ResearchPad - clinical-and-translational-studies-in-diabetes https://www.researchpad.co Default RSS Feed en-us © 2020 Newgen KnowledgeWorks <![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.

]]>
<![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.

]]>
<![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.

]]>
<![CDATA[MON-645 Association of Baseline Cardio-Metabolic Parameters on the Treatment Effects of Empagliflozin When Added to Metformin in Patients with T2D]]> https://www.researchpad.co/article/elastic_article_8606 Sodium-glucose co-transporter-2 inhibitors (SGLT2i) are commonly used as 2nd-line therapy after metformin (MET) in patients with type 2 diabetes (T2D), and are now recommended in those with co-existing cardiovascular (CV) and/or chronic kidney disease (CKD). A better understanding of their clinical efficacy across the spectrum of cardio-metabolic characteristics may help to better individualize therapy. It was previously reported (Häring et al., Diabetes Care 2014) that empagliflozin (EMPA) 10 and 25 mg over 24 weeks vs placebo (PLB), when added to MET, led to clinically meaningful improvements in HbA1c, body weight (BW), and systolic blood pressure (SBP).

We explored the magnitude of these effects across categories of baseline (BL) HbA1c, BW, and SBP, comparing EMPA 10 mg (n=217) and 25 mg (n=213) vs PLB (n=207) in the following subgroups: HbA1c <8.5% and ≥8.5%; BW ≤70, 70-≤80, 80-≤90, and >90 kg; and SBP <120, 120-<140, and ≥140 mmHg. Analyses were performed for all randomized patients receiving ≥1 dose of study drug. Differences between treatment groups were assessed using ANCOVA and interaction tests (by respective BL factor and treatment-assignment). At week 24, EMPA 10 mg and 25 mg significantly (p<0.0001) reduced HbA1c vs PLB; the difference from PLB in adjusted mean [±SE] change was greater in the ≥8.5% vs <8.5% subgroup (EMPA 10 mg: -0.73 [±0.14]% vs -0.51 [±0.08]%, respectively; EMPA 25 mg: -0.97 [0.15]% vs -0.52 [0.08]%, respectively; interaction p: 0.029). EMPA also significantly (p<0.05) decreased BW vs PLB, with a trend for larger reductions in those with the highest BW at BL (EMPA 10/25 mg: -1.31 [±0.42]/-1.70 [±0.44], -1.23 [±0.53]/-0.74 [±0.54], -2.12 [±0.60]/-2.56 [±0.56] and -2.11 [±0.46]/-2.93 [±0.47] for ≤70, 70-≤80, 80-≤90, and >90 kg, respectively; interaction p: 0.075). Finally, EMPA significantly (p<0.05) lowered SBP vs PLB, but, in contrast, without significant differences across SBP categories (EMPA 10/25 mg: SBP <120 mg, -4.17 [±2.07]/-2.71 [±2.15]; SBP 120-<140, -4.35 [±1.48]/-4.98 [±1.49]; SBP ≥140, -4.28 [±2.38]/-6.29 [±2.33] mmHg; interaction p: 0.784). The number of patients reporting ≥1 adverse event (AE) was similar across treatment groups (PLB, 58.7%; EMPA 10 mg, 57.1%; EMPA 25 mg, 49.5%) and the AE profile was consistent with the drug’s established safety profile. Confirmed hypoglycemic AEs were reported in 0.5%, 1.8%, and 1.4% of patients, respectively.

These data suggest that EMPA, when used as 2nd-line therapy after MET, is more effective in decreasing HbA1c and reducing BW in those with higher baseline values of these parameters but not for SBP. In addition to EMPA being a glucose-lowering agent recommended in patients with co-existing CVD and/or CKD, these data may help to tailor therapy as regards to important metabolic efficacy considerations.

]]>
<![CDATA[MON-665 Hypothalamic Gliosis in Adolescents with Type 1 Diabetes and Disordered Eating Behaviors]]> https://www.researchpad.co/article/elastic_article_8535 Background:

The hypothalamus and brainstem are thought to be the principal homeostatic brain areas responsible for regulating appetite and weight. Research suggests that inflammation plays a role in the onset and maintenance of eating-related maladaptive behaviors. Hypothalamic inflammation and reactive gliosis mediate disruptions in energy homeostasis, especially with obesity. Data from SEARCH in Youth for Diabetes has demonstrated high prevalence of disordered eating behaviors (DEB) including insulin omission and binge eating, in individuals with type 1 diabetes (T1D). Limited studies have used neuroimaging techniques for investigation of hypothalamic gliosis in individuals with T1D and DEB.

Objectives: To determine the feasibility of assessing hypothalamic gliosis with structural MRI in adolescents with T1D with and without DEB.

Research design and methods:

Adolescents with T1D, aged 13-19, were invited to participate. Participants with current use of medications known to alter appetite were excluded. Participants completed the Diabetes Eating Problem Survey – Revised (DEPS-R). A score ≥ 20 was considered indicative of DEB. Height, weight and waist circumference were obtained, and BMI was calculated. HbA1C was obtained from their prior clinic visit, within 2 months of the study visit. Participants came in fasting for the MRI study visit. Basal insulin (glargine) was administered the night before, and participants on insulin infusion continued with their basal insulin infusion. Participants received rapid-acting insulin prior to the MRI study, and blood glucose was measured before and after the MRI. Mediobasal hypothalamic (MBH) gliosis was measured by T2 relaxation time.

Results:

Eight subjects (50% female, mean age 17.8±2.3 years) have completed the study without adverse outcomes. Mean HbA1c was 8.5% (range 7.3-10%). Five subjects screened positive for DEB. There was no significant difference in BMI between DEB and non-DEB groups. In this cohort, females had longer T2 relaxation times in left MBH than males (p=0.035). Compared to non-DEB group, participants with DEB had longer T2 relaxation time in left MBH, adjusted for sex and age (p=0.001). In this initial sample, relationships between MBH T2 relaxation times and glycemic control, BMI or waist circumference did not emerge.

Conclusion:

The study protocol with insulin injection and MRI to study the hypothalamic gliosis in individuals with T1D is feasible. Structural MRI indicated increased T2 relaxation times as a marker of hypothalamic gliosis in participants with DEB. Further studies with larger sample size are crucial to validate these findings and to study specific eating behaviors and their associations with MBH gliosis in individuals with T1D.

]]>
<![CDATA[MON-649 Application of the New Cluster-Based Classification of Adult Onset Diabetes in a South Texas Veteran Population]]> https://www.researchpad.co/article/elastic_article_7204 Recently a cluster-based classification of disease phenotypes has been developed as a tool to aid in improved characterization and management of diabetes. The majority of these studies have been completed in European populations, but it is unclear if these are applicable to other populations. Using these cohorts, we categorized patients in a South Texas VA diabetes clinic to evaluate if these phenotypes apply to that population. A retrospective cohort study was completed from August 2019 through October 2019, in which 120 patients’ records in the Audie Murphy VA Diabetes Clinic were reviewed for presence of macro and microvascular complications, type of anti-diabetic medication, lipid profile and HbA1c levels, and fasting C-peptide and GADab status. 86 patients who had anti-GADab and C-Peptide levels measured were then stratified into diabetic phenotype cohorts as defined by Ahlqvist et al. 2018, based on presence of diabetes associated autoantibodies, fasting C-peptide level, insulin use >200 U/day, BMI, and age >65. Six subjects belonged to the Severe Autoimmune Diabetes (SAID) cohort, with average GADab 713±301IU; 66% of the cohort had nephropathy, 33% had retinopathy. The Severe Insulin Deficiency (SIDD) cohort had 9 patients, with average fasting C-peptide of 0.58±0.08ng/ml, 44% of the cohort had retinopathy, nephropathy and CAD as complications. The Severe Insulin Resistant (SIRD) cohort had 26 patients; fasting C-peptide was 4.94±0.43ng/ml, 73% had nephropathy, 38% retinopathy and 46% CAD. The Mild Obesity Related (MOD) cohort had 35 patients with average BMI of 35±0.6 kg/m2 and average A1c 7.9±0.2%. Nephropathy was the most prevalent complication, present in 49% of the cohort. The Mild Age Related (MARD) cohort had 10 patients, with average age of 71±1.0 years, with nephropathy and CAD present in 66% of the cohort. The highest gross prevalence of nephropathy was in the SIRD cohort, whereas highest prevalence of retinopathy was in the SIDD cohort, both of which are concordant with the recently reported study, although not statistically significant (p=0.28 and 0.65, respectively). There was no difference in prevalence of CAD between the different categories of diabetes. These findings in a South Texas VA diabetes clinic population reflect agreement in diabetes associated complications in clusters of diabetes based on insulin resistance and insulin deficiency. Targeted intensification of therapy based on the major underlying pathophysiologic abnormalities may delay or prevent micro and macrovascular complications.

1. Ahlqvist E, et al. Novel Subgroups of Adult-onset diabetes and their association with outcomes: a data-driven cluster analysis of six variables. Lancet Endocrinology and Diabetes. 2018;6: 361-369.

]]>
<![CDATA[MON-643 Diabetes’ Cost to Us Taxpayers: Thirty-Day Readmission and Resource Utilization Among Diabetics Patients Admitted with ST-Elevation Myocardial Infarction: A Propensity Score Match Analysis]]> https://www.researchpad.co/article/elastic_article_7061 PURPOSE: To determine the relationship between diabetes and thirty-days readmission, mortality, morbidity, and health care resource utilization in patients who were admitted with ST-Elevation Myocardial Infarction (STEMI) in the United States. METHOD: A retrospective study was conducted using the AHRQ-HCUP Nationwide Readmission Database for the year 2014. Adults (≥ 18 years) with a primary diagnosis of STEMI (1), along with a secondary diagnosis of diabetes were identified using ICD-9 codes as described in the literature (2). The primary outcome was the rate of all-cause readmission within 30 days of discharge. Secondary outcomes were reasons for readmission, readmission mortality rate, morbidity, and resource use (length of stay and total hospitalization costs and charges). Propensity score (PS) using the 1:1 nearest neighbor matching without replacement was utilized to adjust for confounders (3). Independent risk factors for readmission were identified using a Cox proportional hazards model (4). RESULTS: In total, 116,124 hospital admissions among adults with a primary diagnosis of STEMI were identified, of which 18.05% were diabetics. 1:1 PS matching was performed based on demographic (age, gender, hospital status, etc.) and clinical characteristics (Charlson comorbidity score. The 30-day rate of readmission among diabetics and non-diabetics with STEMI were 9.31% vs. 6.18% (p <0.001). The most common readmission for both groups was recurrent myocardial infarction. During the index admission for STEMI, the length of stay (LOS) among diabetics and non-diabetics patients were not statistically different (4.74 vs 4.58 days, p=0.12). However, the total hospital cost for the diabetic patients was statistically different ($27,027 vs $24,807, p <0.001). Most importantly, diabetics patients’ in-hospital mortality rate during their index admission was significant higher (10.20% vs 5.92%, p <0.001). Amongst those readmitted, the LOS, total hospital cost, or in-hospital mortality among diabetics were not statistically different when compared to their counterparts during their readmission. Diabetes (HR 1.60, CI 1.27-2.02, p <0.001) was an independent predictor associated with higher risks of readmission. Other independent predictors associated with increased 30-day readmission include acute exacerbation of CHF, acute exacerbation of COPD, acute kidney injury, secondary diagnosis of pneumonia, history of COPD, history of ischemic stroke, history of atrial fibrillation & atrial flutter, history of chronic kidney disease, history of iron deficiency, and use of mechanical ventilator. CONCLUSION: In this study, diabetics patients admitted with STEMI have a higher 30 days of readmission rate, total hospital cost, and in-hospital mortality (p <0.001) than their non-diabetic counterparts.

]]>
<![CDATA[MON-642 Genetic Knockout of Intestinal Hexokinase Domain-Containing Protein 1 Affects Whole-Body Glycemic Control and Triglyceride Metabolism]]> https://www.researchpad.co/article/elastic_article_6810 Hexokinase domain-containing protein 1 (HKDC1) is a recently discovered putative fifth hexokinase that is widely expressed in a variety of human and mouse tissues. Previous work indicate that HKDC1 is important for whole-body glucose homeostasis and utilization in pregnancy and aging, and suggest roles for HKDC1 in nonalcoholic fatty liver disease development and progression of hepatocellular carcinoma. Prior work in the lab further showed that global heterozygous-deleted HKDC1 mice exhibit blunted uptake of triglycerides following an olive oil bolus compared to wild-type mice, suggesting a role for intestinal HKDC1 expression in intestinal lipid metabolism (unpublished results). To specifically study the significance of intestinal HKDC1 on whole-body glucose and lipid homeostasis, we utilized Cre-mediated recombination of HKDC1 in which Cre was expressed under the control of the villin gene promoter, creating a mouse model in which HKDC1 expression is specifically deleted in the intestinal epithelium. Quantitative RT-PCR data confirmed the knockout of HKDC1 within the mouse intestine in young and aged mice, while HKDC1 expression in other tissues was comparable to wild-type mice. Next, intestinal HKDC1 knockout mice and their wild-type littermate controls were either maintained on a normal diet or were switched to a high fat diet at 6 weeks of age to simulate the state of impaired glucose tolerance, and the effects of intestinal HKDC1 on glucose and lipid homeostasis were analyzed between 28-34 weeks of age. Mice fed a normal diet did not exhibit any differences in serum glucose or triglyceride during oral/intraperitoneal glucose tolerance tests or oral olive oil bolus, respectively, regardless of intestinal HKDC1 status. Interestingly, mice lacking intestinal HKDC1 that were on a high fat diet demonstrated improved overall glycemic control compared to wild-type mice after the administration of an oral glucose load, all while there were no changes in insulin levels, gluconeogenesis or insulin tolerance related to HKDC1 status. Additionally, introduction of an intraperitoneal glucose load to mice fed a high fat diet did not alter glucose control in the presence or absence of intestinal HKDC1. However, high fat diet-fed mice lacking intestinal HKDC1 did not have a significant increase in serum triglyceride following an oral olive oil bolus, while their stool fat and triglyceride content were comparable to wild-type. Collectively, these data indicate that intestinal HKDC1 has important roles in glucose and triglyceride metabolism within the intestinal epithelium, and further suggest a role in whole-body glucose homeostasis and in the development of insulin resistance and diabetes.

]]>
<![CDATA[MON-635 FDXR Regulates Iron Metabolism and Glucose Metabolism in Liver]]> https://www.researchpad.co/article/elastic_article_6720 Iron is an essential cofactor for many proteins that function in electron transport or oxygen transport as heme or iron-sulfur cluster. On the contrary, iron also has the potential to cause oxidative damage if not carefully regulated and when in labial iron excess. Clinical studies show that elevated serum ferritin levels are observed in most patients with type 2 diabetes and non-alcoholic fatty liver disease (NAFLD). In this context, p53 is shown to induces some mitochondrial iron regulatory genes. The role of crosstalk between p53 and iron metabolism has not been sufficiently examined in the pathogenesis of diabetes and NAFLD.

Here, we examined the role of ferredoxin reductase (FDXR), a key mitochondrial regulator for iron metabolism, as p53-inducible gene with focusing on the hepatocyte and liver. We confirmed that p53 induced FDXR expression in HepG2 cells and SKEHP1 cells. Biochemical analysis demonstrated that FDXR regulated ROS levels via iron metabolism. In vivo analysis, high-fat diet activated the p53-FDXR pathway in mice liver. We generated transgene expression in mice liver using adenovirus infection carrying shRNA or CRISPR Cas9 system. Treatment with the FDXR knockdown increased hepatic iron content and aggravated glucose intolerance. Besides, forkhead box protein O1 (FOXO1), a key transcriptional factor that induces phosphoenolpyruvate carboxylase and glucose-6-phosphatase increased ratio of nuclear localization, indicating hepatic gluconeogenesis activation. Consistently, biochemical analysis in HepG2 cells demonstrated that FDXR regulated insulin-dependent FOXO1 nuclear exclusion through oxidative stress.

In conclusion, p53-inducible FDXR regulates iron metabolism and oxidative stress. FDXR inhibits iron accumulation and oxidative stress in liver and links to suppression of hepatic gluconeogenesis via insulin-dependent FOXO1 nuclear exclusion. The results of this study provide important new insights into relationship between iron metabolism and glucose metabolism as well as potentially identify novel therapeutic targets for the treatment of diabetes and NAFLD.

]]>
<![CDATA[MON-659 Course of Puberty and Growth Spurt in Boys with Type 1 Diabetes]]> https://www.researchpad.co/article/elastic_article_6544 Background: Data on the course of puberty and pubertal growth in boys with Type 1 diabetes (T1D) are sparse.

Objectives: To study the course of puberty, pubertal growth and final height in boys with T1D as well as possible factors affecting these.

Methods: In this retrospective longitudinal study, 68 boys diagnosed with T1D between 1996-2009 who were pre-pubertal at diagnosis and had completed puberty served as the cohort. Collected were data on anthropometric measurements, Tanner stage, and HbA1c levels from diagnosis to final height (F-Ht). F-Ht was compared to parental height and to the data of the national health survey

Results – In the study cohort final height-SDS was lower than that at diagnosis. It was similar to parental Ht-SDS as well as to that of the national health survey (p=0.126). F-Ht was inversely related to average HbA1c during puberty (R=-0.27, p=0.045). Boys who presented with diabetic ketoacidosis at diagnosis were shorter than those who did not throughout the entire follow-up. Age at onset of puberty was significantly related to the age of maternal menarche (R=0.44, p=0.01) and to HbA1c levels in the year preceding puberty onset (R=0.36, p=0.01). Total pubertal growth was inversely related to HbA1c levels in the year preceding onset of puberty (average R=-0.3, p=0.03)

Conclusions: Boys with T1D diagnosed before puberty achieve final height similar to that of their parents and that of the general population. Diabetic ketoacidosis at the diagnosis is associated with diminished F-Ht. Age of pubertal onset and F-Ht are affected by genetic factors as well as by glycemic control before and during puberty.

These results emphasize the importance of tight metabolic control in adolescents, to enable growth within the genetic target.

]]>
<![CDATA[MON-662 Diabetes Risk for Non-Obese Subjects in a Japanese Population]]> https://www.researchpad.co/article/elastic_article_6084 [Background] Obesity is a major risk factor of developing diabetes and cardiovascular diseases, though not all obese people develop these conditions and diseases. Because Asian populations have a lower frequency of obesity in comparison with populations in the United States and Europe, it is important to detect risk factors for developing diabetes in non-obese Japanese populations. [Objectives] To examine risk factors for diabetes, and to consider countermeasures against diabetes development in Japanese populations, especially non-obese individuals. [Methods] This study examined 1,794 individuals (514 males and 1,280 females) who participated in both Adult Health Study health examinations on A-bomb survivors and their controls in Hiroshima and Nagasaki between 1994–1996 (baseline) and 2008–2011. They were aged 48–79 years and had not been diagnosed with diabetes at baseline or cancer. Obesity was defined as a BMI of 23 kg/m2 or greater based on the WHO recommendation for Asians. In accordance with AHA/NHLBI criteria for diagnosis of metabolic syndrome, we defined a diagnosis of metabolic abnormality as having at least two of the criteria other than abdominal obesity. The diagnostic criteria for diabetes were a fasting blood glucose ≥126 mg/dL, a non-fasting blood glucose ≥200mg/dL, a self-report of a diabetes diagnosis, or the initiation of medical treatment for diabetes during the follow-up period. We compared presences of fatty liver and metabolic abnormality, BMI at baseline, and changes of body weight from baseline between the group that developed diabetes and the group did not over a 15-year follow-up. [Results] During the follow-up period until 2001, 66 (7.0%) individuals and 127 individuals (14.8%) from the non-obese and obese groups, respectively, developed diabetes. BMI at baseline and presences of fatty liver and metabolic abnormality were associated with developing diabetes in both non-obese and obese groups. Changes in body weight from baseline were not a significant risk factor of diabetes in this study. Furthermore, we analyzed the association between diabetes risk and appendicular lean mass/height2 (ALM/H2) and handgrip strength based on the diagnostic criteria for sarcopenia among 676 subjects with information of these measurements at baseline. Occurrences of low ALM/H2 were associated with developing diabetes, but an association between low handgrip strength and developing diabetes was not observed. [Conclusion] Regardless of whether obesity was observed or not, presences of metabolic abnormality and fatty liver were significant risk factors. Increased risk of developing diabetes was observed among non-obese individuals with suspected sarcopenia. This study suggests that maintenance of muscle mass may be an effective countermeasure to reduce the risk of developing diabetes.

]]>
<![CDATA[MON-644 Prevalence of Non-Alcoholic Fatty Liver Disease and Liver Fibrosis in Patients with Type 2 Diabetes Mellitus]]> https://www.researchpad.co/article/N0bc9ad8b-dcf3-421b-97d7-9e9a8385585e Non-alcoholic fatty liver disease (NAFLD) is the most common chronic liver disease. The more severe form is non-alcoholic steatohepatitis (NASH) which can progress to liver fibrosis, cirrhosis, and hepatocellular carcinoma (HCC). NASH is more common in patients with type 2 diabetes mellitus (T2DM). However, its true prevalence in unselected patients with T2DM in the United States remains unknown. In 2019, the American Diabetes Association recommended screening for NASH and liver fibrosis in all patients with T2DM with steatosis and/or elevated ALT. Screening focuses on liver fibrosis as associated with increased risk of cirrhosis and HCC. Still, a liver biopsy remains the gold standard to accurately assess the severity of liver disease. The aim of this study was to determine the prevalence of liver fibrosis in unselected patients with T2DM presenting to primary care or endocrinology clinics at a university hospital in the US. Secondary outcomes were to assess the prevalence of steatosis controlled attenuation parameter (CAP) and performance of vibration-controlled transient elastography (VCTE) as a non-invasive tool to identify patients with significant liver fibrosis. Patients with T2DM between ages of 21-79 and without a history of alcohol intake or other causes secondary causes of NAFLD were recruited for the study. Participants underwent screening for NAFLD at the time of their clinic visit by means of point-of-care CAP and VCTE. Initial evaluation also included obtaining patient demographics, routine chemistries, and fasting samples (on visit #2 if not fasting initially) for metabolic measurements and fibrosis biomarkers. Liver biopsies were offered to patients with a liver stiffness measurement (LSM) ≥8.0 kPa (i.e., highly likely to have moderate-to-severe fibrosis or ≥F2), or those with ≥7 kPa if AST ≥20 and had an APRI and/or FIB-4 score suggestive of being at high-risk of liver fibrosis (i.e., at least mild-to-moderate fibrosis or ≥F1). A total of 469 patients were recruited (age 59±12; 56% females; 60% non-Hispanic whites, 30% African Americans, 4% Asian; BMI 33±6 Kg/m2; A1c 7.5±1.7%; FPG 143±60 mg/dL; AST 22±11 U/L; ALT 24±17 U/L; triglycerides 156±151 mg/dL; LDL-C 88±37 mg/dL; HDL-C 47±13 mg/dL). The prevalence of NAFLD by CAP (≥280) was 67% with a mean CAP of 305±3. The prevalence of any fibrosis was 24% patients. Among those with fibrosis, 15% had moderate-to-severe fibrosis or ≥F2. In those that underwent a liver biopsy, 61% had moderate-to-severe fibrosis (F2-3). Our ongoing study demonstrates the high prevalence of liver steatosis and fibrosis in patients with T2DM. NASH is a common but under-recognized complication of T2DM that requires greater awareness among clinicians taking care of patients with diabetes. While the optimal screening strategy remains unclear, an approach based on plasma biomarkers and CAP/VCTE deserves further exploration moving forward.

]]>
<![CDATA[MON-LB112 Socioeconomic Status, Literacy, and Sex Differences in the Progression of Retinopathy in Patients With Type 2 Diabetes in Tokyo, Japan]]> https://www.researchpad.co/article/Nc906dd83-e01e-4369-ba83-c0206887b7fc Socioeconomic status has profound effects on glycemic control and diabetic complications in patients with type 2 diabetes. Sex differences are one of the most important factors in socioeconomic status and may vary among countries or areas. The study aim was to determine if sex differences are associated with glycemic control and diabetic complications in Tokyo, Japan, one of the most educated countries in the world. This study initially enrolled 3307 patients treated from 2017 to 2019 at the medical school hospital located in Tokyo. All enrolled patients were asked to complete behavioral and socioeconomic surveys. A total of 276 type 2 diabetic patients (175 males, age 64.1 ± 0.88 y, disease duration 15.2 ± 0.78 y, mean ± SE y; 101 females, age 64.0 ± 1.1 y, disease duration 15.6 ± 1.01 y) agreed to participate in the study. The survey questionnaire has been previously reported in detail (Patient Preference and Adherence, 10:2151-2162, 2016). The questionnaire attempted to determine estimations of risk preference regarding things like lottery gambling and accident insurance. After reviewing the patients’ answers, however, it became clear that some were illogical, which suggested that these patients did not understand the context of the questions, the hypothetical economical situations, or even the instructions, probably because of lower literacy skills. Thus, we labeled these patients as the unreasonable (UR) group (n = 81), and the patients who provided appropriate answers, even if extremely risk averse or risk loving, were labeled as the reasonable (R) group (n = 195). The prevalence of UR answers generally increased with age (<50 y, 16%; 50-64 y, 10%; 65-74 y, 37%; ≥75 y, 64%) (p < 0.0001). After age adjustment, there was a significant correlation between the UR answers and educational attainment in both sexes. The prevalence of UR answers was significantly higher in females (38.6%) than in males (24%) (p < 0.01), which may be partly because the average number of educational years was lower for females than for males (males, 13.8 y; females, 12.9 y; p < 0.05), but both averages are very high among all countries. The prevalence of retinopathy was significantly higher in the UR than the R group in males (p < 0.05), but not in females. Job and economic status were not associated with prevalence of retinopathy. These results suggest that effects of literacy skills on progression of diabetic retinopathy may be sex dependent. Although the mechanism underlying this finding is unknown, sex may be an important biological factor beyond socioeconomic status in highly educated high-income countries.

]]>
<![CDATA[MON-650 Glucocorticoid- Induced Hyperglycemia, Higher Mortality and Morbidity? a Retrospective Analysis]]> https://www.researchpad.co/article/Ndab18ec5-1b37-4ac0-b119-f77ca2e09294 Introduction: Glucocorticoid (GC)-induced hyperglycemia is a frequent side effect in hospitalized patients. Guidelines recommend treat-to-target treatment between 6-10 mmol/l with insulin, but patient-specific outcome has not been well-studied.

Methods: In this retrospective data analysis, all patient records of a Medical University Clinic from January 2014 to April 2018 were screened for GC administration. We investigated the incidence of hyperglycemia in hospitalized patients after administration of at least 10 mg prednisolone equivalents daily and a minimal length of stay of 3 days. The primary combined endpoint consisted of mortality, cardiovascular events, and infections until 30 days after admission.

Results: 2424 hospitalized patients received systemic GCs and met the inclusion criteria, of which 511 patients (21%) had an underlying diagnosis of diabetes. The overall incidence for GC-induced hyperglycemia was 33.5% (812 patients) and 3.7% of patients (n=89) had at least one documented hypoglycemia during the hospital stay. Compared to normoglycemic patients, GC-induced hyperglycemia was associated with a 40% increase in the risk for the combined primary endpoint (unadjusted odds ratio 1.39, 95%CI 1.16-1.66). This was also true after adjusting the analysis for age, Charlson comorbidity index and GC dose (adjusted odds ratio 1.68, 95% CI 1.25-2.26). Hypoglycemia was also associated with a doubling in the risk for the combined primary endpoint (odds ratio 1.95, 95% CI 1.2-3.17).

Discussion/Conclusion: Mortality, cardiovascular events and rate of infections were markedly higher in patients with GC-induced hyperglycemia compared to normoglycemic patients. Hypoglycemia was infrequent, but also associated with higher risk for adverse outcome. Future studies should evaluate whether glucose control with novel treatment modalities has a beneficial effect on clinical outcomes in patients with GC-induced hyperglycemia.

]]>
<![CDATA[MON-LB110 A Phase 2 Evaluation of a Ready-To-Use Liquid Stable Continuous Subcutaneous Glucagon Infusion for the Treatment of Hypoglycemia Associated Autonomic Failure]]> https://www.researchpad.co/article/N827c2d1a-4dba-4050-adbc-e5c398e833b0 <![CDATA[MON-661 Association of 25-Hydroxyvitamin D Serum Levels with Markers of Glycemic Control in Diabetic and Nondiabetic Patients on Maintenance Hemodialysis]]> https://www.researchpad.co/article/Naf66f508-0a17-475f-8d98-8e5a57962a32 <![CDATA[MON-646 Novel Use of GLP-1 Receptor Agonist Therapy in MODY-1 (HNF4A Mutation)]]> https://www.researchpad.co/article/N3145eab6-1420-4c9b-b71f-696dc9a0510a <![CDATA[MON-660 Hypoglycemia Following OGTT Is More Frequent and Pronounced in CF Compared with Controls]]> https://www.researchpad.co/article/N4fa09ce3-6cf5-41fb-ad08-b4695669266d <![CDATA[MON-663 Prandial Insulin Dosing Based on Carbohydrate Content Does Not Significantly Improve Glycemic Control in Hospitalized Patients with Diabetes]]> https://www.researchpad.co/article/Na2752c46-0c38-490e-b7f4-c15573c26666 Abstract Introduction: Diabetes mellitus (DM) is a highly prevalent concern in hospital medicine. In-hospital hyperglycemia and hypoglycemia are common. Hospitalized patients have variable and unpredictable amounts of carbohydrate content in their meals. We hypothesized that order sets that allow for flexible dosing of prandial insulin using an insulin to carbohydrate ratio (ICR) would provide superior blood glucose control in the complex hospital environment. Methods: We performed a retrospective review of electronic medical records from a single university hospital. The hospital implemented new order sets allowing prandial insulin dosing based on an ICR and inpatient nursing staff received necessary training. We compared glucose levels over the first three days after admission in hospitalized patients prescribed prandial insulin either as a fixed dose or based on an ICR. Patients on fixed dose insulin were selected from a time 3 months prior to the implementation of ICR order sets, to avoid any bias in patient selection. Patients on ICR dosing were selected from 3 months after implementation of ICR order sets, to allow adequate time for initial implementation. Our inclusion criteria included patients admitted to both medicine and surgery services, with Type 1 or Type 2 DM, age between 18-80. Exclusion criteria included transplant patients, patients on insulin infusion, pregnancy, steroid use and dialysis. 65 patients were included in each group. Outcome measures included average blood glucose over 72 hours, fasting and postprandial hypoglycemia (<70 mg/dL) and hyperglycemia incidence (>180 mg/dL). Results: Average glucose over 3 days was 167 +/- 39 mg/dL and 162 +/- 33 mg/dL and did not differ between groups. However, a higher percentage of glucose values were in target range (70-180 mg/dL) in the fixed dosing group (67.9%) compared to ICR (62.5%, p=0.018). The incidence of hypoglycemia was low and did not differ between groups (1.2% in both). However, patients had more overall hyperglycemia with ICR dosing (36% vs 31%, p=0.018), particularly pre-lunch hyperglycemia (52% vs. 38%, p=0.007). Fasting glucose was similar between groups. Conclusions: In conclusion, our study demonstrated that prandial insulin administered based on ICR did not improve overall glycemic control or reduce incidence of hypoglycemia in hospitalized patients with diabetes. In fact, overall and post-meal rates of hyperglycemia were generally higher with ICR dosing. This could be related to inaccurate counting of carbohydrates or delayed timing of insulin administration as it was given after the food was consumed. Additional studies are needed to further evaluate the effectiveness of flexible meal dosing and the impact on patient satisfaction and staff workload. ]]> <![CDATA[MON-644 Prevalence of Non-Alcoholic Fatty Liver Disease and Liver Fibrosis in Patients with Type 2 Diabetes Mellitus]]> https://www.researchpad.co/article/N382b53d7-8375-403b-91b0-cfd78b3871e2

Abstract

Non-alcoholic fatty liver disease (NAFLD) is the most common chronic liver disease. The more severe form is non-alcoholic steatohepatitis (NASH) which can progress to liver fibrosis, cirrhosis, and hepatocellular carcinoma (HCC). NASH is more common in patients with type 2 diabetes mellitus (T2DM). However, its true prevalence in unselected patients with T2DM in the United States remains unknown. In 2019, the American Diabetes Association recommended screening for NASH and liver fibrosis in all patients with T2DM with steatosis and/or elevated ALT. Screening focuses on liver fibrosis as associated with increased risk of cirrhosis and HCC. Still, a liver biopsy remains the gold standard to accurately assess the severity of liver disease. The aim of this study was to determine the prevalence of liver fibrosis in unselected patients with T2DM presenting to primary care or endocrinology clinics at a university hospital in the US. Secondary outcomes were to assess the prevalence of steatosis controlled attenuation parameter (CAP) and performance of vibration-controlled transient elastography (VCTE) as a non-invasive tool to identify patients with significant liver fibrosis. Patients with T2DM between ages of 21-79 and without a history of alcohol intake or other causes secondary causes of NAFLD were recruited for the study. Participants underwent screening for NAFLD at the time of their clinic visit by means of point-of-care CAP and VCTE. Initial evaluation also included obtaining patient demographics, routine chemistries, and fasting samples (on visit #2 if not fasting initially) for metabolic measurements and fibrosis biomarkers. Liver biopsies were offered to patients with a liver stiffness measurement (LSM) ≥8.0 kPa (i.e., highly likely to have moderate-to-severe fibrosis or ≥F2), or those with ≥7 kPa if AST ≥20 and had an APRI and/or FIB-4 score suggestive of being at high-risk of liver fibrosis (i.e., at least mild-to-moderate fibrosis or ≥F1). A total of 469 patients were recruited (age 59±12; 56% females; 60% non-Hispanic whites, 30% African Americans, 4% Asian; BMI 33±6 Kg/m

; A1c 7.5±1.7%; FPG 143±60 mg/dL; AST 22±11 U/L; ALT 24±17 U/L; triglycerides 156±151 mg/dL; LDL-C 88±37 mg/dL; HDL-C 47±13 mg/dL). The prevalence of NAFLD by CAP (≥280) was 67% with a mean CAP of 305±3. The prevalence of any fibrosis was 24% patients. Among those with fibrosis, 15% had moderate-to-severe fibrosis or ≥F2. In those that underwent a liver biopsy, 61% had moderate-to-severe fibrosis (F2-3). Our ongoing study demonstrates the high prevalence of liver steatosis and fibrosis in patients with T2DM. NASH is a common but under-recognized complication of T2DM that requires greater awareness among clinicians taking care of patients with diabetes. While the optimal screening strategy remains unclear, an approach based on plasma biomarkers and CAP/VCTE deserves further exploration moving forward.

]]>