Insulin Glargine Treatment Research Articles

Frequency and Severity of Hypoglycemia Under Conditions of Increased Hypoglycemic Risk with Insulin Efsitora Alfa Versus Insulin Glargine Treatment in Participants with Type 2 Diabetes.

Insulin efsitora alfa (efsitora) is a basal insulin with a flat pharmacokinetic profile and long half-life, enabling weekly dosing. These attributes may provide stable glucose levels. This exploratory phase 1 study aimed to assess the hypoglycemic risk during experimental conditions that mimic situations encountered in daily life. This was a single-site, open-label, two-period, fixed-sequence study in participants with type 2 diabetes (T2D) previously treated with basal insulin. The incidence, duration, and nadir glucose of hypoglycemia were assessed after treatment with efsitora versus insulin glargine (glargine) during three provocation conditions: 24-h prolonged fasting, prolonged fasting with exercise, and double dosing of study insulin. The 54 enrolled adults (BMI 21.8-39.7kg/m2, HbA1c 6.5-9.4%) achieved stable fasting glucose before undergoing provocation. Most hypoglycemic events were level 1 (≥ 54 to < 70mg/dL) and resolved spontaneously or after oral glucose. The incidences of level 1 hypoglycemia for efsitora and glargine were not significantly different: for prolonged fasting, the incidences were 44.7 vs. 42.6% and the difference in proportion was 2.1% (95% CI: - 17.2, 21.4); for prolonged fasting with exercise, the corresponding values were 65.9 vs. 50.0% and 15.9% (- 3.0, 34.8); for double dosing, the corresponding values were 68.1 vs. 61.7% and 6.4% (- 12.8, 25.6). Level 2 hypoglycemia (< 54mg/dL) was infrequent during both treatments and all provocations. No severe hypoglycemia was observed. Mean nadir glucose (range 62.8-66.3mg/dL) and hypoglycemia duration (range 76.6-115.2min) were also similar for the two treatments, depending on the provocation. Overall, weekly efsitora did not increase the incidence, duration, or severity of hypoglycemia compared to daily glargine during provocation periods in patients with T2D. ClinicalTrials.gov identifier NCT04957914.

Assessment of circulating insulin using liquid chromatography-mass spectrometry during insulin glargine treatment in type 2 diabetes: Implications for estimating insulin sensitivity and β-cell function.

To determine the potential impact of the cross-reactivity of insulin glargine U-100 and its metabolites on insulin sensitivity and β-cell measures in people with type 2 diabetes. Using liquid chromatography-mass spectrometry (LC-MS), we measured concentrations of endogenous insulin, glargine and its two metabolites (M1 and M2) in fasting and oral glucose tolerance test-stimulated plasma from 19 participants and fasting specimens from another 97 participants 12 months after randomization to receive the insulin glargine. The last dose of glargine was administered before 10:00 PM the night before testing. Insulin was also measured on these specimens using an immunoassay. We used fasting specimens to calculate insulin sensitivity (Homeostatic Model Assessment 2 [HOMA2]-S%; QUICKI index; PREDIM index) and β-cell function (HOMA2-B%). Using specimens following glucose ingestion, we calculated insulin sensitivity (Matsuda ISI[comp] index) and β-cell response (insulinogenic index [IGI], and total incremental insulin response [iAUC] insulin/glucose). In plasma, glargine was metabolized to form the M1 and M2 metabolites that were quantifiable by LC-MS; however, the analogue and its metabolites cross-reacted by less than 100% in the insulin immunoassay. This incomplete cross-reactivity resulted in a systematic bias of fasting-based measures. By contrast, because M1 and M2 did not change following glucose ingestion, a bias was not observed for IGI and iAUC insulin/glucose. Despite glargine metabolites being detected in the insulin immunoassay, dynamic insulin responses can be used to assess β-cell responsiveness. However, given the cross-reactivity of the glargine metabolites in the insulin immunoassay, fasting-based measures of insulin sensitivity and β-cell function are biased.

Effects of insulin glargine at different times on organ oxidative stress in burned rats with delayed resuscitation

Objective: To examine the antioxidant effect of low dosage insulin glargine intervention at different time in rats with delayed resuscitation after burn, in order to acquire a better time of antioxidant intervention during delayed resuscitation following burn injury. Methods: With 10 rats in each group, 50 male SD rats were assigned to sham injury group, delayed resuscitation group, immediate post-burn insulin glargine treatment group (immediate treatment group), 2 hours post-burn insulin glargine treatment group(2 h treatment group), and 6 hours post-burn insulin treatment group(6 h treatment group) with random number table. Each treatment group received subcutaneous injections of insulin glargine (1.0 U·kg-1·d-1) immediately, two hours and six hours after the burn, while the delayed resuscitation group received the same amount of normal saline six hours after the burn. To imitate delayed fluid resuscitation, the delayed resuscitation group and each therapy group were intraperitoneally injected with normal saline (40 ml/kg) 6 hours after injury. No medicine and fluid resuscitation was administered to the sham injury group. Rats in the sham injury group had their abdominal aortic blood, hearts, and kidney tissues collected immediately after injury, while rats in the other groups had their blood and tissues collected 24 hours later. To analyze the timing of antioxidant intervention, the activities of CuZn-superoxide dismutase (CuZn-SOD), catalase (CAT), glutathione peroxidase (GSH-Px), total antioxidant capacity (T-AOC), xanthine oxidase (XOD) and myeloperoxidase (MPO) in blood glucose and myocardial and renal tissues were measured by spectrophotometry. Results: Compared with the sham group, blood glucose levels in the delayed resuscitation group increased [(10.72±0.80) vs (6.57±0.82)mmol/L,P<0.001], while in the myocardium and kidney, the activities of CuZn-SOD, CAT, GSH-Px and T-AOC decreased (all P<0.05) and the activities of XOD and MPO increased (all P<0.05). Compared with the delayed resuscitation group, blood glucose decreased in the immediate, 2 h, and 6 h treatment groups (all P<0.05). In the immediate and 2 h treatment group, the activities of CuZn-SOD, CAT, GSH-Px and T-AOC in the myocardium and kidney increased(all P<0.05). In the 6 h treatment group, only the activities of GSH-Px in myocardium, CAT and GSH-Px in kidney increased (all P<0.05). Compared with the delayed resuscitation group, in the immediate treatment group, the activities of MPO and XOD in myocardial tissue and XOD in renal tissue decreased (all P<0.05). The activities of MPO and XOD in myocardial and renal tissues of the 2 h treatment group both decreased (all P<0.05). In the 6 h treatment group, the activities of MPO in myocardial tissue and XOD in renal tissue both decreased (all P<0.05). Compared with the immediate treatment group, the activity of GSH-Px in myocardial tissue increased (P<0.05), and the activities of CuZn-SOD, CAT, GSH-Px and T-AOC in renal tissue increased in the 2 h treatment group (all P<0.05). The activities of CuZn-SOD, CAT, GSH-Px and T-AOC in myocardium of 6 h treatment group decreased (all P<0.05). Compared with the immediate treatment group, the activities of XOD and MPO in myocardial tissue and XOD in renal tissue of the 2 h treatment group had no significant difference (all P>0.05), but the activity of MPO in renal tissue decreased (P<0.05). The activities of XOD and MPO in myocardial tissue of the 6 h treatment group increased (all P<0.05). Compared with the 2 h treatment group, the activities of CuZn-SOD, CAT and GSH-Px and T-AOC in myocardium and kidney tissues in the 6 h treatment group decreased (all P<0.05), while the activities of XOD and MPO in myocardium and kidney tissues increased [myocardium: (374±8) vs (290±19) U/g, (0.021 8±0.003 9) vs (0.010 7±0.002 4) U/g, kidney: (157±6) vs (128±9) U/g, (0.026 8±0.004 3) vs (0.013 4±0.003 1) U/g, all P<0.05]. Conclusions: The timing of the intervention is related to the antioxidant effect of insulin glargine during delayed burn resuscitation. The intervention immediately and 2 hours after burn could have a better antioxidant effect compared to the intervention at 6 hours after burn.

Far-red light-activated human islet-like designer cells enable sustained fine-tuned secretion of insulin for glucose control

Diabetes affects almost half a billion people, and all individuals with type 1 diabetes (T1D) and a large portion of individuals with type 2 diabetes rely on self-administration of the peptide hormone insulin to achieve glucose control. However, this treatment modality has cumbersome storage and equipment requirements and is susceptible to fatal user error. Here, reasoning that a cell-based therapy could be coupled to an external induction circuit for blood glucose control, as a proof of concept we developed far-red light (FRL)-activated human islet-like designer (FAID) cells and demonstrated how FAID cell implants achieved safe and sustained glucose control in diabetic model mice. Specifically, by introducing a FRL-triggered optogenetic device into human mesenchymal stem cells (hMSCs), which we encapsulated in poly-(l-lysine)-alginate and implanted subcutaneously under the dorsum of T1D model mice, we achieved FRL illumination-inducible secretion of insulin that yielded improvements in glucose tolerance and sustained blood glucose control over traditional insulin glargine treatment. Moreover, the FAID cell implants attenuated both oxidative stress and development of multiple diabetes-related complications in kidneys. This optogenetics-controlled "living cell factory" platform could be harnessed to develop multiple synthetic designer therapeutic cells to achieve long-term yet precisely controllable drug delivery.

337-OR: Intensive Insulin Treatment in a Patient with Type A Insulin Resistance Syndrome Associated with a Novel Heterozygous Mutation of Trp1120Gly in the Insulin Receptor Gene

Background: Type A insulin resistance syndrome is a rare congenital severe insulin resistance syndrome resulting from mutations in the insulin receptor (IR) gene. We herein report a case treated with continuous subcutaneous insulin infusion (CSII) followed by insulin glargine and pioglitazone. Clinical Case: A 16 year-old girl with BMI of 19.1 kg/m2, complained of primary amenorrhea and elevated glucose for 2 years. She was diagnosed with precocious puberty at the age of 7, and treated with letrozole and triptorelin successively for 6.5 years. Hyperinsulinemia was noted but not ameliorated with metformin treatment. All the treatment was suspended for 2 years before referring to our department. Plasma glucose during OGTT showed fasting glucose was 8.4 mmol/L, and 2-hour post-load was 23.5 mmol/L. HbA1c was 10.8%. Markedly increased fasting (245μU/mL) and post-load serum insulin (628μU/mL) were observed. Next generation sequencing revealed a novel heterozygous missense mutation of Trp1120Gly in the IR gene. The patient received CSII with 0.8U/kg as the starting daily total, and titrated the dosage according to SMBG, followed by insulin glargine and pioglitazone treatment. Her glucose was well controlled, insulin glargine was down to 8U/d at the end of 3 months. Her HbA1c dropped to 7.9%, along with fasting plasma glucose (4.6mmol/L) and serum insulin (95.44μU/mL), while 2-hour postprandial glucose and insulin were still high. Her menarche occurred after one cycle of ethinylestradiol and cyproterone combo tablets. Conclusion: Improvement of glucose control with intensive insulin treatment was observed in a patient with type A insulin resistance syndrome. However, amelioration of insulin resistance was limited. No standard treatment was recommended for this rare syndrome. Thus, large-scale long-term studies assembled worldwide to optimize treatment strategy are needed. Disclosure Y. Yang: None. Z. Huang: None. G. Wei: None. Y. Li: None. W. Deng: None. Y. Li: None. Funding National Natural Science Foundation of China (82070918)

Association of Insulin Glargine Treatment with Bone Mineral Density in Patients with Type 2 Diabetes Mellitus.

PurposeTo assess the association of type 2 diabetes mellitus (T2DM) and insulin glargine treatment with bone mineral density (BMD) in Chinese people.MethodsThis retrospective study included 50 subjects with T2DM: 25 received oral glucose-lowering medication (ORL group), and 25 received oral glucose-lowering medication in combination with insulin glargine injection (CGI group). Thirty non-diabetic control subjects were also included. BMD was measured at lumbar vertebrae 1–4 (L1–L4), spine bone mineral density (sBMD) results summary (L2–L4), femoral neck and trochanter by dual-energy x-ray absorptiometry.ResultsCompared with non-diabetic controls, people with T2DM had significantly lower mean BMD at L2 (1.073±0.120 vs 0.984±0.158), L3 (1.094±0.129 vs 0.991±0.163) and L4 (1.089±0.130 vs 0.982±0.165) (all P<0.05), significantly lower levels of serum calcium (2.02±0.22 vs 2.27±0.17 mmol/L, P<0.05), PTH (24.19±9.71 vs 31.52±8.96 pg/mL, P<0.05), and higher serum phosphate levels (1.43±0.37 vs 1.20±0.15 mmol/L, P<0.05). The CGI group had higher L2, L3 and L4 BMD and sBMD (L2–L4) (P<0.05), higher serum calcium levels (2.19±0.11 vs 1.98±0.20 mmol/L, P<0.05) and lower serum phosphate levels (1.28±0.20 vs 1.58±0.43 mmol/L, P<0.05) versus the ORL group. BMD and serum calcium levels were associated with the application of insulin glargine.ConclusionThese results suggest that insulin glargine may affect bone metabolism in patients diagnosed with T2DM. The study has implications for the selection of hypoglycemic agents for diabetic patients at risk of osteoporosis.

Treatment satisfaction, safety, and effectiveness of biosimilar insulin glargine is comparable in patients with type 2 diabetes mellitus after switching from insulin glargine or insulin degludec: a post-marketing safety study

Objective To evaluate insulin treatment satisfaction, safety, and effectiveness of biosimilar insulin glargine (GLY) in real-world clinical practice for Japanese patients with type 2 diabetes mellitus (T2DM) who switched from originator insulin glargine (100 U/mL) or insulin degludec treatment to GLY treatment. Methods The Insulin Treatment Satisfaction Questionnaire (ITSQ) was used to assess treatment satisfaction in a subgroup analysis of a post-marketing safety study. Hypoglycemia incidence rates and blood glucose control are also reported during the 12-month observation period for GLY-switched patients. Results Of 1104 patients with T2DM enrolled to participate, 565 patients switched from either insulin glargine U100/mL (n = 470) or insulin degludec (n = 95) to GLY. The mean total change from baseline to 3 months for total ITSQ score was 1.35 (95% confidence interval [CI] − 0.13 to 2.83, p = .073) for patients who switched from insulin glargine and 2.63 (95% CI −1.43 to 6.70, p = .195) for patients who switched from insulin degludec to GLY treatment. The mean change from baseline to 12 months in hypoglycemia events reported per month was −0.04% (95% CI −0.12 to 0.03, p = .236) for patients who switched from insulin glargine and no change for patients who switched from insulin degludec (0.00, 95% CI −0.20 to 0.20, p = 1.000). Non-significant mean changes from baseline to 12 months were observed for hemoglobin A1c and fasting plasma glucose in GLY-switched patients. Conclusions Treatment satisfaction does not change significantly in Japanese patients with T2DM who switch to GLY from the reference product or from insulin degludec. Safety and effectiveness over a 12-month period were similar in GLY-treated patients who switched from either insulin glargine or insulin degludec. ClinicalTrials.gov Not applicable.

Exenatide and Renal Outcomes in Patients with Type 2 Diabetes and Diabetic Kidney Disease

Background: Cardiovascular outcomes in clinical trials with type 2 diabetes mellitus (T2DM) patients have shown that glucagon-like peptide-1 receptor agonist can have a beneficial effect on the kidney. This trial aimed to assess the effects of exenatide on renal outcomes in patients with T2DM and diabetic kidney disease (DKD). Methods: We performed a randomized parallel study encompassing 4 general hospitals. T2DM patients with an estimated glomerular filtration rate (eGFR) ≥30 mL/min/1.73 m² and macroalbuminuria, defined as 24-h urinary albumin excretion rate (UAER) >0.3 g/24 h were randomized 1:1 to receive exenatide twice daily plus insulin glargine (intervention group) or insulin lispro plus glargine (control group) for 24 weeks. The primary outcome was the UAER percentage change from the baseline after 24 weeks of intervention. The rates of hypoglycemia, adverse events (AEs), and change in eGFR during the follow-up were measured as safety outcomes. Results: Between March 2016 and April 2019, 92 patients were randomized and took at least 1 dose of the study drug. The mean age of the participants was 56 years. At baseline, the median UAER was 1,512.0 mg/24 h and mean eGFR was 70.4 mL/min/1.73 m². After 24 weeks of treatment, the UAER percentage change was significantly lower in the intervention group than in the control group (p = 0.0255). Moreover, the body weight declined by 1.3 kg in the intervention group (the difference between the 2 groups was 2.7 kg, p = 0.0001). Compared to the control group, a lower frequency of hypoglycemia and more gastrointestinal AEs were observed in the intervention group. Conclusion: Exenatide plus insulin glargine treatment for 24 weeks resulted in a reduction of albuminuria in T2DM patients with DKD.

Efficacy of exenatide and insulin glargine on nonalcoholic fatty liver disease in patients with type 2 diabetes.

The aim of this study was to investigate the efficacy of exenatide and insulin glargine in patients with newly diagnosed type 2 diabetes mellitus (T2DM) and nonalcoholic fatty liver disease (NAFLD). We performed a 24-week randomized controlled multicentre clinical trial. Seventy-six patients were randomly assigned 1:1 to receive exenatide or insulin glargine treatment. The endpoints included changes in liver fat content (LFC), visceral adipose tissue (VAT), and subcutaneous adipose tissue (SAT) measured by magnetic resonance spectroscopy, blood glucose, liver enzymes, lipid profile, body weight, and Fibrosis-4 index (FIB-4). LFC, VAT, SAT, and FIB-4 were significantly reduced after exenatide treatment (ΔLFC, -17.55 ± 12.93%; ΔVAT, -43.57 ± 68.20 cm2 ; ΔSAT, -28.44 ± 51.48 cm2 ; ΔFIB-4, -0.10 ± 0.26; all P < .05). In comparison, only LFC (ΔLFC, -10.49 ± 11.38%; P < .05), and not VAT, SAT, or FIB-4 index (all P > .05), was reduced after insulin glargine treatment. Moreover, exenatide treatment resulted in greater reductions in alanine transaminase (ALT), aspartate transaminase (AST), and gamma glutamyl transpeptidase (GGT) than insulin glargine (P < 0.05). The body weight, waist circumference, postprandial plasma glucose, and low-density lipoprotein cholesterol (LDL-C) in the exenatide group also presented greater reductions than the insulin glargine group (P < .05). The proportion of adverse events were comparable between the two groups. Both exenatide and insulin glargine reduced LFC in patients with drug-naive T2DM and NAFLD; however, exenatide showed greater reductions in body weight, visceral fat area, liver enzymes, FIB-4, postprandial plasma glucose, and LDL-C.

The Role of Insulin Glargine and Human Insulin in the Regulation of Thyroid Proliferation Through Mitogenic Signaling.

Our aim was to investigate whether human insulin (HI) or insulin glargine treatment could promote the proliferation of thyroid cells and determine the association between type 2 diabetes and thyroid disease. Rats were treated with different doses of HI and insulin glargine. Plasma glucose and the phosphorylation levels of the insulin receptor (IR), insulin-like growth factor 1 receptor (IGF-1R), protein kinase B (Akt), and extracellular signal-regulated kinase 1/2 (ERK1/2) were measured. A total of 105 rats were randomly assigned to three groups as follows: control group, HI group, and glargine group. Both drugs promoted the phosphorylation of IR, Akt, and ERK1/2 in a dose-dependent manner (p < 0.05), and the effect of glargine persisted for longer period. Treatment with ultra-therapeutic doses of HI or glargine (p < 0.05) increased the expression of Ki-67 in thyroid cells. The results demonstrated that therapeutic doses of glargine have a longer-lasting hypoglycemic control than HI. Based on the results, HI or glargine did not stimulate thyroid cell proliferation at therapeutic doses, but high doses did.

1113-P: Six Months Comparative Evaluation of Efficacy and Safety of Wockhardt’s Biosimilar Insulin Glargine (Glaritus®) with Reference Insulin Glargine (Lantus®) in Type 2 Diabetes Mellitus in India

Introduction: Glaritus® has been found comparable to reference insulin glargine in physico-chemical characteristics, pre-clinical studies and treatment of type 1 diabetes mellitus (DM). Objective: To compare the immunogenicity, HbA1c reduction and safety of Glaritus® to Lantus® over 6 months treatment in type 2 DM. Methods: This is an ongoing prospective, open-label, randomized, multicentre Phase IV study. Total 180 patients of type 2 DM, who were inadequately controlled on oral antidiabetic drugs, were randomized in 1:1 ratio to Glaritus® and reference insulin glargine treatment. Analysis of 144 patients, who completed 6 month comparative phase, is presented herewith. Results: Baseline characteristics of both the treatment arms were comparable in terms of age, gender distribution and body mass index. Over the treatment period, mean anti-insulin antibody titre increased marginally, mean HbA1c reduced significantly and substantial percentage of patients attained HbA1c value &amp;lt;7% within each treatment arm. However, both arms were comparable (P&amp;gt;0.05) in terms of these changes. Both glargine treatments were found to be safe in terms of hypoglycemic events. Conclusion: Glaritus® was found to be equally effective and safe in patients with inadequately controlled T2DM compared to reference insulin glargine. Disclosure S. Sharma: None. A. Ajmani: None. P. Khosla: None. P. Mukhopadhayay: None. G. Bhatia: None. P. Kg: None. G. Chhaya: None. P. Supe: None. V. Pavithran: None. H. Bora: None. A. Shah: Employee; Self; Wockhardt. S.A. Ingole: Employee; Self; Wockhardt. R. Jain: Employee; Self; Wockhardt. Funding Wockhardt Pharmaceuticals Ltd.

Predictive factors associated with three years of response to HbA1c goals with exenatide QW or insulin glargine: Post-hoc analysis of the DURATION-3 study.

This post-hoc analysis of the DURATION-3 study aimed to identify factors associated with sustained glycaemic response with exenatide once weekly (QW) or insulin glargine (IG) among patients with type 2 diabetes. Response was defined as achieving treatment target of HbA1c <7.0% (<53 mmol/mol) at Week 26; sustained responders maintained the treatment target for ≥80% of remaining visits, including one during the final 6 months. Of 467 patients, 287 (61.5%) completed 156 weeks of treatment. At Week 26, 175 patients (61.0%) (exenatide QW, n = 95; IG, n = 80) achieved an HbA1c response. At Week 156, 84 of 175 responders (48.0%) had sustained response, with more sustained responders with exenatide QW (22.7% vs 13.9% with IG; P < 0.03). Logistic regression identified three predictors of sustained response: (a) exenatide QW vs IG treatment (odds ratio, 2.584 [95% confidence interval, 1.288-5.187]; P = 0.0075), (b) lower HbA1c at Week 26 (0.139 [0.053-0.366]; P < 0.0001), and (c) lower fasting serum glucose at Week 26 (0.693 [0.541-0.888]; P = 0.0037). A regression model was used to estimate the likelihood of sustained response with either treatment. This analysis provides a helpful tool for predicting sustained response with exenatide QW or IG.

Long-term insulin treatment leads to a change in myosin heavy chain fiber distribution in OLETF rat skeletal muscle.

The objective of this study was to investigate molecular and physiological changes in response to long-term insulin glargine treatment in the skeletal muscle of OLETF rats. Male Otsuka Long-Evans Tokushima Fatty (OLETF) and Long-Evans Tokushima Otsuka (LETO) rats aged 24 weeks were randomly allocated to either treatment with insulin for 24 weeks or no treatment, resulting in three groups. Insulin glargine treatment in OLETF rats (OLETF-G) for 24 weeks resulted in changes in blood glucose levels in intraperitoneal glucose tolerance tests compared with age-matched, untreated OLETF rats (OLETF-C), and the area under the curve was significantly decreased for OLETF-G rats compared with OLETF-C rats (P < 0.05). The protein levels of MHC isoforms were altered in gastrocnemius muscle of OLETF rats, and the proportions of myosin heavy chain type I and II fibers were lower and higher, respectively, in OLETF-G compared with OLETF-C rats. Activation of myokines (IL-6, IL-15, FNDC5, and myostatin) in gastrocnemius muscle was significantly inhibited in OLETF-G compared with OLETF-C rats ( P < 0.05). MyoD and myogenin levels were decreased, while IGF-I and GLUT4 levels were increased, in the skeletal muscle of OLETF-G rats ( P < 0.05). Insulin glargine treatment significantly increased the phosphorylation levels of AMPK, SIRT1, and PGC-1α. Together, our results suggested that changes in the distribution of fiber types by insulin glargine could result in downregulation of myokines and muscle regulatory proteins. The effects were likely associated with activation of the AMPK/SIRT1/PGC-1α signaling pathway. Changes in these proteins may at least partly explain the effect of insulin in skeletal muscle of diabetes mellitus.

Long-Term Insulin Treatment Alters Muscle-Related Protein in OLETF Rat Skeletal Muscle

Purpose: The objective of this study was to investigate molecular and physiological changes in response to long-term insulin glargine treatment in the skeletal muscle of Otsuka Long-Evans Tokushima Fatty (OLETF) rats. Methods: Protein changes in the skeletal muscle of type 2 diabetic rats was detected by Western blot analysis, and muscle fiber type composition was assessed by real-time PCR. Results: Insulin glargine (1 U/kg) treatment in OLETF rats (OLETF-G) for 24 weeks were changed in blood glucose levels in intraperitoneal glucose tolerance tests compared with age-matched, untreated OLETF rats (OLETF-C), and the area under the curve was significantly decreased for OLETF-G rats compared with OLETF-C rats (P &amp;lt; 0.05). The protein levels of myosin heavy chain (MHC) isoforms were altered in gastrocnemius muscle of OLETF rats, and the proportions of MHC type I and II fibers were lower and higher, respectively, in OLETF-G compared with OLETF-C rats. Activation of myokines (interleukin [IL]-6, IL-15, fibronectin type III domain containing 5 [FNDC5]/irisin, and myostatin) in gastrocnemius muscle was significantly inhibited in OLETF-G compared with OLETF-C rats (P &amp;lt; 0.05). Moreover, myogenin determination gene D and myogenin levels were decreased, while insulin-like growth factor-I levels were increased, in the skeletal muscle of OLETF-G rats (P &amp;lt; 0.05). Insulin glargine treatment significantly increased the phosphorylation levels of 5’-AMP-activated protein kinase, sirtuin 1, and peroxisome proliferator-activated receptor γ coactivator 1α. Conclusions: Our results suggest that long-term insulin glargine treatment can effectively alter protein expression in the gastrocnemius muscle of OLETF rats. Disclosure H. Kwon: None. O. Hong: None. H. Kwon: None. Y. Kang: None. S. Lee: None. S. Kim: None. S. Yoo: None.

Difference in Hepatic Steatosis and Pancreatic Beta-Cell Mass between Dapagliflozin and Insulin Glargine Treatment at Comparable Levels of Glycemic Control

Background: Although several studies have shown that SGLT2 inhibitors exert protective effects on pancreatic beta cells and hepatic steatosis, the mechanism remains unknown. Therefore, we compared the glucose-lowering effect of the SGLT2 inhibitor dapagliflozin (dapa) on pancreatic beta cell mass and hepatic steatosis with those of insulin glargine. Methods: Six-week-old db/db mice were assigned to one of four groups: untreated (Placebo), treated with dapa (Dapa), treated with insulin glargine (Gla), or treated with both dapa and insulin glargine (Dapa+Gla). After 8 weeks of treatment, we determined blood glucose levels, beta cell mass and liver triglyceride (TG) content. Results: Fed blood glucose levels were significantly lower in the treated groups compared with the Placebo group (Placebo 904.2 ± 35.6 mg/dL, Dapa 425.0 ± 26.7 mg/dL, Gla 406.1 ± 25.8 mg/dL, Dapa+Gla 347.3 ± 24.0 mg/dL). Immunohistochemical analysis revealed that pancreatic beta cell mass was significantly increased in the Dapa and Dapa+Gla groups, but not the Gla group, compared with the Placebo group (Placebo 2.25 ± 0.45 mg, Dapa 5.01 ± 0.52 mg, Gla 3.79 ± 0.32 mg, Dapa+Gla 5.19 ± 0.56 mg). Liver TG content was significantly increased in the Gla group compared with the others (Placebo 24.1 ± 5.7 mg, Dapa 30.6 ± 6.4 mg, Gla 128 ± 25 mg, and Dapa+Gla 54.4 ± 7.1 mg per gram liver). Microarray analysis revealed genes involved in hepatic steatosis such as Cidec and Pparg were significantly upregulated in the Gla group compared with the Placebo group. As for hepatic fatty acid composition, concentrations of C16:0 and C18:1n-9 were significantly increased in the Gla group compared with the Placebo group, while C18:0 was not significantly different between groups. There was no difference in safety including mortality. Conclusion: Beta cell mass was maintained, and hepatic steatosis was not induced, after 8 weeks of treatment with dapa, but with insulin glargine, in db/db mice. Disclosure K. Omori: None. A. Nakamura: Research Support; Self; Sanofi, Mitsubishi Tanabe Pharma Corporation, MSD K.K., Novo Nordisk Inc., Novartis Pharma K.K., AstraZeneca, Ono Pharmaceutical Co., Ltd., Taisho Pharmaceutical Co., Ltd. H. Miyoshi: Speaker's Bureau; Self; Astellas Pharma US, Inc., AstraZeneca, Sumitomo Dainippon Pharma Co., Ltd., Eli Lilly and Company, Mitsubishi Tanabe Pharma Corporation, Kissei Pharmaceutical Co., Ltd., Novo Nordisk A/S, Sanofi. Research Support; Self; Astellas Pharma US, Inc., AstraZeneca, Eli Lilly and Company, Mitsubishi Tanabe Pharma Corporation. Speaker's Bureau; Self; MSD K.K.. K. Takahashi: None. N. Kitao: None. Y. Terauchi: Research Support; Self; MSD K.K.. Speaker's Bureau; Self; MSD K.K.. Advisory Panel; Self; MSD K.K.. Research Support; Self; Ono Pharmaceutical Co., Ltd.. Speaker's Bureau; Self; Ono Pharmaceutical Co., Ltd.. Research Support; Self; Novartis Pharma K.K., Boehringer Ingelheim GmbH. Speaker's Bureau; Self; Boehringer Ingelheim GmbH. Advisory Panel; Self; Boehringer Ingelheim GmbH. Research Support; Self; Mitsubishi Tanabe Pharma Corporation. Speaker's Bureau; Self; Mitsubishi Tanabe Pharma Corporation. Advisory Panel; Self; Mitsubishi Tanabe Pharma Corporation. Research Support; Self; Daiichi Sankyo Company, Limited. Speaker's Bureau; Self; Daiichi Sankyo Company, Limited. Advisory Panel; Self; Daiichi Sankyo Company, Limited. Research Support; Self; Sanwa Kagaku Kenkyusho Co., Ltd.. Speaker's Bureau; Self; Sanwa Kagaku Kenkyusho Co., Ltd.. Research Support; Self; Novo Nordisk Inc.. Speaker's Bureau; Self; Novo Nordisk Inc.. Advisory Panel; Self; Novo Nordisk Inc.. Research Support; Self; Eli Lilly and Company. Speaker's Bureau; Self; Eli Lilly and Company. Advisory Panel; Self; Eli Lilly and Company. Research Support; Self; Sanofi. Speaker's Bureau; Self; Sanofi. Advisory Panel; Self; Sanofi. Research Support; Self; Sumitomo Dainippon Pharma Co., Ltd.. Speaker's Bureau; Self; Sumitomo Dainippon Pharma Co., Ltd.. Research Support; Self; Shionogi &amp; Co., Ltd.. Speaker's Bureau; Self; Shionogi &amp; Co., Ltd., Bayer Yakuhin, Ltd., Astellas Pharma US, Inc., AstraZeneca. Advisory Panel; Self; AstraZeneca, Teijin Pharma Limited. T. Atsumi: Speaker's Bureau; Self; Mitsubishi Tanabe Pharma Corporation, Chugai Pharmaceutical Co., Ltd., Astellas Pharma US, Inc., Takeda Pharmaceuticals U.S.A., Inc., Pfizer Inc., AbbVie Inc.. Research Support; Self; Astellas Pharma US, Inc., Mitsubishi Tanabe Pharma Corporation, Takeda Pharmaceuticals U.S.A., Inc., Chugai Pharmaceutical Co., Ltd., Daiichi Sankyo Company, Limited, Otsuka Holdings Co., Ltd..

Comparison of Glycemic Variability in Chinese T2DM Patients Treated with Exenatide or Insulin Glargine: A Randomized Controlled Trial.

IntroductionIncreasing the frequency of blood glucose monitoring aids the evaluation of glycemic variability and blood glucose control by antidiabetic drugs. It remains unclear, however, whether GLP-1 receptor agonists or basal insulin has a better effect on glycemic variability in type 2 diabetes mellitus (T2DM) patients who are inadequately controlled by metformin. We used a continuous glucose monitoring system (CGMS) to compare patients on a GLP-1 receptor agonist with patients on basal insulin in terms of glycemic variability.MethodsThis prospective randomized study assigned T2DM patients treated with metformin (N = 39) to either exenatide treatment or insulin glargine treatment for 16 weeks. Glycemic variability was assessed using a CGMS; hemoglobin A1c (HbA1c), β-cell function, weight, body mass index (BMI), and waist circumference were also evaluated.ResultsMean blood glucose level, continuous overlapping net glycemic action, mean amplitude of glycemic excursions, percentage of the time that the blood glucose value was > 10.0 mmol/L, and highest blood glucose level (P < 0.01–0.05) significantly decreased in both groups. Standard deviation of the mean glucose value, largest amplitude of glycemic excursions, and waist circumference significantly decreased for those treated with exenatide (P < 0.05), while no changes were observed with insulin glargine treatment. Percentage of the time that the blood glucose value was > 7.8 mmol/L decreased after insulin glargine use (P < 0.05) but not with the exenatide intervention. Similar decreases in fasting blood glucose and HbA1c and increases in the 1/homeostasis model assessment of insulin resistance, disposition index 30, and disposition index 120 were observed in both groups (P < 0.01–0.05). Reductions in weight and BMI were greater with exenatide than with insulin glargine treatment (P < 0.05).ConclusionsIn overweight and obese patients with T2DM inadequately controlled by metformin, exenatide and insulin glargine have similar efficacies in terms of glycemic variability, HbA1c alleviation, and β-cell function, but exenatide has a greater effect on body weight and BMI.

Insulin glargine affects the expression of Igf-1r, Insr, and Igf-1 genes in colon and liver of diabetic rats.

Objective(s):The mitogenic effect of the analogous insulin glargine is currently under debate since several clinical studies have raised the possibility that insulin glargine treatment has a carcinogenic potential in different tissues. This study aimed to evaluate the Igf-1r, Insr, and Igf-1 gene expression in colon and liver of streptozotocin-induced diabetic rats in response to insulin glargine, neutral protamine Hagedorn (NPH) insulin, and metformin treatments.Materials and Methods:Male Wistar rats were induced during one week with streptozotocin to develop Type 2 Diabetes (T2D) and then randomly distributed into four groups. T2D rats included in the first group received insulin glargine, the second group received NPH insulin, the third group received metformin; finally, untreated T2D rats were included as the control group. All groups were treated for seven days; after the treatment, tissue samples of liver and colon were obtained. Quantitative PCR (qPCR) was performed to analyze the Igf-1r, Insr and Igf-1 gene expression in each tissue sample.Results:The liver tissue showed overexpression of the Insr and Igf-1r genes (P>0.001) in rats treated with insulin glargine in comparison with the control group. Similar results were observed for the Insr gene (P>0.011) in colonic tissue of rats treated with insulin glargine.Conclusion:These observations demonstrate that insulin glargine promote an excess of insulin and IGF-1 receptors in STZ-induced diabetic rats, which could overstimulate the mitogenic signaling pathways.

Does hypoglycaemia affect the improvement in QoL after the transition to insulin in people with type 2 diabetes?

PurposeQuality of Life (QoL) of insulin-naïve people with type 2 diabetes mellitus (T2DM) improves after transition to insulin. Little is known about the role of hypoglycaemia in this context. Secondary analyses of the Study of the Psychological Impact in Real care of Initiating insulin glargine Treatment (SPIRIT) aimed to investigate the relationship between hypoglycaemia and QoL when transitioning to insulin.MethodsInsulin-naïve Dutch people with T2DM in suboptimal glycaemic control (HbA1c >53 mmol/mol; 7.0%) on maximum dose of oral glucose-lowering medications were included from 363 primary care practices (n = 911). Participants started insulin glargine and completed QoL-questionnaires (WHO-5 Well-being Index (WHO-5; emotional well-being), Hypoglycaemia Fear Survey-worry scale (HFS-w; hypoglycaemia fear) and Diabetes Symptom Checklist-revised (DSC-r; diabetes symptom distress) at baseline, 3 and 6 months follow-up. Linear GEE analyses were used to investigate the association between symptomatic, nocturnal, severe hypoglycaemia (number of episodes during 3 months prior to visit) and QoL over time.Results52.5% men participated, mean age 62.2 years (SD ± 10.92), and median HbA1c 67 mmol/mol (range 61–77) (8.3%). More symptomatic hypoglycaemic episodes were associated with higher HFS-w and DSC-r scores (P < 0.01). Experiencing multiple nocturnal or severe episodes was related to higher symptom distress as well, when compared to no episodes. These associations did not change significantly over time.ConclusionsHypoglycaemia is associated with lower QoL in terms of hypoglycaemia fear and diabetes symptom distress. The transition to insulin does not affect this relationship, suggesting hypoglycaemia in itself has a detrimental effect on diabetes-related QoL independent of treatment regimen.

Observational Study of the Use of Insulin Glargine as Basal Therapy in Patients With Type 2 Diabetes Mellitus in Morocco

Background: The aim of the study was to assess the real-life efficacy and safety of insulin glargine (Lantus ® , Sanofi) as a basal regimen in patients with type 2 diabetes mellitus (T2DM) who are poorly controlled with oral antidiabetic drugs (OADs) and/or other insulins. Methods: This observational, multicenter study was carried out in Morocco in 2011 and included 497 adult patients with T2DM and a baseline glycated hemoglobin (HbA1c) between 7.5% and 10.5% and for whom a basal regimen with insulin glargine was initiated. Two follow-up visits were scheduled at 12 and 26 weeks after starting treatment. The primary outcome target was HbA1c < 7%. Safety was assessed by the frequency of hypoglycemic episodes. Results: The target HbA1c level of < 7% was reached by 11.5% of patients after 3 months of insulin glargine treatment and 32% after 6 months. Mean HbA1c decreased significantly from 9.37±1.14% at baseline to 7.43±0.87% at 6 months (P < 0.001). Mean fasting blood glucose also decreased significantly from 237.5 ± 66.9 mg/dL at baseline to 129.5 ± 35.1 mg/dL at 6 months (P < 0.001). Approximately 12% of patients reported at least one hypoglycemic episode. No adverse event other than hypoglycemia was reported. Conclusions: This study shows that in a real-life setting, a basal regimen with insulin glargine significantly improves glycemic control in patients with T2DM who are inadequately controlled with OADs or other insulin regimens, with an acceptable hypoglycemia profile. J Endocrinol Metab. 2015;5(6):333-336 doi: http://dx.doi.org/10.14740/jem315w

Fasting Versus Postprandial Hyperglycemia as a Treatment Target to Lower Elevated Hemoglobin A1C

Postprandial hyperglycemia (PPHG) may need addressing when glycemic control cannot be maintained in patients with type 2 diabetes mellitus. We investigated whether glycated hemoglobin A1c (A1c) levels ≥7.0% can indicate postprandial defects warranting prandial therapy after optimized basal insulin therapy. From 6 clinical trials of insulin glargine treatment, data were pooled from 496 patients with A1c ≥7.0% after 24 weeks. Patient characteristics and clinical outcomes were summarized according to fasting plasma glucose (FPG) target achievement (<130 mg/dL), postprandial blood glucose (PPBG) levels, and PPBG increments (ΔPPBG). Basal and postprandial contributions to hyperglycemia were determined. After 24 weeks of insulin glargine titration, A1c change from baseline was greater in patients with FPG <130 mg/dL versus ≥130 mg/dL (-1.35% versus -1.11%, respectively; P = .0275), but with increased confirmed hypoglycemia rates (blood glucose <70 mg/dL; 4.06 events/patient-year versus 3.31 events/patient-year; P = .0170). However, increased severe hypoglycemia rates were observed in patients with FPG ≥130 mg/dL. At week 24, postprandial contributions to hyperglycemia increased (>60% regardless of PPBG). Patients with high FPG had lower, but substantial, relative postprandial contributions versus patients achieving FPG target. A similar pattern was observed according to whether patients had a ΔPPBG ≥50 mg/dL after any meal. After optimized basal insulin therapy, elevated A1c is the most effective indicator of residual PPHG, regardless of existent FPG or PPBG. When confronted with an uncontrolled A1c after reasonable titration of basal insulin, clinicians should be aware of probable postprandial contributions to hyperglycemia and consider prandial therapy.