Increased Insulin Requirements Research Articles

12355 An Adolescent Female With Congenital Lipodystrophy Presenting With Repeated Acute Metabolic Decompensations Rescued By A Novel Leptin Receptor Agonist

Abstract Disclosure: D.M. Chambers: None. Y. Chan: None. M.K. Crocker: None. Patient SH is a now 17-year-old female treated for generalized congenital lipodystrophy with a course complicated by severe hypertriglyceridemia, type 2 diabetes mellitus, hypertension, hepatosteatosis, and intermittent menstrual irregularity. She had been managed successfully with metreleptin for 2 years, but in 2022-2023, she developed repeated episodes of pancreatitis (4 times over a 14-month period) secondary to severe hypertriglyceridemia (serum triglycerides >8000 mg/dL). During her admissions, she had markedly increased insulin requirements (up to 12 units/kg/day) with refractory hyperglycemia despite maximal treatment with metreleptin, empagliflozin, and oral semaglutide. In the clinical context of her acute metabolic worsening, she was suspected of having a neutralizing antibody against metreleptin. Serum leptin was undetectable 1 hour after observed metreleptin doses; direct measurement of neutralizing antibodies is pending. She was transitioned from metreleptin to mibavademab, an investigational leptin receptor agonist, on an expanded use IND. She subsequently experienced significant improvements in her fasting triglyceride levels (<300 mg/dL) with no subsequent episodes of pancreatitis since starting therapy in August 2023. She has also had improvements in other aspects of her metabolic health including decreased insulin requirements with decreasing hemoglobin A1c, decreased need for adjunctive lipid and hypertension therapy, and improving menstrual regularity. Her clinical course demonstrates: 1) clinical indicators of a rare but serious loss of efficacy of metreleptin therapy; 2) adjunctive options for management of generalized lipodystrophy; and, 3) an individual experience with a novel leptin agonist therapy in the treatment of generalized lipodystrophy. Presentation: 6/3/2024

Increased Insulin Requirements in Severe Cases of Covid-19 are Higher Than in Moderate Cases

Increased Insulin Requirements in Severe Cases of Covid-19 are Higher Than in Moderate Cases

Insulin requirements during pregnancy in women with type 1 diabetes treated with insulin pump.

Insulin requirement in women with Type 1 diabetes (T1DM) changes throughout pregnancy. The aim of this study was to determine the total change in insulin requirements and the effect of gestational weight gain (GWG) and pre-gestational BMI on insulin requirements during pregnancy in women with T1DM treated with continuous subcutaneous insulin infusion and continuous glucose monitoring. This historical cohort study included all consecutive women with T1DM who were monitored during pregnancy at the high-risk pregnancy clinic at a tertiary medical center during April 2011-April 2019. One Way Repeated Measures ANOVA with Bonferroni adjustment was conducted to compare the effects of gestational age on insulin requirements and a Two Way Repeated Measures ANOVA was employed to test for the interaction between gestational age intervals and maternal BMI and GWG. Data regarding insulin requirements of 185 pregnancies were included in the analyses. There was a significant effect of gestational age on total insulin (Wilks' Lambda=0.34, F(6,14)=4.52, p=0.009), basal insulin (Wilks' Lambda=0.41, F(6,14)=3.30, p=0.031) and bolus insulin (Wilks' Lambda=0.43, F(6,14)=3.02, p=0.041). Total insulin/kg requirements increased by 5.5% from 13-20weeks to 20-26weeks, 19% from 20-26weeks to 26-33weeks, and 17.4% from 26 to 33weeks to delivery (p for trend=0.009). Overall, insulin requirements increased by 42.1% from conception to delivery (p<0.01). There was no significant main effect of maternal BMI or GWG on insulin requirements. There is a significant increase in insulin requirements per kg during pregnancy in women with T1DM who were treated with an insulin pump.

Type 2 diabetes and pregnancy: management from preconception to the postpartum

With the increasing prevalence of diabetes, we are more frequently confronted to treat pregnant women with pre-existing type 2 diabetes. Thereby, we need to take several factors into account such as glycemic control before and during pregnancy, comorbidities such as overweight/obesity and hypertension, as well as existing complications and the need for changes in diabetes treatment. Pregnancy leads to increased insulin requirements, particularly from the second trimester onwards. In this context, a healthy lifestyle and control of weight gain are also necessary. This article provides an overview of the interdisciplinary management of type 2 diabetes before and during pregnancy and in the postpartum period.

COVID-19 Pneumonia and Increased Insulin Requirement in Known Diabetic Patients: A Prospective Observational Study.

Background COVID-19-related critical illness affects multiple organs and causes a variety of metabolic derangements in the body's physiology that are not proven with the current level of evidence. Insulin resistance and deranged blood sugar control due to COVID-19 have been major problems when managing diabetic patients with hyperglycaemia when they are admitted with COVID-19 pneumonia. There is a lack of abundant literature to prove the excess insulin requirements of COVID-19 and to quantify their insulin needs scientifically. This study aims to quantify the degree of insulin dose increments in these patients. Materials and methods The study is a single-centre prospective observational study done in COVID-19 wards at a tertiary care hospital in India. The diabetic patients admitted with COVID-19 pneumonia between June 2020 and December 2020 were included in the study. Seventy-five patients with fair control of diabetes (HbA1C <7.5) were included in the study. Their average daily insulin requirement was calculated for the first seven days of admission. This was tabulated and compared to their baseline insulin requirement before being unwell due to COVID-19. A sub-group analysis was also done to show the relation between severity of illness and glycaemic dysregulation. Result Invariably, all patients were found to be hyperglycaemic on admission. Insulin need has increased to 1.5 to 2.5 times the baseline values in the first 24 hours of admission. This insulin dose requirement stayed high around the same levels for all seven days of observation. The average mean value of the daily insulin dose for the seven days of study was calculated to be 132 units. This is more than twice the mean baseline daily insulin requirement of 62 units during the pre-COVID-19 period. Subgroup analysis showed that the severe group had poor glycaemic control, requiring higher doses compared to their own baseline and also to the moderate group. Conclusion COVID-19 pneumonia significantly increases insulin resistance and insulin requirements during illness in fairly controlled known diabetic patients with insulin. Managing this COVID-19-induced hyperglycaemia requires 1.5 to 2.5 times the baseline insulin doses.

The Impact of Using Carbohydrate Counting on Managing Diabetic Patients: A Review.

Carbohydrate counting (CC) is a meal planning practice for diabetic patients, focusing on tracking the amount of carbohydrates in grams consumed at meals to manage blood glucose (BG) levels. The purpose of this narrative review is to evaluate the impact of CC in helping people with diabetes manage their condition. It reveals that CC offers superior glycemic control and flexibility compared to other food planning techniques. Specifically, when applied to children and teenage patients diagnosed with type 1 diabetes mellitus (T1DM), CC demonstrates the potential for substantial improvements in metabolic control without any adverse effects on weight or increased insulin requirements. In the context of T1DM, the combination of CC and the use of automated bolus calculators (ABCs) contributes to lowering glycated hemoglobin (HbA1c) levels. Furthermore, the study highlights that CC also holds promise in the management of type 2 diabetes mellitus (T2DM). In T2DM patients, adhering to a low glycemic index (GI) diet has proven to be more effective in controlling HbA1c and fasting BG levels compared to a higher GI diet or standard dietary control. This research underscores the evolving significance of CC as a pivotal component in diabetes management, attributed to increased awareness and education among patients. CC emerges as a versatile tool that can benefit individuals with various forms of diabetes by enhancing their glycemic control and overall quality of life. The findings affirm the impact of CC in improving patient outcomes, solidifying its status as a vital strategy in the multifaceted landscape of diabetes care.

THU027 Challenges In The Management Of Extreme Hyperglycemia In An Acromegalic Patient

Abstract Disclosure: M. Sonbol: None. M. Novitskaya: None. J. Monye: None. S. Jafri: None. E. Japp: None. Introduction: Hyperglycemia in acromegalic patients presents a unique challenge given the disruption GH has on glucose homeostasis. Chronic hypersecretion of GH causes severe insulin resistance which can progress to uncontrolled DM. We describe a patient with acromegaly requiring &amp;gt;180 units/day of insulin in the perioperative period while awaiting transsphenoidal surgery. Clinical Case: A 49-year-old female with HTN and recent diagnosis of uncontrolled type 2 DM presented with several months of blurry vision and headaches. She had several prior admissions for hyperglycemia and DKA (with normal C-peptide, and negative GAD-65 and islet cell autoantibodies) despite compliance with insulin therapy. Her HbA1c was 12.2% on 2 units/kg TDD of insulin. Imaging was significant for a sellar/suprasellar solid mass with cystic components measuring 8.3 x 6.3 x 7.8 cm encasing bilateral internal carotid arteries, encroaching the left orbital apex, and applying mass effect on bilateral frontal lobes, and right temporal lobe and midbrain. Labwork was significant for IGF-1 1083 ng/mL (n&amp;lt;238), and GH of 96.4 ng/mL (n&amp;lt;8). FSH and LH were suppressed, with otherwise normal pituitary hormone levels. Interestingly, the patient did not exhibit classic clinical features of acromegaly such as macroglossia, enlarged digits or coarse facial features. Transsphenoidal biopsy demonstrated mature PIT-1 lineage NET with expression of GH and PRL. Given the significant tumor mass effect, she was placed on dexamethasone 4 mg q12h. Preoperatively, her blood glucose worsened and reached 500 mg/dL despite &amp;gt;180 units of insulin/day on a subcutaneous insulin regimen. Glycemic management was escalated with addition of regular insulin gtt up to 25 units/hr to achieve target blood glucose of 140-180 mg/dL. After successful surgical resection of the tumor, HbA1c decreased to 7.7% on 1.3 units/kg TDD of insulin, metformin and empagliflozin at eight weeks postoperatively. Clinical Lessons: Unusual presentations of rapidly increasing insulin requirements in newly diagnosed DM should raise clinical suspicion for secondary causes such as acromegaly. The degree of insulin resistance is often out of proportion to the patient’s body habitus given the GH-mediated lipodystrophy and adipose tissue dysfunction. In this case, the patient’s insulin requirement was 2 units/kg TDD of insulin, with her BMI being only 22.14 kg/m2. Given the need for semi-urgent surgery due to the tumor’s mass effect, SSA therapy or GH-receptor antagonist was not initiated, and insulin therapy was the mainstay for preoperative glucose management. In severe cases of acromegaly-related hyperglycemia, subcutaneous insulin alone may not be sufficient for adequate glucose control, especially in the setting of preoperative steroids, and large doses of IV insulin may be needed to reach inpatient glucose goals. Presentation: Thursday, June 15, 2023

SAT108 What A Simple Switch Can Achieve; A Case Of Severe Insulin-induced Lipohypertrophy

Abstract Disclosure: T. Ayub: None. L.A. Robles: None. S. Guntupalli: None. C.E. Guillen Lopez, MD: None. Introduction: Lipohypertrophy, a benign “tumor-like” swelling of the fatty tissue, is a common dermatological complication of subcutaneous insulin therapy. Here, we describe a case of severe skin lipohypertropy causing poorly controlled glycemic control requiring high insulin doses. However, after rotating the injection sites, followed a significant decrease in total daily dose (TDD) of insulin. Clinical Case: A 69-year-old female with a past medical history of type 2 diabetes mellitus (DM) for the last 16 years presented with uncontrolled blood glucose and gradually increasing insulin requirements. Hemoglobin A1c was 9.3%. Body mass index (BMI) of 32.59kg/m2. Home regimen insulin included long-acting insulin (Levemir), 50 units in the morning and 150 units at night, plus short-acting insulin (Humalog), 62 units with meals. Exenatide, Insulin Glargine, and Metformin were not tolerated in the past due to GERD-like side effects. An insulin pump was offered, but she preferred insulin injections. Patient endorsed good injection technique and adequate rotation between the inner and outer thighs. Surprisingly, physical examination revealed skin discoloration with hypertrophy on both thighs’ bilateral medial and later surfaces. Based on the history and skin examination, a clinical diagnosis of insulin-induced Lipohypertrophy was made. Patient was instructed to switch injection sites to the buttocks and provided with a new insulin regimen. Three months after initial visit, hemoglobin A1c dropped to 7.2%, and TDD of insulin was reduced by 48%, to Levemir 46 units twice daily, Humalog 30 units with breakfast/lunch, and 34 units with dinner. After seven months, her hemoglobin A1c dropped to 7% without further changes to the insulin regimen. Despite these changes, the lipohypertrophy had minimal changes. Discussion: The pathophysiology of lipohypertrophy is linked to a direct anabolic effect of insulin on local skin, inducing fat and protein synthesis. Risk factors include failure to rotate injection sites, needle reuse, female gender, high BMI, and long disease duration. Insulin injection in the lipohypertrophy areas can delay insulin absorption, causing glucose variability with unpredictable hyper and hypoglycemia episodes. There is no established therapeutic method to treat severe lipohyperthohy; avoiding further injection into that area is crucial, then surgical intervention can be considered. Currently, the best preventative and therapeutic strategies for insulin-induced lipohypertrophy include rotating injection sites and a single use of needles. Conclusion: This case emphasizes the importance of detailed inspection and palpation of insulin injecting sites regularly and how early intervention can lead to significant improvement in glycemic control, as described in our case. Presentation: Saturday, June 17, 2023

THU012 Incidental Pituitary Adenoma In A Patient With Ectopic ACTH Secreting Cushing Syndrome - A Diagnostic Conundrum

Abstract Disclosure: M.S. Nali: None. R.R. Yatavelli: None. Background: Cushing’s syndrome (CS) is a rare condition with an estimated incidence of 2-3 cases/million. Endogenous CS can be divided into ACTH -dependent (80%) and ACTH Independent (20%) with Ectopic Cushing’s syndrome (ECS) accounting for 10-20% of all cases of ACTH-dependent CS. Herein we present a case with indolent onset ACTH-dependent CS who on initial work-up showed a pituitary microadenoma raising the suspicion for Cushing disease, but the source of excess ACTH was found to be from a pulmonary neuroendocrine tumor. Clinical Case: A 44-yr-old female with history of type 1 DM, Obesity, BMI 43.60, Sleep apnea was evaluated elsewhere for suspected Cushing’s due to increased insulin requirements and progressive weight gain. Outside labs showed cortisol of 4.5 ug/dl on 1 mg DST &amp; 8 mg DST cortisol was 3 ug/dl. MRI of the pituitary showed a 3.5x 2.8x 1.8 mm microadenoma &amp; she was initially presumed to have Cushing’s disease secondary to pituitary microadenoma. The patient was seen by neurosurgery who referred to endocrine for localization of cortisol excess by IPSS. Clinically she had moon facies, hirsutism, dorsocervical fat pad, violaceous striae on abdomen. On further laboratory evaluation her ACTH: 88 (0-46) and random cortisol 14 ug/dl with normal rest of pituitary hormones. Her 24-hour urine free Cortisol was 45ug/d (3.5 - 45) and late-night salivary cortisol: 74 &amp;&amp;lt;50 (Ref. range &amp;lt;100 ng/dl) on couple of nights, respectively. Due to non-suppressed cortisol on high dose DST, a CT chest was obtained which showed a 2cms non calcified nodule in the left lower lobe of lung. Transbronchial biopsy was performed, cytopathology showed well differentiated neuroendocrine tumor, likely carcinoid and stained strongly positive for ACTH confirming ectopic ACTH producing tumor. Gallium-68 Dotatate Scan showed abnormal increased uptake in the known left lung nodule. The patient was recommended for surgical removal of neuroendocrine tumor, but she could not tolerate anesthesia and had to undergo stereotactic body radiation therapy (SBRT) for the lung lesion. Repeat ACTH levels 2 months post SBRT showed the ACTH levels were elevated and lesion was still persistent on imaging, however on discussion with rad oncology, the neuroendocrine tumors tend to take longer to show response on imaging and plan is to repeat imaging and biochemical work up in couple of months. Conclusion: The diagnosis of CS and recognizing the source of hormonal excess poses significant challenges Pituitary adenomas are incidentally discovered in up to 10% of the normal population &amp; IPSS is advised for patients with ACTH-dependent Cushing's syndrome and an adenoma smaller than 6 mm, however in patients with equivocal findings, it is important to look for other sources of ACTH prior to any invasive procedure. The source of ectopic ACTH secretion should be established after diagnosis because the excision of an ACTH-producing tumor can be curative. Presentation: Thursday, June 15, 2023

Excessive BMI is associated with higher C-peptide level at recognition but also with its greater loss in two years clinical observation in children with new onset type 1 diabetes.

The prevalence of obesity in general pediatric population increases without sparing children with T1D. We intended to find factors associated with the possibility of preserving endogenous insulin secretion in individuals with long-standing T1D. At onset, higher BMI is associated with higher C-peptide level, which may indicate to be one of the favorable factors involved in preserving residual β-cell function. The study determines the influence of BMI on C-peptide secretion in children newly diagnosed with T1D in two years observation. We assessed the possible relationship between selected pro- and anti-inflammatory cytokines, body mass at recognition and β-cell function status. 153 pediatric patients with newly diagnosed T1D were divided into quartiles according to BMI-SDS index. We separated a group consisted of patients with BMI-SDS >1. Participants were followed up for two years and examined for changes in body weight, HbA1c, and insulin requirement. C-peptide was assessed at baseline and after two years. We evaluated the patients' levels of selected inflammatory cytokines at baseline. Subjects with higher BMI-SDS presented higher serum C-peptide levels and lower insulin requirements at diagnosis than children with lower body weight. The two-year follow-up showed that C-peptide levels of obese patients dropped more rapidly than in children with BMI-SDS within normal limits. The group with BMI-SDS >1 showed the greatest decrease in C-peptide level. Despite statistically insignificant differences in HbA1c at diagnosis between the study groups, in the fourth quartile and BMI-SDS >1 groups, HbA1c as well as insulin requirements increased after two years. The levels of cytokines varied the most between BMI-SDS <1 and BMI-SDS >1 groups and were significantly higher within BMI-SDS >1 group. Higher BMI, associated with enhanced levels of inflammatory cytokines, relates to preservation of C-peptide at T1D recognition in children but is not beneficial in the long term. A decrease in C-peptide levels combined with an increase in insulin requirements and in HbA1c among patients with high BMI occur, which may indicate a negative effect of excessive body weight on the long term preservation of residual β-cell function. The process seems to be mediated by inflammatory cytokines.

"Multidisciplinary Team Management of a Pregnant Woman With Newly Diagnosed Multiple Pulmonary Embolisms and Foetal Compromise, When to Deliver?"

Thromboembolic disease, including pulmonary embolism (PE) is the leading cause of direct maternal mortality in the UK (UKOSS, [1]). In women with diabetes, there is usually an increase in resistance to insulin within the placenta and taking corticosteroids often causes an increase in insulin requirements. A sudden reduction at term is an indication of a failing placenta and increases the risk of sudden stillbirth, requiring an expedited delivery.

NURSE AND PATIENT PERCEPTION IN SELF-MONITORING OF DAWN EFFECT TO ENHANCE SELF-MANAGEMENT IN DIABETES MELLITUS PATIENT’S: A QUALITATIVE CASE STUDY

Background: A phenomenon in diabetes mellitus patients is called dawn effect, the condition of hyperglycemia suddenly increasing insulin requirement in the morning caused by nonattendance of nighttime hypoglycemia. Self-monitoring can be minimizing the impacts of dawn effect. Self-management can be actualized to oversee the blood glucose levels fluctuation in diabetes mellitus patients. Objective: to gain self-monitoring influencing factors of dawn effect phenomenon, and increase self-management in diabetic patient and nurse knowledge in Temanggung, Central Java Methods: A qualitative study design was used in this research with semi-structured interviews and open-ended questions. Participants were selected using purposive sampling technique from primary healthcare and secondary healthcare of both nurse and patient. Twelve participants consisted of senior nurse (n=5), patients with type 2 diabetes mellitus (n=7). Information of psychometric diabetes self-management scale and blood glucose monitoring were day by day collected within the morning. Result: Nurses' perception of the dawn effect is still relatively low due to a lack of knowledge and competence in self-management of diabetes patients. They followed the doctor's advice. In addition, the patient's perspective of blood glucose monitoring was taken into account, despite the fact that they did not have a glucometer from a mobile device (lack of self-management and dawn effect). Furthermore, all participants (n=7) increase in blood glucose level in the morning. Invasive glucometer has a high accuracy, but inducing finger discomfort, uncomfortable, and increase risk of infection when it checked daily. Conclusion: Perceptions of nurse and patient about self-monitoring can improve patient self-management and prevent the occurrence of dawn effects.

Euglycemic diabetic ketoacidosis (EDKA) after pancreaticoduodenectomy: An under-recognized metabolic abnormality with outcome implications

Euglycemic diabetic ketoacidosis is a metabolic condition characterized by relative euglycemia, ketonemia, and metabolic acidosis that occurs through mechanisms resembling starvation. Pancreaticoduodenectomy is a complex abdominal operation that subjects patients to a prolonged fasting and an inflammatory state. This study examined the incidence of euglycemic diabetic ketoacidosis and potential opportunities for early diagnosis and management in patients undergoing pancreaticoduodenectomy. A single-institution retrospective review of 350 patients who underwent pancreaticoduodenectomy between 2017 and 2020 was performed. Primary endpoints were peak beta-hydroxybutyrate levels, peak lactate levels, lowest pH, peak base deficits, and urinary output within the first 24 hours, postoperatively. Additional endpoints included incidence of postoperative pancreatic fistula, delayed gastric emptying, total complications, postoperative hospital length of stay, readmission rates, and changes in insulin regimen at discharge. Of the 350 cases reviewed, 39 (11.1%) patients developed euglycemic diabetic ketoacidosis. Male sex and pancreatic cancer were associated with a risk for euglycemic diabetic ketoacidosis (P < .05). Patients with euglycemic diabetic ketoacidosis had significantly higher peak beta-hydroxybutyrate levels than patients without euglycemic diabetic ketoacidosis (mean difference= 19.8 mg/dL, 95% confidence interval= 14.7-24.9, P < .001), and were nearly four times more likely to require insulin at discharge (odds ratio 3.8, 95% confidence interval= 1.1-13.0, P < .05). This is the first large descriptive study that investigates euglycemic diabetic ketoacidosis after pancreaticoduodenectomy. Euglycemic diabetic ketoacidosis after pancreaticoduodenectomy is associated with significantly higher beta-hydroxybutyrate levels and new or increased insulin requirement at discharge. Our study demonstrates potential markers for euglycemic diabetic ketoacidosis after pancreaticoduodenectomy, offering an opportunity to identify and successfully treat this disease in a timely manner.

SGLT2 inhibitor versus carbohydrate-restricted isocaloric diet: reprogramming substrate oxidation in type 2 diabetes

ObjectiveBased on the whole-body energy metabolism and insulin action, the difference between increased excretion of carbohydrate in urine by SGLT2i and reduced same amount of oral carbohydrate intake are scarce. This study aimed to compare the effect of carbohydrate availability with reduced oral intake (carbohydrate-restricted isocaloric diet: CRIC diet) or lost in urine, as urinary glucosuria on sodium/glucose cotransporter-2 inhibitor (SGLT2i) treatment, focus on the insulin requirement and the macronutrient oxidation within insulin treated type 2 diabetes.MethodsThis is randomized 3-arm open-label prospective study. Subjects treated with titrated basal-bolus insulin regimen subsequent to three diet regimens, control diet (CON), administration of canagliflozin 100 mg/day to CON (SGLT2i), or CRIC diet, with a week admission to the endocrinology ward followed by 12 weeks outpatients’ management. The main outcome measures including the total insulin dose (TID) required to achieve euglycemia, fasting and postprandial energy expenditure (EE) and respiratory quotient (RQ) at 1-week and 12-week.ResultsWe enrolled 23 patients with type 2 diabetes (male/female: 14/9, age: 53.6 ± 14.2 years, body mass index: 26.9 ± 4.8 kg/m2, HbA1c: 12.5 ± 1.6%). The TID was similar with CON and SGLT2i at both 1 and 12-weeks. Although comparable net carbohydrate availability in SGLT2i and CRIC groups, the TID was significantly higher in the CRIC (p = 0.02) compare to the SGLT2i at both 1 and 12-weeks. Fasting EE was similar in all groups, postprandial EE was significantly elevated in the SGLT2i and CRIC groups compared to the CON group (p = 0.03 and 0.04). Compare to the CON, lower basal fasting RQ (p = 0.049) and decreased delta-RQ (postprandial RQ/fasting RQ) indicated continuous lipid substrate utilization in the SGLT2i (p = 0.04) and CRIC (p = 0.03) groups.ConclusionThe CRIC diet resulted in a similar fasting and postprandial EE and substrate oxidation compared to the SGLT2i. The increased insulin requirement in the CRIC diet indicates that a relatively highly lipid and protein consumption, compared to the SGLT2i and CON, may influence insulin requirement.

PMON01 Alpelisib (PI3-K Inhibitor) Induced Severe Insulin Resistance Complicated by Diabetic Ketoacidosis (DKA) with Rapid Reversal Following Discontinuation: A Case Report

Abstract Background Alpelisib is a phosphatidylinositol-3-kinase (PI3K) inhibitor, recently approved for treatment of metastatic breast cancer with PIK3CA mutation. The PI3K is involved in insulin signaling pathway and is responsible for translocation of GLUT-4 transporters in insulin responsive tissues and thus modulates insulin sensitivity. Impairment of PI3K pathway results in insulin resistance. Hyperglycemia is a known side effect of alpelisib, however there are only 5 reported cases of alpelisib induced DKA in literature. We describe a patient with Type 2 DM and metastatic breast cancer started on alpelisib with resultant rapid worsening of insulin resistance requiring substantially increased doses of insulin ultimately leading to DKA. She later had rapid reversal of insulin resistance with discontinuation of alpelisib. The degree and rapid onset/reversal of insulin resistance is highlighted in this case. Case 59-year-old female with Type-2 DM, metastatic breast cancer with PIK3CA mutation was started on alpelisib 300mg daily after inadequate response to other agents. Her insulin regimen prior to starting was degludec(U100) 35 units daily and humalog(U100) 30 units with meals. In the first week of starting alpelisib, her continuous glucose monitor(CGM) showed a dramatic increase in glucose values &amp;gt;400 mg/dL accompanied with polyuria and polydipsia. Anti-GAD and Islet-cell-antibodies were negative with C-peptide of 1.55 ng/mL with glucose of 378 mg/dL. Patient was hospitalized with DKA during month 4 of treatment after continuous up titration of her insulin therapy outpatient. With resolution of DKA, patients’ glucoses were well controlled when transitioned to a regimen of degludec 50 units and humalog 12 units with meals. Once alpelisib was restarted during this hospitalization, patient's glucoses increased from 140mg/dL to &amp;gt;400 mg/dL in just 4 hours after administration. Patient was ultimately discharged on a significantly higher dose insulin regimen of degludec 140 units daily and humalog 85 units TID as well as metformin and dulaglutide. A restaging scan demonstrated progression of her cancer and alpelisib was hence discontinued. We instructed the patient to decrease the dose of insulin from the day alpelisib is discontinued to degludec 10 units (.15 units/kg) and a correction scale with meals to assess new insulin requirements. Within the first 24 hours, patient's glucose improved significantly and remained well controlled with degludec 10 units daily and Humalog 5 units with meals. Conclusion The degree of alpelisib induced insulin resistance is often severe with significant increase in insulin requirements. The time to onset and reversal of alpelisib induced insulin resistance is often rapid and providers need to anticipate a rapid increase in insulin requirements within a few days of starting alpelisib and adjust doses promptly to prevent potential complication of DKA. Providers should also anticipate a rapid decrease in insulin requirements within 24 hours of discontinuation to prevent potential hypoglycemic events. Presentation: Monday, June 13, 2022 12:30 p.m. - 2:30 p.m.

Benefits and warnings after one year of Minimed 780 G hybrid closed loop pump treatment in type 1 diabetes adults

The benefits of a hybrid closed loop insulin pump system are generally compared to non-automated insulin pump treatment of type 1 diabetics whose glycemic control was often unsatisfactory. Here we report the results of a monocentric cohort of type 1 diabetics with a good glycemic control before the switch to the hybrid system. 83 adult patients were followed up for 12 months after the implementation and training of the hybrid system. We observed a significant improvement in the glycemic mean index at 3 and 6 months but not at 12 months, accompanied by a 10% increase in insulin requirements over the first few months. Surprisingly, the time spent in hypoglycemia did not decrease. An analysis shared with patients leads us to propose several measures to consider before switching to a hybrid closed loop system.

PB2251: TWO POLYCYTHEMIA VERA PATIENTS WITH A DIAGNOSIS OF CONCOMITANT HEREDITARY HEMOCHROMATOSIS

Background: Hereditary Hemochromatosis (HH) is an inherited iron metabolism disorder characterized by excessive iron accumulation in the liver, heart, pancreas and other endocrine organs. Although it is often associated with mutations in the HFE gene, it can also be caused by mutations associated with HJV, TFR-2 and ferroportin. JAK2 V617F (+) Polycythemia Vera (PV) is the most common cause of acquired primary erythrocytosis and has been reported very rarely in patients with HH. Aims: We presented two polycythemia vera patients with a diagnosis of concomitant hereditary hemochromatosis. Methods: Presence of HFE gene mutation and jak-2 V617F mutation was determined by PCR test Results: Case 1: N.G, a 67-year-old male patient with a history of hypertension, insulin-dependent diabetes mellitus and cerebrovascular accident was diagnosed with PV in another center in 2007. The patient was JAK2 V617F (+) and the tests performed in our laboratory after phlebotomies were EPO: 7.8 mIU/ml, ferritin: 34 ng/dl, transferrin saturation: 49%. Bone marrow aspiration biopsy revealed hypercellularity with erythroid and megakaryocytic hyperplasia. Although Hb/Hct levels were within the targeted range with hydroxyurea 500 mg 2x1 treatment, he was followed up with frequent phlebotomies due to persistent pruritus. After phlebotomy, there was a significant improvement in his pruritus. He was using clopidogrel as antiaggregant treatment. During follow-up, there was deterioration in blood glucose regulation and an increase in insulin requirement. In June 2018, he developed widespread hyperpigmentation on his skin. Due to unregulated diabetes, hyperpigmentation, and high ferritin levels despite frequent phlebotomy, he was examined for HH. He was found to be heterozygous positive for the HFE gene H63D mutation. The patient is still being followed up with HU 2X1 and phlebotomy without any problem. Case 2: E.H, a 57-year-old male patient with a history of hypertension and type 2 diabetes mellitus was diagnosed with PV in 2015. He was JAK2 V617F(+) and at diagnosis EPO:3.7 mIU/ml, ferritin:1403 ng/ml, transferrin saturation:63%. Bone marrow aspiration biopsy revealed hypercellularity and erythroid hyperplasia. Since he was a low-risk patient under the age of 60 and had no history of thrombosis, he was followed up with ASA 100 mg/day and intermittent phlebotomies. Similar to the first case, persistent pruritus was present despite the normal Hb/Hct level. Since hyperferritinemia was not expected in polycythemia vera and the patient was diabetic, he was examined for HH. In the HFE gene analysis, the H63D mutation was found to be heterozygous. Due to the frequent need for phlebotomy, the patient is considered to start treatment with hydroxyurea, and the follow-up still continues. Summary/Conclusion: The association of HH and PV has been rarely reported in the literature, and its clinical significance is not clearly known. In the presence of unexplained high ferritin levels in PV, even if the clinical findings are unclear, screening for HH may be recommended as an appropriate approach. The role of HFE genotypes in the development of myeloproliferative diseases is unknown. Clinical data accumulation is needed to elucidate iron metabolism and prognostic features in PV patients with HFE mutations. Keywords: polycythemia vera, hereditary hemochromatosis, JAK2 V617F, HFE mutation

Abstract #1184998: A Case of using U-500 During Pregnancy for Optimal Glycemic Control

Insulin resistance is a common and challenging complication faced by many women during pregnancy. Due to severe resistance, patients can have very high insulin requirements making its management challenging for physicians. This has been a well-established phenomenon due to the human placental lactogen which decreases insulin sensitivity in pregnant women. U-500 regular insulin is a concentrated insulin used in patients with high insulin requirements however its use during pregnancy has not been fully established. We present a case of a pregnant female who was insulin naive prior to pregnancy, who was successfully managed with U-500 to achieve optimal glycemic control. A 24 year old woman with history of Type 2 diabetes (controlled by diet alone) presented to her endocrinologist at 8 weeks gestation. Her last Hemoglobin A1c prior to pregnancy was 7.1%. Due to elevated fasting blood sugars, she was initially started on Metformin 1 gram twice a day along with Glargine 10 units daily. Due to persistently elevated fasting and post prandial blood sugars, meal time insulin was also initiated using Lispro. Patient’s insulin had to be gradually up titrated to 100 units daily in her first trimester using the traditional basal bolus regimen. She continued to have increasing insulin requirements, peaking at 300 units in the third trimester with the abovementioned basal bolus regimen. The decision was made to switch patient to U-500 to assist with glucose optimization. With the use of U-500, patient was able to maintain the required tight pregnancy blood glucose goals. For the remainder of her pregnancy, she stayed on U-500 100 units thrice daily. Patient eventually delivered a 6 pound healthy baby without any complications. Post-partum, patient’s insulin requirements improved significantly within the first two weeks and was taken off all insulin. She continues to remain well controlled on only Metformin 1g twice a day. The use of U-500 is typically for patients requiring more than 200 units of insulin daily. There have not been enough studies with the use of U-500 in the pregnant population. We present a case where U-500 was safely used in a pregnant woman in the setting of extreme insulin resistance for a safe and healthy pregnancy. Furthermore, to our knowledge there have been no cases showing the use of U-500 during pregnancy with complete resolution of insulin requirement post-partum. Our case demonstrates that U-500 can be considered in clinical trials for further assessment of its safety and efficacy in pregnant subjects with severe insulin resistance.

Glycated hemoglobin at diagnosis of type 1 diabetes and at follow-up in children and adolescents during the COVID-19 pandemic in Germany.

BackgroundThis study investigated the diagnostic delay and the subsequent quality of care during the Covid‐19 pandemic among children with new‐onset type 1 diabetes.MethodsWe compared the HbA1c levels of 3111 children at diagnosis of type 1 diabetes and of 2825 children at a median follow‐up of 4.7 months (interquartile range, 4.1–5.4) together with their daily insulin requirement during the Covid‐19 pandemic with the two previous years via multivariable linear regression, using data from the German Diabetes Registry DPV.ResultsDuring the Covid‐19 pandemic, HbA1c levels were higher at diagnosis of type 1 diabetes (mean estimated difference, 0.33% [95% confidence interval, 0.23–0.43], p < 0.001), but not at follow‐up (mean estimated difference, 0.02% [−0.02–0.07]). Children with diabetes onset during the Covid‐19 pandemic had a significantly higher daily insulin requirement after initiation of therapy (mean estimated difference, 0.08 U/kg [0.06–0.10], p < 0.001). Both the increase in HbA1c and daily insulin requirement were evident only after the first wave of the pandemic.ConclusionsThis increase in HbA1c at diagnosis of type 1 diabetes during the Covid‐19 pandemic may indicate a delay in seeking medical care due to the pandemic. However, this did not affect short‐term glycemic control. The increased insulin requirement at follow‐up could suggest a more rapid autoimmune progression during the pandemic.

IDF21-0439 Type 2 Diabetes Mellitus History in the Prognosis of Hospitalized COVID-19 Patients – A Prospective Observational Study

Background: COVID-19 is found to affect Type 2 Diabetes Patients drastically. Aim: To evaluate the association between a known history of diabetes mellitus (DM) and its clinical outcomes in hospitalized COVID-19 diabetic patients. Method: This prospective cohort study categorized COVID-19 positive patients admitted to a secondary care hospital in South India into DM patients and Non-DM patients. Data regarding the past medical and medication history was collected on the day of admission and the patients were regularly followed up till discharge or death. The outcome measures including duration of hospital stay, mortality, need for ICU care/mechanical ventilation were compared between the two groups. Data is extracted and statistically analyzed using Pearson correlation. Results: A total of 118 patients were observed, 53 patients were diabetic and 65 were non-diabetic. Out of the 53 hyperglycemic patients, 39 patients were on metformin therapy while 15 patients were on insulin before admission due to COVID-19. A higher mortality rate was observed in the DM group when compared with the Non-DM group [26.4% (14) vs 9.23% (6)]. An increased random blood glucose level at the time of admission had a positive correlation with mortality (p = 0.003). While insulin administration prior to admission had negative correlation with mortality [R value is -0.282 (p = 0.02)], increased insulin requirement during hospitalization is associated with poor outcomes [R value is 0.327 (p = 0.002)]. Discussion: People with diabetes when infected with COVID-19 are at a greater risk of morbidity and mortality. The study highlights the need of rational management of hyperglycemia in COVID patients with a history of diabetes mellitus.