Lower C-peptide Levels Research Articles

The Double-Edged Sword of Immunotherapy—Durvalumab-Induced Polyendocrinopathy—Case Report

Introduction: Immunotherapy is one of the greatest advancements in oncological patient care. The broader the treatment application, the more common the adverse events associated with the therapy. Immune checkpoint inhibitors (ICI) are currently used in numerous malignancies. These drugs influence the immune cells’ interactions, which translates to interruption of immune evasion and increased anti-tumor activity. However, the disruption of immunological signaling pathways often leads to adverse events, such as endocrinological insufficiencies, among which thyroid is the most common. Moreover, the co-appearance of several insufficiencies has been previously described. Case report: A 73-year-old female treated with durvalumab due to non-small cell lung carcinoma was admitted to the emergency unit due to symptoms of ketoacidosis. She had a history of well-controlled type 2 diabetes mellitus and autoimmune thyroiditis. Laboratory results showed increased anti-GAD antibodies, while the low C-peptide level indicated type 1 diabetes mellitus. Moreover, over the course of longer observation, the patient presented with abrupt aggravation of her autoimmune thyroiditis. Conclusions: The new onset of endocrinological insufficiencies is a rare adverse event of immunotherapy. Clinicians must pay particular attention to any signs indicating these life-threatening conditions. In case of the appearance of any endocrinological adverse event, the close cooperation of oncologists and endocrinologists is required to enhance patients’ quality of life.

8114 The Need For Autoantibody Screening And Diagnostic Criteria For Immune-Checkpoint Inhibitor-Induced Type 1 Diabetes

Abstract Disclosure: A. Gupta: None. H. Sanekommu: None. A.B. Ravin: None. M. Akula: None. J. Cheng: None. Background: Immune-checkpoint inhibitors (ICIs) such as Nivolumab have been extensively studied, especially in relation to their side-effect profiles. Patients on Nivolumab are prone to immune-related adverse events (irAEs) including type 1 diabetes mellitus, thyroiditis, and hypopituitarism. Prior studies have indicated that ICIs can unmask existing diabetic autoimmunities, but currently no specific guidelines exist for autoantibody screening prior to initiating treatment. We report a unique case of a young patient with newly diagnosed immune-checkpoint inhibitor-induced type 1 diabetes (ICI-T1DM) who was found to have mixed autoantibody results. Clinical Case: This is a 31-year-old male who was diagnosed with fibrolamellar hepatocellular carcinoma (pT23N0) and underwent partial hepatic resection later that year. Repeat imaging showed new hepatic lesions, thus Nivolumab was initiated. He received a total of three cycles, after which he presented to the hospital with symptoms of fever and nausea; labs were consistent with diabetic ketoacidosis (DKA) for which he was treated with IV insulin and aggressive hydration with successful resolution. Nivolumab was stopped and the patient was discharged on a basal-bolus insulin regimen. Further outpatient workup was significant for A1c 5.9% (n<5.7%), C-peptide (with glucose 220mg/dL) 0.7 (n=0.8-3.9ng/mL), glutamic acid decarboxylase autoantibody (GAD Ab) 11 (n<5.0U/mL). Insulin antibody and islet cell antibody IgG were negative. Due to the acute onset in the presentation and the recent use of Nivolumab, the patient was diagnosed with ICI-T1DM. He remained insulin-dependent after discharge. Unfortunately, soon after, he began showing signs of liver failure and ultimately underwent liver transplantation. Conclusion: This case highlights two crucial aspects - the importance of screening for autoantibodies prior to initiating an ICI and the necessity for guidelines in diagnosing ICI-T1DM. Given the evidence linking positive GAD Ab to a higher risk of developing DKA and earlier onset ICI-T1DM, it is beneficial to screen patients for these autoantibodies prior to ICI initiation to identify those more susceptible to developing ICIDM1. It may also be beneficial to obtain a C-peptide level prior to initiation to evaluate for endogenous insulin production. Additionally, while several factors support the diagnosis of ICI-T1DM such as recent ICI use, acute DKA presentation, low C-peptide levels, and the need for exogenous insulin, there is currently no specific criteria for the formal diagnosis of ICI-T1DM. Consequently, the decision to continue an ICI remains uncertain until specific diagnostic criteria are established for healthcare providers. Presentation: 6/2/2024

Type 1 Diabetes as a Risk Factor for Chronic Kidney Diseases and Renal Failure in Adolescents: A Systematic Review

Objectives: The purpose of this systematic review is to investigate the risk factors and association of the incidence of diabetic kidney disease in adolescents with type 1 diabetes (T1D) patients. Methods: We conducted a thorough search of PubMed, SCOPUS, Web of Science, Google Scholar, and Science Direct to find pertinent literature. Rayyan QRCI was utilized during the entire process. Results: We included eight studies with a total of 11,468 T2D patients and 4966 (43.3%) were females. The available literature on the association between T1D and CKD among adolescents lacks epidemiological data on the prevalence and sex differences. Higher eGFR, diabetes duration, low C-peptide levels, glycemic control, age at a clinic visit, advanced glycation end products, and BMI were reported as significant risk factors for developing renal impairment in adolescents with T1D. Conclusion: The results of this research point to the necessity of a standardized screening procedure for the early identification and appropriate treatment of DKD. In order to provide an accurate assessment of this illness, methodological approaches should be taken into account. Furthermore, it's imperative to educate teenagers with T1D about the possibility of DKD, which can result in renal failure and even death. Future improvements in the quality of life for teenagers with T1D are anticipated as a result of this awareness.

Stevens-Johnson Syndrome/Toxic epidermal necrolysis complicated with fulminant type 1 diabetes mellitus: a case report and literature review

BackgroundStevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) are rare but life-threatening skin lesion triggered by hypersensitive drug reaction. They are characterized by extensive epidermal necrosis and skin exfoliation. Fulminant type 1 diabetes mellitus (FT1DM) is featured by a rapid-onset of hyperglycemia with ketoacidosis due to severely destroyed β-cell function. Fulminant type 1 diabetes mellitus as a sequela of SJS/TEN has rarely been reported.Case presentationWe present a 73-year-old female patient who developed SJS/TEN skin allergic reaction after taking carbamazepine and phenytoin for 35 days. Then, hyperglycemia and diabetic ketoacidosis occurred 20 days after discontinuation of antiepileptic drugs. A very low serum C-peptide level (8.79 pmol/l) and a near-normal glycosylated hemoglobin level met the diagnostic criteria for fulminant T1DM. Intravenous immunoglobulin (IVIG) and insulin were promptly administered, and the patient recovered finally.ConclusionsThis rare case indicates that monitoring blood glucose is necessary in SJS/TEN drug reaction, and comprehensive therapy with rehydration, insulin, antibiotics, and IVIG may improve the prognosis.

Periodontal tissue susceptibility to glycaemic control in type 2 diabetes.

To assess the direct effect of intensive glycaemic control on periodontal tissues in patients with diabetes mellitus. Twenty-nine patients with type 2 diabetes were enrolled and hospitalized to receive a 2-week intensive glycaemic control regimen. We observed and analysed the systemic and oral disease indicators before and after treatment and clarified the indicators related to periodontal inflammation. A significant reduction in glycaemic and periodontal parameters, including glycated albumin levels and periodontal inflamed surface area (PISA), was observed after treatment. The changes in PISA per tooth, indicative of periodontal healing, exhibited a bimodal distribution; the patients were divided into two groups on this basis. Correlations were observed between the changes in PISA per tooth and fasting plasma glucose, acetoacetic acid, and beta-hydroxybutyrate levels in the PISA-improved group. Significantly lower levels of C-peptide, coefficient of variation of R-R interval, and ankle-brachial pressure index were observed before treatment in the PISA non-improved group. Glycaemic control treatment can effectively improve periodontitis in patients with type 2 diabetes, even in the absence of specific periodontal treatments. However, the periodontal responsiveness to glycaemic control treatment depends on the systemic condition of the patient.

Contribution of methamphetamine and insulin to the death of a woman suffering from type I diabetes - which played the greater role?

This report presents a fatal case of a young female Type I diabetic patient who developed convulsions and loss of consciousness after taking methamphetamine and spending some time in a dance club. During the convulsions, she was given sugar and when no response occurred, her boyfriend who was not experienced in the use of insulin administered a dose of insulin to her. The woman lost consciousness and died despite the efforts of the emergency service. A biochemical analysis revealed a high level of insulin (196.67 mU/L) and low levels of glucose (2.96 mmol/L) and C-peptide (26 pmol/L). Toxicological analysis revealed a methamphetamine concentration of 389 ng/mL and an amphetamine concentration of 19 ng/mL. The forensic perspective of the difficult determination of the contribution of each of the factors to the death, i.e., the pre-existing medical condition (Type I diabetes), the use of methamphetamine, the physical exertion at the dance club, and, finally, the non-indicated administration of insulin, is discussed. The ruling of the court is also reported.

The impact of malnutrition on secondary diabetes and calcific pancreatitis: A comprehensive review

Introduction: Malnutrition in low- and middle-income countries significantly impacts the development of secondary diabetes and calcific pancreatitis. Aim and Methods: This review summarizes the prevalence, characteristics, and findings from key studies over the past decade on the link between malnutrition and secondary diabetes, focusing on protein-deficient pancreatic diabetes (PDPD) and fibro-calculous pancreatic diabetes (FCPD). A comprehensive literature search was conducted in PubMed, Scopus, and Google Scholar for articles published between 1995 and 2023. Studies included were peer-reviewed articles focusing on the link between malnutrition and secondary diabetes, conducted in LMICs, and discussing the prevalence, clinical characteristics, and outcomes of PDPD and FCPD. Both observational and interventional studies were considered. Results: The review of studies revealed several key findings: · PDPD is characterized by lower C-peptide levels and varied responses to glibenclamide post-nutritional rehabilitation. · FCPD patients show rapid calcification, diminished exocrine and beta-cell function, and more severe exocrine deficiency compared to PDPD. · Both PDPD and FCPD patients often present with lower BMI and significant renal involvement. · Recent studies indicate improved nutritional status and prognosis of FCPD patients with enhanced medical care. · Insulin-requiring diabetes in Ethiopia is strongly linked with poor education, poverty markers, and childhood malnutrition. · Lean diabetes, linked to childhood malnutrition, is characterized by low-normal BMI, early onset, and rapid beta-cell failure. Discussion: The development of diabetes following early malnutrition can be attributed to several interconnected mechanisms involving metabolic, endocrine, and epigenetic factors. Early nutritional intervention trials are crucial to prevent glucose abnormalities and diabetes later in life. Studies highlight that improving early-life nutrition can enhance beta-cell function, reduce insulin resistance, and mitigate long-term metabolic dysfunction. Lean diabetes, linked to childhood malnutrition, presents unique challenges but can be addressed through targeted nutritional support. Conclusion: The review underscores the significant impact of malnutrition on the development of secondary diabetes and calcific pancreatitis in LMICs. Addressing malnutrition through early nutritional interventions is crucial to mitigate the risk of chronic conditions and improve metabolic health outcomes. Continued research and targeted public health strategies are essential to break the cycle of malnutrition and disease in vulnerable populations.

Type 1 Diabetes Genetic Risk in 109,954 Veterans With Adult-Onset Diabetes: The Million Veteran Program (MVP).

To characterize high type 1 diabetes (T1D) genetic risk in a population where type 2 diabetes (T2D) predominates. Characteristics typically associated with T1D were assessed in 109,594 Million Veteran Program participants with adult-onset diabetes, 2011-2021, who had T1D genetic risk scores (GRS) defined as low (0 to <45%), medium (45 to <90%), high (90 to <95%), or highest (≥95%). T1D characteristics increased progressively with higher genetic risk (P < 0.001 for trend). A GRS ≥90% was more common with diabetes diagnoses before age 40 years, but 95% of those participants were diagnosed at age ≥40 years, and their characteristics resembled those of individuals with T2D in mean age (64.3 years) and BMI (32.3 kg/m2). Compared with the low-risk group, the highest-risk group was more likely to have diabetic ketoacidosis (low GRS 0.9% vs. highest GRS 3.7%), hypoglycemia prompting emergency visits (3.7% vs. 5.8%), outpatient plasma glucose <50 mg/dL (7.5% vs. 13.4%), a shorter median time to start insulin (3.5 vs. 1.4 years), use of a T1D diagnostic code (16.3% vs. 28.1%), low C-peptide levels if tested (1.8% vs. 32.4%), and glutamic acid decarboxylase antibodies (6.9% vs. 45.2%), all P < 0.001. Characteristics associated with T1D were increased with higher genetic risk, and especially with the top 10% of risk. However, the age and BMI of those participants resemble those of people with T2D, and a substantial proportion did not have diagnostic testing or use of T1D diagnostic codes. T1D genetic screening could be used to aid identification of adult-onset T1D in settings in which T2D predominates.

C-peptide Level in Patients With Uncontrolled Type 2 Diabetes Mellitus on Oral Anti-diabetic Drugs.

In the development and progression of type 2 diabetes mellitus, β-cell dysfunction occurs after insulin resistance. Despite poor glycaemic control, there is a practice of increasing the dose of oral anti-diabetics or adding more drugs to the regimen due to the common perception that low endogenous insulin secretion is related to type 1 diabetes mellitus only and patient'spoor compliance to injectables. Keeping this perspective in mind, this study was conducted to assess the prevalence of beta cell dysfunction by low serum C-peptide levels and its correlation with poor glycaemic control. A total of 134 patients with type 2 diabetes mellitus for more than 10 years on oral anti-diabetic drugs fulfilling our eligibility criteria were enrolled in our study. Blood samples for fasting blood sugar and fasting C-peptide level were taken before breakfast and uptake of anti-diabetic drugs. Correlation analysis was performed to evaluate the relationship between fasting C-peptide and glycaemic control with respect to glycated haemoglobin (HbA1c). Of the patients,19.40% had insufficient beta cell reserve serumlevels (C-peptide < 0.5 ng/ml), of which most of the patients (14/26 = 53.85%) had poor glycaemic control (HbA1c < 8.0%). Overall, there was a significant correlation between poor glycaemic control with respect to HbA1c and low serum C-peptide levels (p < 0.05). We found a significant association of beta cell dysfunction (low fasting C-peptide level) with the use of insulin secretagogue. The proportion of patients with C-peptide levels less than 0.5 ng/ml was lower in patients using sodium-glucose cotransporter-2 (SGLT-2) inhibitors as compared to insulin secretagogue. SGLT-2 inhibitors should be preferred over other anti-diabetic drugs as an add-on to existing metformin therapy. Insulin requirement must be assessed in patients who have long-term type 2 diabetes mellitus.

Evaluating the effectiveness of a novel somatostatin receptor 2 antagonist, ZT-01, for hypoglycemia prevention in a rodent model of type 2 diabetes.

Background: Elevated levels of somatostatin blunt glucagon counterregulation during hypoglycemia in type 1 diabetes (T1D) and this can be improved using somatostatin receptor 2 (SSTR2) antagonists. Hypoglycemia also occurs in late-stage type 2 diabetes (T2D), particularly when insulin therapy is initiated, but the utility of SSTR2 antagonists in ameliorating hypoglycemia in this disease state is unknown. We examined the efficacy of a single-dose of SSTR2 antagonists in a rodent model of T2D. Methods: High-fat fed (HFF), low dose streptozotocin (STZ, 35mg/kg)-induced T2D and HFF only, nondiabetic (controls-no STZ) rats were treated with the SSTR2 antagonists ZT-01/PRL-2903 or vehicle (n = 9-11/group) 60min before an insulin tolerance test (ITT; 2-12U/kg insulin aspart) or an oral glucose tolerance test (OGTT; 2g/kg glucose via oral gavage) on separate days. Results: This rodent model of T2D is characterized by higher baseline glucose and HbA1c levels relative to HFF controls. T2D rats also had lower c-peptide levels at baseline and a blunted glucagon counterregulatory response to hypoglycemia when subjected to the ITT. SSTR2 antagonists increased the glucagon response and reduced incidence of hypoglycemia, which was more pronounced with ZT-01 than PRL-2903. ZT-01 treatment in the T2D rats increased glucagon levels above the control response within 60min of dosing, and values remained elevated during the ITT (glucagon Cmax: 156 ± 50 vs. 77 ± 46pg/mL, p < 0.01). Hypoglycemia incidence was attenuated with ZT-01 vs. controls (63% vs. 100%) and average time to hypoglycemia onset was also delayed (103.1 ± 24.6 vs. 66.1 ± 23.6min, p < 0.05). ZT-01 administration at the OGTT onset increased the glucagon response without exacerbating hyperglycemia (2877 ± 806 vs. 2982 ± 781), potentially due to the corresponding increase in c-peptide levels (6251 ± 5463 vs. 14008 ± 5495, p = 0.013). Conclusion: Treatment with SSTR2 antagonists increases glucagon responses in a rat model of T2D and results in less hypoglycemia exposure. Future studies are required to determine the best dosing periods for chronic SSTR2 antagonism treatment in T2D.

Diabetes mellitus geïnduceerd door immuuntherapie: een casus

Immunotherapy-induced diabetes mellitus: a case-report A 73-year-old man presented with diabetic ketoacidosis (DKA) after the recent initiation of immunochemotherapy to treat a lung adenocarcinoma. Pembrolizumab is an IgG4 monoclonal antibody targeting an immune checkpoint protein called ‘programmed cell death protein 1’ (PD-1), which results in antitumoral immunity. Immune checkpoint inhibitors (ICI), such as pembrolizumab, are known for their ability to cause immune-related adverse events (irAEs). Immunotherapy-induced diabetes mellitus (DM) occurs predominantly with the inhibition of PD-1 or its ligand (‘programmed cell death protein 1 ligand’ (PD-L1)). The onset is typically acute with a rapidly progressive deficiency of the endogenous insulin production, resulting in hyperglycaemia and a low or absent serum level of C-peptide with a relatively low to normal HbA1c in the acute phase. The significant loss of endogenous insulin production makes DKA a frequent first presentation. This rapid pathophysiological evolution was present in the discussed patient, who developed DM in less than 6 weeks and needed insulin therapy to establish an adequate glycaemic control. Given the increasingly widespread use of ICI in the treatment of various tumours, caution has to be taken to identify these potentially life-threatening irAEs. Awareness and alertness to glycemia on blood sampling, as well as patient education regarding red flags are fundamental, in addition to adequate recognition and treatment of (potential) ketoacidosis.

Distinct changes to pancreatic volume rather than pancreatic autoantibody positivity: insights into immune checkpoint inhibitors induced diabetes mellitus

BackgroundImmune checkpoint inhibitors (ICI) are promising treatment options for various cancers. However, their use is associated with immune-related adverse events (irAEs), including ICI-induced diabetes mellitus (ICI-DM). This study aimed to investigate the clinical features of ICI-DM, with a particular focus on alterations to pancreatic volume.MethodsWe conducted a retrospective review of 2829 patients who received ICI treatment at the Chang Gung Memorial Hospital, Linkou, between January 2014 and December 2021. New-onset diabetes or diabetic ketoacidosis (DKA) was identified in ten patients receiving ICI therapy. Pancreatic volumes were assessed by manual segmentation of computed tomography (CT) images before and after ICI-DM diagnosis.ResultsAmong these ten patients, nivolumab was the most commonly used ICI (50.0%), followed by pembrolizumab (30.0%) and atezolizumab (20.0%). One patient received combination therapy with nivolumab and ipilimumab. The median age was 63.01 years (range: 40.1 − 87.8). ICI-DM developed after a median of 13.5 cycles (range: 2 − 42) of ICI treatment or 9.85 months (range:1.5 − 21.3) since ICI initiation. The initial presentation was DKA in 60.0% of patients. All patients had low or undetectable C-peptide levels (range: <0.033 − 0.133 nmol/L) and were negative for most type 1 diabetes mellitus (T1DM)-related autoantibodies; only one patient tested positive for glutamic acid decarboxylase antibodies. CT imaging revealed significant pancreatic atrophy, with a median pancreatic volume decrease of 19.92% (P = 0.038) from baseline and sustained significant decline at last follow-up (median − 37.14%, P = 0.012).ConclusionsICI-DM is often accompanied by pancreatic atrophy and approximately two-thirds of patients initially present with DKA. Although the majority of ICI-DM patients lack T1DM-related autoantibodies, identifying diminished pancreatic volumes through CT imaging provides valuable clues into the subclinical aspects of ICI-DM development, aiding in the prevention of diabetic emergencies.Trial registrationNot applicable.

Phenotype and predictors of insulin independence in adults presenting with diabetic ketoacidosis: a prospective cohort study

Aims/hypothesisThe aim of this work was to describe the phenotype of adults presenting with a first episode of diabetic ketoacidosis (DKA) in Cape Town, South Africa, and identify predictors of insulin independence at 12 and 60 months after presentation.MethodsA prospective, descriptive cohort study of all individuals, 18 years or older, presenting for the first time with DKA to four public-sector hospitals of the Groote Schuur Academic Health Complex was performed. Clinical, biochemical and laboratory data including GAD antibody and C-peptide status were collected at baseline. Insulin was systematically weaned and stopped in individuals who achieved normoglycaemia within the months after DKA. Individuals were followed for 12 months and then annually until 5 years after initial presentation with ketoacidosis.ResultsEighty-eight individuals newly diagnosed with diabetes when presenting with DKA were included and followed for 5 years. The mean ± SD age was 35±10 years and the median (IQR) BMI at diagnosis was 28.5 (23.3–33.4) kg/m2. Overall, 46% were insulin independent 12 months after diagnosis and 26% remained insulin independent 5 years after presentation. Forty-one participants (47%) tested negative for anti-GAD and anti-IA-2 antibodies and had C-peptide levels >0.3 nmol/l; in this group, 68% were insulin independent at 12 months and 37% at 5 years after diagnosis. The presence of acanthosis nigricans was strongly associated with insulin independence (OR 27.1 [95% CI 7.2, 102.2]; p<0.001); a positive antibody status was associated with a lower likelihood of insulin independence at 12 months (OR 0.10 [95% CI 0.03, 0.36]; p<0.001). On multivariable analysis only acanthosis (OR 11.5 [95% CI 2.5, 53.2]; p=0.004) was predictive of insulin independence 5 years after diagnosis.Conclusions/interpretationThe predominant phenotype of adults presenting with a first episode of DKA in Cape Town, South Africa, was that of ketosis-prone type 2 diabetes. These individuals presented with obesity, acanthosis nigricans, negative antibodies and normal C-peptide and could potentially be weaned off insulin at follow-up. Classic type 1 diabetes (lower weight, antibody positivity, low or unrecordable C-peptide levels and long-term insulin dependence) was less common. The simple clinical sign of acanthosis nigricans is a strong predictor of insulin independence at 12 months and 5 years after initial presentation.Graphical

A case of pancreatic glans insulinoma with low C-peptide level

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Undetected Exogenous Insulin Administration in a Child: Assessment of Assay Limitations and Impact on the Practice of Laboratory Medicine

Abstract Introduction/Objective The development of new synthetic insulin analogues over the past few decades has significantly impacted the management of hypoglycemia. However, accurately measuring these analogues presents challenges due to variable cross-reactivity with many insulin assays. Failure to consider cross-reactivity may lead to the misdiagnosis of exogenous insulin administration. Methods/Case Report A 13-year-old female with a history of type 1 DM was presented to an outside hospital emergency department with symptoms indicative of hypoglycemia. Multiple child protective services (CPS) referrals are noted. The patient had experienced several episodes of hypoglycemia over the prior week with blood glucose in the 30-40 mg/dL range. There were no associated symptoms of diarrhea, emesis, or fatigue. The patient was transferred to a pediatric hospital were preliminary investigations indicated abnormally low blood glucose levels with low insulin and C-peptide levels. Further evaluation was initiated to determine the underlying cause of these episodes and to ensure appropriate adjustments in insulin dosing and regimen. Initially, the Elecsys insulin assay (Roche Diagnostics) was utilized to quantify insulin levels which shows a low cross-reactivity for insulin lispro and glargine. To validate the hypothesis of an undetected exogenous insulin overdose, blood samples were sent to another laboratory employing The Advia Centaur insulin assay (Siemens) which exhibits a higher cross-reactivity for insulin lispro and glargine (89%-143%, respectively), indicating a higher recognition and measurement sensitivity for these insulin analogues. The analysis using this assay revealed significantly elevated insulin levels, corroborating the presence of an insulin overdose. The sample at the time of presentation at the outside hospital was confirmed to be 434.1 mU/L. A sample collected 17 hours later had an insulin level of 23.5 mU/L. Results (if a Case Study enter NA) NA Conclusion This case study highlights the critical issue of undetected insulin overdose in a child and emphasizes the limitations of the initial insulin assay employed. Improving assay sensitivity and reliability will enhance patient care and safety. This case study reminds clinicians and laboratory professionals of the need for ongoing quality assurance and vigilance in their practices.

A Cross-sectional Study to Assess Beta-Cell Function in Individuals with Recently Diagnosed Young-Onset Type 2 Diabetes Mellitus and Its' Complications.

The primary objective was to assess beta-cell function of recently-diagnosed young-onset type 2 diabetes mellitus (T2DM) individuals using basal and stimulated C-peptide levels. The secondary objective was to examine the association between C-peptide with metabolic factors and diabetes complications. A cross-sectional study was conducted for young-onset T2DM individuals aged 18-35 years with a disease duration of not more than 5 years. Plasma C-peptide was measured before and after intravenous glucagon injection. Demographic data, medical history and complications were obtained from medical records and clinical assessment. Continuous data were expressed as median and interquartile range (IQR). Categorical variables were described as frequency or percentage. Multivariable linear regression analysis was used to determine factors associated with C-peptide levels. 113 participants with young-onset T2DM with a median (IQR) age of 29.0 (9.5) years and 24 (36) months were included in this study. The median (IQR) basal and stimulated C-peptide was 619 (655) pmol/L and 1231 (1024) pmol/L. Adequate beta-cell function was present in 78-86% of the participants based on the basal and stimulated C-peptide levels. We found hypertension, obesity and diabetic kidney disease (DKD) to be independently associated with higher C-peptide levels. In contrast, females, smokers, those on insulin therapy and with longer duration of disease had lower C-peptide levels. Most recently diagnosed young-onset T2DM have adequate beta-cell function. Elevated C-peptide levels associated with obesity, hypertension and diabetic kidney disease suggest insulin resistance as the key driving factor for complications.

When Hormones are Being Difficult: A Rare Case and the Literature Review of Pembrolizumab-Induced Polyendocrinopathy.

Immune Checkpoint inhibitors (ICIs) such as nivolumab, pembrolizumab, and ipilimumab are monoclonal antibodies against cytotoxic T lymphocyte antigen 4 (CTLA4) or program death (PD)1 and its ligand PDL1. Agents targeting PD1, such as pembrolizumab, have shown widespread efficacy in the past and are also associated with a wide range of immune-related adverse events (irAEs), including endocrine toxicities. A 31-year-old female with a medical history significant for Stage IIb Breast cancer on chemo and immunotherapy (pembrolizumab) presented with nausea, vomiting, and generalized abdominal pain. Laboratory studies showed a blood glucose level of 356 mg/dl, elevated Anion gap 18 meq/L, beta-hydroxybutyrate 46 mg/d, and low C-peptide levels <0.10 ng/ml. The patient was treated for Diabetic Ketoacidosis (DKA). Further testing revealed high Thyroid Stimulating Hormone (TSH) levels along with elevated thyroid peroxidase levels of 38 IU/L. After discharge from the hospital on insulin and levothyroxine therapy, the patient reported increasing fatigue and further testing revealed low cortisol levels <0.5 mcg/dl with elevated ACTH consistent with primary adrenal insufficiency. The patient was started on hydrocortisone therapy with improvement in symptoms. Endocrine toxicities are not uncommon in patients receiving pembrolizumab, but polyendocrinopathy in a relatively rare side effect of pembrolizumab. Only a few cases of pembrolizumab-induced polyendocrinopathy have been reported so far which we have mentioned in this article. While patients are on immunotherapy, close monitoring for clinical signs & symptoms can lead to an early diagnosis, substantially improving morbidity and mortality.

SAT150 "Sawtooth" Hypoglycemia: Rare Case Of IGF-2 Mediated Hypoglycemia With Elevated Proinsulin Level And "Sawtooth" Pattern On CGMS

Abstract Disclosure: P. Goparaju: None. M. Zena: None. Background: IGF-2 mediated hypoglycemia is usually associated with low Insulin, C-peptide and Proinsulin levels. We present an extremely rare case of IGF-2 mediated hypoglycemia with elevated Proinsulin level and an unusual “saw tooth” pattern on Continuous glucose monitoring system(CGMS). Clinical Case: 53-year-old male with history of metastatic Liposarcoma was admitted to the hospital with severe hypoglycemia. Whipple’s triad was positive on presentation, patient had symptoms of altered sensorium, blood glucose of 24 mg/dl, and symptoms improved upon correction of hypoglycemia. The patient was admitted to the ICU and IV dextrose was initiated.As Liposarcomas are known to be associated with Non-islet cell tumor hypoglycemia (NICTH), treatment with Prednisone was started. Prior to this, initial hypoglycemia workup was sent when blood sample was drawn during a hypoglycemia episode. Patient has no personal or family history of Diabetes. Adrenal insufficiency was ruled out with morning cortisol of 17.8 ug/dl. Serum glucose was low at 40mg/dl, Insulin&amp;lt;1(0-17 pmol/L), C-peptide level low at 0.4 (0.8-3.9 ng/ml), IGF-1 level was low at 68 (74-225 ng/ml), normal IGF-2 at 626 (333-967 ng/ml) and increased IGF-2/IGF-1 ratio of 9.2(Normally around 3:1). All the lab work above is consistent with IGF-2 mediated hypoglycemia with low Insulin, C-peptide and IGF-1 levels and increased IGF-2/IGF-1 ratio. Interestingly, he has an elevated Proinsulin level of 36.9 (0.0-10.0 pmol/L) which is very unusual.Prednisone was started at 20mg daily to which there was reasonable response, dose was eventually increased to 60mg daily before he was safely sent home. He was discharged on a CGMS and the data was downloaded 2 weeks later. He had an interesting “Saw tooth” pattern of glycemia on the daily glucose graphs. As the patient had access to live data, he was trying to correct the falling blood glucose which briefly improved the readings but was quickly followed by another drop and this sequence carried on leading to a unique blood glucose pattern on the CGMS. Conclusion: Proinsulin level is usually suppressed in IGF-2 mediated hypoglycemia. Our case is unusually associated with high Proinsulin level. One hypothesis is the possible structural similarities leading to lab assay interactions between Proinsulin and “Pro-IGF-2”, which is thought to be one of the main molecules responsible for hypoglycemia in this condition. More studies in future will be helpful to study this possible association. Our case also had a remarkable “Saw tooth” pattern on CGMS glucose graphs which is very rarely seen in clinical practice.

SAT159 A Unique Case Of IGF-2 Induced Hypoglycemia As First Manifestation Of Hepatocellular Carcinoma

Abstract Disclosure: I. Ali: None. M. Alnaher: None. A. Arida: None. Introduction: Hypoglycemia is one of the manifestations of non-islet cell tumor-induced hypoglycemia (NICTH). In hepatocellular carcinoma (HCC), it has been reported in 4-27% of patients, and it is associated with poor prognosis. Case: Patient is a 70-years-old Female with past medical history of prediabetes and untreated Hepatitis C infection who presented with sever weakness and was found to have blood glucose of 37. She was started on Dextrose 10% with improvement of her symptoms. During hospital course she had recurrent episodes of symptomatic hypoglycemia. Patient denied any family history of diabetes with no access to diabetes medication. Blood work showed elevated AST, ALT with low albumin, low prealbumin and AM cortisol 13, Sulfonylureas screen is Negative. Result of 72 hours hypoglycemia protocol while blood glucose level was 48 mg/dl as follow: Proinsulin, Intact 1.6 mmol/L (Ref: less than 8.0), insulin like growth factor -1 (IGF-1): 10 ng/ml (26-226), IGF-2: 69 ng/ml (180-580) so IGF-2/IGF-1 ratio of 6.9Insulin: 0.2 uIU/ml (1.9-23), C-Peptide 0.1 ng/ml (0.5-3.3) and Beta hydroxybutyrate: 0.1 mmol/L. CT abdomen: 7.0 x 7.2 x 10.5 cm right hepatic lobe mass with extension to right portal vein that is most consistent with hepatocellular carcinoma with background liver cirrhosis with portal hypertension without ascites. Right hepatic artery tumor biopsy showed moderately differentiated HCC. Patient was started on steroid therapy then octreotide. Multidisciplinary meeting discussed in details treatment options and prognosis including treatment of her cancer with surgery vs chemoradiation therapy, but patient and her family opted for DNR/DNI, and patient passed away during that admission. Discussion: Even though HCC-related hypoglycemia is a known phenomenon, knowledge about prevention and treatment is lacking. The suggested mechanism of hypoglycemia in NICTH include increased consumption of glucose by tumor in malnourished patients with low glycogen deposits and defective gluconeogenesis or may be caused by IGF-2 overproduction that crosses capillary membranes and stimulates insulin receptor. Hypoglycemia work up reveals low levels of insulin, pro-insulin, C-peptide, and β-hydroxybutyrate. Levels of GH and IGF-1 will also be low due to the suppressive effect of IGF-2. Total IGF-2 may be elevated or normal but the ratio of IGF-2/IGF-1 is usually elevated 3:1. Management of an IGF-2 producing tumor with surgical resection, radiation, and/or chemotherapy can potentially resolve hypoglycemia. Medical therapy with glucocorticoids has been utilized by promoting hepatic gluconeogenesis and lipolysis and reducing peripheral glucose uptake. Glucocorticoids also help to decrease the levels of IGF-2 either by decreased tumor production or increased clearance. Case reports have documented the use of glucagon, growth hormone, and octreotide, however, effects are limited. Presentation: Saturday, June 17, 2023

SAT174 Doege-Potter Syndrome In A Patient With Solitary Fibrous Tumor Of The Lung

Abstract Disclosure: N. Mon: None. S.S. Krishnasamy: None. Doege-Potter Syndrome is a non-islet cell tumor hypoglycemia (NICTH) due to a solitary fibrous tumor (SFT) with overexpression of Insulin-like growth factor 2 (IGF2). We report a case of refractory hypoglycemia in a patient with SFT of the lung. Case presentation: A 67-year-old homeless male with hypertension, chronic smoker presented with altered mental status after his blood glucose was found 34mg/dl by EMS. His confusion improved after D50W. He could not recall the event but he reported that he missed his dinner prior to the event. He denied taking any antidiabetic medications. He was diagnosed with left lung solitary fibrous tumor without metastases a week ago after he presented to ER with dyspnea, cough and wheezing. CT chest reported a 21x15.6x18.7 cm lesion with mass effect on the left hemidiaphragm, mediastinum shift to the right and occluded left lower lobe bronchi. Core needle biopsy of the mass revealed SFT with necrosis. He was discharged with Medrol dosepak 4mg daily for presumptive treatment of COPD exacerbation and a plan for elective surgery. While in the ER his BG improved to 136mg/dl after D50W. Few hours later BG dropped to 42mg/dl and D10W infusion was started. Physical exam was unremarkable except bilateral pedal edema. Work up showed BG 42mg/dl, Insulin 3.3 (2.6-24.9 uIU/mL), C peptide 0.39 (1.1-4.4ng/mL), Proinsulin 4.7 (&amp;lt;18.8pmol/L), beta-hydroxybutyrate &amp;lt;0.05 (0.02-0.27mmol/l), 8AM cortisol 10.7 (7.0-25.0 ug/dl), albumin 3.2mg/dl, HbA1c 5.8%, IGF1 53ng/mL (34-245ng/mL), IGF2 203ng/mL (267-616ng/mL) with a IGF2:IGF1 ratio of 3.8. In our patient, the IGF2:IGF1 ratio was not &amp;gt;10 since his IGF 2 was suppressed by the recent steroid use. The rest of the clinical and biochemical features strongly suggested NICTH. His preoperative evaluation showed new onset HFrEF with volume overload. He underwent staged percutaneous coronary interventions with stents placement. He was given hydrocortisone 50mg q6H then to q8H during hospitalization and discharged home with hydrocortisone 40mg TID. He underwent radical resection of lung tumor after optimization of his cardiac condition. He was on stress dose of steroid during surgery. Since he was on high dose steroid for &amp;gt; 3months, hydrocortisone dose was tapered slowly after the surgery. Final biopsy reported solitary fibrous tumor extending to parenchymal staple line. Tumor cells are positive for CD34 and STAT6, and negative for desmin, SMA, and SOX10. He recovered uneventfully and was discharged home with prednisone 5mg daily and follow up in endocrine clinic. Conclusion: NICTH is a rare paraneoplastic syndrome characterized by low levels of insulin, C-peptide, proinsulin, and beta-hydroxybutyrate. A ratio of IGF-2/IGF-1 more than 10 confirms NICTH; however, normal ratio cannot exclude the diagnosis and factors such as low IGFBP 3 or steroid therapy for other conditions need to be considered. Surgery is the mainstay of treatment. Presentation: Saturday, June 17, 2023