gliclazide at a starting dose of around 20-40mg (vs. 80mg - 320mg daily for managing type 2 diabetes). It remains unclear clear why this population is particularly sensitive to gliclazide, and there is limited information on glucagon levels in these patients. The ”Glucagon in MODY” study was a non-randomized interventional pilot study (NCT03246828), aiming to investigate whether fasting and post-prandial glucagon levels are raised in MODY3 & MODY1 patients, and whether gliclazide treatment leads to more physiological glucose-induced glucagon suppression in this population. Methods: We recruited 10 patients from MODY clinics, whose diabetes was managed with gliclazide +/- metformin only at the time of the study. They each underwent a 2h 75g oral glucose tolerance test (OGTT) before and after omitting their gliclazide for 3 days. Blood samples were taken at 30min intervals for glucose, c-peptide and glucagon. Paired t-test was used to compare baseline fasting values on and off gliclazide, and two-way repeated measures ANOVA with post-hoc multiple comparisons was used to compare the OGTT timepoints versus baseline. Results: Study population characteristics were as follows (median ±CI): age 46±9.8, 6 females, BMI 23.9±1.1, HbA1c 52.5±13.6mmol/mol, gliclazide dose 60±29mg per day; 6 MODY3 and 4 MODY1. Fasting blood glucose values were significantly elevated off gliclazide (p<0.001) and rose by an average of 10mmol/L during the OGTT, as expected in this population; however two-way ANOVA did not show a significant difference on vs. off gliclazide. Neither fasting c-peptide nor glucagon values were significantly different on vs. off gliclazide, and while c-peptide rose in both groups, glucagon levels were only suppressed at 60min on gliclazide (p=0.035). When c-peptide and glucagon values were corrected for blood glucose levels during the OGTT, there was no significant change from baseline in c-peptide values on vs off gliclazide. However, glucagon values were significantly decreased on gliclazide from 60min onwards (p<0.01), and there was no correlation with corrected c-peptide values (p=0.2). Conclusion: In our limited study population of 6 MODY3 and 4 MODY1 patients, gliclazide appears to restore appropriate glucose-induced glucagon suppression during a 75g OGTT, which is not related to changes in c-peptide levels. This suggests that pancreatic alpha-cell regulation may be a previously unrecognized mechanism by which sulfonylurea treatment improves glycemic control in MODY. Presentation: Sunday, June 18, 2023

Disclosure: H. Abdelrahman: None. B. DeMoranville: None. Case: A 40 year old man with history of NAFLD and type 2 diabetes mellitus with HbA1c 12.2% on metformin 750 mg daily, presented with diabetic ketoacidosis (DKA) with blood glucose 275 mg/dL and anion gap 24 (AG 10-12). He had been started on empagliflozin 25 mg daily four days prior as outpatient. He was treated with IV insulin and hydration per DKA protocol. Labs showed C-peptide 3.0 ng/mL (1.1-4.4 ng/mL), Anti-GAD Ab 0.01 nmol/L (<0.02 mol/L), negative anti-insulin cell Ab. He was discharged on glargine 10u qHS, lispro 2u AC plus corrective scale, and metformin 750 mg BID. On outpatient follow-up, pre-meal glucose remained under 130 mg/dL, not requiring corrective insulin. He was started on semaglutide 0.5mg weekly and insulin was discontinued. At 3 months, his HbA1c improved to 5.8%. Self-monitoring glucose levels were at goal. Discussion: This case illustrates glucotoxicity due to significant hyperglycemia causing beta-cell apoptosis and resulting in insulin deficiency. The initiation of SGLT2 inhibitors (SGLT2i) when insulin deficiency and peripheral resistance are at their peak increases risk of DKA. This patient with type 2 diabetes presented with blood glucose 275 mg/dL in DKA four days after starting empagliflozin, a SGLT2i. SGLT2i increase risk of DKA due to dehydration from glucosuria, inhibiting ketone body excretion by the kidneys, causing a state of carbohydrate deficit and hypovolemia that promotes glucagon release from alpha-cells, an increased glucagon-to-insulin ratio, and thus triggers ketogenesis.1 In glucose toxicity, intra-cellular hyperglycemia-induced molecular dysfunction results in beta-cell apoptosis. Islet cells cultured in a glucotoxic environment (20 mmol/l) had suppressed insulin content, but fully reversed the intra-cellular calcium response after one week of culturing in a euglycemic environment, demonstrating recovery of the molecular steps promoting insulin release. 2 Treatment with insulin close to euglycemic goals promotes the reversal of glucose toxicity. Our patient recovered beta-cell function several weeks after the glucotoxic episode and was able to discontinue insulin therapy. With the addition of semaglutide, a GLP-1 receptor agonist, which potentiates glucose-dependent insulin release to control post-prandial hyperglycemia, he was able to maintain euglycemia and an HbA1c 5.8%. Conclusion Patients with type 2 diabetes mellitus may present in diabetic ketoacidosis due to glucose toxicity which can be reversed with short-term insulin therapy. References 1) Nasa P, et al. Euglycemic diabetic ketoacidosis: A missed diagnosis. World J Diabetes. 2021 May 15;12(5):514-523. 2) Tariq M, et al. Prolonged culture of human pancreatic islets under glucotoxic conditions changes their acute beta cell calcium and insulin secretion glucose response curves from sigmoid to bell-shaped. Diabetologia. 2022 Dec 2. Epub ahead of print. PMID: 36459178. Presentation: Thursday, June 15, 2023

Disclosure: D.T. Broome: Grant Recipient; Self; NIH U54DK118612-04. Research Investigator; Self; Fractyl Laboratories, Novo Nordisk. Maturity-onset diabetes of the young (MODY) is an inherited form of monogenic diabetes caused by a mutation in a single gene. HNF1A-MODY is the most common treatment-requiring form of MODY with a reported frequency of 1.2%1. Early genetic diagnosis leads to more precise treatment, and sulfonylureas have been recognized as first-line treatment in patients with HNF1A-MODY. Although sulfonylurea treatment is often effective early in the disease course, patients often experience sulfonylurea treatment failure. As a result, there has been recent investigation into additional treatment options that are effective. Glucagon-like peptide-1 receptor agonists (GLP-1 RA) have previously been published for use in patients with HNF1A-MODY2,3, and recognized as a potential effective treatment in patients with HNF1A-MODY. Although GLP-1 RAs have been reported for use as injectable agents, there is currently no evidence reporting their effectiveness as oral medications. In this report, we present a novel case of use of oral semaglutide as adjuvant treatment to sulfonylurea in a patient with HNF1A-MODY. A 48-year-old female with a history of diabetes since age 22, later confirmed as HNF1A-MODY at age 45 (Heterozygous HNF1A mutation, c.608G>A (p.Arg203His), NM_000545.5), was glimepiride for 3 years and without micro- or macrovascular complications. She developed a 15-lb weight gain, and her HbA1c increased to 7% (HbA1c gradually increasing from 5.4% to 7.0% over 3 years) despite her taking glimepiride 4 mg twice daily prescribed by her primary care physician. Thereafter, her primary care physician prescribed oral semaglutide 3 mg once daily for 4 weeks, which was titrated to 7 mg once daily. After initiation of oral semaglutide, her glimepiride was reduced to 2 mg once daily, her HbA1c improved to 5.4%, and she lost 30 lbs over a 6-month timeframe. This is the first report demonstrating the benefits of oral GLP-1 RA treatment in a patient with HNF1A-MODY, and this clinical case provides further support of use GLP-1 RA use as adjuvant treatment to sulfonylurea in patients with HNF1A-MODY. References: 1. Pihoker C, Gilliam LK, Ellard S, et al. SEARCH for Diabetes in Youth Study Group. Prevalence, characteristics and clinical diagnosis of maturity onset diabetes of the young due to mutations in HNF1A, HNF4A, and glucokinase: results from the SEARCH for Diabetes in Youth. J Clin Endocrinol Metab. 2013;98:4055-4062. 2. Østoft SH, Bagger JI, Hansen T, et al. Glucose-lowering effects and low risk of hypoglycemia in patients with maturity-onset diabetes of the young when treated with a GLP-1 receptor agonist: a double-blind, randomized, crossover trial. Diabetes Care. 2014;37:1797-1805. 3. Docena MK, Faiman C, Stanley CM, Pantalone KM. Mody-3: novel HNF1A mutation and the utility of glucagon-like peptide (GLP)-1 receptor agonist therapy. Endocr Pract. 2014;20:107-111. Presentation: Saturday, June 17, 2023