Intensive Insulin Treatment Research Articles

1913-P: Differences in Glucose Absorption in African American (AA) Patients Presenting with DKA and Severe Hyperglycemia (SH)

Approximately 70% of obese AA patients with new-onset diabetes presenting with DKA and SH have near-normoglycemia remission with intensive insulin treatment. In addition to improvements in insulin secretion and/or sensitivity as potential mechanisms of remission, we hypothesize that gut glucose absorption may be associated with remission. To estimate gut glucose absorption, we developed a novel mathematical model that simultaneously estimates SI and gut glucose half-life (GIGt1/2, inversely related to glucose absorption). This study aimed to compare insulin sensitivity estimates of the novel model to estimates from Dalla Man’s OGTT model and also assess GIGt1/2. We included 42 AA patients who presented with new-onset DKA (n= 17) and SH (n=25). All subjects had a 75-gm 2-hour OGTT 1 week after insulin remission (REM) or at 3 months after continuous insulin therapy (no-REM). We estimated insulin sensitivity using our novel first-order absorption OGTT model (SInew) and GIGt1/2 and Dalla Man’s OGTT model (SI). SInew was highly concordant with SI (R=0.61, P<0.001; Concordance=0.90). When separating subjects by DKA status, there were significant differences in the frequency of remission status (χ2=5.00, P=0.03). Subjects with DKA+REM (98±19 min) had a significantly longer GIGt1/2 compared to those with SH+no-REM (47±9 min, P=0.02). GIGt1/2 between DKA+no-REM (108±46 min) and SH+no-REM was also significantly different (P=0.045). SH+REM showed a statistical trend to be different from SH+no-REM (P=0.07). There were no significant differences identified between DKA+REM, DKA+no-REM and SH+REM. The SInew from our novel OGTT model is highly concordant with SI from Dalla Man’s OGTT model. Our model additionally estimates GIGt1/2 and indicates slower gut glucose absorption is associated with remission. This new model shows that obese African American patients presenting with new-onset DKA or SH may benefit from interventions that target gut glucose absorption. Disclosure D. Stefanovski: None. G.E. Umpierrez: Advisory Panel; Self; Boehringer Ingelheim Pharmaceuticals, Inc., Janssen Pharmaceuticals, Inc. Research Support; Self; AstraZeneca, Merck & Co., Inc., Novo Nordisk Inc., Sanofi US. R.C. Boston: None. P. Vellanki: Consultant; Self; Boehringer Ingelheim Pharmaceuticals, Inc., Merck & Co., Inc. Research Support; Self; National Institutes of Health. Funding National Institutes of Health (K12HD085850 to P.V.)

148-LB: Efficacy and Safety of Adding an Oral Hypoglycemic Agent or a GLP-1 Receptor Agonist to Insulin in Patients with Type 1 Diabetes: A Network Meta-analysis

Objective: Despite intensive insulin treatment in patients with type 1 diabetes (T1D), their glycemic levels often do not reach the recommended 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, and Embase from 1970 until January 2019 to identify randomized controlled trials (RCTs) in T1D patients treated with insulin and oral hypoglycemic agents or glucagon-like peptide-1 receptor agonists. We performed network meta-analyses using Bayesian models and generated rankings of the different hypoglycemic agents by generation mixed treatment comparison. Results: With 23 RCTs (n =3,839), 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% Crl: -0.66, -0.20). Total daily insulin dose was significantly lower in the insulin and sotagliflozin group by 6.4 U/day than other groups. Compared with insulin alone, body weight was decreased in the group with insulin and canagliflozin by 4.5 kg, insulin and sotagliflozin by 2.8 kg, insulin and liraglutide by 4.5kg, and insulin and exenatide by 5.1 kg, respectively. Severe hypoglycemic episodes did not differ between the groups. Conclusions: In patients with T1D, sotagliflozin treatment combined with insulin decreased HbA1c levels, insulin dose, and body weight without hypoglycemia compared with insulin monotherapy. Combined treatment of canagliflozin, liraglutide, or exenatide with insulin was also effective in weight loss compared with insulin alone in these patients. Disclosure Y. Kim: None. S. Hwang: None. S. Lim: None.

Effect of basal insulin supplement therapy on diabetic retinopathy in short‐duration type 2 diabetes: A one‐year randomized parallel‐group trial

BackgroundIn this study, we compared the effect on diabetic retinopathy (DR) between oral antidiabetic drugs (OADs) alone and in combination with basal insulin‐supported OADs therapy (BOT). [Correction added on 11 November 2019, after first online publication: In under Background section, “DR” has been corrected into “diabetic retinopathy (DR)”.]MethodsBetween January 2015 and January 2018, this study enrolled 290 patients (age 18‐65 years) with diabetes duration between 0 and 5 years. Patients were randomly assigned to receive OADs or BOT after 14 days intensive insulin treatment. Examinations were performed at the beginning and end of the study.ResultsFewer patients developed DR in the BOT than OADs group (8 [6.06%] vs 12 [8.3%], respectively), and all cases of DR were non‐proliferative. Blood glucose concentrations were higher in the BOT than OADs group at the 3rd month, but lower in the former at the 6th and 12th month. The rate of reaching target HbA1c ≤7% was lower in the BOT than OADs group at the 3rd month (63.6% vs 72.2%, respectively), similar between the two groups at the 6th month (60.6% vs 66.6%, respectively) and higher in the BOT group at the 12th month (75.0% vs 61.1%, respectively). The SD of fasting blood glucose (FBG), coefficient of variation of FBG, SD of blood glucose (SDBG), and mean amplitude of glycemic excursions were lower in the BOT than OADs group. Changes in the levels of three cytokines (interleukin [IL]‐1β, IL‐6, and IL‐17α) were significantly less in the BOT than OADs group.ConclusionsTwelve months of BOT decreased the incidence of DR in short‐duration type 2 diabetes by reducing glycemia more effectively, stably, and completely than OADs alone.

Safety of artificial pancreas in hepato-biliary-pancreatic surgery: A prospective study

BackgroundAn artificial pancreas (AP) is useful for intensive insulin treatment (IIT). In this study, the safety and efficacy of an AP in the perioperative period of highly invasive hepato-biliary and pancreatic surgery (HBPS) was validated. MethodsFifty patients underwent IIT with an AP during the HBPS perioperative period, including hepatectomy greater than two sectors (MH), pancreatoduodenectomy (PD), and liver transplantation (LT). The primary endpoint was occurrence of hypoglycemia (<60 mg/dL). Secondary endpoints were perioperative glycemic control and postoperative complications. This study was registered at UMIN-CTR (UMIN000016451). ResultsThe mean patient age was 62.8 years. The most common surgical procedures were PD (n=24, 48%), MH (n=22, 44%), and LT (n=4, 8%). No hypoglycemia occurred in this study. The mean glycemic control rate and coefficient of variation of blood glucose during AP use were 26.4 ± 21.2% and 16.2 ± 8.3, respectively. The mean blood glucose level was 122.9 ± 15.7 mg/dL during AP application. ConclusionThe AP was safe during IIT, with no hypoglycemia observed perioperatively in patients who underwent highly invasive HBPS. Further studies are required to address the efficacy of AP with IIT in highly invasive situations.

SUN-162 Long-Term Evaluation of Intensive Insulin Therapy in Patients with Type 2 Diabetes Mellitus (Value-It Study)

Background: This study aimed to determine long-term effect of intensive insulin therapy on prevention, progression, and development of chronic diabetes complications, both micro- and macrovascular events. This study also aimed to evaluate long-term sustainability of glycemic control of patients on intensive insulin treatment. Methods: A retrospective review of adult Type 2 diabetes mellitus (T2DM) patients on intensive insulin therapy for ≥7 years. Demographic data, co-morbidities, body mass index (BMI), HbA1c, hospitalization were collated. Majority received intensive insulin therapy with combination of premixed 70/30 given two times a day and fast short acting analogue given premeals three times a day, with the addition of glargine or degludec once a day in some. Results: Among 76 patients, 62% were males and 38% were females. Mean age at diagnosis and last visit were 53 and 65 years, respectively. At time of diagnosis, patient had the following co-morbidities: hypertension (32%), dyslipidemia (13%), non-dialyzable chronic kidney disease (4%), thyroid disease (1%), pulmonary tuberculosis (1%). In terms of long-term complications, only one patient had an acute coronary event, 2 patients had CKD needing dialysis with only 9% recorded to have cerebro-vascular accident during follow-up. There were no blindness and amputation observed. There is a statistical difference between HbA1c levels at time of diagnosis (8.53 ± 1.86) and last follow up (7.83 ± 1.71) (P = 0.00). After a median follow up of 12 years (7-22 years), glycemic control was sustained with an HbA1c of ≤ 7% and ≤ 8% in 32% and 45% of patients, respectively. Conclusion: With intensive insulin therapy, micro- and macrovascular complications can be prevented significantly. Long-term sustainability of glycemic control was also achieved.

Hyperglycemic hyperosmolar state in an adolescent with type 1 diabetes mellitus.

SummaryHyperglycemic hyperosmolar state (HHS) and diabetic ketoacidosis (DKA) are the most severe acute complications of diabetes mellitus (DM). HHS is characterized by severe hyperglycemia and hyperosmolality without significant ketosis and acidosis. A 14-year-old Japanese boy presented at the emergency room with lethargy, polyuria and polydipsia. He belonged to a baseball club team and habitually drank sugar-rich beverages daily. Three weeks earlier, he suffered from lassitude and developed polyuria and polydipsia 1 week later. He had been drinking more sugar-rich isotonic sports drinks (approximately 1000–1500 mL/day) than usual (approximately 500 mL/day). He presented with HHS (hyperglycemia (1010 mg/dL, HbA1c 12.3%) and mild hyperosmolality (313 mOsm/kg)) without acidosis (pH 7.360), severe ketosis (589 μmol/L) and ketonuria. He presented HHS in type 1 diabetes mellitus (T1DM) with elevated glutamate decarboxylase antibody and islet antigen 2 antibody. Consuming beverages with high sugar concentrations caused hyperglycemia and further exacerbates thirst, resulting in further beverage consumption. Although he recovered from HHS following intensive transfusion and insulin treatment, he was significantly sensitive to insulin therapy. Even the appropriate amount of insulin may result in dramatically decreasing blood sugar levels in patients with T1DM. We should therefore suspect T1DM in patients with HHS but not those with obesity. Moreover, age, clinical history and body type are helpful for identifying T1DM and HHS. Specifically, drinking an excess of beverages rich in sugars represents a risk of HHS in juvenile/adolescent T1DM patients.Learning points:Hyperglycemic hyperosmolar state (HHS) is characterized by severe hyperglycemia and hyperosmolality without significant ketosis and acidosis.The discrimination between HHS of type 1 diabetes mellitus (T1DM) and type 2 diabetes mellitus (T2DM) in initial presentation is difficult.Pediatrician should suspect T1DM in patients with HHS but not obesity.Age, clinical history and body type are helpful for identifying T1DM and HHS.Children with T1DM are very sensitive to insulin treatment, and even appropriate amount of insulin may result in dramatically decreasing blood sugar levels.

Predictors of Long-Term Glycemic Remission After 2-Week Intensive Insulin Treatment in Newly Diagnosed Type 2 Diabetes.

Although several studies suggest that improved β-cell function is a key determinant of glycemic remission in type 2 diabetes, other predictors remain unclear. The aim of this clamp-based study was to identify predictors of 2-year glycemic remission after short-term intensive insulin treatment. A 2-year follow-up was planned in 124 drug-naive patients with type 2 diabetes who received continuous subcutaneous insulin infusion (CSII) for 2 weeks. Euglycemic-hyperinsulinemic clamps and IV glucose tolerance tests were performed to assess the insulin sensitivity [glucose infusion rate (GIR)] and acute insulin response (AIR) before and after CSII. First-phase insulin secretion was restored, and the GIR was significantly improved (P < 0.0001) after the 2-week CSII. Glycemic remission rates were 47.6% and 30.7% after 12 and 24 months of follow-up, respectively. Cox analysis revealed that a higher post-CSII glucose level [hazard ratio (HR), 1.38; 95% CI, 1.15 to 1.66; P = 0.0005] and older age at diabetes diagnosis (HR, 1.34; 95% CI, 1.05 to 1.72; P = 0.02) accounted for an increased risk of hyperglycemic relapse. A 1 SD increase in the AIR (HR, 0.75; 95% CI, 0.57 to 0.99; P = 0.04), GIR (HR, 0.67; 95% CI, 0.48 to 0.93; P = 0.016) after CSII, and baseline GIR (HR, 0.71; 95% CI, 0.51 to 0.99; P = 0.047) was inversely associated with this risk. Younger age at diabetes diagnosis, higher baseline insulin sensitivity, and lower glucose levels after insulin treatment significantly favored a 2-year glycemic remission. This long-term remission was attributed to both improved insulin sensitivity and enhanced β-cell function after short-term intensive insulin treatment.

Effects of flash glucose-sensing technology-based continuous glucose monitoring on compliance of patients with type 2 diabetes mellitus: study protocol for a randomized controlled trial

Background and objectives: Multiple insulin injection therapy has been widely used in the intensive treatment of diabetes mellitus and enabled more patients to obtain good glycemic control. Intensive insulin treatment such as multiple insulin injection every day had been proven to have effects on the protection of islet and delay the onset of diabetic complications. However, during the insulin intensive therapy, severe hypoglycemia must be avoided by intensive glucose monitoring because it can increase the risks of stroke and cardiovascular disease. Conventional invasive intensive blood glucose monitoring is limited in clinical practice because it can cause patient pain and inconveniences. Patient's poor compliance in blood glucose monitoring would restrict the application of insulin intensive therapy in patients outside the hospital. The latest method of flash glucose-sensing technology-based continuous glucose monitoring (CGM) made insulin intensive therapy safer and less painful for a patient with diabetes mellitus. However, little is reported on the effects of flash glucose-sensing technology based CGM in patients receiving multiple daily injections of insulin. This study will provide evidence to validate whether flash glucose-sensing technology-based CGM can increase the behavioral self-monitoring and compliance with self-management of a Chinese patient with diabetes mellitus receiving multiple daily injections of insulin compared with conventional invasive blood glucose monitoring. Subjects and methods: This is a prospective, single-center, open-label, randomized controlled trial. Forty patients with type 2 diabetes mellitus who receive multiple daily injections of insulin at the Department of Endocrinology, Northern Jiangsu People's Hospital, Yangzhou University, China between August 2018 and December 2019 are included in this study. These patients are randomly divided to undergo conventional blood glucose monitoring (n = 20) or a flash glucose-sensing technology-based CGM group (n = 20). Patient recruitment began in August 2018 and will end in June 2019. Analysis of primary outcome measure will be completed in June 2019. The study will end in December 2019. Study protocol: 1.0. The protocol was approved by the Medical Ethics Committee of Northern Jiangsu People's Hospital (approval No. 2018045) and is performed in strict accordance with the Declaration of Helsinki formulated by the World Medical Association. All participants provide written informed consent. Outcome measures: The primary outcome measure is the compliance of glycemic monitoring. The secondary outcome measures include the time taken for reaching the goal of glycemic control, HbA1c, self-management scores, the number of hypoglycemia attacks, and Hamilton Anxiety Scale score. Discussion: This study will provide evidence to validate whether flash glucose-sensing technology can increase patient's compliance of intensive insulin treatments, control blood glucose, and improve quality of life. Trial registration: This study was registered with the Chinese Clinical Trial Registry (registration number: ChiCTR1800017456) on July 31, 2018.

Status and trends in the use of insulin analogs, insulin delivery systems and their association with glycemic control: comparison of the two consecutive recent cohorts of Japanese children and adolescents with type 1 diabetes mellitus.

Background Treatment for type 1 diabetes mellitus (T1DM) has greatly changed by the general use of insulin analogs and continuous subcutaneous insulin infusion (CSII). To investigate whether these advances have been translated into continued improvement in glycemic control in Japanese children and adolescents, we analyzed the registration data of the two consecutive recent cohorts of Japanese childhood-onset T1DM patients. Methods The registration data including hemoglobin A1c (HbA1c), hypoglycemia and insulin regimen were compared between the two cohorts (862 patients in the 2008 cohort and 1090 in the 2013 cohort). Results The proportion of subjects with multiple daily insulin injection therapy (MDI) and CSII significantly increased (p<0.0001) from 67.4% and 9.7% to 71.8% and 23.4%, respectively. In the 2013 cohort, almost all patients were treated with basal-bolus treatment using insulin analogs. The use of CSII increased in all age groups, especially in the age group 0-5 years. The rates of overall, moderate and severe hypoglycemia significantly declined from 10.24, 10.18 and 0.056 events/100 persons/period in the 2008 cohort to 0.66, 0.62 and 0.033 in the 2013 cohort (p<0.0001, <0.0001, 0.04), respectively. Contrarily, there were no significant changes in HbA1c values between the two cohorts. Conclusions The popularization of the basal-bolus treatment using insulin analogs hascontributed to a significant decrease in hypoglycemia. In contrast, the intensive insulin treatment may not be enough for the satisfactory improvement of glycemic control in Japanese children and adolescents with T1DM. Considerable points remain, such as diabetic education and support to motivate patients.

Role of Automated Insulin Delivery (Artificial Pancreas) in Islet Transplantation: An In Silico Assessment

Human pancreatic islet transplantation is a minimally-invasive procedure that is gaining recognition for the treatment of type 1 diabetes (T1D). Selected patients with unstable T1D, hypoglycemia unawareness, history of severe hypoglycemia, and glycemic lability, not successfully stabilized with intensive insulin treatment, can be offered this alternative therapy that has been shown to provide long-term glycemic control with near-normalization of hemoglobin A1c in the absence of severe hypoglycemia. Today, downsides of pancreatic islet transplantation include the need for chronic recipient immunosuppression and the limited supply of pancreatic islets. In addition, attaining long-term insulin independence remains a challenge. In this context, stabilization of a patient’s metabolic system with islet transplantation that is augmented by automated insulin delivery (AID) technology could be of significant interest. In this chapter, we want to frame and illustrate the problem of developing a combined bio-artificial system that includes an islet graft and mechanical AID. Our discussion will propose modeling approaches potentially deployable in describing glucose homeostasis after islet transplantation and will be supported by a series of in silico studies simulating post-transplant glycemic patterns and the impact of AID control strategies. To run our analyses, we used the UVA/Padova T1D Simulator – a simulation platform accepted by FDA as a substitute to animal trials in the pre-clinical evaluation of insulin treatment strategies, appropriately modified to describe the glucose-insulin regulation system in transplanted individuals. The results presented here are a very preliminary in silico assessment of the benefits of combining islet transplantation and AID. Further research, which relies on glucose and insulin data collected from transplanted patients, will be needed to optimize modeling and control strategies.

Continuous subcutaneous insulin infusion versus multiple daily injections in children and young people at diagnosis of type 1 diabetes: the SCIPI RCT.

The risk of developing long-term complications of type 1 diabetes (T1D) is related to glycaemic control and is reduced by the use of intensive insulin treatment regimens: multiple daily injections (MDI) (≥ 4) and continuous subcutaneous insulin infusion (CSII). Despite a lack of evidence that the more expensive treatment with CSII is superior to MDI, both treatments are used widely within the NHS. (1) To compare glycaemic control during treatment with CSII and MDI and (2) to determine safety and cost-effectiveness of the treatment, and quality of life (QoL) of the patients. A pragmatic, open-label randomised controlled trial with an internal pilot and 12-month follow-up with 1 : 1 web-based block randomisation stratified by age and centre. Fifteen diabetes clinics in hospitals in England and Wales. Patients aged 7 months to 15 years. Continuous subsutaneous insulin infusion or MDI initiated within 14 days of diagnosis of T1D. Data were collected at baseline and at 3, 6, 9 and 12 months using paper forms and were entered centrally. Data from glucometers and CSII were downloaded. The Health Utilities Index Mark 2 was completed at each visit and the Pediatric Quality of Life Inventory (PedsQL, diabetes module) was completed at 6 and 12 months. Costs were estimated from hospital patient administration system data. The primary outcome was glycosylated haemoglobin (HbA1c) concentration at 12 months. The secondary outcomes were (1) HbA1c concentrations of < 48 mmol/mol, (2) severe hypoglycaemia, (3) diabetic ketoacidosis (DKA), (4) T1D- or treatment-related adverse events (AEs), (5) change in body mass index and height standard deviation score, (6) insulin requirements, (7) QoL and (8) partial remission rate. The economic outcome was the incremental cost per quality-adjusted life-year (QALY) gained. A total of 293 participants, with a median age of 9.8 years (minimum 0.7 years, maximum 16 years), were randomised (CSII, n = 149; MDI, n = 144) between May 2011 and January 2015. Primary outcome data were available for 97% of participants (CSII, n = 143; MDI, n = 142). At 12 months, age-adjusted least mean squares HbA1c concentrations were comparable between groups: CSII, 60.9 mmol/mol [95% confidence interval (CI) 58.5 to 63.3 mmol/mol]; MDI, 58.5 mmol/mol (95% CI 56.1 to 60.9 mmol/mol); and the difference of CSII - MDI, 2.4 mmol/mol (95% CI -0.4 to 5.3 mmol/mol). For HbA1c concentrations of < 48 mmol/mol (CSII, 22/143 participants; MDI, 29/142 participants), the relative risk was 0.75 (95% CI 0.46 to 1.25), and for partial remission rates (CSII, 21/86 participants; MDI, 21/64), the relative risk was 0.74 (95% CI 0.45 to 1.24). The incidences of severe hypoglycaemia (CSII, 6/144; MDI, 2/149 participants) and DKA (CSII, 2/144 participants; MDI, 0/149 participants) were low. In total, 68 AEs (14 serious) were reported during CSII treatment and 25 AEs (eight serious) were reported during MDI treatment. Growth outcomes did not differ. The reported insulin use was higher with CSII (mean difference 0.1 unit/kg/day, 95% CI 0.0 to 0.2 unit/kg/day; p = 0.01). QoL was slightly higher for those randomised to CSII. From a NHS perspective, CSII was more expensive than MDI mean total cost (£1863, 95% CI £1620 to £2137) with no additional QALY gains (-0.006 QALYs, 95% CI -0.031 to 0.018 QALYs). Generalisability beyond 12 months is uncertain. No clinical benefit of CSII over MDI was identified. CSII is not a cost-effective treatment in patients representative of the study population. Longer-term follow-up is required to determine if clinical outcomes diverge after 1 year. A qualitative exploration of patient and professional experiences of MDI and CSII should be considered. Current Controlled Trials ISRCTN29255275 and EudraCT 2010-023792-25. This project was funded by the National Institute for Health Research (NIHR) Health Technology Assessment programme and will be published in full in Health Technology Assessment; Vol. 22, No. 42. See the NIHR Journals Library website for further project information. The cost of insulin pumps and consumables supplied by F. Hoffman-La Roche AG (Basel, Switzerland) for the purpose of the study were subject to a 25% discount on standard NHS costs.

Normal Glucose Tolerance (NGT) in Obese African-Americans (AA) with Ketosis-Prone Diabetes (KPDM)

KPDM is characterized by new-onset DKA and near-normoglycemia remission (HbA1c &amp;lt;7%, fasting blood glucose [BG] &amp;lt;130 mg/dl, and maintain glycemic control for at least one week off insulin) with intensive insulin treatment. Glycemic status at insulin remission varies from NGT, prediabetes or diabetes on OGTT. We hypothesized that patients with NGT at near-normoglycemia remission will have higher insulin sensitivity (Si) and secretion and longer hyperglycemia relapse-free survival. Obese AA who presented with DKA (n=33) and severe hyperglycemia (n=42) (BG &amp;gt;400 mg/dl with no DKA) underwent 2 hour 75-gm OGTT a week after insulin remission. NGT, prediabetes and diabetes were defined as per ADA criteria. At near-normoglycemia remission, Si was calculated using the OGTT minimal model analysis. Insulin secretion was calculated as incremental area under the curve of insulin (IncreAUCi) with insulin levels from OGTT. Disposition index (DI) was calculated as Si x IncreAUCi. Hyperglycemia relapse was defined as fasting BG ≥ 130 mg/dl, HbA1c &amp;gt;7% or 2 random BG ≥ 180 mg/dl. There were no differences in baseline characteristics among patients with NGT (12%), prediabetes (45%) and diabetes (43%). DI was higher in patients with NGT vs. prediabetes vs. diabetes (1.88±1.63 vs. 1.05±1.14 vs. 0.35±0.92, p&amp;lt;0.001). The difference in DI was explained by higher Si than IncreAUCi in NGT compared to prediabetes and diabetes (Si:4.2±4.4 vs. 2.4±3.5 vs. 1.2±2.5 10-4.(mU/l)-1.min-1, p&amp;lt;0.001; IncreAUCi: 6571±3451 vs. 6585±4947 vs. 4450±3051, p=0.14 mU/ml2). Multivariate Cox regression showed that age, sex, DKA presentation, OGTT status, and DI were not associated with long-term relapse-free survival. There were no differences in any variables between patients presenting with DKA or severe hyperglycemia. NGT at near-normoglycemia remission is characterized by higher insulin sensitivity than higher insulin secretion. However, none of these markers were associated with long-term hyperglycemia-free survival. Disclosure P. Vellanki: Consultant; Self; Boehringer Ingelheim Pharmaceuticals, Inc.. Research Support; Self; Boehringer Ingelheim Pharmaceuticals, Inc., AstraZeneca. D. Stefanovski: None. V. Narwani: None. I. Anzola: None. L. Peng: None. D. Smiley-Byrd: Speaker's Bureau; Self; Sanofi, Merck &amp; Co., Inc., Novo Nordisk Inc. G.E. Umpierrez: Research Support; Self; Sanofi US, Merck &amp; Co., Inc., Novo Nordisk Inc., AstraZeneca. Advisory Panel; Self; Sanofi, Intarcia Therapeutics, Inc..

The Impact of Different Initial Insulin Dose Regimens in Short-Term Intensive Insulin Therapy

Objective: To compare the effects of different initial insulin dose regimens during the short-term insulin intensive treatment in newly diagnosed type 2 diabetes patients, in order to investigate the rational of formula based initiation regimen. Methods: Fifty six patients with newly diagnosed type 2 diabetes, 33 males and 23 females, aged 27-65 years old, BMI 25.43 ± 2.90 kg/m2, were randomly assigned into 2 groups: the formula group (whose insulin dose was initiated according to the formula recommended in our previous study, 28 cases) and the empirical group (according to current guidelines, 28 cases). Short-term intensive insulin therapy was performed, and the glycemic goal was gradually achieved. The time to glycemic goal(TGG), TDD-1, the frequency of hypoglycemia and the glycemic variability were compared. Results: The average TGG in the formula group(2.68 ± 1.44 days) is shorter than that in the empirical group (3.61 ± 1.60 days, P &amp;lt;0.05). There is no significant difference in the initial insulin dose (44.28 ± 9.10 IU, P&amp;gt; 0.05) of the formula group compared with the TDD-1 (46.91 ± 13.26 IU), whereas the initial insulin dose (34.09 ± 5.21 IU, P &amp;lt;0.05)of the empirical group is less than TDD-1. Compared with the TDD-1, while 70% of the estimate TDD-1(eTDD-1),which is calculated according to the formula as the initial insulin regimen,may not meet the requirements (P &amp;lt;0.001), 100% of the eTDD-1 is also too much for them (P &amp;lt;0.001).All the indicators for glycemic variability such as mean MBG, MGSD, M value, MAGE and LAGE during the initial three days are not significantly different between the two groups (P&amp;gt; 0.05). There is also no significant difference between 2 groups in the incidence of hypoglycemia(P&amp;gt; 0.05). Conclusion: Formula based initial insulin regimen is helpful in shortening TGG without increasing within-day glycemic variability or hypoglycemia events.It is recommended that 80% of the eTDD-1 can be used as the initial insulin regimen for the intensive treatment in most newly diagnosed T2DM patients. Disclosure H. Xinwei: None.

The risk of symptomatic hypoglycemia over 4 years of intensive insulin treatment and combined therapy in type 2 diabetes patients

Searchable abstracts of presentations at key conferences in endocrinology ISSN 1470-3947 (print) | ISSN 1479-6848 (online)

Short-term insulin intensive therapy decreases MCP-1 and NF-κB expression of peripheral blood monocyte and the serum MCP-1 concentration in newlydiagnosed type 2 diabetics.

To observe the effect of short-term insulin intensive treatment on the monocyte chemoattractant protein-1 (MCP-1) as well as on the nuclear factor-kappa B (NF-κB) expression of peripheral blood monocyte. This is also in addition to observing the serum MCP-1 level in newlydiagnosed type 2 diabetic patients and probing its anti-inflammation effects. Twenty newly-diagnosed type 2 diabetic patients were treated with an insulin intensive treatment for 2 weeks. MCP-1 and NF-κB expression on the monocyte surface were measured with flow cytometry, the serum MCP-1 level was measured by enzyme linked immunosorbent assay (ELISA) during pretreatment and post-treatment. After 2 weeks of the treatment, MCP-1 and NF-κB protein expression of peripheral blood monocyte and serum MCP-1 levels decreased significantly compared with those of pre-treatment, which were (0.50 ± 0.18)% vs (0.89 ± 0.26)% (12.22 ± 2.80)% vs (15.53 ± 2.49)% and (44.53 ± 3.97) pg/mL vs (49.53 ± 3.47) pg/mL, respectively (P < 0.01). The MCP-1 expression on monocyte surface had a significant positive relationship with serum MCP-1 levels (r = 0.47, P < 0.01). Short-term insulin intensive therapy plays a role in alleviating the increased inflammation reaction in type 2 diabetics.

New Glucose-Lowering Agents for Diabetic Kidney Disease.

The prevalence of diabetes mellitus is increasing and is associated with a range of complications including nephropathy. New antidiabetic agents are sought which also have positive effects to diminish diabetic complications. Examples of promising new classes of such agents are glucagon-like peptide-1 receptor agonists, dipeptidyl peptidase-4 inhibitors, and sodium-glucose cotransporter 2 inhibitors. In addition to cardiovascular protective effects such as weight loss and decreased blood pressure of some of these agents, there is evidence for renoprotective effects with these agents. This review elaborates on the main results of renoprotective effects of these 3 treatment classes. In conclusion, currently available trials have demonstrated renoprotective effects for certain glucagon-like peptide-1 receptor agonists, liraglutide and semaglutide, and the sodium-glucose cotransporter 2 inhibitors, empagliflozin and canagliflozin. Dipeptidyl peptidase-4 inhibitors did not show a significant renoprotective effect. Nevertheless, larger studies with respect to renoprotective effects of these 3 drug classes are currently being performed, and thus, no conclusions for all of these agents can yet be made.

Growth Trajectory in Children with Type 1 Diabetes Mellitus: The Impact of Insulin Treatment and Metabolic Control

Background: Linear growth was reported to be negatively affected by type 1 diabetes mellitus (T1DM), in relation to disease duration and poor metabolic control. It is unclear whether a subtle growth failure still persists despite the optimization of therapy. Our aim was to analyse pubertal growth, adult height, and metabolic profile in a cohort of children with T1DM undergoing intensive insulin treatment by multiple daily injections or continuous subcutaneous insulin infusion (CSII). Methods: One-hundred and four children (51 males) with prepubertal onset of T1DM were prospectively followed up to final height attainment. Results: Age at puberty onset was 11.7 ± 1.1 years in males and 10.9 ± 1.3 in females. Age at adult height attainment was 16.4 ± 1.6 years in males and 14.1 ± 1.8 years in females. Pubertal height gain was 24.4 ± 4.9 cm in males and 19.0 ± 3.8 cm in females. HbA_1c, HDL cholesterol, and triglyceride levels increased during puberty. HDL cholesterol levels were higher in patients treated with CSII. Height standard deviation score (SDS) at diagnosis (0.52 ± 1.04) was higher than target height SDS (0.01 ± 1.07), but declined afterwards, and both height SDS at puberty onset (0.22 ± 1.1) and adult height SDS (–0.1 ± 1.02) were not significantly different from target height SDS. BMI SDS showed a positive trend from diagnosis to puberty onset and stabilized later (–0.04 ± 1.4 at T1DM onset, 0.55 ± 2.1 at puberty onset, and 0.53 ± 2.1 at adult height attainment). Conclusions: Although subtle abnormalities of growth still persist, the modern advancements of insulin therapy are able to normalize puberty and final height of children with T1DM.

Cost calculation for a flash glucose monitoring system for UK adults with type 1 diabetes mellitus receiving intensive insulin treatment

AimsTo estimate the costs associated with a flash glucose monitoring system as a replacement for routine self-monitoring of blood glucose (SMBG) in patients with type 1 diabetes mellitus (T1DM) using intensive insulin, from a UK National Health Service (NHS) perspective. MethodsThe base-case cost calculation was created using the maximum frequency of glucose monitoring recommended by the 2015 National Institute for Health and Care Excellence guidelines (4–10 tests per day). Scenario analyses considered SMBG at the frequency observed in the IMPACT clinical trial (5.6 tests per day) and at the frequency of flash monitoring observed in a real-world analysis (16 tests per day). A further scenario included potential costs associated with severe hypoglycaemia. ResultsIn the base case, the annual cost per patient using flash monitoring was £234 (19%) lower compared with routine SMBG (10 tests per day). In scenario analyses, the annual cost per patient of flash monitoring compared with 5.6 and 16 SMBG tests per day was £296 higher and £957 lower, respectively. The annual cost of severe hypoglycaemia for flash monitoring users was estimated to be £221 per patient, compared with £428 for routine SMBG users (based on 5.6 tests/day), corresponding to a reduction in costs of £207. ConclusionsThe flash monitoring system has a modest impact on glucose monitoring costs for the UK NHS for patients with T1DM using intensive insulin. For people requiring frequent tests, flash monitoring may be cost saving, especially when taking into account potential reductions in the rate of severe hypoglycaemia.

Current status and issues of the artificial pancreas: abridged English translation of a special issue in Japanese.

Surgical stress induces hyperglycemia and gives rise to glucose toxicity, which causes infectious diseases, resulting in unfavorable surgical outcomes. Intensive insulin treatment can control short- and long-term complications in patients with not only diabetes mellitus, but also surgical diabetes; however, it is associated with an increased risk of hypoglycemia. The wearable artificial pancreas was originally developed to control glucose levels in patients with type 1 diabetes, progressing to a device with enhanced stability and safety for these patients. Its usability has further progressed to include patients with type 2 diabetes. The bedside artificial pancreas is the only closed-loop-type artificial pancreas which can maintain stable glycemic control in accordance with a target blood glucose range, based on the patient's actual blood glucose levels. Moreover, this stable glycemic control with a low variation in blood glucose concentration within the target range is produced without any hypoglycemia. Significant advances of this device will now occur due to the approval of treatment for perioperative glycemic control by the Japanese Health Care Insurance System in 2016. Along with an increase in the number of mainly elderly patients with low glucose tolerance, it is expected that the role of the artificial pancreas will increase in the future. Considering the current state and expense of regenerative and transplant medicine, along with donor shortages, further development of the artificial pancreas and associated glycemic control can be expected.

Intensive insulin therapy increases glutathione synthesis rate in surgical ICU patients with stress hyperglycemia.

ObjectiveThe glutathione system plays an essential role in antioxidant defense after surgery. We assessed the effects of intensive insulin treatment (IIT) on glutathione synthesis rate and redox balance in cancer patients, who had developed stress hyperglycemia after major surgery.MethodsWe evaluated 10 non-diabetic cancer patients the day after radical abdominal surgery combined with intra-operative radiation therapy. In each patient, a 24-hr period of IIT, aimed at tight euglycemic control, was preceded, or followed, by a 24-hr period of conventional insulin treatment (CIT) (control regimen). Insulin was administered for 24 hours, during total parenteral nutrition, at a dosage to maintain a moderate hyperglycemia in CIT, and normoglycemic blood glucose levels in IIT (9.3±0.5 vs 6.5±0.3 mmol/L respectively, P<0.001; coefficient of variation, 9.7±1.4 and 10.5±1.1%, P = 0.43). No hypoglycemia (i.e., blood glucose < 3.9 mmol/L) was observed in any of the patients. Insulin treatments were performed on the first and second day after surgery, in randomized order, according to a crossover experimental design. Plasma concentrations of thiobarbituric acid reactive substances (TBARS) and erythrocyte glutathione synthesis rates (EGSR), measured by primed-constant infusion of L-[2H2]cysteine, were assessed at the end of each 24-hr period of either IIT or CIT.ResultsCompared to CIT, IIT was associated with higher EGSR (2.70±0.51 versus 1.18±0.29 mmol/L/day, p = 0.01) and lower (p = 0.04) plasma TBARS concentrations (2.2±0.2 versus 2.9±0.4 nmol/L).ConclusionsIn patients developing stress hyperglycemia after major surgery, IIT, in absence of hypoglycemia, stimulates erythrocyte glutathione synthesis, while decreasing oxidative stress.