ResearchPad - glucose-metabolism https://www.researchpad.co Default RSS Feed en-us © 2020 Newgen KnowledgeWorks <![CDATA[Prolyl hydroxylase domain 2 reduction enhances skeletal muscle tissue regeneration after soft tissue trauma in mice]]> https://www.researchpad.co/article/elastic_article_14698 The transcription factor Hypoxia-inducible factor 1 (HIF-1) plays a pivotal role in tissue regeneration. HIF-1 is negatively controlled by O2-dependent prolyl hydroxylases with a predominant role of prolyl hydroxylase 2 isoform (Phd2). Transgenic mice, hypomorphic for this isoform, accumulate more HIF-1 under normoxic conditions. Using these mice, we investigated the influence of Phd2 and HIF-1 on the regenerative capability of skeletal muscle tissue after myotrauma. Phd2-hypomorphic and wild type mice (on C57Bl/6 background) were grouped with regeneration times from 6 to 168 hours after closed mechanic muscle trauma to the hind limb. Tissue samples were analysed by immuno-staining and real-time PCR. Bone marrow derived macrophages of wild type and Phd2-hypomorphic mice were isolated and analysed via flow cytometry and quantitative real-time PCR. Phd2 reduction led to a higher regenerative capability due to enhanced activation of myogenic factors accompanied by induction of genes responsible for glucose and lactate metabolism in Phd2-hypomorphic mice. Macrophage infiltration into the trauma areas in hypomorphic mice started earlier and was more pronounced compared to wild type mice. Phd2-hypomorphic mice also showed higher numbers of macrophages in areas with sustained trauma 72 hours after myotrauma application. In conclusion, we postulate that the HIF-1 pathway is activated secondary to a Phd2 reduction which may lead to i) higher activation of myogenic factors, ii) increased number of positive stem cell proliferation markers, and iii) accelerated macrophage recruitment to areas of trauma, resulting in faster muscle tissue regeneration after myotrauma. With the current development of prolyl hydroxylase domain inhibitors, our findings point towards a potential clinical benefit after myotrauma.

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<![CDATA[Rev-erbα heterozygosity produces a dose-dependent phenotypic advantage in mice]]> https://www.researchpad.co/article/elastic_article_14626 Numerous mutational studies have demonstrated that circadian clock proteins regulate behavior and metabolism. Nr1d1(Rev-erbα) is a key regulator of circadian gene expression and a pleiotropic regulator of skeletal muscle homeostasis and lipid metabolism. Loss of Rev-erbα expression induces muscular atrophy, high adiposity, and metabolic syndrome in mice. Here we show that, unlike knockout mice, Nr1d1 heterozygous mice are not susceptible to muscular atrophy and in fact paradoxically possess larger myofiber diameters and improved neuromuscular function, compared to wildtype mice. Heterozygous mice lacked dyslipidemia, a characteristic of Nr1d1 knockout mice and displayed increased whole-body fatty-acid oxidation during periods of inactivity (light cycle). Heterozygous mice also exhibited higher rates of glucose uptake when fasted, and had elevated basal rates of gluconeogenesis compared to wildtype and knockout littermates. Rev-erbα ablation suppressed glycolysis and fatty acid-oxidation in white-adipose tissue (WAT), whereas partial Rev-erbα loss, curiously stimulated these processes. Our investigations revealed that Rev-erbα dose-dependently regulates glucose metabolism and fatty acid oxidation in WAT and muscle.

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<![CDATA[MON-LB113 Insulin Resistance in Type 1 Diabetes Managed With Metformin (INTIMET): Rationale and Study Design of a Randomised Placebo-Controlled Trial]]> https://www.researchpad.co/article/elastic_article_8817 Background: Insulin resistance is an under-recognised cardiovascular risk factor in type 1 diabetes (T1D). Individuals with T1D exhibit insulin resistance relative to those without diabetes. In T1D, tissue-specific insulin resistance (muscle, hepatic, adipose) is likely to partly drive increased cardiovascular risk. Adjunctive metformin improves muscle insulin sensitivity in T1D adolescents, but factors that predict responsiveness remain unknown.Objective: To report the rationale and design of the INTIMET study, a double-blind randomised, placebo-controlled trial of metformin in T1D.Methods: Forty adults aged 20-50 years with T1D, and 20 age- gender- and BMI- matched non-diabetic controls will be studied. T1D inclusion criteria are diagnosis > 10 years, HbA1c 9.5% and fasting C-peptide < 0.3nmol/L. Liver and muscle insulin sensitivity will be determined by the 2-stage hyperinsulinemic (20 and 60 mUm2)-euglycemic (5.5 mmol/L) clamp method with deuterated glucose. Subjects with T1D will be randomised to metformin extended-release 1500mg/d or matched placebo for 26 weeks. The primary endpoint is the change in hepatic insulin sensitivity, measured by suppression of endogenous glucose production (EGP) with the low-dose insulin clamp. Secondary endpoints include change in muscle and adipose tissue insulin sensitivity, arterial stiffness, HbA1c, glucose variability, frequency of hypoglycemia, insulin dose, anthropometry, body composition, lipid profile, liver fat and stiffness. Conclusion: The INTIMET study will quantify muscle, liver and adipose insulin-resistance in T1D, determine whether metformin is effective in improving insulin resistance in T1D and identify factors that predict metformin-responsiveness.

The trial is registered (Australian New Zealand Clinical Trial Registry, ACTRN12619001440112) and is actively recruiting in Sydney, Australia.

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<![CDATA[SAT-685 Euglycemic Diabetic Ketoacidosis in T1d: The Era of SGLT-2 Inhibitors and Keto-Diet]]> https://www.researchpad.co/article/elastic_article_8814 Introduction Euglycemic diabetic ketoacidosis (DKA) is a challenging diagnosis since near normal blood sugar levels can be misleading. In the present case, we describe a patient with Type 1 Diabetes (T1D) on SGLT2 who underwent a strict low carb diet. Case Report A 70-year-old female with past medical history of unspecified diabetes mellitus and primary hypothyroidism presented to emergency room complaining of nausea and dizziness of four days with decreased oral intake. She was alert and oriented, normal weight (52 kg, BMI 20 kg/m2) with stable vital signs, except for mild tachypnea (22/min). Initial labs showed serum glucose 136 mg/dL, bicarbonate 10 mmol/L (normal 20-31), anion gap of 27, venous blood gas pH 7.1, B-hydroxybutyrate 8.8 mmol/L (normal 0.02-0.27), glucosuria > 500 mg/dL, and moderate ketonuria. Screening for ethyl alcohol and ethylene glycol was negative. Lactic acid, cardiac enzymes, renal and liver function tests were normal. She was diagnosed with diabetes mellitus at age 37, on insulin since then. No alcohol use. Her new primary care physician found an A1C of 9.0% for which metformin 1000mg oral twice a day and empagliflozin 12.5 mg oral daily were added and aspart insulin was discontinued. Daily glargine remained at 20 units daily. She was advised to lose weight for which she started a keto-diet 4 weeks prior to this presentation. She had lost 15 pounds since then accompanied by polyuria and polydipsia. Upon admission, she received IV insulin and IV fluids. An endocrinology consultation was requested for euglycemic DKA secondary to SGLT2 complicated by starvation ketosis. Antibodies against glutamic acid decarboxylase were positive at 250 IU/mL (normal < 5). She was discharged on glargine, aspart insulins and oral medications were discontinued. Conclusion This case shows the importance of identifying the specific type of diabetes for appropriate individualization of therapy. Following a keto-diet in unrecognized T1D can trigger ketoacidosis in the setting of SGLT2 inhibitors leading to euglycemic diabetes ketoacidosis.

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<![CDATA[SAT-668 Liver Function Test in Type 1 Diabetes Mellitus and Prevalence of Other Autoimmune Disease in Type 1 Diabetes Mellitus]]> https://www.researchpad.co/article/elastic_article_8788 Background

Recent studies suggest that non-alcoholic fatty liver disease (NAFLD) may be more common in type 1 diabetes. The pathogenesis of NAFLD has been hypothesized that, hepatic fat accumulation may be due to hyperglycemia induced activation of the transcription factors.

Type 1 DM inducing autoimmune process can also affect other organs. So screening for celiac disease, Hashimoto’s thyroiditis and other autoimmune disorders is necessary.

Aims:

1.

To evaluate the prevalence of NAFLD in type 1 DM. And to correlate glycosylated hemoglobin (HbA1c) with aspartate transaminase (AST) and alanine transaminase (ALT).

2.

To determine the prevalence of autoimmune disease like hypothyroidism, celiac disease, vitamin B12 deficiency and Vitiligo in type 1 DM.

3.

To study the prevalence of microvascular complications and correlate it with HBA1c.

Study design

Cross sectional study

Methods:

Eighty patients with type 1 DM were taken, liver function test, HbA1c and TSH was sent. BMI was calculated. We calculated prevalence of elevated AST and ALT in all patients and correlated with HbA1c.

All patients were screened for other autoimmune disorders. Screening for celiac disease was done by celiac antibodies and antibodies positive patients underwent duodenal biopsy. Thyroid screening was done by TSH and anti TPO antibodies. Vitamin B12 levels were also measured.

Patients also underwent screening for microvascular complications to see its prevalence.

Statistical Analysis

Categorical data was represented in the form of frequencies and proportions. Chi square test was used as test of significance for qualitative data. Continuous data was represented as mean and standard deviation.

Pearson correlation or Spearman’s correlation was done to find the correlation between two quantitative variables and qualitative variables and quantitative variables respectively.

Results:

Mean age of subjects was 21.38 ± 6.16 years, 57.6% were females and 42.4% were males, mean HBA1c was 10.45 ± 2.54, mean AST was 24.71 ± 15.85 and mean ALT was 22.08 ± 15.13. In the study significant positive correlation was observed between HbA1c and ALT, i.e. With increase in HbA1c there was increase in ALT and vice versa. There was no significant correlation between HbA1c and AST.

In the study 21.2% were hypothyroid, 29.4%had Celiac disease, 1.2% had Vitiligo and 23.5% had B12 deficiency. In the study there was no significant association between Micro vascular complications and HbA1c.

In the study 3.5% had neuropathy, 7% had retinopathy, 4.7% had nephropathy.

Conclusion:

Elevated ALT can be associated with NAFLD related risk factors. Type 1 diabetics with elevated ALT should be evaluated. And patients with type 1 DM should undergo screening for other autoimmune disease.

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<![CDATA[SAT-670 The Perfect Storm for Diabetic Ketoacidosis]]> https://www.researchpad.co/article/elastic_article_8786 Background

Diabetic Ketoacidosis (DKA) is a life-threatening endocrine emergency characterized by metabolic acidosis occurring in the setting of hyperglycemia due to relative insulin deficiency leading to lipolysis and production of serum ketones. Clinical circumstances can potentiate this process, such as acute infection or insulin discontinuation. Additionally, patients on SGLT2-inhibitors are at risk for euglycemic DKA. In people with type 2 diabetes, DKA is uncommon; however, a combination of precipitating factors in these patients can lead to a greater risk of DKA, particularly in the setting of SGLT2-inhibitor use.

Clinical Case

A 63 year old male with past medical history significant for uncontrolled type 2 diabetes (10 year duration, HgA1c=11.2%, on insulins detemir and aspart, metformin, and empagliflozin), coronary artery disease, and treatment refractory antibody-negative polymyositis (baseline CPK levels ~1000-2000, on a burst of prednisone for flare) presented with fever (101.2F), fatigue, myalgias, and nausea with poor oral intake and insulin cessation after recent IV zoledronic acid infusion for prevention of steroid-induced osteoporosis. He was found to be acidemic with bicarbonate=16, AG=18, Cr=1.6 (baseline 1.1), lactic acid=2.9, glucose=245, glucosuria/ketonuria, serum osmolality=295, and CPK=3613. No infectious etiology was found. Differential diagnosis of precipitating factors of DKA includes: steroid-induced hyperglycemia with lipolysis and insulin resistance; starvation ketosis from poor oral intake due to bisphosphonate-induced flu-like illness; metformin-associated lactic acidosis in setting of acute kidney injury; ketone production secondary to insulin cessation in setting of febrile illness; and SGLT2-inhibitor use with dehydration secondary to decompensated hyperglycemia. He was treated for DKA with insulin and volume resuscitation. He was discharged with discontinuation of empagliflozin.

Conclusion

In people with type 2 diabetes and multiple medical problems, a collusion of clinical factors leading to acidemia can occur simultaneously and lead to a drastically increased risk of DKA, especially in the setting of SGLT2-inhibitor use. Clinicians should have heightened awareness of minor predisposing factors that in combination can increase risk of DKA in a patient with type 2 diabetes.

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<![CDATA[SUN-692 Comprehensive and Structured Care Program for Patients with Type 2 Diabetes Mellitus: A Preliminary Report from Raipur, Chhattisgarh State of India]]> https://www.researchpad.co/article/elastic_article_8779 Aim: To assess the glycemic outcomes of T2DM patients enrolled in comprehensive structured care program at the outpatient clinic of Apollo Sugar at Raipur, India. Methods: This is a preliminary, prospective, single-center, observational study on T2DM patients from Jan 2018 to December 2018. Uncontrolled diabetes or patients with comorbid conditions with the duration of disease for more than one year and age ≥18 years and who gave consent to enroll in the program were included in the study. The structured care program is a 6 months program where patients were continuously engaged by counseling them on diabetes management- diet and exercise, self-monitoring of blood glucose, health interactions with the remote health coach through a mobile app. Baseline demographics and clinical data were collected at the time of enrollment and were followed up for 6 months. HbA1c reduction is the target measurement of this program. Descriptive statistics were used to analyze and report the data. A paired t-test is used to check the significant reduction in HbA1c from baseline to follow up Results: Total 102 patients were included in this study. Mean (SD) age was 50.7 (10.5) years, males were 78 (76%) and females were 24 (24%). The mean (SD) duration of diabetes and BMI were 7.9 (7.0) years and 27.5 (4.5) kg/m2 respectively. At the time of enrollment, patients were at mean HbA1c of 9.0(2.1)%, fasting (F) and post-prandial (PP) blood (BG) glucose was 194(68) mg/dL and 247(94) mg/dL respectively. Among these patients 38% had neuropathy and 15% had retinopathy as their complications. These patients were regularly followed up over the phone call to counsel on diabetes management with a healthy diet, exercise, self-monitoring of blood glucose, and medication compliance. After 6 months followup the HbA1c, FBG, and PPBG were 7.6 (1.5) %, 139 (50) mg/dL, and 196 (75) mg/dL, respectively with a significant mean reduction of 1.4%, 56 mg/dL, and 51 mg/dL (p <0.001). Further analysis of glycemic outcomes between these patients on oral hypoglycemic agents (OHAs) and OHAs+insulin, the reduction in HbA1c (1.5%) was not significant. Conclusion: Our study demonstrates that a structured care program might bring a clinically significant glycemic control through tight adherence to SMBG, diet, exercise, and medication. To establish these results a study in large sample is in progress.

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<![CDATA[SAT-649 Comparison of the Accuracy and Concordance of 3 CGM Devices vs SMBG During Aerobic Exercise]]> https://www.researchpad.co/article/elastic_article_8749 Introduction: Real-time continuous glucose monitoring (rt-CGM) and flash glucose monitoring (FGM) devices have become important tools for managing type 1 diabetes. These devices are approved for management decisions in steady-state conditions, however there is a decline in accuracy during aerobic exercise with respect to MARD and lag time.1 It is possible that newer technologies may be superior to previous devices.

Question: With the newest rtCGM, FGM, and long-term CGM devices, do we continue to see an increase in MARD during continuous aerobic exercise? Is there a difference between glucose readings of the 3 devices when worn simultaneously during exercise?

Design: A single subject with T1DM, experienced in glucose management during exercise, wore 3 devices simultaneously - the DEXCOM G6 (San Diego, CA; rt-CGM1, worn on the abdomen), the Eversense (Germantown, DM; long-term CGM or rt-CGM2, implanted in the left arm), and the Abbott Freestyle Libre 14-day (Chicago, IL; FGM, worn on the right arm). The rt-CGM2 was calibrated using a blood glucose meter (Ascensia Contour Next) which was also used for comparator SMBG. Glucose was recorded 10 minutes before and after exercise and every 10 minutes during a 60 minute run at moderate intensity. 6 exercise sessions were averaged for data analysis. Subject wore an insulin pump and reduced the basal rate by 50% 90 minutes prior to exercise and resumed the basal immediately post-exercise. Carbohydrates were not used within 3 hours prior to exercise but could be consumed during exercise if needed to avoid hypoglycemia.

Results: Glucose value during 60 minutes of exercise dropped from mean of 167 to 114 mg/dL with SMBG, 174 to 115 mg/dL with rt-CGM, 175 to 115 with rt-CGM2, and 150 to 106 mg/dL with FGM. Average measured glucose was 140.0, 145.8, 145.6, and 129.3 mg/dL for SMBG, rt-CGM1, rt-CGM2, and FGM respectively. P-value <0.05 for FGM. MARD (calculated compared to SMBG) for 10 minutes pre-exercise, during exercise, and post-exercise for rt-CGM1 was 5.1%, 11.7%, and 8.6% respectively. For rt-CGM2 MARD was 7.7%, 11.4%, and 10.0% respectively. For FGM, MARD was 12.7%, 5.3%, and 21.3% respectively. Overall MARD was 9.8% for rt-CGM1, 10% for rt-CGM2, and 8.0% for FGM.

Conclusions: Blood glucose values dropped with aerobic exercise with observed lag between CGM and SMBG. Rt-CGM1 and Rt-CGM2 showed increased MARD vs SMBG during exercise. Interestingly, lower MARD was seen for FGM during aerobic exercise likely due to bias towards lower glucose levels at baseline as reported by FGM. There was no significant difference seen during exercise between rt-CGM1 and rt-CGM2 despite the differing location of the sensors (transdermal vs subcutaneous) and method of glucose analysis (glucose oxidase vs fluorescence).

References: (1) Zaharieva et al. Diabetes Technol Ther 2019; 21: 313-321.

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<![CDATA[SAT-632 Involvement of NF-κB-p65 in BAG3 Regulation After Stress Stimuli]]> https://www.researchpad.co/article/elastic_article_8743 We previously identified the limb salvage QTL1 (LSQ-1) on mouse chromosome 7 as a locus that offered protection against ischemic injury following induction of hind limb ischemia (HLI) a model of experimental peripheral arterial disease (PAD) in mice. To better understand the role of the LSQ-1 locus in post ischemic adaptation we characterized several genes within this locus and identified a number of genes that were important in tissue adaptation to ischemia, including BCL2-associated athanogene 3 (BAG3). BAG3 is an anti-apoptotic protein that plays an important role in cell survival through the regulation of autophagy. BAG3 expression is induced in the gastrocnemius muscles of mice after hind limb ischemia but how ischemia regulates BAG3 expression is poorly understood. Additionally, the activation of NF-κB transcription factor is essential for cell survival after stress stimuli. We hypothesized that BAG3 upregulation following stress stimuli is regulated by NF-κB. We determined whether NF-κB is involved in BAG3-mediated survival of primary human skeletal muscle cells (HSMC) during ischemia and diabetic conditions. Within 6 hours of treatment, ischemia induced BAG3 mRNA (no ischemia vs ischemia: 1.0 ±0.09 vs 1.41±0.02; p<0.01) and protein expression (BAG3/total protein, no ischemia vs ischemia 1.0±0.01 vs 1.38±0.06; p<0.01). Knockdown of BAG3 expression by shRNA induced early cell damage in HMSC under ischemic conditions as measured by HMGB1 expression (HMGB1/total protein; control plasmid vs shRNA, 1.0±0.09 vs 1.71±0.04; p<0.01). Knockdown of p65 subunit of the NF-κB by shRNA significantly diminished BAG3 mRNA expression after ischemia (control plasmid vs shRNA: 2.11±0.18 vs 1.48±0.05; p<0.05). Moreover, treatment of HSMC with 750 uM palmitic acid (PA) and 100nM insulin for 3 days to mimic diabetic conditions significantly increased the expression of BAG3 mRNA (control vs PAL+Ins, 1.0±0.14 vs 2.27±0.08; p<0.01) and protein (BAG3/total protein, control vs PAL+Ins, 1.0±0.03 vs 1.39±0.11, p<0.01). Knocking down p65 attenuated these increase in BAG3 mRNA (PAL+Ins vs shRNA+PAL+Ins, 2.27±0.08 vs 1.56±0.02 p<0.01) and protein (BAG3/total protein; PAL+Ins vs shRNA+PAL+Ins, 1.39±0.11 vs 0.99±0.1; p<0.05) Thus, 1) BAG3 expression is important in cell survival under ischemic conditions, and 2) NF-kB plays a key role in upregulating the expression of BAG3 under diabetic and ischemic conditions.

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<![CDATA[MON-637 DREADD-Induced POMC<sup>ARC</sup>Neuron Activation Increases Fasting Plasma Glucose Levels Through Changes in Hepatic Gluconeogenic Gene Expression but Not Changes in the HPA Axis Activity]]> https://www.researchpad.co/article/elastic_article_8742 POMC neurons expressed in the ARC are essential for energy balance and glucose homeostasis. It has been suggested the involvement of these neurons in the control of endocrine axes, such as the HPA. During fasting, POMCARC neurons are silenced as an effort to reduce body weight loss and to avoid hypoglycemia. During this process glucocorticoid secretion and activation of enzymes involved in the hepatic gluconeogenesis take place in order to preserve the homeostasis. In this study, to clarify the contribution of POMCARC neurons to the adaptive changes in energy homeostasis, glucose metabolism and HPA axis activity induced by food deprivation we used DREADDs to specifically activate POMCARC. Bilateral injections of the AAV carrying the excitatory DREADD (hM3DGq) or only the reporter gene (mCherry) have been performed into the ARC of Pomc-ires-cre and WT mice. Two weeks later the animals were fasted for 36hr, treated with saline (5 i.p. injections each 8hrs) and blood samples were collected from the facial vein at 10am. Two weeks apart, the same animals were submitted to another period of fasting and treated with CNO (1mg/Kg, 5 i.p. injections each 8hrs). Four hours after the last injection of CNO, the mice were anesthetized, blood and the liver were collected and then the animals perfused for brain harvesting. Body weight measurements have been performed before and after the 36hrs period of fasting. Another set of Pomc-ires-cre (hM3DGq or mCherry) and WT animals were fasted (36hrs), treated with CNO (5X) and subjected to GTT. DREADD–induced activation of POMCARC neurons has been confirmed by the increased cFos/mCherry expression after CNO treatment only in Pomc-ires-cre animals expressing hM3DGq. We observed that the specific activation of POMCARC neurons did not change the fasting-induced activation of HPA axis. Surprisingly, we observed reduced body weight loss and higher plasma glucose in Pomc-ires-cre animals expressing the hM3DGq and treated with CNO. The GTT showed an impaired glucose tolerance after activation of POMCARC neurons. The increased fasting glucose plasma levels was associated with increased G6pc (Glucose-6-phosphatase) mRNA expression but with no effect on other hepatic gluconeogenic genes. The present study reveals that POMCARC neurons are not involved in the increased HPA axis activity in prolonged fasting conditions. Considering the classical anorexigenic/thermogenic and the glucose-lowering action of POMCARC neurons, the present data reveal an unpredicted reduced body weight loss and impaired glucose tolerance induced by activation of these neurons during fasting. These data reinforce the notion that POMCARC neurons are heterogeneous and might be playing dual effects on energy homeostasis. Of note, because part of ARC neurons shares a common progenitor, some of the functions ascribed to POMC neurons could be mediated by non-POMC neurons expressing the Cre transgene.

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<![CDATA[SAT-636 The Fast-Evolving Connected Diabetes Care Landscape: Transforming Diabetes Care with Telehealth and Technology]]> https://www.researchpad.co/article/elastic_article_8740 Background and Aims

Recent years have brought about a new form of “connected diabetes care,” defined as digital diabetes management systems based around (1) smartphone apps, (2) devices with built-in connectivity, and (3) remote human and automated coaching and support. Given their potential to help improve health outcomes, the rapid pace of innovation, and the dearth of information about them to guide patients, providers, and payers, we provide an update on the landscape of and trends in connected diabetes care offerings.

Methods

Prominent connected diabetes care providers that have published results are categorized and characterized. Similarities and differences are identified and the state of available evidence is evaluated.

Results

Connected diabetes care offerings were analyzed for items including: health conditions managed, care team composition, connected medical devices, and evidence. We expect these players will further expand offerings across chronic conditions, strive to integrate more deeply with the traditional healthcare system, deploy greater automation to promote scalability, and find clever ways to promote and support the use of continuous glucose monitoring in type 2 diabetes. Future evidence generation for this field should have more standardized methodology.

Conclusions

The field of connected diabetes care has tremendous potential to improve outcomes, but it is in its infancy in terms of awareness, uptake, and effectiveness. Further, questions regarding offerings’ abilities to support most people with diabetes sustainably remain. However, existing evidence is sufficient to support further exploration and refinement of the model as the next step in team-based diabetes care.

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<![CDATA[SAT-613 Comparison of CV Risk Scores to Evaluate Cardiovascular Risks in Thai Type 2 Diabetes]]> https://www.researchpad.co/article/elastic_article_8722 Objective: Various cardiovascular risk scores have been developed and the RAMA-EGAT risk score was developed by Thai database with minority of diabetes. This study aims to compare the predictability of the ADVANCE, UKPDS, SCORE, Framingham Risk Score (FRS) and RAMA-EGAT risk score for carotid atherosclerosis, arterial stiffness and peripheral arterial disease in Thai T2DM patients. Methods: A cross-sectional study was conducted in T2DM patients without established CVD at a tertiary care hospital. Demographic and DM-specific data were collected. Carotid intima-media thickness (CIMT), carotid plaque, cardio-ankle vascular index (CAVI) and ankle-brachial index (ABI) were measured as the markers of atherosclerosis. Risks of CVD were calculated according to the ADVANCE, UKPDS, SCORE, FRS and RAMA-EGAT risk scores. These risk scores were correlated with the atherosclerotic markers by odds ratio using logistic regression and the proper points of the risk scores to predict atherosclerosis were calculated by the areas under the curve (AUC). Results: There were 180 T2DM participants with the mean age of 60-year-old, diabetes duration of 13 years and mean A1C 7.4%. The highest sensitive risk score was FRS, following by UKPDS, SCORE, ADVANCE and RAMA-EGAT risk score, which indicated high-risk patients as 44.8%, 27.6%, 18.9%, 13.8% and 0% accordingly. There were 40.3% of the patients with arterial stiffness detected by CAVI > 9, 24.0% with carotid atherosclerosis defined by CIMT > 0.07 mm or presenting of carotid plague and 8.3% with ABI < 0.9. The odds ratios (OR) of 4 risk scores increased by the quartiles for carotid plaque, CIMT, CAVI and ABI while the OR of RAMA-EGAT scores increased by the quartiles only for carotid plaque. The highest quartile of ADVANCE, UKPDS, SCORE and FRS significantly (P<0.01) increased the risk of abnormal CIMT; OR 2.64-8.75, carotid plaque; OR 1.51-11.21, CAVI; OR 11.38-19.00, and ABI; OR 1.18-12.57. The highest quartile of RAMA-EGAT score significantly increased the risk of carotid plaque; OR 5.35 (1.44-19.91) P<0.01. ROC analysis revealed that ADVANCE > 3.0% in 4-year, UKPDS > 11% in 10-year, fatal-SCORE > 6% in 10-year and FRS > 18% in 10-year were predictive of carotid atherosclerosis with sensitivity of 76-84% and specificity of 61-69% and they were predictive of arterial stiffness with the sensitivity of 71-80% and specificity of 64-68%. Conclusion: There was no significant difference when comparing the predictability of the ADVANCE, UKPDS, FRS and SCORE risk estimation for carotid atherosclerosis, arterial stiffness and peripheral arterial disease and they were more correlative with atherosclerotic markers than RAMA-EGAT score in Thai type 2 diabetic patients.

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<![CDATA[SUN-684 The Dance of Diabetes]]> https://www.researchpad.co/article/elastic_article_8716 Nonketotic hyperglycemic chorea-ballism (NKHCB) is a rare movement disorder typically associated with uncontrolled type 2 diabetes. It is often the result of a focal lesion of the contralateral basal ganglia. Here we present a case of a patient who presented with hyperglycemic chorea as the initial manifestation of their diabetes. A 73 year old caucasian female with no known past medical history was brought to the emergency room with involuntary movements of the left face, arm and leg. These movements were sudden in onset and not suppressible. Her vitals were stable on arrival and exam was benign apart from choreiform movements of the left arm, left leg and left perioral muscles. Her labs were significant for a random blood glucose level of 418 mg/dl and HbA1c of 12%. As part of her workup she underwent a CT head which showed an asymmetric hyperdensity involving the right putamen. She underwent additional workup of chorea to exclude infection, vitamin deficiencies, heavy metal poisoning, electrolyte imbalances, liver dysfunction, all of which returned negative. She eventually underwent an MRI of the brain which showed symmetric, mildly bright T1 signal within both putamen suggestive of mild bilateral calcium deposition bilaterally. The patient was further evaluated by neurology who felt that her overall clinical presentation and imaging findings were consistent with a diagnosis of NKHCB. She was placed on an insulin regimen with significant improvement in blood glucose levels. Her symptoms resolved within two weeks as noted on outpatient follow up. NKHCB is a rare condition that manifests in the setting of uncontrolled nonketotic diabetes mellitus. The exact underlying pathophysiology of changes seen on imaging of patients with NKHCB is not fully understood. The diagnosis is based on typical clinical and radiological features including the presence of ballistic or choreiform movements in the setting of marked hyperglycemia and the absence of ketoacidosis. This case is unusual as her chorea was the presenting symptom of her diabetes which was previously undiagnosed. The characteristic radiological feature is a high signal intensity basal ganglia lesion on the T1-weighted brain MRI. The mainstay of treatment includes normalization of the blood glucose, although in some cases antipsychotic use has been described. In most cases, complete resolution of symptoms has been reported within 10 months. Given the excellent prognosis with management of blood glucose, non ketotic hyperglycemia is an important differential to consider in a patient presenting with chorea-hemiballismus.

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<![CDATA[SAT-686 Type 1 Diabetes Diagnosed in an 83 Year Old Man After Nivolumab Therapy]]> https://www.researchpad.co/article/elastic_article_8705 BACKGROUND

Immune checkpoint inhibitors are increasingly being used for a variety of cancers and are a promising treatment option. Immune related adverse effects are their major side effects, most common being hypophysitis and hypothyroidism. While diabetes and adrenalitis have only been rarely reported, these too are becoming more common. We present a case of type 1 diabetes associated with Nivolumab therapy diagnosed in an 83-year-old man.

CASE

An 83 year old male with past medical history of emphysema, coronary artery disease, hypertension, non-small cell lung cancer treated with lobectomy, hepatitis C cirrhosis with hepatocellular carcinoma with metastasis to lungs, who completed 10 cycles of Nivolumab presented to oncology clinic with complains of polyuria, polydipsia and a weight loss of 10 pounds over the last one week. Lab work showed a blood glucose of 743 with an anion gap of 18 and bicarb of 18. B-hydroxy butyrate was 3.19. He was admitted to our ICU for diabetic ketoacidosis. He did not have a history of diabetes mellitus. No family history of diabetes was reported. His Hemoglobin A1c was found to be 10.1. He had normal blood sugars before starting Nivolumab therapy. His C-peptide was found to be low at 0.61. Insulin antibody, Islet cell antibody, Zinc transporter antibody and GAD antibodies were negative. He was discharged on basal bolus Insulin regimen. He is being followed in our endocrinology clinic and continues to be insulin dependent.

CONCLUSION

Nivolumab is PD-1 (programmed cell death) inhibitor, which is used as cancer immunotherapy in multiple advanced cancers including hepatocellular carcinoma. Clinically significant endocrinopathies are documented in <5% of patients treated with PD-1 inhibitors. The cause of Diabetes by PD-1 inhibitors is not well defined but believed to be caused by destruction of pancreatic beta cells due to inhibition of autoimmunity by autoreactive T cells. Literature review showed only 42 published cases of PD-1 inhibitor induced type 1 diabetes. Average age at presentation was 62 years and about 69% patients were in DKA at diagnosis. In a recently published study involving 1163 patients who received PD-1 inhibitors, only 21 cases of diabetes were identified, 12 of those were with new onset DM and only 1 case was due to Nivolumab use.

Since this type of endocrinopathy is mainly reported in case reports, we will need more research for further understanding of the pathology so that we can keep a watch out for this adverse effect and prevent life- threatening complications.

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<![CDATA[SAT-657 The Gut Microbiome Regulates Host Glucose Homeostasis via Peripheral Serotonin]]> https://www.researchpad.co/article/elastic_article_8701 The gut microbiome is an established regulator of aspects of host metabolism, such as glucose handling. Despite the known impacts of the gut microbiota on host glucose homeostasis, the underlying mechanisms are unknown. The gut microbiome is also a potent mediator of gut-derived serotonin synthesis, and this peripheral source of serotonin is itself a regulator of glucose homeostasis. Here, we determined whether the gut microbiome influences glucose homeostasis through effects on gut-derived serotonin. Using both pharmacological inhibition and genetic deletion of gut-derived serotonin synthesis, we find [1] that the improvements in host glucose handling caused by antibiotic-induced changes in microbiota composition are dependent on the synthesis of peripheral serotonin.

[1] The gut microbiome regulates host glucose homeostasis via peripheral serotonin. Proc Natl Acad Sci U S A. 2019 Oct 1;116(40):19802-19804. Martin AM, Yabut JM, Choo JM, Page AJ, Sun EW, Jessup CF, Wesselingh SL, Khan WI, Rogers GB, Steinberg GR, Keating DJ.

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<![CDATA[SUN-682 Type Two Diabetes Patient in Remission After Twelve Years of Diagnosis]]> https://www.researchpad.co/article/elastic_article_8698 Introduction

Type 2 diabetes (T2D) has been defined as a lifelong condition which is inevitably progressive.1 The idea that beta cell function certainly declines with time in diabetic people who have developed T2D has been definitively disproven.2 It has been recognised that the processes that cause T2D can be reversed and T2D remission can be achieved.2

Many studies show that, by changing life style dramatically, controlling diabetes can improve significantly and a significant proportion of patients can also reduce or come off their glucose-lowering therapies.3 This has been formally proven in DIRECT, with clear evidence of gradual continuing improvement in beta cell functional capacity over at least 12 months.4 Remission was linked to weight loss, as two third of those who lost more than 10kg were in remission after two years.4

Methods

A case study was done on a 66 years old male, who is diabetic for the last 12 years, with other comorbidities: hypertension and hypercholesterolemia.

He presented with Hemoglobin A1C (HbA1c) of 7.4% with BMI of 37.7 kg/m2 on four oral hypoglycaemic agents and basal insulin of 20 units per day.

His treatment was changed by adding Glucagon-like peptide-1 receptor agonists (GLP-1 RA) for better glycemic control and weight reduction in a setting of a multidisciplinary team approach, including endocrinologist, diabetes educator, dietitian and physical trainer.

Results

Over the last one year and two months, patient was able to stop all his diabetes medication including GLP-1 RA. Over three years follow ups patient achieved weight reduction of 17.3% with HbA1c of 6.5% and additional other metabolic factor benefits.

Conclusion

Even with 12 years of diabetes, reversibility of T2D can still be achieved with weight reduction of over 15%. We will wait for another 10 months to reconfirm our data for two years remission.

References

1. Steven S, Taylor R. Restoring normoglycaemia by use of a very low calorie diet in long‐and short‐duration Type 2 diabetes. Diabetic Medicine. 2015 Sep;32(9):1149-55.

2. Nagi D, Hambling C, Taylor R. Remission of type 2 diabetes: a position statement from the Association of British Clinical Diabetologists (ABCD) and the Primary Care Diabetes Society (PCDS). British Journal of Diabetes. 2019 Jun 27;19(1):73-6.

3. Wing RR, Blair E, Marcus M, Epstein LH, Harvey J. Year-long weight loss treatment for obese patients with type II diabetes: does including an intermittent very-low-calorie diet improve outcome?. The American journal of medicine. 1994 Oct 1;97(4):354-62.

4. Taylor R, Al-Mrabeh A, Zhyzhneuskaya S, Peters C, Barnes AC, Aribisala BS, Hollingsworth KG, Mathers JC, Sattar N, Lean ME. Remission of human type 2 diabetes requires decrease in liver and pancreas fat content but is dependent upon capacity for β cell recovery. Cell metabolism. 2018 Oct 2;28(4):547-56.

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<![CDATA[SUN-644 Effects of Steroid Hormones on Lipogenesis and Insulin Sensitivity - an Insight into the Involvement of the Wnt Signaling Pathway]]> https://www.researchpad.co/article/elastic_article_8697 Gestational diabetes mellitus (GDM), a condition in which the state of pregnancy induces the development of diabetes, is characterized by heightened maternal insulin resistance. The levels of sex steroid hormones generally increase during pregnancy. It is thought that imbalance in the levels of steroids like estradiol (E2) and progesterone (P4) with respect to each other, may increase susceptibility towards GDM. To understand the metabolic effects of these steroids, ovariectomized (OVX) rats were treated with E2 or P4 at dosages mimicking the true hormonal status as in pregnancy. E2 significantly reduced the body weight gain (145.4±1.4% to 108.3±0.8%, p<0.001, n≥12) as well as the cumulative food intake (391.3±14.6 g to 312.5±9.0 g, p<0.001) over the course of the 23 day-treatment period. It also decreased the quantity of accumulated gonadal white adipose tissue (GWAT) in the body (3.3±0.2 g to 1.1±0.1 g, p<0.001) and repressed expression of lpl (1.3±0.2 fold, p<0.05) and other lipogenesis markers. P4, on the other hand, enhanced lpl expression (3.7±0.2 fold, p<0.001), but did not affect the total quantity of GWAT. Further, E2 treatment brought about an increase in the expression of insulin sensitivity markers like insr in the GWAT (4.5±0.6 fold, p<0.001) and soleus skeletal muscle (6.2±0.3 fold, p<0.001), as well as an increase in the protein levels of GLUT4.

GDM susceptibility in pregnant women is most commonly associated with SNPs in the tcf7l2 gene, the product of which is an effector of the canonical Wnt signaling pathway. It has also been reported that certain actions of steroid hormones are mediated by Wnt signaling. Moreover, we found that tcf7l2 and other components of this pathway (β-catenin protein, lrp5) were up-regulated following treatments with E2 (3.8±0.2 fold, p<0.001 in GWAT; 5.3±0.2 fold, p<0.001 in soleus) and P4 (2.1±0.2 fold, p<0.05 in GWAT; 2.9±0.3 fold, p<0.001 in soleus). We therefore hypothesized that the metabolic actions of these steroids may be mediated by Wnt signaling. To test this hypothesis, we conducted experiments in which OVX rats treated with steroids as described above, were additionally treated with niclosamide (NIC), a Wnt pathway inhibitor. NIC in conjunction with E2 increased GWAT accumulation and lipogenesis, thereby reversing the action of E2. NIC treatment in OVX rats did not change these parameters, indicating that this effect is specific to the inhibition of Wnt signaling modulated by E2. Additionally, NIC inhibited the E2-modulated increase in insulin sensitivity in GWAT and soleus. Taken together, the results suggest that the actions of E2 on insulin sensitivity and lipogenesis are mediated by the Wnt signaling pathway. No such observation was made with respect to the effect of P4 on lipogenesis. Understanding the mechanistic actions of these steroids may play an important role in devising methods to prevent conditions like GDM before its onset.

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<![CDATA[SUN-695 Should Vitamin B12 Status Monitoring Be Implemented for Patients Taking Metformin?]]> https://www.researchpad.co/article/elastic_article_8648 Introduction: Cobalamin (vitamin B12) is used in multiple metabolic processes, functioning primarily as a coenzyme with Methylmalonyl-CoA mutase and Methionine synthase in humans. Without functioning enzyme, substrate levels build up which are neurotoxic, leading to neurological debilitation. Lack of enzyme also halts cellular replication processes causing severe anemia. Since numerous studies have found decreased cobalamin levels in patients who regularly take metformin1, then could regular monitoring of cobalamin levels in such patients prevent these outcomes?

Case Presentation: We present a 50-year-old female who reported to the ED with general weakness and shortness of breath after having a seizure. Her medical history included type 2 diabetes mellitus being treated with metformin and a history of seizures controlled by carbamazepine since childhood.

Neurological exam abnormalities consisted of DTRs that were 1/4 on all proximal and distal upper and lower extremities and absent fine sensory and vibratory sensation on ankles and feet bilaterally. Patient was also ataxic. Hgb A1c was 14%. Head CT, chest x-ray, EKG, and cardiac markers found no abnormalities. CBC found a profound pancytopenia with WBC 1.6, RBC 1.27, Hgb 5.2, MCV 119, MCH 40.9, MCHC 34.3, RDW 18.2, and platelets 113. Blood smear was normal. Bone marrow sample showed normochromic macrocytic cells with no other abnormalities. Folate level was normal and cobalamin was found to be low (61.5 pmol/L). Intrinsic factor antibodies were negative. Extensive autoimmune workup was also negative.

Discussion: Our patient’s neurological symptoms and pancytopenia were found to be due to multiple factors. R. Pawlak, found that metformin use had a 2.45 (p < 0.0001) times higher odds of developing B12 deficiency in comparison to non-metformin users1. This was also supported by a systemic review of the impact of metformin

Carbamazepine is known for its effects on decreasing the absorption of folate and has statistically been found to decrease cobalamin significantly as well.

There are several B12 assessment methods available to providers, including serum/plasma B12, Mean Corpuscular Volume (MCV), Homocysteine (Hcy), Holotranscobalamin II (holoTCII), and serum and urinary Methylmalonic Acid (MMA). Urinary MMA has been found to be the most specific and sensitive of these markers when adjusted by kidney function (through serum creatinine levels) and while fasting

Conclusion: Currently, there are no screening guidelines by the U.S.P.S.T.F or American Diabetes Association for cobalamin deficiency. However, neurologic deficits and macrocytic anemia could be prevented through monitoring cobalamin levels in diabetics receiving metformin treatment. This monitoring might be needed more in patients with seizure disorderon Carbamazebin.

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<![CDATA[MON-LB116 FGF-21 Is A Reliable Marker Of Insulin Resistance Before The Occurrence Of Glucose Intolerance]]> https://www.researchpad.co/article/elastic_article_8645 Background and aims: Fibroblast growth factor (FGF)-21 is a polypeptide that results in metabolic rearrangement mostly related to glucose and lipid metabolism. Serum FGF-21 level is elevated in obesity and in type 2 diabetes. The goal of this study is to evaluate the relationship between FGF-21 and peripheral insulin resistance in a wide range of baseline BMI and glucose metabolism status. Materials and methods: seventy one participants reported to the clinical research center in a fasting state twice. BMI and fat mass were calculated. Glucose metabolism was determined by fasting glucose, hemoglobin A1c and OGTT. Serum lipids panel was measured. Peripheral insulin resistance was determined using the hyperinsulinemic euglycemic clamp study. FGF-21 level was measured using enzyme-linked immunosorbent assay before and after clamp study. Study was approved by university institutional review board. Results: Of 71 participants, 48 were obese and 23 were lean. Normal glucose metabolism was documented in 43 individuals. Serum FGF-21 was significantly elevated in insulin resistant compared to insulin sensitive subgroups (0.28 ng/ml ± 0.136 vs. 0.14 ng/ml ± 0.112. p < 0.001). Despite the fact that FGF-21 is elevated in all obese population, the level was significantly higher in the insulin resistant obese subgroup compared to the insulin sensitive obese one (0.30 ng/ml ± 0.167 vs. 0.17 ng/ml ± 0.126. P =0.003). Furthermore, significantly higher FGF-21 level was also found in lean insulin resistant compared to lean insulin sensitive subgroups (0.18 ng/ml ± 0.106 vs. 0.09 ng/ml ± 0.061, p = 0.04]. Adjustment to preexisting impaired glucose tolerance did not affect the correlation between FGF-21 level and insulin resistance which remained statically significant in the seemingly healthy obese and lean subgroups. Conclusion: Serum FGF-21 level strongly correlates to peripheral insulin resistance in both obese and lean population. Nonetheless, FGF-21 level rises way before glucose metabolism abnormality can be detected. Our study suggests a cutoff level for each subgroup which may enable clinicians to risk-stratify patients and allow for early intervention.

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<![CDATA[MON-619 Predictors of Complications with Fasting the Holy Month of Ramadan in Patients with Diabetes]]> https://www.researchpad.co/article/elastic_article_8643 Background: For a whole month, every year Muslims fast daily from dawn to sunset. Those with health conditions that put them at risk are exempted from fasting, yet most of patients with diabetes choose to fast. Clinical and metabolic complications of diabetes during this month are issues of concern for patients and their managing physicians. This study is designed to evaluate the impact of fasting Ramadan on safety of patients.

Methods: A multicentercross-sectional survey was conducted in four hospitals under the Ministry of National Guard Health Affairs; King Abdulaziz Hospital,Al-Ahsa, Imam Abdulrahman bin Faisal Hospital, Dammam, King Abdulaziz Medicalcities, Riyadh and Jeddah. All patients with diabetes followed in the diabetes clinics of all four centers who fulfilled the study inclusion and exclusion criteria were approached within three months post Ramadan and consented for participation in the survey, then filled a self-administered validated questionnaire that consisted of 15 items.

Results: Socio-demographic,clinical, and laboratory characteristics of 1438 patients with diabetes were analyzed. The majority 1207 (83.9%) had type II diabetes, and 828 (57.6%) were females.The mean age was 57.9 ± 14.9 years, and mean BMI 25.25 ± 5.39.The majority 1060 (73.7%) had concomitant diseases. 36 (2.5%)were on diet therapy alone, 147 (10.2%) on metformin monotherapy, and 261 (18.2%) on insulin therapy alone. The remaining 994 (69.1%) were on combination of insulin and oral agents. Health education was received on average by 688 (57.8%) of patients. Out of the 1191 (82.8%) who fasted the full month, 497 (41.7%) experienced acute glycemic complications. Multivariate analyses revealed that significant predictors for unsafe fasting were: type I diabetes [OR 1.8 (95%CI 1.2 - 2.8), p-value 0.007], insulin therapy [OR 1.8 (95% CI 1.4 - 2.3), p-value0.0001], previous history of breaking fast for glycemic reasons [OR 2.1 (95% CI1.5 - 2.9), p-value 0.0001], and not receiving health education [OR 1.6 (95% CI1.2 - 2.0), p-value 0.0006]. Blood sugar control, presence of concomitant diseases, and history of diabetes related hospitalization were not statistically significant predictors [(OR 1.25, 95% CI, 0.9 - 1.7, p-value 0.15),(1.3, 95% CI, 0.9 - 1.8, p-value 0.14), (1.1, 95% CI, 0.8 - 1.6, p-value 0.45)] respectively.

Conclusion: A significant proportion of patients with diabetes do not receive specific education pertinent to fasting Ramadan. Lack of health education, in addition to; type I diabetes, insulin therapy, and previous experience of complications are predictors for unsafe fasting. This highlights the need for better structured educational programs and further research in the field.

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