Short-term Intensive Insulin Therapy Research Articles

1032-P: Time-in-Range during Short-Term Intensive Insulin Therapy Is Associated with Clinical Outcomes in Patients with Newly Diagnosed Type 2 Diabetes

Background: Short-term intensive insulin therapy (SIIT) can reverse β cell dysfunction and induce glycemic remission in patients with newly diagnosed type 2 diabetes. Elimination of glucotoxicity to the maximum extent was considered the major mechanism. This study aimed to investigate the association of time in range (TIR) of predefined glycemic targets during SIIT with clinical outcomes after the therapy. Methods: SIIT was given to 95 patients with newly diagnosed T2DM using insulin pump. Strict glycemic control (premeal, bedtime or 3am BG 3.9-6.0 mmol/L, 2hBG 3.9- 8.0 mmol/L) was achieved and maintained for 2 weeks. TIR was defined by calculating the percentage of daily eight-point blood glucose values (before and 2 hours after each meal, at bedtime and 3am) within the above-mentioned near-normoglycemic targets. Intravenous glucose tolerance tests were performed before and after SIIT with acute insulin response (AIR), HOMA IR and HOMA B calculated. Patients were followed for 1 year after withdrawal of insulin. Results: Overall mean TIR was 68±11% during SIIT. After SIIT, both AIR and HOMA B increased while HOMA IR decreased. TIR during SIIT was significantly associated with improvement of AIR (r=0.36, P<0.001) but not with change of HOMA B (r=0.11, P=0.29) or HOMA IR (r=-0.17, P=0.11). One-year remission was observed in 59% (56/95) patients. Higher proportion of patients with TIR≥70% obtained glycemic remission for over 1 year compared with those with TIR<70% (71.4% vs. 49.1%, P=0.036) . In a logistic regression model, TIR≥70% was associated with higher 1- year glycemic remission after adjusting for Age, BMI and baseline A1c (OR 2.60, 95% CI 1.10-6. 13, P=0.03). Conclusion: Higher TIR during SIIT indicates better recovery of βcell function and long-term glycemic outcomes. Disclosure L. Liu: None. L. Xu: None. W. Ke: None. P. Zhang: None. C. Xu: None. D. Zang: None. Y. Li: None. Funding National Key Research and Development Program of China (2018YFC1314100); Key Research and Development Program of Guangdong Province (2019B020230001); National Natural Science Foundation of China (81800716)

1047-P: The Change of HOMA-IR Predicted the Remission Time in Patients with Newly Diagnosed Type 2 Diabetes after Intensive Insulin Therapy

Objectives: Insulin resistance is one of strong predictions on the remission in patients with newly diagnosed type 2 diabetes (T2DM) after short-term insulin intensive therapy (SIIT). Therefore, the purpose of this study is to explore if the short-term change of insulin resistance can predict the long-time remission. Methods: This study enrolled 160 patients with newly diagnosed type 2 diabetes mellitus (103 male, aged 49.8±10.4 yrs,HbA1c11±2.1%). All of them have been treated by 2-week continuous subcutaneous insulin infusion as SIIT when new diagnosed. HOMA-IR was compared just at the termination of SIIT and later then follow up every 3 months regularly for 5 years. Results: After short-term intensive treatment, up to 84.4%, 81.3% and 26.9% of patients achieved disease remission with T2DM at the termination of CSII, the 3rd month and 5th year follow up without use of medication. The average remission time were 27+/-615 months. The average changes of HOMA-IR in the first 3 months after SIIT were 30%+/-52%. This short-term change percent of HOMA-IR was positive related to the statue of remission at 5th-year follow-up (r = 0.778, p <0.0001). The ROC curve analysis showed below. Conclusions: Maintaining the improving insulin resistance after short-term insulin intensive therapy is essential for the long-time remission from T2DM. Lifestyle interventions might be helpful. Disclosure W. Xuesi: None. Z. Huang: None. L. Liu: None. Y. Li: None. Funding National Key Research and Development Program of China (2018YFC1314100)

SUN-681 Does Short Term Intensive Insulin Therapy in Newly Diagnosed Type 2 Diabetes Mellitus Delay Eventual Insulin Dependence

In patients with type 2 diabetes mellitus (T2DM), dysfunction of β-cells starts years before the diagnosis of T2DM and rapidly worsens after overt hyperglycemia. Use of short-term intensive insulin therapy (STIIT) at the time of diagnosis of overt hyperglycemia has shown clinical recovery of β-cells for up to 2 years. A systematic literature review of studies looking for the effect of STIIT, used within two years of diagnosis of T2DM, on the duration from relapse of hyperglycemia to eventual insulin dependence is presented in this abstract.The key phrases ‘type 2 diabetes mellitus’, ‘short-term insulin therapy’, ‘β-cell failure’, and ‘permanent insulin dependence’ were used to search English literature. For simplicity the duration of diabetes in these studies was divided into three periods: Period 1- Diagnosis of T2DM to initiation of STIIT, Period 2- End of STIIT until relapse of hyperglycemia i.e. total glycemic remission period, and Period 3- Relapse of hyperglycemia to permanent dependence on insulin therapy. Studies were excluded if all of their participants had diagnosis of T2DM for more than 2 years at the time of inclusion, i.e., if period 1 was more than 2 years.Six clinical trials involving STIIT were identified (Period 2). No studies that examined the clinical course of T2DM in their patients beyond the relapse of hyperglycemia (Period 3) were identified.This literature review identified a lack of data about this important clinical question- do ‘recovered’ β-cells from STIIT exhibit a better response to non-insulin therapies after the end of period 2 and, hence, delay the secondary β-cell failure in period 3? There is a need to conduct studies with longer follow up to characterize the differences in the disease course between patients treated with STIIT and patients treated with non-insulin therapies. This can help us understand scope of STIIT beyond the initial functional remission of β-cells.

MON-LB120 MODY3 With Insulin Coding Gene Mutation and Craniofacial Microsomia: A Case Report

Background: Maturity onset diabetes in young 3 (MODY 3) is caused by mutation of the hepatic nuclear factor 1 alpha (HNF-1A) gene. Craniofacial macrosomia (CFM) is associated with an abnormal development of craniofacial structures during the embryonic period. Maternal diabetes and genetic predisposition have been associated with CFM1. There are rare reports about an association of MODY 3 and CFM. Clinical case: An 11-year-old male patient presented with right side CFM (mild mandibular hypoplasia, internal auditory canal absence, severe pinna hypoplasia, abnormal orbital size and location, O3.M0.E3.N0.S02) noted at 8 months of age. Preoperative examination revealed A1c at 10.9%. After short term intensive insulin therapy, he had standard bread meal test: fasting glucose 8.11 mmol/L, insulin 13.9 mIU/L (3-25), C-peptide 1.25 ng/ml (0.81-3.85); 1 hour glucose 10.05 mmol/L, insulin 27 mIU/L, C-peptide 2.42 ng/ml; 2 hour glucose 8.17 mmol/L, insulin 16.09 mIU/L, C-peptide 2.11 ng/ml. GADA, IAA and ICA were negative. The mother was diagnosed diabetes at age 27years, when the patient was 8-month-old, and received insulin therapy. The mother was blind by age 35years due to diabetic retinopathy and died of DKA at 38-years-old. The patient’s 16-year-old brother had left side CFM (O2.M1.E2.N0.S0) and his OGTT was normal. The father was diagnosed with impaired glucose tolerance. The family had whole genome sequencing by Sanger technique, and resequenced the mutation with side primers. The CGA to CAA mutation was present at the 686 loci of exon 3 of HNF1A gene in the patient and mother. The HNF1A exon 3 mutation of CGA to CAA resulted in the change of arginine to glutamine which by the HGMA database is recognized as a reported MODY3 gene mutation. There was a mutation of G to A in the 4 loci of exon 1 of the insulin coding region in chromosome 11 in both the patient and elder brother. Neither elder brother nor father had the CGA mutation of HNF1A. Conclusion: There has not been a previous report of a relationship between HNF1A and CFM. In this case, the elder brother had CFM without a HNF1A mutation which does not support a connection between CFM and HNF1A. The two brothers both had CFM and insulin coding gene mutations which would represent a new association not previously described. Further testing is needed to confirm a relationship between the two. Reference: 1. Chen Q, Zhao Y, Shen G, Dai J. Etiology and Pathogenesis of Hemifacial Microsomia. J Dent Res 2018; 97(12): 1297-305. 2. Gougoutas AJ, Singh DJ, Low DW, Bartlett SP. Hemifacial microsomia: clinical features and pictographic representations of the OMENS classification system. Plast Reconstr Surg 2007; 120(7): 112e-20e.

Effect of short-term intensive insulin therapy on α-cell function in patients with newly diagnosed type 2 diabetes.

The effect of intensive insulin therapy on hyperglucagonemia in newly diagnosed type 2 diabetes (T2DM), and its associations with β-cell function, has not been elucidated. This study assessed the effect of 12 weeks of intensive insulin therapy on hyperglucagonemia in newly diagnosed T2DM and its associations with β-cell function, with reference to the effects of 12 weeks of oral hypoglycemic agents (OHAs).One hundred eight patients with newly diagnosed T2DM were enrolled from January 2015 to December 2015. The patients were randomly divided to receive, for 12 weeks, either intensive insulin therapy or OHAs. Meal tolerance tests were conducted at baseline before treatment (0 week), at 12 weeks (end of treatment), and 12 months after the initiation of treatment. The levels of glucagon, proinsulin, C-peptide (CP), and blood glucose were measured at timepoints 0, 30, and 120 minutes during the meal tolerance test.Intensive insulin treatment was associated with a decrease in glucagon levels (at 0, 30, and 120 minutes) and proinsulin/CP, and an increase in the insulin-secretion index ΔCP30/ΔG30 and ΔCP120/ΔG120, at 12 weeks and 12 months during the follow-up, compared with the corresponding effects of OHAs. Intensive insulin therapy could reduce but failed to normalize glucagon levels at 12 weeks. There were no correlations between the change of percentages in total area under the curve of glucagon and other glycemic parameters (proinsulin/CP; ΔCP30/ΔG30; or ΔCP120/ΔG120). Patients who received intensive insulin therapy were more likely to achieve their target glycemic goal and remission, compared with those who received OHAs.Short-term intensive insulin therapy facilitates the improvement of both β-cell and α-cell function in newly diagnosed T2DM mellitus. Decline of β-cell secretion and concomitant α-cell dysfunction may both be involved in the pathogenesis of T2DM.

Hypoglycemia during Short-Term Intensive Insulin Therapy and Its Association with Long-Term Glycemic Remission in Patients with Newly Diagnosed Type 2 Diabetes.

Background Short-term intensive insulin therapy induces long-term glycemic remission in half of patients with newly diagnosed type 2 diabetes. The concomitant hypoglycemia needs further analysis. Methods We collected data from three randomized trials conducted with the same inclusion and exclusion criteria at our institution from 2002 to 2015. Continuous subcutaneous insulin infusion (CSII) was provided to achieve the glycemic goals within a week and then maintained for 14 days. Hypoglycemia episodes during short-term treatment and the one-year drug-free glycemic remission were observed. Results A total of 244 patients were included. The per day episode of mild hypoglycemia (3.0-3.9 mmol/L) was higher in the remission group than in the nonremission group (0.26 ± 0.20 vs. 0.18 ± 0.21, P = 0.005). However, a moderate hypoglycemia episode (<3.0 mmol/L) per day was insignificantly lower in the remission group (0.02 ± 0.04 vs. 0.03 ± 0.04, P = 0.005). However, a moderate hypoglycemia episode (<3.0 mmol/L) per day was insignificantly lower in the remission group (0.02 ± 0.04 vs. 0.03 ± 0.04, P = 0.005). However, a moderate hypoglycemia episode (<3.0 mmol/L) per day was insignificantly lower in the remission group (0.02 ± 0.04 vs. 0.03 ± 0.04, P = 0.005). However, a moderate hypoglycemia episode (<3.0 mmol/L) per day was insignificantly lower in the remission group (0.02 ± 0.04 vs. 0.03 ± 0.04, Conclusions Mild hypoglycemic episodes during the continuing insulin dose reduction period indicate a long-term drug-free euglycemic remission in patients with newly diagnosed type 2 diabetes. However, the insulin dosage should be reduced even more quickly in the future treatment to decrease the potential harms.

Practical application of short-term intensive insulin therapy based on the concept of \u201ctreat to target\u201d to reduce hypoglycaemia in routine clinical site

The aim is to devise a new short-term intensive insulin therapy (N-SIIT) based on the concept of “treat to target” to avoid hypoglycaemia and was applied it to various diabetic state. We determined dosage of 1 basal and 3 bolus “treat” insulin based on “target” blood glucose level and changed each insulin dose by small units (2 units) every day for 2 weeks. We evaluated the effects of N-SIIT in 74 subjects with type 2 diabetes (male 45, female 29, 64.9 ± 16.6 years old, HbA1c 10.4 ± 2.6%). Glargine U300 (“treat”) and morning blood glucose level (“target”) was significantly correlated with increasing insulin dose and decreasing blood glucose level in day 1–7, indicating that insulin amount was determined by target blood glucose level and lowered next target blood glucose level. Remission rates were 67.3% (Hypoglycaemia rate 5.6 %) in N-SIIT and 47.3% (Hypoglycaemia rate 38.1%) in conventional SIIT. Required amount of insulin would be automatically determined, depending on each patient pathophysiology and life style. This method is pretty simple, flexible and cheap, and provides information about the dynamic pathophysiological alteration of insulin resistance and glucotoxicity from the profile of blood glucose levels and insulin shot.

Intermittent Intensive Insulin Therapy for Type 2 Diabetes: Effects on Hypoglycemia, Weight Gain, and Quality of Life Over 2 Years

Objective: In early type 2 diabetes (T2DM), the administration of short-term intensive insulin therapy (IIT) can induce glycemic remission for a year thereafter, but this effect ultimately wanes. In this context, intermittently repeating short-term IIT could provide a strategy for maintaining the otherwise transient benefits of this intervention. However, the viability of this strategy would be contingent upon not inducing undesirable effects of insulin therapy such as excessive hypoglycemia and fat deposition. We thus sought to evaluate the effect of administering short-term IIT every 3 months on hypoglycemia, weight gain, and quality of life in early T2DM. Methods: In this 2-year pilot trial, 24 adults with T2DM of 2.0 ± 1.7 years duration and hemoglobin A1c of 6.4 (46 mmol/mol) ± 0.1% were randomized to 3 weeks of IIT (glargine, lispro) followed by either (1), repeat IIT for up to 2 weeks every 3 months or (2), daily metformin. IIT was titrated to target near-normoglycemia (premeal glucose 4 to 6 mmol/L; 2-hour postmeal <8 mmol/L). Participants were assessed every 3 months, with quality of life (QOL) evaluated annually. Results: The rate of hypoglycemia (<3.5 mmol/L) was low in the metformin and intermittent IIT arms (0.37 versus 0.95 events per patient-year; P = .28). There were no differences between the groups in changes over time in overall, central, or hepatic fat deposition (as reflected by weight [P = .10], waist-to-hip ratio [P = .58], and alanine aminotransferase [P = .64], respectively). Moreover, there were no differences between the groups in QOL at 1- and 2-years. Conclusion: Intermittent short-term IIT may be safely administered in early T2DM without excessive adverse impact on hypoglycemic risk, anthropometry, or QOL. Abbreviations: ALT = alanine aminotransferase; HbA1c = hemoglobin A1c; IIT = intensive insulin therapy; ISSI-2 = insulin secretion-sensitivity index-2; OGTT = oral glucose tolerance test; QOL = quality of life; SF-36 = medical outcomes study 36-item short-form health survey; T2DM = type 2 diabetes.

Effects of Structured Simplified Short-term Intensive Insulin Therapy on Long-term Glycemic Remission

Effects of Structured Simplified Short-term Intensive Insulin Therapy on Long-term Glycemic Remission

2320-PUB: Effects of Sequential Therapy Using Metformin plus Pioglitazone following Short-Term Intensive Insulin Therapy in Patients with Newly Diagnosed T2DM

Aims: Short-term intensive insulin therapy (SIIT) reverses β cell dysfunction in early T2DM, but this effect vanes overtime. This study aimed to investigate the effects of metformin plus pioglitazone sequential therapy on maintenance of the effect of SIIT. Methods: SIIT were applied in 50 patients with newly diagnosed T2DM to normalize blood glucose for 2 weeks. Patients were then randomly assigned to receive either sequential therapy (metformin 0.5g bid plus pioglitazone 15mg bid) or lifestyle change alone for 3 months. OGTTs were performed with plasma glucose and insulin measured. Results: As showed in the figure, plasma glucose profiles and insulin response during OGTT were improved similarly by SIIT in both groups. At 3 months of follow-up, GHbA1c (6.2±0.6% vs. 6.5±0.4%, P=0.12) in the sequential treatment group was slightly lower though without statistical significance. In OGTT, blood glucose 30, 60 and 90 minutes was significantly lower in the sequential treatment group, which led to lower AUCglucose (1456.1±266.3 vs. 1644.8±184.5 mmol/L*min, P=0.03) and higher AUCinsulin to AUCglucose ratio (2.5±1.9 vs. 1±1.1, P=0.01). HOMA B, HOMA IR, Mesuda index and ISSI-2 were all similar between the two groups. Conclusion: Metformin plus pioglitazone as sequential therapy might improve glycemic control and β cell function after SIIT in newly diagnosed T2DM. Disclosure L. Liu: None. L. Hai: None. W. Ke: None. Y. Li: None. Funding National Key Research and Development Program of China (2018YFC1314102)

268-OR: Insulin Resistance in the Liver, but Not Muscle or Adipose, Is Essential for Remission from Newly Diagnosed Type 2 Diabetes by Short-Term Insulin Intensive Therapy

To clarify the effects of insulin resistance from different tissues on the remission from newly diagnosed type 2 diabetes (T2DM) following short-term insulin intensive therapy (SIIT). This study enrolled 37 healthy controls and 160 patients with newly diagnosed type 2 diabetes mellitus (n=160, HbA1c11±2.1%). They were randomly divided to four groups, CSII alone for 2 weeks, or combination with an insulin sensitizer (CSII + metformin or CSII + rosiglitazone), or an antioxidant (CSII + α-lipoic acid). HOMA-IR, Adipo-IR and intramyocellular lipid (IMCL), were compared before and after termination of CSII. After short-term intensive treatment, 77.5% patients achieved normal HOMA-IR but little change in the Adipo-IR. The IMCL were nearly normalized except for those in metformin group, impacted by the lower insulin dose. The improvement of HOMA-IR and FFA, not IMCL or Adipo-IR, statistically related to the percentage declines of FPG (r=0.317 and 0.275), while only the HOMR-IR was associated with ΔPPG% (r=0.284). And 40.6% patients achieved sustained normal HOMA-IR in the first 3 months after CSII and attained 50% remission rate at the 5-year, far beyond 8.9% in the other patients (HR = 2.82 95% CI is1.813-4.388, p&amp;lt;0.001). Besides, slight superiority has occurred with HOMA-IR, Adipo-IR and IMCL in the CSII+ rosiglitazone group. In brief, short-term CSII therapy, with or without insulin sensitizers, is extremely effective in improving insulin resistance, even normalizing the HOMA-IR and IMCL. Sustained normal hepatic insulin resistance is essential for remission from T2DM. Insulin reversed ectopic fat in muscle with dose effect and the combination therapy with rosiglitazone is superior. Disclosure X. Wan: None. Z. Huang: None. Y. Li: None.

110-LB: The Comparison of Glycemic Remission and Nonremission Patients after Sitagliptin Combination with Short-Term Intensive Insulin Therapy

Short-term intensive insulin therapy (IIT) could induce long-term glycemic remission. Sitagliptin increased endogenous GLP-1 content to achieved glucose control. The combination of sitagliptin with IIT might enhance the effect of improving alpha cell and beta cell function. 72 newly diagnosed type 2 diabetes patients with hypoglycemic therapy naïve were enrolled, with 47.6±9.0 years in age, with BMI of 25.2±2.7 kg/m2, FPG of 11.1±3.4mmol/L, and HbA1c of 10.6±2.3%. Continuous subcutaneous insulin infusion (CSII) were used as IIT, which were maintained for 14 days after patients achieving euglycemia. The treatment course of sitagliptin was 90 days. After cessation of sitagliptin, 45.8% of patients (33/72) achieved 1-year glycemic remission without any hypoglycemic medications. Compared the baseline of remission and non-remission groups, the baseline fasting plasma glucose (FPG) of remission group was lower (10.0±3.0 vs. 12.0±3.5mmol/L, p=0.012), but the levels of HbA1c, acute insulin response (AIR), HOMA-B and HOMA IR were not different between groups. After CSII cessation, FPG of remission group was still lower than non-remission group (5.8±0.8 vs. 6.9±1.1mmol/L, p&amp;lt;0.001), beta cell function and insulin resistance were improved significantly(HOMA-B: 62.96(25.94) vs. 40.67(41.79), p=0.026; HOMA-IR: 1.56(0.54) vs. 1.74(0.99), p=0.003). Analyzed insulin dosage of the 14th day after achieving glycemic target, basal insulin dosage was lower in remission group (9.6±5.6IU/d, vs. 14.4±7.1IU/d, p=0.002). In conclusion, lower levels of FPG at baseline and after IIT, less basal insulin usage during IIT, and better improvement of beta-cell function and insulin resistance suggested the possibility of glycemic remission after combination of IIT and sitagliptin therapy. Disclosure W. Ke: None. L. Liu: None. X. He: None. Y. Li: None.

1101-P: The Effect of Smoke on Short-Term Insulin Intensive Therapy for Male Patients with New Diagnosis Type 2 Diabetes

Our previous study showed that short-term intensive insulin therapies (SIIT) can improve insulin resistance by eliminating glucolipotoxicity and induce remission in newly diagnosed T2DM patients. It's interesting that smokers seem to recover worse than non-smokers. The purpose of this study is to clarify the effect of smoking on T2DM remission from SIIT. 103 male patients (aged 47±10 ys, HbA1C 11.2±2.1%, 59 smokers) after 2-week SIIT therapy were studied. At the 1-year follow-up, the remission rate was much lower in the smokers than non-smokers (36/59 vs. 35/44). Though their insulin secretion and HbA1C were similar at the end of therapy, the smokers have statistically higher TG and worse HOMA-IR. These results indicated that smoking might affect the remission rate mainly by the weaker improved metabolism of lipids. Disclosure X. Wan: None. Z. Huang: None. L. Liu: None. Y. Li: None.

2325-PUB: Estimation Formula for the Long-Term Glycemic Remission in Patients with Newly Diagnosed Type 2 Diabetes Receiving Short-Term Intensive Insulin Therapy

Aims: Half of the patients with newly diagnosed type 2 diabetes who received short-term continuous subcutaneous insulin infusion (CSII) were able to achieve a long-term drug-free glycemic remission. It is meaningful to develop an estimation formula to predict the glycemic remission. Methods: We collected data from three prospective trials conducted from 2002 to 2015. A 2∼3 weeks of CSII was provided for the patients with newly diagnosed diabetes to achieve and maintain normal glucose. The one-year drug-free remission rate was observed. Differences between patients with remission and those without remission were evaluated. Estimation formula was developed by using the logistic regression models. The receiver operating characteristic (ROC) curve was used to determine the sensitivity and specificity of the estimation formula at different score cutoffs. Results: Data of 244 patients were analyzed. After comparisons, age, gender, body mass index (BMI), high-density lipoprotein cholesterol (HDL-C), red cell distribution width (RDW), ratio of fasting plasma glucose to HbA1c (FPG/HbA1c) at baseline, FPG, postprandial plasma glucose (PPG) and the homeostasis model assessment of insulin resistance (HOMA-IR) after short-term CSII treatment were analyzed. We developed a formula as follows: R=11.936-1.626*HDL-1.56*FPG/HbA1c-0.14*RDW-0.496*FPG’ (FPG’ means FPG after short-term CSII). When R is greater than 0.5, it indicates a possible glycemic remission. The sensitivity, specificity, accuracy, positive predictive value and negative predictive value were 82.8%, 62.2%, 73.7%, 73.3% and 74.2%, respectively. Conclusions: We provide a prediction formula for long-term glycemic remission. For those who is predicted glycemic non-remission, sequential treatment after CSII secession may be beneficial for the long-term glucose control. Disclosure L. Xu: None. L. Liu: None. X. Wan: None. Z. Huang: None. Y. Li: None.

Effects of Short-term Intensive Insulin Therapy on Long-term Complications in Type 2 Diabetes

Effects of Short-term Intensive Insulin Therapy on Long-term Complications in Type 2 Diabetes

The effect of short-term intensive insulin therapy on circulating T cell subpopulations in patients with newly diagnosed type 2 diabetes mellitus

AimsTo evaluate the effect of short-term intensive insulin therapy on circulating T cell subpopulations in patients with newly diagnosed type 2 diabetes mellitus (T2DM). MethodsA total of 113 patients with T2DM and 28 normal subjects were enrolled. Demographic parameters and biochemical markers were collected at baseline, and flow cytometry was applied to determine the proportion of T cell subpopulations in participants. Then the patients underwent continuous subcutaneous insulin injection (CSII) treatment with euglycemia for 2 weeks, and the T cell subpopulations were measured again after CSII treatment. ResultsCompared with normal subjects, the proportion of Th1 cells and the ratio of Th1/Th2 increased, the proportion of Treg cells decreased in patients with T2DM (p < 0.05 for all). The ratio of Th1/Th2 was positively correlated with glycosylated hemoglobin A1c (HbA1c) and negatively correlated with high density lipoprotein cholesterol (HDL-C). Furthermore, there were negative associations between the proportion of Treg cells and fasting plasma glucose, HbA1c, triglyceride, low density lipoprotein cholesterol, and positive association between the proportion of Treg cells and HDL-C. After CSII treatment, the proportion of Th1 cells and the ratio of Th1/Th2 decreased (p < 0.05 for both), the proportion of Treg cells increased in patients with T2DM (p < 0.05). ConclusionsShort-term intensive insulin therapy could modulate circulating T cell subpopulations in patients with T2DM, which might alleviate inflammatory responses caused by hyperglycemia.This study was registered with ChiCTR-OPN-17010405.

Predicting and understanding the response to short-term intensive insulin therapy in people with early type 2 diabetes

ObjectiveShort-term intensive insulin therapy (IIT) early in the course of type 2 diabetes acutely improves beta-cell function with long-lasting effects on glycemic control. However, conventional measures cannot determine which patients are better suited for IIT, and little is known about the molecular mechanisms determining response. Therefore, this study aimed to develop a model that could accurately predict the response to IIT and provide insight into molecular mechanisms driving such response in humans. MethodsTwenty-four patients with early type 2 diabetes were assessed at baseline and four weeks after IIT, consisting of basal detemir and premeal insulin aspart. Twelve individuals had a beneficial beta-cell response to IIT (responders) and 12 did not (nonresponders). Beta-cell function was assessed by multiple methods, including Insulin Secretion-Sensitivity Index-2. MicroRNAs (miRNAs) were profiled in plasma samples before and after IIT. The response to IIT was modeled using a machine learning algorithm and potential miRNA-mediated regulatory mechanisms assessed by differential expression, correlation, and functional network analyses (FNA). ResultsBaseline levels of circulating miR-145-5p, miR-29c-3p, and HbA1c accurately (91.7%) predicted the response to IIT (OR = 121 [95% CI: 6.7, 2188.3]). Mechanistically, a previously described regulatory loop between miR-145-5p and miR-483-3p/5p, which controls TP53-mediated apoptosis, appears to also occur in our study population of humans with early type 2 diabetes. In addition, significant (fold change > 2, P < 0.05) longitudinal changes due to IIT in the circulating levels of miR-138-5p, miR-192-5p, miR-195-5p, miR-320b, and let-7a-5p further characterized the responder group and significantly correlated (|r| > 0.4, P < 0.05) with the changes in measures of beta-cell function and insulin sensitivity. FNA identified a network of coordinately/cooperatively regulated miRNA-targeted genes that potentially drives the IIT response through negative regulation of apoptotic processes that underlie beta cell dysfunction and concomitant positive regulation of proliferation. ConclusionsResponses to IIT in people with early type 2 diabetes are associated with characteristic miRNA signatures. This study represents a first step to identify potential responders to IIT (a current limitation in the field) and provides important insight into the pathophysiologic determinants of the reversibility of beta-cell dysfunction.ClinicalTrial.gov identifier: NCT01270789.

Fasting Plasma Glucose Indicates Reversibility of the Acute Insulin Response after Short-Term Intensive Insulin Therapy in Patients with Various Duration of Type 2 Diabetes.

Recovery of acute insulin response (AIR) is shown to be associated with long-term outcomes of patients with early type 2 diabetes treated with short-term intensive insulin therapy (SIIT). However, the complexity of measuring an AIR limits its utility in a real-world clinical setting. The aim of the study was to assess fasting indicators that may estimate recovery of the AIR after SIIT. We enrolled 62 patients with type 2 diabetes mellitus (T2DM) of varying disease duration who had poor glycemic control. Participants were treated with SIIT using insulin pumps to achieve near normoglycemia for 7 days. The AIR before and after the therapy were measured by intravenous glucose tolerance tests. After the therapy, AIR increased from −16.7 (−117.4, 52.4) pmol/L·min to 178.7 (31.8, 390.7) pmol/L·min (P < 0.001) while hyperglycemia was alleviated; this improvement was observed in all disease duration categories. AIR was almost absent when fasting plasma glucose (FPG) > 10 mmol/L, while both AIR (R = −0.53, P < 0.001) and its improvement from baseline (△AIR, R = −0.52, P < 0.001) were negatively associated with FPG after SIIT when FPG < 10 mmol/L. In multivariate analyses, FPG after SIIT and baseline fasting C peptide were independent indicators of both AIR after the therapy and ∆AIR; HDL-C after the therapy also predicted AIR after the therapy. We concluded that recovery of the AIR could be obtained in T2DM patients of varying disease duration by SIIT and it could be conveniently estimated using posttreatment fasting plasma glucose and other fasting indicators.

Fasting Plasma Glucose Indicates Reversibility of Acute Insulin Response after Short-Term Intensive Insulin Therapy in Patients with Type 2 Diabetes of Various Duration

Objective: In patients with early type 2 diabetes, short-term intensive insulin therapy (SIIT) reverses ß cell dysfunction measured by acute insulin response (AIR). However, the complicated procedures limit large-scale use of AIR. Also unclear is whether SIIT is effective in patients with longer duration. This study is performed to assess fasting indicators estimating recovery of AIR after SIIT for type 2 diabetes of various duration. Research Design and Methods: Patients with type 2 diabetes (n=62) who had poor glycemic control were enrolled. Near-nomoglycaemia was achieved and maintained for 7 days with insulin pump. AIR was measured by intravenous tolerance tests before and after SIIT. Results: Both fasting plasma glucose (FPG, 12.0 ± 3.0 vs. 7.71± 1.6 mmol/L, P&amp;lt;0.001) and 2h-postprandial glucose (17.3 ± 5.2 vs. 11.5 ± 3.7 mmol/L, P&amp;lt;0.001) decreased significantly after SIIT. AIR was improved from -16.7 (-117.4, 52.4) pmol/L·min to 178.7 (31.8, 390.7) pmol/L·min (P&amp;lt;0.001). Increase of AIR (?AIR)was observed in all disease duration categories (329.2±380.6, 312.8±347.8, and 123.8 ±186.3 pmol/L·min for patients with disease duration of &amp;lt;2 years, 2-6 years, and &amp;gt;6 years respectively, P=0.10). AIR was almost absent when FPG was over 10 mmol/L. However, when FPG after SIIT was less than 10 mmol/L it was negatively associated with AIR (R= -0.53, P&amp;lt;0.001) and ?AIR (R= -0.52, P&amp;lt;0.001). In multivariate analysis, AIR after the therapy and ?AIR could be estimated as follows: Estimated AIR (pmol/L·min) = 447.6 × baseline fasting C peptide (nmol/L) - 138.0× FPG after SIIT (mmol/L) + 925.2 (R2=0.42); estimated ?AIR (pmol/L·min) = 401.4 × baseline fasting C peptide (nmol/L) - 136.8 × FPG after SIIT (mmol/L) -357.6 × HDL-C after SIIT (mmol/L) + 1380.0(R2=0.50). Conclusions: Recovery of AIR could be obtained in patients with various duration of type 2 diabetes, and it could be estimated conveniently by FPG and other fasting indicators. Disclosure L. Liu: None. S. Yang: None. J. Liu: None. L. Hai: None. J. Liu: None. Y. Li: None.

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.