bluuebunny/crossref_metadata_2025 huggingface dataset:
Is Hypoglycemia Caused by G6PD Deficiency?
Authors: Agarwal Shubham , Unjom Zubina , Gilden Janice L , Singh Aditi , Shaik Shayaan
Published: May 2021

Background: Individuals with G6PD deficiency are mostly asymptomatic but develop hemolytic anemia with the use of certain medications, chemicals, or food. Hemolytic anemia episodes in patients with G6PD deficiency have been observed to occur following hypoglycemia. Case: An 18-year-old, vigorously exercising African American male was referred to the endocrine clinic for post-prandial hypoglycemia (Blood glucose (BG) of 47 mg/dl) accompanied by palpitations, lightheadedness, dyspnea, diaphoresis, and tremulousness. He admitted to having short symptomatic episodes, almost daily over four years. His mother has sickle cell trait, and due to the need for blood typing, a qualitative direct fluoroscopic screening test was positive for G6PD deficiency. Physical examination revealed a height of 5’2” with a weight of 126 lbs. (BMI: 22.7 kg/m2), blood pressure of 97/55 mmHg, and heart rate of 62/minute. The patient was a normal male with low set ears, and no other abnormalities, except for questionable non-genetic short stature. Fingerstick BG was 62 mg/dl. Lab tests showed a fasting BG of 90 mg with concomitant proinsulin of 8.2 pmol/l (≤ 18.8 pmol/l), fasting insulin of 8.98 mIU/l (≤ 25 mIU/l), 2-hour post-prandial insulin of 33.4 µIU/ml (5.0–55.0 µIU/ml), and a c-peptide 1.24 ng/ml (0.81–3.85 ng/ml). Uric acid, TSH, Free T4, LH, FSH, Prolactin, IGF-1, PTH, free and total testosterone were all normal. Fasting cortisol level was normal with an elevated ACTH of 72 pg/ml (0–47 pg/ml), low 25-hydroxyvitamin D at 18.5 ng/ml (30–100 ng/ml), and a flat oral glucose tolerance test. A continuous glucose monitor revealed average daily glucose of 85 mg/dl with 34% of the time spent < 80 mg/dl. A high carbohydrate diet with frequent meals improved symptoms with normal fingerstick BG. However, due to the concern that hypoglycemia can be related to G6PD deficiency, hemoglobin electrophoresis, and gene testing for G6PD were done to confirm this diagnosis, and they were both normal. In addition, a bone density scan was done, which revealed osteopenia. He was started on vitamin D supplementation. Conclusion: Case reports exist of G6PD deficient hospitalized patients with type 1 diabetes mellitus and DKA in recovery, who have had new onset hemolytic anemia, proposing that relative hypoglycemia can be responsible for this effect. Multiple screening tests have been developed for the detection of G6PD deficiency, which assay the normal function of the enzyme and reduction of NADP to NADPH. However, confirmatory testing needs to be conducted if the screening test is positive. Although this adds to the burden of testing, screening tests can result in false positives and lead to a misdiagnosis, as in our case. References: Messina MF et al. Hemolytic crisis in a non-ketotic and euglycemic child with glucose-6-phosphate dehydrogenase deficiency and onset of type 1 diabetes mellitus. J Pediatr Endocrinol Metab. 2004 Dec;17(12):1671–3
Mitochondrial Diabetes: The Clinical Spectrum of MIDD and MELAS in Association With the A3243G Mutation
Authors: Bukhari Khulood , Pennant Marjorie
Published: May 2021

Introduction: Maternally inherited diabetes and deafness (MIDD) is a multisystem disorder characterized by insulinopenia and sensorineural hearing loss. This rare form of monogenic diabetes is most commonly associated with the A3243G mutation of mitochondrial DNA (mtDNA). The same mutation is seen in 80 percent of patients with MELAS (Mitochondrial encephalomyopathy with lactic acidosis and stroke-like episodes). MIDD and MELAS have overlapping features suggesting a continuum of expression for the A3243G mutation. Clinical Case: A 41-year-old male was referred for genetic testing and counseling by his ophthalmologist following detection of bilateral punched-out retinal pigment epithelium (RPE) lesions on routine exam. His medical history was significant for type 1 diabetes mellitus (T1DM) diagnosed at the age of 21 and bilateral sensorineural hearing loss diagnosed at the age of 38. The referral was triggered by patient reported family history of MELAS in two of his brothers who were both diagnosed at the age of 10 and died at the ages of 20 and 27. Whether the patient was previously tested during early childhood remains unclear. His medical history was negative for stroke-like episodes or seizures. Neurologic evaluation revealed mild fluent aphasia with paraphasic errors and some comprehension difficulties. MRI of the brain without contrast showed no focus of restricted diffusion. Mitochondrial DNA sequence analysis was performed. A pathogenic variant (m.3243 A>G) was detected in the MT-TL1 gene at approximately 25% heteroplasmy. The patient was advised to avoid metformin given increased risk for lactic acidosis. He was also instructed against use of statins. At the age of 45, the patient presented to the emergency department (ED) with a complaint of headache, vertigo and incoordination. Physical examination revealed left homonymous hemianopsia, right horizontal nystagmus and bilateral upper extremity dysmetria. MRI of the brain without contrast showed a large area of predominantly cortical restricted diffusion involving the right temporal and occipital region with associated T2/FLAIR hyper-intensity. Cross over between the PCA and MCA territories was suggestive of a stroke-like episode related to MELAS. The patient received a bolus of IV arginine at 0.5 g/kg followed by an IV infusion of 0.5 g/kg/day for 3 days. He was later transitioned to oral arginine 5g three times daily and was discharged to a rehab facility. Clinical Lesson: This case demonstrates the evolution of MIDD to MELAS, supporting the concept that both syndromes represent a spectrum of the same disease. A few case reports describe the progression of MIDD to MELAS. Why some patients develop MELAS and others develop MIDD is unclear but may be related to heteroplasmy. Early identification of MIDD and MELAS is crucial given associated comorbidities and unique management issues.
Severe Fasting Hypoglycemia Mimicking Insulinoma in Three Patients With Insulin Autoimmune Syndrome
Authors: Rossini Alessandro , Cassibba Sara , Scaranna Cristiana , Corsi Anna , Bellante Rosalia , Trevisan Roberto
Published: May 2021

Insulin autoimmune syndrome (IAS) is a rare cause of hypoglycemia characterized by the presence of insulin autoantibodies (IAA) in patients without prior exposure to exogenous insulin. Differential diagnosis with other causes of hypoglycemia may be complex. We report three IAS cases with severe fasting hypoglycemia, referred to our Unit for the diagnostic workup of insulinoma. All three patients (two women and a man, age 66, 44, and 50 years) had history of severe fasting hypoglycemia leading to loss of consciousness along with weight gain. Both insulin and C-peptide were high, but their levels varied greatly among patients, ranging from 24 to 1500 μU/ml (n.v. <16.3) and from 11 to 27 ng/mL (n.v. < 4,2), respectively. Imaging studies for insulinoma were negative. In all patients, evidence of elevated IAA (ranging from 310 to 660 UA, n.v. < 5) allowed diagnosis of IAS. Two patients were taking alpha lipoic acid, a sulphydryl compound consistently associated to IAS, while in the other the HLA-DRB1*0403 haplotype, conferring susceptibility to IAS, was detected. Continuous monitoring glucose (CGM) (iPro2; Medtronic Diabetes, CA, USA) showed in all patients the presence of prolonged hypoglycemia (with time spent with blood glucose below 54 mg/dL ranging from 9 to 20% of total monitoring time), and in one case the coexistence of high glucose levels after meals. One patient responded well to diazoxide treatment, while the others required both chronic steroid therapy and the use of plasmaphereses. Conclusion: Clinical manifestations of IAS vary widely among patients, without a direct correlation between symptoms severity and levels of both insulin and IAA; prandial hyperglycemia may also be present, leading to increases in glycated hemoglobin. Our patients displayed severe fasting hypoglycemic attacks that initially posed the suspicion of insulinoma. The assessment of IAA is thus mandatory in cases of fasting hypoglycemia, before proceeding to more expensive and probably unnecessary diagnostic and therapeutic procedures. CGM is a useful tool in evaluation and management of IAS, allowing the assessment of hypoglycemia duration and the detection of the wide glycemic variability secondary to the complex mechanism of insulin binding to IAA.
Severe, New-Onset Diabetes Mellitus Triggered by COVID-19 Infection Followed by Euglycemia Upon Recovery: A Case Report
Authors: Yu Ian , Sutherland Anne , Diaz Monica C Abreu , Cespedes Lissette Maria
Published: May 2021

Background: New-onset diabetes mellitus (DM) and severe metabolic complications in association with COVID-19 has been reported in the literature. Studies indicate a bidirectional relationship between COVID-19 and DM. Not only does severe DM lead to an increased risk for COVID-19 complications, but COVID-19 infection itself may precipitate new-onset DM. Clinical Case: A 45-year-old male with no known past medical history and normal body mass index presented after being found unresponsive at home. One week prior to admission, he tested positive for SARS-CoV-2 virus. On admission, laboratory evaluation showed: serum glucose 1090 mg/dl [70–109 mg/dL], anion gap 31 [<12], serum sodium 159 meq/L [133–145 meq/L], serum bicarbonate 18 meq/L [23–30 meq/L], creatinine 2.9 mg/dL [0.7–1.2 mg/dL], serum osmolality 438 mosm/k [280–295 mosm/k], venous pH 7.29 [7.32–7.42], venous bicarbonate 20 mmol/L [24–28 mmol/L], lactic acid 5.0 mmol/L [0.5–2.2 mmol/L], serum acetone positive 1+, urine ketone 20, hemoglobin 16.1 g/dL [14–18.0 g/dL] and HbA1c 13.5% [4.8–5.9%]. A diagnosis of diabetes with hyperosmolarity was made and he was admitted to the medical intensive care unit for treatment. Rapid resolution of hyperglycemia and hyperosmolarity was achieved with insulin infusion and intravenous fluids. He was transitioned to subcutaneous insulin on hospital day 2 and glycemic control was maintained using a basal/bolus insulin regimen. However, he experienced a prolonged two-month hospitalization due to complications including acute respiratory distress syndrome requiring mechanical ventilation and tracheostomy placement, pleural effusions with need for chest tube placement, and acute renal failure requiring short-term hemodialysis support. He was discharged to a rehabilitation facility on insulin glargine 15 units daily. Two-months after discharge, no weight changes were noted. Insulin was discontinued due to fasting serum glucose around 100 mg/dL and HbA1c 5.9%. Six-weeks later, a random serum glucose was 135 mg/dL and HbA1c 6.6%. He remains off glucose-lowering medications to date. Conclusion: We report an interesting case of new-onset diabetes with hyperosmolarity associated with COVID-19 infection with rapid achievement of euglycemia upon resolution of viral infection. Our case adds to growing evidence demonstrating a possible diabetogenic effect due to COVID-19 infection. There is also a complex interplay between SARS-CoV-2 virus and DM leading to a higher risk for complications. Questions remain regarding the long-term effects of COVID-19 on glucose metabolism. Patients with similar clinical presentations warrant close follow-up since it may be possible to de-escalate or discontinue hypoglycemic agents.
The Perfect Storm: Rapid Progression of Diabetic Ketoacidosis in Pediatric Diabetes in the Setting of COVID-19
Authors: Modarelli Rachel , Hendrix Grace , DeRusso Michelle , Ozment Caroline , Balikcioglu Pinar Gumus
Published: May 2021

Introduction: The COVID-19 pandemic has introduced countless challenges to the medical field and has brought increased attention to pediatric patients with pre-existing diagnoses such as diabetes. While pediatric patients have lower rates of COVID-19 mortality, the presence of pre-existing conditions can heighten the severity of their clinical presentation. Here we discuss how COVID-19 may contribute to the pathophysiology of DKA.

Case Presentation: Our patient is a 6-year old female with known type 1 diabetes for 6 months, with positive GAD 0.25 nmol/L, c-peptide 0.3 ng/ml, blood glucose 555 mg/dl, HbA1c 10.9, beta hydroxybutyrate (βOHB) 3.21mmol/l, pH 7.35, HCO3 21 mEq/L at her initial presentation, and insulin requirement <0.5 IU/kg/day (in honeymoon). She presented to an outside hospital due to acute onset of abnormal breathing and altered mental status. The day prior, she had one episode of emesis, diarrhea, and abdominal pain, but no fever. She was reported to be agonal breathing with a GCS of 8 and unresponsive to physical or verbal stimuli. She was intubated shortly after arrival and given mannitol. Initial labs included a glucose 486 mg/dL, pH 6.88, bicarbonate 4 mEq/L, lactate 5.8 mmol/L, βOHB 11.9 mmol/L, and anion gap 29 mEq/L, all consistent with severe DKA. With a known family member with COVID-19, she was tested and found to be COVID-19 positive. She was transferred via flight to a higher level of care. Remarkably, she was appropriate for extubation the following day with return to her baseline mental status with improved acidosis. On day three of hospitalization, she developed further COVID-19 symptoms which included sore throat, productive cough, fatigue, headache, and high fever. These symptoms persisted four more days until she was afebrile and discharged home in good condition.

Conclusion: Our patient’s rapid progression and severity of illness, including the need for intubation, requires the discussion of how COVID-19 might affect diabetes and suggests opportunities for improvement in clinical practice in children with preexisting diabetes. 1) COVID-19 might change the underlying pathophysiology and cause severe metabolic complications. Possible mechanisms might include a) binding to angiotensin-converting enzyme 2 (ACE2) receptors, which are expressed in key metabolic organs and tissues, including pancreatic beta cells, leading to insulin resistance and islet cell destruction b) enabling a proinflammatory “cytokine storm” in the setting of higher basal proinflammatory state from diabetes. Additionally, ketoacidosis and altered mental status have been discovered in patients with COVID-19 without diabetes, which could potentiate the symptoms of DKA. 2) Prompt recognition and treatment of DKA is warranted as caregivers may attribute the symptoms to COVID-19 rather than DKA and recognition could be too late if symptoms are as acute as described in this case report.
Climate Changes’ Effect on Blood Pressure in Diabetic Patients
Authors: Madrigal-Campos David Alberto
Published: May 2021

There has been noted a correlation between atmospheric temperature and some chemical, hematological and homeostatic variables on blood presure. Blood pressures’ variation was determined in diabetic patients with no high blood pressure issues living in a region with hot summers of 90–100º F (BP Hot) and cold winters with snow (BP cold). Chihuahua city has such weather conditions. 221 patients were included, 44 were women (20%) and 177 men (80%). The timeline was from May 2016 to January 2019 were all the cardiovascular events were noted. Group I had 89 patients (40.2%), having Diabetes Mellitus for more than 20 years. Average age of the group is 70 years old (60 - 84 years old). The increase in systolic blood pressure (BP) was of 27.5 mmHg (15–30 mmHg) and of the diastolic BP of 10 mmHg. As extra data it was noted that pulse increased 10 beats per minute (bpm). As a clinical presentation, 35 patients (39.3%) patients were found to be in NYHA class I, 27 (30.3%) in class II, and 27 (30.3%) in class III. Dyslipidemia was present in 70 (78.6%) of them, hypertensive cardiomyopathy (per ECG or Echocardiogram) in 37 (41.5%). From this group, 27 (30.3%) were admitted in the ER for uncontrolled blood presure with no symptoms, 45 (50.5%) admitted for high BP with symptoms (headaches, dizzines, epistaxis or conjuctival hemorrhage), 9 (10.1%) were admitted due to heart insuficiency and 4 (4.4%) sudden cardiac death. Group II included 132 patients (59.8%) with less than 20 years with DM and an average age of 64 years old (53–71 years of age). The increase in systolic BP was of 8.5 mmHg (less than 10 mmHg) and diastolic BP of 5.8 mmHg. Heart rate varied by 3.3 bpm (less than 5). Clinical presentacion of NYHA class I were 89 (67.4%) patients, 30 (22.7%) in class II, and 13 (9.8%) in class III. 92 (69.6%) patients presented dyslipidemia, and 30 (22.7%) hypertensive cardiomyopathy. Out of this group, 30 (22.7%) patients were admitted due to high BP without symptoms and 17 (12.8%) were admitted with high BP and symptoms. It is concluded that patients that have been diabetic for a longer time, with greater cardiovascular problems and older in age have a diminished reaction to the body’s control mechanisms and react more to the cold weather.
Evaluation of Small Fiber Peripheral Neuropathy With Infrared Thermographic Camera in Prediabetes
Authors: Vasconcellos Larissa Frazao , Mágero Felipe Rodrigues Lima , de Farias Maria Elba Bandeira , Bandeira Francisco Farias
Published: May 2021

Introduction: The typical microvascular complications of diabetes may ocasionaly occur in patients with prediabetes (PD). Diabetic peripheral neuropathy (DPN) is associated with poor glycemic control as well as with the metabolic syndrome components independently of HbA1c levels. Small fiber DPN is one of the most chalenging diagnosis due to the usualy normal physical examination as well as electrophysiological nerve evaluation. The thermographic camera has emerged as a novel tool for the detection of small nerve fiber dysfunction. The aim of the present study was to evaluate thermography of the plantar foot in individuals with PD. Methods: This was a cross-sectional study with a sample of 51 patients aged 27 to 71 years. Patients were divided into the following three groups: control (n = 18), diabetic (n = 17), and prediabetic (n = 16). The diagnosis of PD was made according to ADA standards. Thermographic analysis of the plantar region was performed using a FLIR C2 camera. Results: Overall, 510 foot regions were analyzed. There were significant diferences in plantar temperatures between prediabetes vs controls as follows: hallux (L: 25.24 ± 2.02 vs 23.6 ± 1.79 ºC; p=0.009/ R: 25.44 ± 2.05 vs 23.89 ± 1.73 ºC; p=0.01); fifth metatarsal (L: 26.31 ± 1.72 vs 24.88 ± 1.38 °C; p=0.006 /R: 26.12 ± 1.60 vs 24.74 ± 1.41 °C; p= 0.006); and calcaneus (L: 26.46 ± 1.71 vs 24.93 ± 1.41 °C; p=0.005 / R: 26.58 ± 1.85 vs 25.07 ± 1.18 °C; p=0.004). There were no similar results for temperatures in individuals with diabetes comparing with prediabetes: hallux (L:25.24 ± 2.02 vs 25.76 ± 2.30 °C; p=0.24 /R: 25.44 ± 2.05 vs 25.64 ± 1.92 °C; p=0.38); fifth metatarsal (L: 26.31 ± 1.72 vs 26.03 ± 1.27 °C; p=0.3 / R: 26.12 ± 1.60 vs 26.21 ± 1.57 °C; p=0.43); and calcaneus (L26.46 ± 1.71 vs 26.82 ± 1.41 °C; p=0.23 / R: 26.58 ± 1.85 vs 26.99 ± 1.42 °C; p=0.24). Conclusion: We found siginificant abnormalities in temperature of various sites of the plantar region in PD feets suggesting that small fiber damage may occur before the onset of type 2 diabetes.
Evaluation of the Prognostic Significance of Adipose Tissue Hormones in the Development of Diabetic Retinopathy in Patients With Type 2 Diabetes Mellitus
Authors: Kyryliuk Mykhailo L , Mogilevskyy Sergiy Yu , Serdiuk Valeriy M
Published: May 2021

Relevance: There are evidences of the participation of adipose tissue hormones (ATH) in the development of diabetic microangiopathy and retinal neovascularization. The disign of methods for the mathematical evaluation of the prognosis of the development of diabetic retinopathy (DR) with the participation of ATH is an actual problem in modern diabetology. Goal: Elaboration of a mathematical model for assessing the prognostic significance of ATH to study the likelihood of developing and progressing DR in patients with type 2 diabetes mellitus (T2DM). Materials and Methods: An open observational single-center one-stage selective study was conducted. The study was approved by the Local Ethics Committee. 59 patients (187 eyes) with T2DM and DR (men and women; mean age - 58.20±0.18 years; mean T2DM duration - 9.19±0.46 years; mean HbA1C - 9.10±0.17 %), were assigned to 3 groups, based on the stage of DR (according to fundus instrumental examination), and underwent the study. The diagnostic predictive value was assessed by discriminant analysis. Models with linear combinations of the serum leptin, adiponectin and resistin, triglyceride (TG), also HbA1C, type of antidiabetic therapy (ADT) were developed, and, subsequently, formulas for classification-relevant discriminant functions were derived. ADT included metformin, either alone (type 1 ADT), or in combination with oral anti-hyperglycemic medication (type 2 ADT) or insulin therapy (type 3 ADT). The classification functions (CF) computed based on the variables found from the above developed models provided the basis for predicting the development of DR. Results: The formulas for CF from model are as follows: CF1 = 0.29 * TG + 1.55 * HbA1 + 1.81 * ADT_Type + 0.04 * Leptin + 0,34* Adiponectin + 0,91* Resistin – 13,82; CF2 = 0.05*TG + 1.36 * HbA1 + 3.01 * ADT_Type + 0.08 * Leptin + 0,35* Adiponectin + 1,01 * Resistin – 15.95. A step-by-step approach to diagnostic decision making should be used. First, blood samples are tested for serum leptin, adiponectin and resistin, TG, blood HbA1, and the patient is assigned a code for ADT_Type (1, 2 or 3). Second, CF1 and CF2 values are calculated. Finally, the two values are compared to determine which is greater. The predictive decision is made by selecting the classification function with the greater value. Thus, if CF1>CF2, the process can be stabilized at this stage given an adequate glycemic control (through compensation of carbohydrate metabolism) and body-mass control as well as patient compliance. If CF1<CF2, the pathological process may progress to the next stage or even within stage 3, and there is an urgent need to reduce BMI, and to correct the ADT and the blood lipid profile. Conclusion: Informativeness and statistical significance of model is 71.4 % and p=0.040, respectively.
Extracellular Vesicle Influence on Wound Healing
Authors: Visentin Erica C , Pogue Robert E , Rosa Thiago , Marra Brenda
Published: May 2021

Diabetes is a highly prevalent disease in the world and it is involved in several chronic complications, such retinopathy, nephropathy, neuropathy, cardiovascular disease and the diabetic foot. Up to 28% of diabetic foot ulcers result in some form of amputation that lead to reduced productive activity and quality of life, as well as increased social costs. Advance in the understanding of the healing process changes in diabetic individuals is fundamental to improve diabetic foot care. Extracellular vesicles are intercellular communication agents that influence physiological and pathological processes. The objective of this research was to examine the influence of extracellular vesicles collected of diabetic individuals on cell proliferation, viability and migration in wounds. The procedures included in vitro assay of migration, senescence, cellular viability and oxide nitric production. Extracellular vesicles have been shown to stimulate the cell migration process and this function was not poorly influenced by metabolic control. References: 1. International Diabetes Federation. Diabetes Atlas, 2019. www.diabetesatlas.org. 2. Than UTT, Guanzon D, Leavesley D, Parker T. Association of Extracellular Membrane Vesicles with Cutaneous Wound Healing. Int J Mol Sci. 2017;18(5):956. 3. Van Niel G, D’Angelo G, Raposo G. Shedding light on the cell biology of extracellular vesicles. Nat Rev Mol Cell Biol. 2018;19(4):213–228.

4. Lampugnani MG. Cell migration into a wounded area in vitro. Methods Mol Biol. 1999;96:177–182.5. Sociedade Brasileira de Diabetes. Diretrizes da Sociedade de Diabetes 2017–2018. ISBN: 978-85-93746-02-4. São Paulo: Editora Clannad, 2017.6. Sociedade Brasileira de Cardiologia. Atualização da Diretrizes da Sociedade de Dislipidemia e Prevenção da Aterosclerose - 2017. ISBN: 0066-783X, vol 109, nº2, supl 1, agosto, 2017.7. Leroyer AS, Tedgui A, Boulanger CM. Microparticles and type 2 diabetes. Diabetes Metab. 2008;34 Suppl 1:S27-S32.8. International Society for Extracellular Vesicles. Minimal information for studies of extracellular vesicles 2018 (MISEV2018): a position statement of the International Society for Extracellular Vesicles and update of the MISEV2014 guidelines. Journal of Extracellular Vesicles, 7:1, 2018.9. Deng F, Wang S, Zhang L. Endothelial Microparticles Act as Novel Diagnostic and Therapeutic Biomarkers of Diabetes and Its Complications: A Literature Review. Biomed Res Int. 2016;2016:9802026.
Mild Cognitive Impairment Screening in Older Adults With Type 2 DM
Authors: Pirela Daniela Victoria , Cevallos Victor , Ruiz Jorge G
Published: May 2021

Introduction: Older adults (O-A), more than 65 years old, are a heterogeneous group of patients in terms of functionality, social support and health status that implies a wide range of co-morbidities including mild cognitive impairment (MCI) and unidentified dementia. De-intensification of treatment is recommended for O-A with T2DM, tight glycemic control and high risk of hypoglycemia. Assessment of all geriatric domains (medical, functional, social and psychological including screening for MCI) is encouraged to support a complete clinical picture that leads to appropriate targets and adequate therapeutic approach. The literature suggests that de-intensification of treatment in this population is uncommon, which calls for the development of new strategies to prevent potential harm, however we also question if previously established tools are being used. Methods: We performed a retrospective chart review of a community-dwelling Veterans with at least two office visits in the Geriatric Clinic between January 1st 2018 to December 31st 2019. 210 patients with 65 years of age or older with T2DM and A1C < 7.5 were found. 64 (30%) of the patients where on hypoglycemic medication including sulfonylureas or insulin. From this subgroup, only 9 (14%) patients where recommended to de-intensify therapy. 189 (90%) of all the patients were screened for memory disorders. Interestingly 20 patients (31%) of those using sulfonylureas or insulin as part of their diabetes treatment were not screened, which was a higher percentage compared to 48 (25%) patients not on hypoglycemic medications also not screened for memory disorders. Conclusion: similar to previous studies de-intensification is uncommon not only among endocrinologist but in other sub-specialties involved in the care of the Geriatric population. This data emphasizes the importance of using previously developed treatment tools specially in those with at higher risk of overtreatment side effects such as older adults with tight glycemic control and hypoglycemic medication
Screening for Diabetic Retinopathy in Endocrinology Clinics by Using Handheld Cameras and Applying Artificial Intelligence Algorithms
Authors: Dvey-Aharon Zack , Huhtinen Petri
Published: May 2021

According to estimations of the World Health Organization (WHO), there are almost 500M people in the world that suffer from diabetes. Projections suggest this number will surpass 700M by 2045 with global prevalence surpassing 7%. This huge population, alongside people with pre-diabetics, is prone to develop diabetic retinopathy, the leading cause of vision loss in the working age. While early screening can help prevent most cases of vision loss caused by diabetic retinopathy, the vast majority of patients are not being screened periodically as the guidelines instruct. The challenge is to find a reliable and convenient method to screen patients so that efficacy in detection of referral diabetic retinopathy is sufficient while integration with the flow of care is smooth, easy, simple, and cost-efficient. In this research, we described a screening process for more-than-mild retinopathy through the application of artificial intelligence (AI) algorithms on images obtained by a portable, handheld fundus camera.

156 patients were screened for mtmDR indication. Four images were taken per patient, two macula centered and two optic disc centered. The 624 images were taken using the Optomed Aurora fundus camera and were uploaded using Optomed Direct-Upload. Fully blinded and independently, a certified, experienced ophthalmologist (contracted by Optomed and based in Finland) reviewed each patient to determine ground truth. Indications that are different than mtmDR were also documented by the ophthalmologist to meet exclusion criteria. Data was obtained from anonymized images uploaded to the cloud-based AEYE-DS system and analysis results from the AI algorithm were promptly returned to the users.

Of the 156 patients, a certified ophthalmologist determined 100% reached sufficient quality of images for grading, and 36 had existing retinal diseases that fall under exclusion criteria, thus, 77% of the participants met the participation criteria. Of the remaining 120 patients, the AEYE-DS system determined that 2 patients had at least one insufficient quality image. AEYE-DS provided readings for each of the 118 remaining patients (98.3% of all patients). These were statistically compared to the output of the ground truth arm. The patient ground truth was defined as the most severe diagnosis from the four patient images; the ophthalmologist diagnosed 54 patients as mtmDR+ (45% prevalence). Of the 54 patients with referable DR, 50 were diagnosed and of the 64 mtmDR- patients, 61 were correctly diagnosed by the AI. In summary, the results of the study in terms of sensitivity and specificity were 92.6% and 95.3%, respectively.

The results indicated accurate classification of diabetic patients that required referral to the ophthalmologist and those who did not. The results also demonstrated the potential of efficient screening and easy workflow integration into points of care such as endocrinology clinics.
Efficient Restoration of Beta Cell Dedifferentiation by Calorie Restriction With High Fat/Low Carbohydrate Diet in Obese Diabetes Model and the Possible Role of GLP-1
Authors: Ishida Emi , Lei Xiao , Horiguchi Kazuhiko , Matsumoto Shunichi , Yoshino Satoshi , Nakajima Yasuyo , Yamada Eijiro , Yamada Masanobu
Published: May 2021

In type 2 diabetes, pancreatic beta cells are gradually ‘exhausted’ and fall into beta cell dysfunction, which proceeds more severe insulin dependence. Among the proposed mechanisms of beta cell dysfunction such as endoplasmic reticulum stress and oxidative stress, the beta cell heterogeneity has attracted the researcher’s interest recently. In 2012, Talchai et al. revealed that the beta cells were dedifferentiated in diabetic mice model, and nowadays it is considered as one form of the beta cell heterogeneity and is observed broadly among diabetic animal models and human patients. Previously we showed that food restriction had the best effect to restore beta cell gene expression in obese diabetic model mice, among the known diabetic treatments which we tested. In the current study, we aimed to unveil the molecular basis in the improvement of beta cell dedifferentiation during the calorie restriction. First, we utilized the high-fat/low carbohydrate diet (HF) or low-fat/high carbohydrate (HC) diet, to determine whether fat restriction or sugar restriction reduces the beta cell dedifferentiation in obese mice. When calorie intake was restricted evenly, both HF diet and HC diet decreased the body weight and hyperglycemia in db/db mice equally. Albeit the same metabolic profile, db/db group fed with HC diet had more enlarged islets and more dedifferentiated beta cell features than db/dbs fed with HF diet, which indicated the compensatory beta cell response in HC diet group. Moreover, HC diet group showed more severe fatty liver than HF diet group, along with the elevated synthesis and accumulation of triglycerides and cholesterol in liver. It is speculated that the insulin resistance in liver might impact on the beta cell dedifferentiation. Next, we analyzed the effect of glucagon-like peptide 1 (GLP-1) on beta cell dedifferentiation, since GLP-1 is secreted more from intestine by protein and fat intake, rather than by sugar intake. Also, increasing number of reports have suggested the improving effect of GLP-1 on beta cell dysfunction and fatty liver. Indeed, GLP-1 administration altered the reduced beta cell/alpha cell ratio in db/db mice, which indicated the restoration of beta cell heterogeneity. We are now investigating if GLP-1 administration reimburse the beta cell dedifferentiation in db/db mice fed with HC diet, to illuminate the role of incretins in beta cell dedifferentiation induced by unbalanced nutrition during diet. Also, we will present the RNA sequencing data of the liver in db/db mice fed with HF and HC diet, to elucidate the key molecules and genes which connect the beta cell function and metabolic state in liver.
Insertion of a Synthetic Switch Into Insulin Provides Metabolite-Dependent Regulation of Hormone-Receptor Activation
Authors: Chen Yen-Shan , Gleaton Jeremy , Yang Yanwu , Dhayalan Balamurugan , Phillips Nelson B , Liu Yule , Broadwater Laurie , Jarosinski Mark , Chatterjee Deepak , Lawrence Michael C , Hattier Thomas , Michael Dodson M , Weiss Michael Aaron
Published: May 2021

Insulin signaling requires conformational change: whereas the free hormone and its receptor each adopt autoinhibited conformations, their binding leads to large-scale structural reorganization. To test the coupling between insulin’s “opening” and receptor activation, we inserted an artificial ligand-dependent switch into insulin. Ligand binding disrupts an internal tether designed to stabilize the hormone’s native closed and inactive conformation, thereby enabling productive receptor engagement. This scheme exploited a diol sensor (meta-fluoro-phenylboronic acid at GlyA1) and internal diol (3,4-dihydroxybenzoate at LysB28). The sensor recognizes monosaccharides (fructose > glucose). Studies of insulin signaling in human hepatoma-derived cells (HepG2) demonstrated fructose-dependent receptor autophosphorylation leading to appropriate downstream signaling events, including a specific kinase cascade and metabolic gene regulation (gluconeogenesis and lipogenesis). Addition of glucose (an isomeric ligand with negligible sensor affinity) did not activate the receptor. Similarly, metabolite-regulated signaling was not observed in control studies of (i) an unmodified insulin analog or (ii) an analog containing a diol sensor in the absence of internal tethering. Although as expected CD-detected secondary structure was unaffected by ligand binding, heteronuclear NMR studies revealed subtle local and nonlocal monosaccharide-dependent changes in structure. Insertion of a synthetic switch into insulin has thus demonstrated coupling between hinge-opening and holoreceptor signaling. In addition to this basic finding, our results provide proof of principle for a mechanism-based metabolite-responsive insulin. In particular, replacement of the present fructose sensor by an analogous glucose sensor may enable translational development of a “smart” insulin analog designed to mitigate risk of hypoglycemia in the treatment of diabetes mellitus.
Loss of Intestine-Specific FFA3 Has Protective Effects Against Diet-Induced Obesity and Hyperglycemia in Mice on a Western Diet
Authors: Lednovich Kristen Roan , Gough Sophie , Priyadarshini Medha , Layden Brian T
Published: May 2021

Free fatty acid receptor 3 (FFA3) is a recently-deorphaned G protein-coupled receptor belonging to the free fatty acid receptor family. Its ligands are short-chain fatty acids (SCFAs), which are key nutrients that play a diverse role in physiological function, including the regulation of metabolic homeostasis and glycemic control. FFA3 is broadly expressed in a multitude of tissues including the intestine, pancreas, and central nervous system, and is thought to contribute to metabolic homeostasis via a summation of its tissue-specific effects. Consequently, FFA3 has been identified as a potential drug target for metabolic diseases including obesity and type-2 diabetes. FFA3 is highly expressed in enteroendocrine cells (EECs) within the intestinal epithelium - the major site of SCFA generation - and is hypothesized to play a role in the secretion of postprandial incretin hormones, which are a group of specialized gut peptides that regulate a variety of metabolic and digestive functions following a meal. However, due to a paucity of data, the role of FFA3 within the intestine and its effects on physiology and metabolism is largely unclear. Previous in vivo studies involving this receptor have largely relied on global knockout mouse models, making it difficult to isolate its effects in EECs. To overcome this challenge, we have generated a novel intestine-specific knockout mouse model for FFA3, utilizing Cre-mediated recombination under the expression of the villin promoter. Here, we report the first in vivo characterization of FFA3 in the intestine and reveal novel insights into receptor function. Following model validation, we conducted a general metabolic assessment of male Villin-Cre-FFA3 mice on normal chow and observed no major congenital or time-dependent defects. Because dietary changes are known to alter gut microbial composition, and thereby SCFA production, a pilot study was performed on male Villin-Cre-FFA3 mice and their littermate controls to probe for a phenotype on a high-fat, high-sugar “western diet.” Mice were placed on either normal chow (NC) or western diet (WD) at 10 weeks of age and metabolically profiled for 25 weeks. Our data reveals that Villin-Cre-FFA3 mice on WD, but not NC, were protected from diet-induced metabolic dysfunction, and displayed significantly lower levels of fat mass as well as modestly improved glycemic control. Our findings suggest a novel role of FFA3 in mediating the metabolic consequences of a western diet - a state of high inflammation, dysbiosis and metabolic stress. Moreover, these data support an intestine-specific role of FFA3 in both glucose and lipid metabolism, and further suggest the receptor’s role in whole-body metabolic homeostasis and in the development of adiposity and hyperglycemia.
Tgm2-p62-p53 Complex May Function as an Autophagic Regulator Through Fyn and Involve in Diabetic Kidney Disease
Authors: Uehara Ryota , Yamada Eijiro , Uehara Masaya , Nakajima Yasuyo , Horiguchi Kazuhiko , Ishida Emi , Matsumoto Shunichi , Okada Shuichi , Yamada Masanobu
Published: May 2021

Diabetic kidney disease (DKD) is one of the major diabetic complications and the leading cause of the end stage renal disease. Recently autophagy was shown to regulate DKD. Previously we reported that Fyn regulates muscle mass by suppressing autophagy through Fyn-STAT3-VPS34 signaling pathway. More recently, we demonstrated that Fyn also down-regulates autophagy in HK2 cells, an in vitrocell model of renal proximal tubular epithelial cells (RPTC). Phospho-proteomic analysis revealed that Fyn phosphorylates Transglutaminase 2 (Tgm2), a known autophagic inhibitor, at Y369 and Y617. Moreover, we found that Fyn-dependent phosphorylation of Tgm2 regulates autophagy. It has been reported that Tgm2 forms complexes with p53 and p62 (a known autophagy regulator) to mediate degradation of p53 at autophagosome in cancer cells and p53 functions as a DKD inducer. We found that p53 expression was decreased in Tgm2 knock-downed HK2 cells suggesting that Tgm2-p62-p53 complex also modulates autophagy in RPTC. We previously showed that Fyn and autophagy is regulated by energy status, therefore we next examined whether energy levels changed the subcellular localization of p53, p62 and Tgm2 in HK2 cells in vivousing the marker, Aquaporin 1. Confocal microscopic studies revealed that ad libitum-fed mice showed increased punctate of p62 in RPTC suggesting that autophagy was reduced. Fyn, Tgm2 and p53 shaped the dotted form mainly in the basement membrane of the cells. Interestingly, all these molecules moved to the cytoplasm in fasted state, where decreased p62 punctations were observed indicating increased autophagy. More importantly, in HFD fed mice, diet-induced rodent models of metabolic disorders, we found that protein expression of p53 was increased due to decreased levels of degradation with inhibition of autophagy implicated by decreased p62 punctations in RPTC. Taken together, these data suggest that the metabolic status may regulate Fyn to not only phosphorylate Tgm2 and modulates Tgm2-p62-p53 complex but also change their co-localizations of Fyn, p53 and Tgm2 in RPTC to regulate autophagy leading to pathogenesis of DKD.
The Short-Term Impact of Roux-en-Y Gastric Bypass on Enteroendocrine Hormone Distribution and Density in Rhesus Macaques
Authors: True Cadence , Kirigiti Melissa Ann , Lindsley Sarah Rene , Scamarone Jackelin , Bauman Leigh Ann , Kievit Paul
Published: May 2021

Roux-en-Y gastric bypass (RYGB) surgery results in profound weight loss and improvements in glucose homeostasis through a likely combination of malabsorption and changes in GI tract signaling. One component of GI tract signaling implicated in RYGB effects are enteroendocrine hormones, which are produced along the tract and regulate GI tract motility, pancreas exocrine and endocrine functions, including insulin release, and central nervous system control of feeding. While RYGB has been shown to cause post-prandial serum increases of several enteroendocrine hormones, the mechanism for how this occurs in the GI tract is still unknown. The current study examined GI tract tissue 13 weeks after RYGB or sham-surgery combined with pair-feeding (Sham/PF) in adult rhesus macaques. In situ hybridization analysis revealed no RYGB-induced changes compared to Sham/PF animals in the overall distribution of enteroendocrine hormones, with cholecystokinin (CCK) and glucose-dependent insulinotropic peptide (GIP) cells found predominantly in the proximal small intestine and preglucagon, encoding glucagon-like peptide-1 (GLP-1), and peptide tyrosine tyrosine (PYY) cells found predominantly in the ileum and colon. Immunohistochemistry was performed to further characterize the impact of RYGB on enteroendocrine cell density. No differences were observed in CCK cell densities in the proximal tract following RYGB, nor were there any differences in PYY and GLP-1 densities in the distal intestine. The only observed difference was an increase in serotonin and chromogranin A cell densities in the ileum of the RYGB group compared to the Sham/PF group. Serotonin has diverse actions from regulating GI tract motility to central nervous system signaling via the vagus nerve. Additional studies are planned to investigate how this up-regulation of serotonin may impact metabolic physiology after RYGB.
High-Fat Diet Accelerates Pathological Progression and Intestinal Inflammation in a Type 2 Diabetes Rodent Model
Authors: Reilly Austin , Ren Hongxia
Published: May 2021

Insulin signaling lowers postprandial glucose by stimulating cell surface translocation of the insulin sensitive glucose transporter 4 (GLUT4). In order to better understand how insulin resistance contributes to the pathophysiological progression of type 2 diabetes, we generated human GLUT4 promoter-driven insulin receptor knockout (GIRKO) mice and characterized their metabolic features relative to control mice. Although the role of insulin resistance in diabetes is beyond dispute, our previous studies showed that GIRKO mice fed normal chow diet (NCD) had an unexpectedly low rate of frank diabetes despite severe insulin resistance in muscle, fat, and brain.

In the current study, we first sought to determine whether GIRKO mice would respond to high-fat diet (HFD) challenge with worsened glycemic outcome compared to control mice on HFD. Secondly, we sought to determine whether HFD-induced pathologies in GIRKO mice were caused by adaptations in the gastrointestinal (GI) tract and microbiome. We discovered that after beginning the HFD-feeding regimen, GIRKO mice rapidly developed hyperinsulinemia and hyperglycemia without excessive adiposity gain. Furthermore, GIRKO mice displayed dyslipidemia via increased hepatic lipid accumulation and serum lipid content. We used indirect calorimetry to characterize the metabolic features of single-housed mice. HFD-fed GIRKO mice had comparatively lower respiratory exchange ratio (RER), indicating relatively greater lipid metabolism compared to control mice on HFD. Despite having increased circulating incretins, GIRKO mice had impaired oral glucose tolerance and limited glucose-lowering benefit from Exendin-4 (Ex-4) injections. Since HFD promotes inflammation in the gastrointestinal (GI) tract, we performed gene expression analysis and pathway analysis of duodenal mRNAs to investigate whether inflammatory response, glucose transport, and lipid transport were altered in HFD-fed GIRKO mice. Among the top pathways discovered in pathway analysis were those involved with inflammatory signaling, carbohydrate transport, and xenobiotic metabolism, which supports that HFD-fed GIRKO mice have increased GI tract inflammation which may promote impaired glucose homeostasis.

In conclusion, our studies suggest that HFD increased intestinal inflammation and exacerbated insulin resistance, which catalyzed the pathological progression of diabetes. Future studies are necessary to identify the molecular and cellular signaling pathways which culminate in frank diabetes, which may lead to therapeutic targets for regulating glucose homeostasis in the context of insulin resistance.