Insulin Group Research Articles

Metformin and insulin treatment of gestational diabetes: effects on inflammatory markers and IGF-binding protein-1 \u2013 secondary analysis of a randomized controlled trial

BackgroundGestational diabetes mellitus (GDM) is characterized by disturbed glucose metabolism and activation of low-grade inflammation. We studied whether metformin treatment has favorable or unfavorable effects on inflammatory markers and insulin-like growth factor-binding protein 1 (IGFBP-1) in GDM patients compared with insulin, and whether these markers associate with major maternal or fetal clinical outcomes.MethodsThis is a secondary analysis of a previous randomized controlled trial comparing metformin (n = 110) and insulin (n = 107) treatment of GDM. Fasting serum samples were collected at the time of diagnosis (baseline, mean 30 gestational weeks [gw]) and at 36 gw. Inflammatory markers serum high-sensitivity CRP (hsCRP), interleukin-6 (IL-6), matrix metalloproteinase-8 (MMP-8) and glycoprotein acetylation (GlycA) as well as three IGFBP-1 phosphoisoform concentrations were determined.ResultsIn the metformin and insulin groups combined, hsCRP decreased (p = 0.01), whereas IL-6 (p = 0.002), GlycA (p < 0.0001) and all IGFBP-1 phosphoisoforms (p < 0.0001) increased from baseline to 36 gw. GlycA (p = 0.02) and non-phosphorylated IGFBP-1 (p = 0.008) increased more in patients treated with metformin than those treated with insulin. Inflammatory markers did not clearly associate with pregnancy outcomes but non-phosphorylated IGFBP-1 was inversely associated with gestational weight gain.ConclusionsMetformin had beneficial effects on maternal serum IGFBP-1 concentrations compared to insulin, as increased IGFBP-1 related to lower total and late pregnancy maternal weight gain. GlycA increased more during metformin treatment compared to insulin. The significance of this observation needs to be more profoundly examined in further studies. There were no evident clinically relevant relations between inflammatory markers and pregnancy outcome measures.Trial registrationThe trial comparing metformin and insulin treatment was registered in ClinicalTrials.gov (NCT01240785) November 3, 2010. Retrospectively registered.

Lecithin/isopropyl myristate reverse micelles as transdermal insulin carriers: Experimental evaluation and molecular dynamics simulation

Reverse micelles are nanoaggregates of surfactants that spontaneously form in a non-aqueous solvent. As a transdermal carrier for delivery of hydrophilic drugs, they can effectively control the release of drugs and improve their bioavailability thus achieving therapeutic levels throughout the body. Here, we prepared insulin-loaded reverse micelles composed of isopropyl myristate (IPM) and lecithin as the solvent and the surfactant, respectively. We tuned the amount of lecithin and volume of insulin leading to significant variations in viscosity. The optimal permeation flux was (6.98 ± 2.85) to (8.95 ± 4.74) μg/cm2/h with a gel viscosity of 1079.56–2956.45 cP. The in vitro insulin permeation through hairless mice skin from reverse micelles gel followed zero-order kinetics (R2 = 0.9234–0.9853) over a period of 24 h with case-II transport mechanism. The in vivo study of optimized reverse micelles gel in alloxan-induced diabetic rabbits demonstrated prolonged hypoglycemic effects of at least 12 h after transdermal administration. The optimal relative bioavailability (RBA) value was 136.74% versus the subcutaneous insulin group. We evaluated coarse grained molecular dynamics simulations (CGMD) to explore the permeation mechanism of reverse micelles to improve transdermal drug delivery and modify the viscosity on insulin release. The results indicated that reverse micelles deform after contacting the stratum corneum and penetrate further through it. There is reduced insulin release with increasing viscosity. The CGMD results confirmed the experimental findings.

The Effect of Intraarticular Insulin on Chondral Defect Repair.

The aim of this study is to evaluate the effects of intraarticular insulin on the treatment of chondral defects. Twenty-four mature New Zealand rabbits were randomly divided into 3 groups as control (Group 1), microfracture (Group 2), and microfracture and insulin (Group 3). Four-millimeter full-thickness cartilage defects were created to the weight-bearing surface on the medial femoral condyles of each rabbit. In the first group, any additional interventions were not performed. Microfracture was performed on defects in groups 2 and 3. Additionally, 10 IU of insulin glargine was administrated into the knee joints of the third group. Three months after surgery, the knee joints were harvested and cartilage quality was assessed according to Wakitani and ICRS (International Cartilage Repair Society) scores histopathologically. Insulin injections were performed into the knees of 2 additional rabbits without creating a cartilage defect to evaluate the potential adverse effects of insulin on healthy cartilage (Group 4). The total ICRS and Wakitani scores of the insulin group were found to be significantly lower than the microfracture group but similar to the control group. No negative effects of insulin on healthy cartilage were detected. Intraarticular insulin after surgery has led to a statistically significant decrease in systemic blood sugar levels whereas the decrease observed after administration to intact tissues was not statistically significant. Insulin had a negative influence on the quality of cartilage regeneration and had no effect on healthy cartilage. Intraarticular insulin administration does not cause significant systemic effects in intact tissue.

Protective effect of insulin on burn serum-challenged cardiomyocytes in vitro

To investigate the protective effect of insulin on burn serum-challenged cardiomyocytes in vitro. Primary culture of cardiomyocytes from Sprague-Dawley (SD) 2-day-old neonate rats were divided into sham group, burn group, insulin group, and insulin activation inhibitor LY294002 pretreatment group (LY group). The model of cardiomyocytes injury induced by burn serum of 3-month-old SD rats [the serum of abdominal aortic was collected at 6 hours after modelling 30% total surface area (TBSA) III degree scald rat] was reproduced. In the insulin group, 10% burn serum and insulin (10 U/L) were added into cell culture medium, and in the LY group, LY294002 (50 μmol/L) was pretreated for 30 minutes before the addition of burn serum and insulin. Sham group was only given 10% serum of sham injured rats (sham rats were only placed in 37 centigrade warm water). After the cells were cultured for 12 hours, the release of tumor necrosis factor-α (TNF-α), interleukin-6 (IL-6) and creatine kinase (CK) were determined by enzyme-linked immunosorbent assay (ELISA). The cardiac troponin T (cTnT) protein expression was examined by Western Blot. Apoptosis of cardiomyocytes was observed after Hoechst 33258 staining. Compared with the sham group, the cardiomyocytes were damaged and released inflammatory cytokines after burn serum-challenged. The levels of TNF-α, IL-6 and CK increased [TNF-α (ng/L): 273±48 vs. 21±6, IL-6 (ng/L): 416±83 vs. 44±11, CK (U/L): 1.44±0.24 vs. 0.14±0.08, all P < 0.01], while the expression of cTnT protein decreased (cTnT/β-actin: 0.12±0.04 vs. 0.86±0.34, P < 0.01), and the cardiomyocyte apoptosis increased [(19.1±5.6)% vs. (5.2±1.3)%, P < 0.01]. Insulin could significantly reduce the damage of cardiomyocytes, decrease the release of TNF-α, IL-6 and CK induced by burn serum [TNF-α (ng/L): 105±37 vs. 273±48, IL-6 (ng/L): 176±77 vs. 416±83, CK (U/L): 0.82±0.26 vs. 1.44±0.24, all P < 0.05], the expression of cTnT protein significantly increased (cTnT/β-actin: 0.41±0.16 vs. 0.12±0.04, P < 0.05), and the cells apoptosis rate significantly decreased [(10.7±3.2)% vs. (19.1±5.6)%, P < 0.05]. Further blocking experiments showed that LY294002 could mitigate the protective effects of insulin. For cardiomyocytes challenged by burn serum, insulin may decrease inflammation, apoptosis and then protect the cardiomyocytes.

Evaluasi Efektivitas Biaya Penggunaan Terapi Kombinasi Obat Antidiabetes-Antihipertensi Pada Pasien Diabetes Mellitus Tipe 2 Dengan Hipertensi Di RSUP Sanglah

Infectious diseases have been shifted by degenerative metabolic diseases. Metabolic disease whose prevalence tends to increase is type 2 diabetes mellitus characterized by decreased insulin secretion due to insulin retention which interferes with pancreatic beta cell function, which if not handled properly will result in chronic complications. The most common complication of diabetes is hypertension, which is around 54.2%. Patients with diabetes mellitus and hypertension must take life-long therapy. This will have an impact on patient costs. In addition, the use of drug therapy for diabetes mellitus can be given with several different combinations, so the costs and outcomes of the therapy produced also vary. The varied use of drug therapy results in differences in the costs and outcomes of the therapy. Based on the results of research that has been done, the calculation of Average Cost Effectiveness Ratio (ACER) and Incremental Cost Effectiveness Ratio (ICER) shows that the most cost-effective therapeutic option is the use of antidiabetic therapy combinations of insulin sensitivity enhancers with long-acting insulin and antihypertensive groups CCB (Calcium Channel Blocker). Therefore, it can be concluded that the combination therapy of antidiabetic and antihypertensive with the most cost effectiveness based on ACER and ICER values ??is a combination of antidiabetic drug groups that increase insulin sensitivity and long-acting insulin with antihypertensive CCB.

Effect of Acacia senegal on TGF-β1 and vascular mediators in a rat model of diabetic nephropathy

Context: Transforming growth factor-β1 (TGF-β1), endothelin-1 and angiotensin II are responsible for extracellular matrix accumulation within the kidney in diabetic nephropathy.Objective: This study evaluated the effect of adding Gum Arabic (GA) and insulin on serum glucose, renal function, TGF-β1, endothelin-1, and angiotensin II in rats with diabetic nephropathy.Methods: Sixty male Sprague-Dawley rats were divided into; normal, normal plus GA, diabetic rats (DM), DM plus insulin, DM plus GA, and DM plus insulin plus GA groups. Levels of glucose and creatinine in serum, TGF-β1, angiotensin II, and endothelin-1 in renal homogenate and HbA1c were measured.Results: Serum creatinine, TGF-β1, angiotensin II, and endothelin-1 were increased in diabetic rats. GA decreased serum glucose, TGF-β1, angiotensin II, endothelin-1, and HbA1c in diabetic rats. GA and insulin decreased serum glucose, creatinine, TGF-β1, angiotensin II, endothelin-1, and HbA1c in diabetic rats.Conclusion: Co-administration of GA with insulin to rats with diabetic nephropathy improved the glycemic state, renal function, TGF-β1, endothelin-1, and angiotensin II.

1507-P: Dose–Response Relationship between Periodontal Inflamed Surface Area and Glycated Haemoglobin Level in Patients with Type 2 Diabetes Mellitus on Insulin Therapy and on Oral Antidiabetic Therapy

A bidirectional inflammatory link exists between periodontitis and diabetes mellitus. Diabetes increases the prevalence and severity of periodontitis and periodontitis affects glycemic control. Treatment of diabetes is with oral antidiabetic drugs (OAD), insulin or their combinations. Insulin achieves faster glycemic control and has other beneficial effects. This study was undertaken to compare the prevalence, extent and severity of periodontal disease, to correlate periodontal inflamed surface area (PISA) with Glycated Hb (HbA1c) and to find the dose response relationship between PISA and HbAic in type 2 diabetes mellitus (T2DM) on insulin therapy and on OAD therapy. The study comprised of 130 T2DM patients on oral antidiabetic drugs therapy (OAD group) and 130 T2DM patients on insulin therapy (INSULIN group). All subjects were assessed for periodontal parameters (BOP, PPD, CAL, OHI-S Index, PI Index and PISA) and systemic parameters (HbA1c, FPG, PPG). The proportion of periodontitis was lower in INSULIN group (46.2%) as compared to OAD group (83.1%). Extent and severity of periodontitis and PISA were lower in INSULIN group as compared to OAD group. HbA1c was positively correlated with PISA in OAD group(r=0.391)(p &amp;lt;0.001) and in INSULIN group (r=0.492) (p &amp;lt;0.001). A dose response relationship between PISA and HbA1c has been observed and an increase in HbA1c of 1% is associated with an increase in PISA of 195mm2 (p &amp;lt;0.001). Multiple linear regression models showed that shifting from OAD to INSULIN results in the decrease of PISA by 605.4mm² (p &amp;lt;0.001). This indicates to the beneficial effects of insulin on periodontal tissues. Dose response relationship between HbA1c and PISA confirm the bidirectional relationship between diabetes mellitus and periodontal disease. Disclosure R.J. Vadakkekuttical: None. S. Pattayil: None. C. Radhakrishnan: None.

2194-PUB: Structured Basal-Bolus Insulin Injection in Hospitalized Patients with Type 2 Diabetes: Tertiary Teaching Hospital Experience

Objectives: Although the efficacy of basal-bolus insulin regimen (BBI) in type 2 diabetes (T2D) patients has been demonstrated in clinical studies, few studies have revealed changes in glycemic control following the introduction of BBI in hospital practice. This study was aimed to evaluate the effect of structured BBI in clinical practice for hospitalized patients with T2D. Methods: We retrospectively analyzed non-critically ill T2D patients treated with insulin, who were hospitalized for glycemic control at Seoul National University Hospital (SNUH) from 2004 to 2018. The effects of BBI in T2D patients after 2007, when the current BBI protocol was introduced to SNUH, compared to that of the other types of insulin in T2D patients until 2007. Patients were propensity-score-matched in a 1:1 ratio. Results: Among 294 BBI treated patients (age, 60.4 ± 13.8 years; male, 141 [48.0%]; HbA1c, 10.4 ± 1.9%) and 294 other insulin-treated patients (age, 59.9 ± 12.6 years; male, 148 [50.3%]; HbA1c, 10.3 ± 1.9%), mean admission pre-prandial blood glucose level were 181.0 ± 37.7 mg/dl and 200.0 ± 34.0 mg/dl, respectively (P &amp;lt;0.05). Blood glucose target of &amp;lt;140 mg/dl was achieved in 56.1% of patients in the BBI group and in 33.7% of those in the other insulin group on the sixth day of admission. The mean first target achievement day was 3.6 ± 1.3 days in the BBI group and 4.2 ± 1.5 days in other insulin groups, respectively (P &amp;lt;0.05). Events of hypoglycemia (≤70 mg/dL) and severe hypoglycemia (&amp;lt;55 mg/dL) were not different between the groups. Conclusion: In this study of clinical practice in a tertiary hospital, structured BBI showed significantly improved glycemic control compared to other types of insulin regimens for T2D patients. Disclosure S. Moon: None. H. Jang: None. Y. Yang: None. S. Kwak: None. H. Jung: None. K. Park: None. Y. Cho: None.

937-P: Effects of Insulin and Exenatide on Glycemic Control and ß-Cell Function in Newly Diagnosed Type 2 Diabetic Patients with Severe Hyperglycemia

Objective: To assess the efficacy of short-term insulin therapy compared with exenatide treatment on glycemic control, beta-cell function, insulin sensitivity, and long-term glycemic control in newly diagnosed type 2 diabetic patients with severe hyperglycemia. Methods: Newly diagnosed type 2 diabetic patients with HbA1c above 9% were treated with intensive insulin injection for 10-14 days in the hospital or outpatient clinic. The oral glucose tolerance test (OGTT) was performed after intensive insulin treatment. After the OGTT, the patients were randomized to receive either insulin therapy (NPH injection twice daily) or exenatide therapy (exenatide injection twice daily) for further 4 months. The patients started to take oral antidiabetes drugs after 4 months of randomization. The OGTT was repeated 6 months after randomization to evaluateβ-cell function and insulin sensitivity again. The subjects were continually followed up for another 1 year to evaluate long-term glycemic control. Results: We recruited 44 patients and 40 patients were randomized to insulin group (n = 22) and exenatide group (n = 18). The HbA1c level between insulin group and exenatide group at 6th month (6.74 ± 1.12% vs. 6.88 ± 0.76%; P = 0.681) and 18th month (6.60 ± 0.92% vs. 7.13 ± 0.83%; P = 0.093) of the study showed comparable results. The glucose area under the curve, insulinogenic index, and total insulin secretion improved significantly in both groups after 4 months of treatment. Compared with the exenatide group, the homeostasis model assessment of β-cell function index, insulinogenic index, and total insulin secretion were better in the insulin group. Conclusions: A 4-month course of both the insulin and exenatide treatment could achieve good glycemic control in newly diagnosed type 2 diabetes with severe hyperglycemia. However, the insulin treatment could improve more β-cell function than exenatide therapy. Disclosure T. Wu: None. H. Chen: None.

SO022EVALUATION OF GLOMERULAR HEMODYNAMIC CHANGES BY SGLT2 INHIBITION IN TYPE 2 DIABETIC RATS USING IN VIVO IMAGING TECHNIQUES

Abstract Background and Aims In recent clinical trials, the SGLT2 inhibitor (SGLT2i) slowed the progression of kidney disease compared with the placebo in patients with type 2 diabetes. Improvement of glomerular hyperfiltration via tubuloglomerular feedback (TGF) is considered to be one of the possible pathways for renal protection with SGLT2 inhibition (SGLT2i) in diabetic kidney disease (DKD). We have successfully developed the novel method to measure single-nephron GFR (SNGFR) in mice using multiphoton laser microscopy and demonstrated that the adenosine/adenosine A1 receptor (A1aR) pathway plays a pivotal role in the TGF mechanism in the type 1 diabetic model, Akita mice (Kengo Kidokoro, David Z. I. Cherney et al. Circulation. 2019). It has been suggested that the mechanism of improvement effects in glomerular hyperfiltration by SGLT2i is different in type 1 diabetes and type 2 diabetes. However, the detailed regulatory mechanism of GFR by SGLT2i is not fully understood in type 2 diabetes. This study aims to clarify the effects of SGLT2i on glomerular hemodynamics in type 2 diabetic rats. Method Zucker lean (ZL) rats and Zucker diabetic fatty (ZDF) rats were used. In the first experiment, SNGFR and diameters of glomerular afferent/efferent arterioles were measured in both groups. Next, we examined the change of SNGFR and diameters of glomerular afferent/efferent arterioles, as well as urinary excretions of glucose and sodium in ZDF after a single-dose administration of SGLT2i (luseogliflozin; 10mg/kg, gavage) for 120 minutes, which generated the following three groups: SGLT2i group, SGLT2i + adenosine A1 receptor (A1aR) antagonist (8-cyclopentyl-1,3-dipropylxanthine, 1mg/kg) group, and insulin group. Results SNGFR in the ZDF group was significantly higher than in the ZL group. The diameter of the afferent arteriole and efferent arteriole was also wider in ZDF rats than in ZL rats. The SNGFR and diameter of the afferent arteriole were significantly decreased after a single-dose administration of SGLT2i in ZDF. However, there was no significant diameter change in the efferent arteriole. Moreover, a decrease of SNGFR was not observed in the A1aR antagonist group after SGLT2i administration. Urinary excretions of glucose and sodium showed a similar pattern in the SGLT2i and SGLT2i+ A1aR antagonist groups. Conclusion The adenosine/A1aR pathway plays an important role in the regulation of the tonus of the afferent arteriole and is involved in the suppression of glomerular hyperfiltration by SGLT2 inhibition in type 2 diabetes.

P997Risk of stroke and mortality in patients with atrial fibrillation and insulin dependent versus non-insulin dependent diabetes mellitus

Abstract Funding Acknowledgements Pfizer pharmaceutical corporation Background Diabetes is a known risk factor for thromboembolic events in patients with non-valvular atrial fibrillation (NVAF). Whether patients on insulin therapy are at an increased risk for stroke compered to patients treated solely by oral antidiabetic medications is not yet established. Aim To assess the risk of ischemic stroke and mortality in patients with NVAF and diabetes mellitus (DM) treated by insulin vs. oral antidiabetic treatment. Methods A prospective, historical cohort study based on the Clalit Health Services (CHS) electronic medical records database, including all individuals age ≥ 21 years with a first diagnosis of NVAF between January 2010 to December 2016 and a minimal follow-up period of 1 year. Patients were divided into two groups based on their diabetes therapy regiment (insulin vs. oral antidiabetic medications). Results Overall study population included 12,231 patients with AF and DM, of them 3510 (28.7%) had an insulin-requiring diabetes. The median age was 72.4 years (IQR 65-80) in the insulin- treated group and 75.2 (IQR 68-83) in the orally treated group, with a slight majority of women in both groups, 51.6% and 53.5% respectively. Patients in the insulin group had significantly higher co-morbidity rates including hypertension (HTN) (93.6% vs. 91.2%; p &amp;lt; 0.001), congestive heart failure (CHF) (38% vs. 22.2%%; p &amp;lt; 0.001), previous cerebrovascular accident/ transient ischemic attack (CVA/TIA) (23.1% vs.14.5%; p &amp;lt; 0.001) and vascular diseases (62.1% vs. 46.5%; p &amp;lt; 0.001). Moreover, patient on insulin therapy were significantly less treated with anticoagulation medications at baseline compered to patients not treated with insulin (38.9% vs. 46.6%; p &amp;lt; 0.001). The incidence of stroke per 100 person-years was 2.62 in the insulin-treated group and 2.02 in the oral-treated group. Although, diabetes patients on insulin therapy had a significantly increased risk for stroke compared to patients not treated with insulin in the univariate analysis (HR: 1.34; 95%CI: 1.13- 1.60), this association was not found to be significant after adjusting for confounding variables (HR: 1.17; 95%CI: 0.96- 1.41). The rate of mortality per 100 person-years was 19 in the insulin-treated group and 12.6 in the oral-treated group. The risk for overall mortality was significantly higher in the insulin-treated group compared to the non-insulin group (HR: 1.38; 95%CI: 1.29- 1.48), as found in the multivariate Cox model, adjusted for age, gender, Creatinine clearance, HTN, CHF , CVA/TIA, vascular diseases, duration of diabetes and use of anticoagulation therapy. Conclusion In this cohort of patients with newly diagnosed NVAF and DM, patients on insulin are at increased risk of all cause mortality and a have a trend of increased risk of stroke after accounting for other recognized risk factors for stroke and mortality in this population.

Melatonin prevents deterioration of erectile function in streptozotocin-induced diabetic rats via sirtuin-1 expression.

A review of the literature indicated that sirtuin-1 expression, a regulator of nitric oxide bioavailability in erectile dysfunction (ED) after melatonin therapy, has not yet been investigated. The objective of this study was to evaluate the protective effects of melatonin for erectile function with sirtuin-1 protein expression in type 1 diabetic rat models. Fifty male Sprague Dawley rats were placed into five groups. Except for those in the control group (C), each animal received a single dose (60mg/kg) of streptozotocin to induce diabetes. The animals were placed into the diabetes (D) group, insulin (I) group (6 U/kg/day), melatonin (Mel) group (10mgkg-1 day-1 ) and combined treatment (I+Mel) group. Ten weeks later, the serum testosterone levels, intracavernosal pressure (ICP), mean arterial pressure (MAP), malondialdehyde (MDA), cyclic guanosine monophosphate (c-GMP), 8-hydroxydeoxyguanosine (8-OHdG), nitric oxide synthase (NOS), caspase-3 activity, sirtuin-1 and endothelial nitric oxide synthase (eNOS) protein expression and histological findings were assessed. The mean ICP/MAP ratio for the D group was lower than the mean ratios for the other groups. The treatment groups, particularly the I+Mel group, exhibited lower 8-OHdG and MDA levels and caspase-3 activity than the D group. The sirtuin-1 and eNOS expression and cavernosal tissue (CT) histology seemed to have been preserved by the melatonin and/or insulin therapy. These results were indicative of a profound protective effect of melatonin by the activation of sirtuin-1 protein expression against hyperglycemia-induced oxidative CT injury.

2198-PUB: The Impact of Basal Insulin Initiation to Background Sulfonylurea Treatment on Hypoglycemia Occurrence: Evaluation of the Balkan Cohort of Dune Study

Background: Optimal glycemic control and proper basal insulin initiation timing when non-insulin treatment becomes insufficient is critical in type 2 diabetes mellitus (T2DM). The DUNE study investigated the effectiveness and safety of newly initiated basal insulin in T2DM patients compared to those who already received insulin. The impact of background therapy with sulfonylureas (SU) on insulin dose and hypoglycemia occurrence was also explored. Methods: The DUNE study was a 12-week, prospective, single-arm, observational study of adults with T2DM. The present sub-analysis included the patients from the Balkan region (Slovenia and Serbia). The first group (n=83) included patients with newly initiated basal insulin and the second group (n=94) included patients who were already treated with basal insulin for up to 12 months. Patients also received other non-insulin antihyperglycemic drugs. Results: The proportion of patients receiving SUs was higher in the group with newly initiated basal insulin (72.3% vs. 55.3%; p&amp;lt;0.001). Basal insulin treatment included NPH or 1st generation basal insulin analogues (BIA) (98.8% vs. 1.2% for newly initiated basal insulin and 83% vs. 17% for already initiated basal insulin), due to local reimbursement policy. Daily insulin doses were lower in newly initiated basal insulin group (11.7±5.58U vs. 18.6±9.18U; p&amp;lt;0.001), the difference remained significant also after 12 weeks of observation (17.5±11.8U vs. 22.6±10.69U; p&amp;lt;0.01). A trend towards higher hypoglycemia occurrence in the newly initiated basal insulin group was observed, despite the lower insulin dose, but with higher percentage of treatment with SUs as a background treatment. Conclusions: Continuation of SUs in T2DM patients, both newly initiated and already initiated with basal insulin therapy (NPH or first-generation insulin analog), should be considered with caution due to the potentially enhanced effect on the risk of hypoglycemia. Disclosure A. Janez: None. M. Lunder: None. M. Janic: None. N. Grulovic: None. D. Zdravkovic: None. A.Z. Jotic: None. K. Lalic: Speaker’s Bureau; Self; AstraZeneca, Boehringer Ingelheim, Merck, Novo Nordisk, Sanofi. N. Lalic: None.

Risk Factors for Hypoglycemia in Inpatients with Total Parenteral Nutrition and Type 2 Diabetes: A Post HOC Analysis of the Insupar Study

Objective: Treatment of hyperglycemia with insulin is associated with increased risk of hypoglycemia in type 2 diabetes mellitus (T2DM) patients receiving total parenteral nutrition (TPN). The aim of this study was to determine the predictors of hypoglycemia in hospitalized T2DM patients receiving TPN. Methods: Post hoc analysis of the INSUPAR study, which is a prospective, open-label, multicenter clinical trial of adult inpatients with T2DM in a noncritical setting with indication for TPN. Results: The study included 161 patients; 31 patients (19.3%) had hypoglycemic events, but none of them was severe. In univariate analysis, hypoglycemia was significantly associated with the presence of diabetes with end-organ damage, duration of diabetes, use of insulin prior to admission, glycemic variability (GV), belonging to the glargine insulin group in the INSUPAR trial, mean daily grams of lipids in TPN, mean insulin per 10 grams of carbohydrates, duration of TPN, and increase in urea during TPN. Multiple logistic regression analysis showed that the presence of diabetes with end-organ damage, GV, use of glargine insulin, and TPN duration were risk factors for hypoglycemia. Conclusion: The presence of T2DM with end-organ damage complications, longer TPN duration, belonging to the glargine insulin group, and greater GV are factors associated with the risk of hypoglycemia in diabetic noncritically ill inpatients with parenteral nutrition. Abbreviations: ADA = American Diabetes Association; BMI = body mass index; CV% = coefficient of variation; DM = diabetes mellitus; GI = glargine insulin; GV = glycemic variability; ICU = intensive care unit; RI = regular insulin; T2DM = type 2 diabetes mellitus; TPN = total parenteral nutrition.

Effects of Retinoic Acid and Insulin on Glycogen Content and Expression Levels of Glycogenic Proteins in Differentiating L6 Myocytes

Abstract Objectives The skeletal muscle is critical for the control of glucose homeostasis partially through glycogenesis. The effects of retinoic acid (RA) on glycogen content and expressions of key glycogenic proteins without or with insulin in L6 rat myocytes deserve to be studied. Methods L6 myocytes at confluence were induced to differentiation using DMEM with 2% horse serum. Cells were incubated in medium with vehicle control or 1 μM RA without or with 10 nM insulin for 2, 4, and 6 days. Glycogen was extracted and analyzed using α-amyloglucosidase and released glucose assay. Proteins in cell lysates from parallel groups were extracted and subjected to analysis using western blotting. The expression levels of glycogen synthase (GS), phospho-glycogen synthase (Ser 641) (p-GS), glycogen synthase kinase 3-β(GSK3β), and phospho-glycogen synthase kinase 3-β (p-GSK3β) were determined using their specific antibodies, and then quantified with ImageJ software. Results The RA + insulin group had higher glycogen content than the control group on days 2 to 6. A synergistic effect of RA and insulin were observed on day 2. GS expression was synergistically induced in the RA + insulin group on each day. The total p-GS normalized to β-actin in the RA + insulin group was higher than that in the control on day 2. However, the ratio of p-GS/GS in the RA + insulin group was lower than that in the control on day 2 and in RA group on day 6, respectively. GSK3β expression levels in insulin and RA + insulin groups were higher than that in the control on day two. The total p-GSK3β normalized to β-actin showed an increase in the insulin group compared to the RA group on day 6. The p-GSK3β/GSK3β ratio in the insulin group was higher than that in RA and RA + insulin groups on day 6. Conclusions Treatments with RA and insulin increase the glycogen content in L6 cells via upregulation of glycogenesis. A synergy of RA and insulin can be seen. The increases of total GS and decreases of p-GS/GS ratio contribute to the elevation of GS activity. RA likely exerts its glycogenic effects through changes of the total GS level and phosphorylation by GSK3β. Funding Sources Internal fund at the Univenrsity of Tennessee.

Effect of Metformin vs. Placebo in Combination with Insulin Analogues on Bone Markers P1NP and CTX in Patients with Type 2 Diabetes Mellitus.

Preclinical studies have shown a potential osteoanabolic effect of metformin but human studies of how metformin affects bone turnover are few. A post hoc sub-study analysis of an 18-month multicenter, placebo-controlled, double-blinded trial in type 2 diabetes mellitus (T2DM), randomizing participants to metformin versus placebo both in combination with different insulin analogue regimens (Metformin + Insulin vs. Placebo + Insulin). Patients were not treatment naive at baseline, 83% had received metformin, 69% had received insulin, 57.5% had received the combination of metformin and insulin before entering the study. Bone formation and resorption were assessed by measuring, N-terminal propeptide of type I procollagen (P1NP) and C-terminal telopeptide of type I collagen (CTX) at baseline and end of study. The influence of gender, age, smoking, body mass index (BMI), T2DM duration, glycosylated hemoglobin A1c (HbA1c), c-reactive protein (CRP) and insulin dosage was also included in the analyses. The levels of bone formation marker P1NP and bone resorption marker CTX increased significantly in both groups during the trial. P1NP increased less in the Metformin + Insulin compared to the placebo + insulin group (p = 0.001) (between group difference change), while the increases in CTX levels (p = 0.11) were not different. CRP was inversely associated (p = 0.012) and insulin dosage (p = 0.011) was positively related with change in P1NP levels. BMI (p = 0.002) and HbA1C (p = 0.037) were inversely associated with change in CTX levels. During 18months of treatment with metformin or placebo, both in combination with insulin, bone turnover increased in both groups. But the pattern was different as the bone formation marker (P1NP) increased less during Metformin + Insulin treatment, while change in bone resorption (CTX) was not significantly different between the two groups.

Slowed Metabolic Decline After 1 Year of Oral Insulin Treatment Among Individuals at High Risk for Type 1 Diabetes in the Diabetes Prevention Trial-Type 1 (DPT-1) and TrialNet Oral Insulin Prevention Trials.

We assessed whether oral insulin slowed metabolic decline after 1 year of treatment in individuals at high risk for type 1 diabetes. Two oral insulin trials that did not show efficacy overall and had type 1 diabetes as the primary end point were analyzed: the Diabetes Prevention Trial–Type 1 (DPT-1) and the TrialNet oral insulin trials. Oral glucose tolerance tests at baseline and after 1 year of treatment were analyzed. Among those at high risk (with a Diabetes Prevention Trial–Type 1 Risk Score [DPTRS] ≥6.75), the area under the curve (AUC) C-peptide increased significantly from baseline to 1 year in each oral insulin group, whereas the AUC glucose increased significantly in each placebo group. At 1 year, the AUC C-peptide/AUC glucose (AUC Ratio) was significantly higher in the oral insulin group than in the placebo group in each trial (P < 0.05; P = 0.057 when adjusted for age in the TrialNet trial) and in both trials combined (P < 0.01 with or without adjustment for age). For a DPTRS <6.75, oral insulin groups did not differ from placebo groups in the AUC Ratio. The findings suggest that 1 year of treatment with oral insulin slows metabolic deterioration in individuals at high risk for type 1 diabetes. Moreover, the findings further suggest that metabolic end points can be useful adjuncts to the diagnostic end point in assessments of preventive treatments for the disorder.

Autophagy and mTOR Pathways Mediate the Potential Renoprotective Effects of Vitamin D on Diabetic Nephropathy.

Introduction Not only is diabetic nephropathy (DN) the most common cause of end-stage renal disease worldwide, but it also increases the risk of mortality up to fourteen times compared to normoalbuminuric diabetic patients. Aim The aim of the current study was the evaluation of the renoprotective effects of vitamin D in DN and the possible interplay between autophagy and mTOR pathways. Materials and Methods Fifty male Wistar albino rats were divided (10/group) into control, DN group, insulin-treated DN group, vitamin D-treated DN group, and combined insulin and vitamin D-treated DN group. Assessments of systolic blood pressure, albuminuria, creatinine clearance, serum glucose, insulin, urea, creatinine, inflammatory cytokines, oxidative stress markers, and rat kidney gene expression of mTOR were performed. Histopathological and immunohistochemical assessments of autophagy marker LC3 in rat kidneys were also performed. Results DN was associated with significant increases in SBP, urinary albumin, serum glucose, urea, creatinine, inflammatory cytokines, MDA, and mTOR gene expression (P < 0.05). However, there was significant decrease in creatinine clearance, serum insulin, GSH, and H score value of LC3 when compared with control group (P < 0.05). The combination of insulin and vitamin D treatment significantly restored DN changes when compared with the other treated groups, except in oxidative stress markers where there was an insignificant difference between the combination-treated and insulin-treated groups (P > 0.05). Conclusion It has been concluded that vitamin D is a potent adjuvant therapy in treatment of DN via downregulation of mTOR gene expression, stimulation of autophagy, and antioxidant, anti-inflammatory, and hypotensive effects.

SAT-662 Effects of SGLT Inhibitors or GLP1 Analogues on Glucose Homeostasis and Body Weight in Patients with Type 1 Diabetes: A Network Meta-Analysis

Objective: Despite intensive insulin treatment in patients with type 1 diabetes (T1D), many of them do not reach the glycemic target goal. We performed a network meta-analysis to evaluate the efficacy and safety of additional therapy to insulin in patients with T1D. Methods: We searched CENTRAL, MEDLINE, EMBASE, and Science Citation Index Expanded from January 1970 until September 2019 to identify randomized controlled trials (RCTs) in T1D patients treated with insulin and metformin, sodium-glucose cotransporter (SGLT) inhibitors or glucagon-like peptide-1 receptor agonists (GLP-1 RAs). We performed direct and indirect network meta-analysis using Bayesian models and generated rankings of the different hypoglycemia agents by generating mixed treatment comparison. Results: With 23 RCTs (n = 5,151), we performed the network meta-analysis using eight groups; 1) insulin alone, 2) insulin and metformin, 3) insulin and canagliflozin, 4) insulin and dapagliflozin, 5) insulin and empagliflozin, 6) insulin and sotagliflozin, 7) insulin and liraglutide, and 8) insulin and exenatide. Compared with insulin alone, HbA1c was significantly lower in the group treated with insulin and sotagliflozin (mean difference: -0.43%; 95% credible intervals: -0.62 to -0.23). Total daily insulin dose was significantly lower in the insulin and sotagliflozin group by 6.3 U/day than in insulin alone group. Compared with insulin alone, body weight was significantly decreased in the group treated with canagliflozin by 4.5kg, sotagliflozin by 2.8kg, and exenatide by 5.1 kg, respectively. Severe hypoglycemic episodes did not differ between the groups. Conclusions: In patients with T1D, sotagliflozin add-on to insulin decreased HbA1c levels, daily insulin dose, and body weight without hypoglycemia compared to insulin monotherapy. Combined treatment of canagliflozin or exenatide with insulin was effective in weight loss compared with insulin alone in these patients.

SAT-623 Glucose Intolerance Modifies the Association Between Insulin-Like Growth Factor-1 and All-Cause Mortality

Background: Despite an increase in literature on insulin-like growth factor-1 (IGF-1) and its impact on insulin sensitivity, there remains controversy over its association with all-cause mortality. Insulin interacts with IGF-1 and its binding proteins, forming a growth hormone/IGF-1/insulin axis that may be impaired in Type II diabetes and/or prediabetes. We hypothesized that the association between insulin and IGF-1 with all-cause mortality differs in those with glucose intolerance (GI) in a nationally representative U.S. population with long-term follow-up. Methods: A total of 5,283 non-pregnant adults >20 years from the National Health and Nutrition Examination Survey (NHANES)-III (1988-1994) were linked to the National Death Index through 2015. Glucose intolerance was classified as per fasting blood sugar (≥100 mg/dl), hemoglobin A1c (≥5.7%), medication use, or self-reported diagnosis. IGF-1 was categorized into sex-specific quartiles. To analyze the joint impact of insulin and IGF-1, we also categorized participants into four groups: Group I) IGF-1 <230 ng/mL & insulin ≥11 uIU/mL, II) IGF-1 <230 & insulin <11, III) IGF-1 ≥230 & insulin ≥11, and IV) IGF-1 ≥230 & insulin <11. Our primary outcome was all-cause mortality. We used survey design-adjusted Cox regression to estimate the risk of all-cause mortality, adjusting for confounders. Results: Among the 5,283 subjects, 2,214 (42%) had GI. Participants had a mean follow-up of 22.1 years, during which 1,835 (34%) of them died. Those with GI in the highest quartile of IGF-1 had an unadjusted 64% lower risk of all-cause mortality compared to the lowest quartile (GI = unadjusted OR [95% CI]: 0.37 [0.24,0.55]). This association, although protective, was significantly less protective than those with normal glucose tolerance (NGT) (unadjusted OR: 0.16 [0.12,0.23]). After adjusting for confounders, these associations became insignificant (GI = aOR: 1.02 [0.73,1.42], NGT = aOR: 1.04 [0.74,1.46]). When estimating risk of mortality among joint groups of insulin and IGF-1 levels, those in Group I with NGT had 20% increased adjusted odds of mortality (1.30 [1.01,1.71]), while in GI subjects, there was an insignificant increased odds of mortality (1.17 [0.84, 1.62]). Neither subgroup in Group 2 had significant adjusted odds of mortality relative to Group 4. Group 3 subjects with GI had an adjusted, insignificant 24% increased odds of mortality (1.24 [0.91, 1.70]) compared to 70% increased odds in NGT subjects (1.69 [1.18, 2.42]). Conclusion: The differences in odds of all-cause mortality across IGF-1 quartiles in glucose tolerant vs. intolerant individuals suggests that IGF-1 may play less of a protective role in Type II diabetes and prediabetes. Among those with normal glucose, higher insulin levels, regardless of IGF-1 levels, was associated with all-cause mortality. This association did not hold in those with glucose intolerance.