The triggering pathway, the metabolic amplifying pathway, and cellular transduction in regulation of glucose-dependent biphasic insulin secretion.

Introduction: Insulin secretion is a highly regulated process critical for maintaining glucose homeostasis. This abstract explores the intricate interplay between three essential pathways: The Triggering Pathway, The Metabolic Amplifying Pathway, and Cellular Transduction, in orchestrating glucose-dependent biphasic insulin secretion.Mechanism: During the triggering pathway, glucose metabolism in pancreatic beta-cells leads to ATP production, closing ATP-sensitive potassium channels and initiating insulin exocytosis. The metabolic amplifying pathway enhances insulin secretion via key metabolites like NADH and glutamate, enhancing calcium influx and insulin granule exocytosis. Additionally, the cellular transduction pathway involves G-protein coupled receptors and cyclic AMP, modulating insulin secretion.Result and Conclusion: These interconnected pathways ensure a dynamic insulin response to fluctuating glucose levels, with the initial rapid phase and the subsequent sustained phase. Understanding these pathways' complexities provides crucial insights into insulin dysregulation in diabetes and highlights potential therapeutic targets to restore glucose-dependent insulin secretion.

Real-world study of the concomitant use of biphasic insulin aspart 30/70 with GLP-1 receptor agonist versus first-generation basal insulin with GLP-1 receptor agonist in type 2 diabetes.

AIMS: Combining insulin with a glucagon-like peptide-1 receptor agonist (GLP-1RA) to treat type 2 diabetes (T2D) is common. While many studies have investigated concomitant therapy with basal insulin+GLP-1RA, few have reported on premixed insulin+GLP-1RA. We aimed to address this gap using data from the Clinical Practice Research Datalink Aurum database in England. METHODS: This retrospective cohort study with propensity score matching assessed glycaemic levels and other clinical outcomes in people with T2D, comparing biphasic insulin aspart 30/70 (BIAsp 30) + GLP-1RA with basal insulin (insulin detemir/glargine U100) + GLP-1RA (from 2006 to 2021). RESULTS: In total, 4770 eligible people were identified; 1511 had a BIAsp 30 + GLP-1RA regimen and were propensity score-matched to an equal number receiving basal+GLP-1RA. There was no significant difference in glycated haemoglobin (HbA1c) reduction between cohorts at 6 months (p = 0.15), with a decrease of -1.07 (95% CI: -1.16; -0.98) %-points (-11.7 mmol/mol [95% CI: -12.7; -10.7]) in the BIAsp 30 + GLP-1RA cohort, versus -0.97 (95% CI: -1.07; -0.88) %-points (-10.6 mmol/mol [95% CI: -11.7; -9.6]) in the basal+GLP-1RA cohort. Body mass index (BMI) decreased by -0.35 kg/m2 (95% CI: -0.52;-0.18) at 6 months with BIAsp 30 + GLP-1RA, versus -0.72 kg/m2 (95% CI: -0.90;-0.54) with basal+GLP-1RA (p = 0.003). BMI was influenced by the initiation sequence of GLP-1RA in relation to insulin (p < 0.0001). Hypoglycaemia rates were low and not significantly different between cohorts. CONCLUSIONS: Combining BIAsp 30 + GLP-1RA provides glycaemic control with no significant difference to that of propensity score-matched people receiving basal insulin+GLP-1RA, with no increase in hypoglycaemia risk or weight gain.

Bioequivalence of Reference and Biosimilar Preparations of Premixed Biphasic Insulin Aspart: A Comparative Clamp Study.

Biphasic insulin aspart 30 is a premixed formulation containing a soluble fraction of insulin aspart (30%) and a protamine-crystallized fraction (70%) that was developed to combine the rapid-acting and prolonged advantages of commercially available insulins. The aim of this bioequivalence study was to compare the pharmacokinetics (PKs) of GP-bi-asp and Novo-bi-asp, and evaluate the pharmacodynamic (PD) properties as well as the safety of these drugs in the hyperinsulinemic euglycemic clamp (HEC) procedure. This was a phase 1, randomized, double-blind, 2-sequence, 2-period crossover study. Thirty-four male volunteers who met the inclusion criteria underwent the HEC procedure following a single subcutaneous injection of 0.4 IU/kg of either GP-bi-asp or Novo-bi-asp in the abdomen. After the treatment, the subjects' plasma glucose levels were monitored for 24 hours and the glucose infusion rate (GIR) was adjusted to maintain the target blood glucose level. The PD parameters were calculated using GIR values. Insulin aspart concentrations were measured in blood plasma using validated ELISA assays to evaluate the PK parameters of the investigated drugs. The 90% confidence intervals for the geometric mean ratios of PK (Cins and AUCins-T ) parameters of Gp-bi-asp and Novo-bi-asp were close to 100% and within the 80%-125% limits for establishing bioequivalence. The safety profiles of both drugs were also comparable.

Optimizing The Daily Units Of Insulin; Insulin Degludec Aspart Versus Premixed Insulin Aspart In The Standard Of Care Regimen For Type 2 Diabetics.

BACKGROUND: This study aimed to evaluate the impact of Insulin Degludec Aspart on daily insulin dose in comparison with premixed insulin aspart. METHODS: It was a Quasi-Experimental study conducted in the Department of Pharmacology, Army Medical College, National University of Medical Sciences, Rawalpindi and the Department of Medicine, Pak Emirates Military Hospital, Rawalpindi. One hundred and twenty participants with documented type 2 diabetes, taking premixed insulin aspart therapy were enrolled in the study. Sixty participants were substituted with insulin degludec aspart from premixed insulin aspart. Daily units of insulin were recorded for 12 weeks and compared for both groups. SPSS version 26 was used for analysing the study results. RESULTS: Participants of the insulin degludec aspart group showed a significant reduction in the daily insulin dose compared to the premixed insulin aspart group. Fifty-two units per day were administered in the participants of the premixed insulin aspart patients while insulin degludec aspart participants received 40 units of median daily insulin dose (p-value<0.001). CONCLUSIONS: Insulin degludec aspart proved superior to premixed insulin aspart in a reduction in the daily dose of insulin with insulin degludec aspart.

Genetic ablation of synaptotagmin-9 alters tomosyn-1 function to increase insulin secretion from pancreatic ß-cells improving glucose clearance.

Stimulus-coupled insulin secretion from the pancreatic islet ß-cells involves the fusion of insulin granules to the plasma membrane (PM) via SNARE complex formation-a cellular process key for maintaining whole-body glucose homeostasis. Less is known about the role of endogenous inhibitors of SNARE complexes in insulin secretion. We show that an insulin granule protein synaptotagmin-9 (Syt9) deletion in mice increased glucose clearance and plasma insulin levels without affecting insulin action compared to the control mice. Upon glucose stimulation, increased biphasic and static insulin secretion were observed from ex vivo islets due to Syt9 loss. Syt9 colocalizes and binds with tomosyn-1 and the PM syntaxin-1A (Stx1A); Stx1A is required for forming SNARE complexes. Syt9 knockdown reduced tomosyn-1 protein abundance via proteasomal degradation and binding of tomosyn-1 to Stx1A. Furthermore, Stx1A-SNARE complex formation was increased, implicating Syt9-tomosyn-1-Stx1A complex is inhibitory in insulin secretion. Rescuing tomosyn-1 blocked the Syt9-knockdown-mediated increases in insulin secretion. This shows that the inhibitory effects of Syt9 on insulin secretion are mediated by tomosyn-1. We report a molecular mechanism by which ß-cells modulate their secretory capacity rendering insulin granules nonfusogenic by forming the Syt9-tomosyn-1-Stx1A complex. Altogether, Syt9 loss in ß-cells decreases tomosyn-1 protein abundance, increasing the formation of Stx1A-SNARE complexes, insulin secretion, and glucose clearance. These outcomes differ from the previously published work that identified Syt9 has either a positive or no effect of Syt9 on insulin secretion. Future work using ß-cell-specific deletion of Syt9 mice is key for establishing the role of Syt9 in insulin secretion.

Cost-effectiveness of insulin degludec/insulin aspart versus biphasic insulin aspart in Chinese population with type 2 diabetes.

Objective: To evaluate the long-term cost effectiveness of insulin degludec/insulin aspart (IDegAsp) vs. biphasic insulin aspart 30 (BIAsp 30) for the treatment of people with type 2 diabetes mellitus (T2DM) inadequately managed on basal insulin in China. Methods: The CORE (the Center for Outcomes Research) Diabetes Model, which has been published and verified, was used to simulate disease progression and calculate the total direct medical costs, life years (LYs) and quality-adjusted life years (QALYs) over 30 years, from the perspective of Chinese healthcare system. The patient demographic information and clinical data needed for the model were gathered from a phase III treat-to-target clinical trial (NCT02762578) and other Chinese cohort studies. Medical costs on treating diabetes were calculated based on clinical trial and local sources. The diabetes management and complications costs were derived from published literature. A discounting rate of 5% was applied to both health and cost outcomes. And one-way and probabilistic sensitivity analyses were carried out to test the reliability of the results. Results: Compared with BIAsp 30, treatment with IDegAsp was associated with an incremental benefit of 0.001 LYs (12.439 vs. 12.438) and 0.280 QALYs (9.522 vs. 9.242) over a 30-year time horizon, and increased CNY (Chinese Yuan) 3,888 (390,152 vs. 386,264) for total costs. IDegAsp was cost-effective vs. BIAsp 30 therapy with an incremental cost-effectiveness ratio of CNY 13,886 per QALY gained. Results were robust across a range of sensitivity analyses. Conclusion: Compared with BIAsp 30, IDegAsp was a cost-effective treatment option for people with T2DM with inadequate glycemic management on basal insulin in China.

Elevated alanine aminotransferase is associated with biphasic insulin secretion in the healthy elderly Han Chinese population.

OBJECTIVE: To evaluate the relationship between alanine transaminase (ALT) level and biphasic insulin secretion (BPIS) in healthy elderly Han Chinese individuals. METHODS: This cross-sectional study enrolled healthy elderly participants aged ≥60 years that were part of a health examination programme. In order to explore the correlation and severity of the clinical condition, those with any possible confounding factors known to affect insulin secretion or liver function were excluded from the study. BPIS was calculated using an equation developed previously by this research team. RESULTS: This study enrolled 39 845 healthy elderly individuals (19 058 males and 20 787 females). Participants were stratified into four quartile groups according to their ALT level. In both males and females, the increasing ALT quartiles (ordinal variable) were associated with greater values of log-transformed first-phase insulin secretion (FPIS) and second-phase insulin secretion (SPIS). The correlation and the linear regression model showed that increasing ALT level was significantly correlated with higher log-transformed FPIS and SPIS. CONCLUSIONS: ALT was positively correlated with BPIS in a healthy elderly population in both men and women. Elevated ALT may serve as an indicating factor for developing metabolic syndrome and type 2 diabetes mellitus in healthy elderly individuals.

Dynamin deficiency causes insulin secretion failure and hyperglycemia.

Pancreatic ß cells operate with a high rate of membrane recycling for insulin secretion, yet endocytosis in these cells is not fully understood. We investigate this process in mature mouse ß cells by genetically deleting dynamin GTPase, the membrane fission machinery essential for clathrin-mediated endocytosis. Unexpectedly, the mice lacking all three dynamin genes (DNM1, DNM2, DNM3) in their ß cells are viable, and their ß cells still contain numerous insulin granules. Endocytosis in these ß cells is severely impaired, resulting in abnormal endocytic intermediates on the plasma membrane. Although insulin granules are abundant, their release upon glucose stimulation is blunted in both the first and second phases, leading to hyperglycemia and glucose intolerance in mice. Dynamin triple deletion impairs insulin granule exocytosis and decreases intracellular Ca2+ responses and granule docking. The docking defect is correlated with reduced expression of Munc13-1 and RIM1 and reorganization of cortical F-actin in ß cells. Collectively, these findings uncover the role of dynamin in dense-core vesicle endocytosis and secretory capacity. Insulin secretion deficiency in the absence of dynamin-mediated endocytosis highlights the risk of impaired membrane trafficking in endocrine failure and diabetes pathogenesis.

Comparison of Blood Glucose Variability Between Exenatide and Biphasic Insulin Aspart 30 in Chinese Participants with Type 2 Diabetes Inadequately Controlled with Metformin Monotherapy: A Multicenter, Open-Label, Randomized Trial.

INTRODUCTION: To compare blood glucose variability (GV) in Chinese participants with type 2 diabetes mellitus (T2DM) whose blood glucose levels are inadequately controlled with metformin monotherapy after twice-daily exenatide or biphasic insulin aspart 30 (BIAsp30). METHODS: In this 16-week multicenter, randomized clinical trial, 104 participants were randomized 1:1 to receive exenatide (exenatide group) or BIAsp30 (BIAsp30 group) twice daily. All participants continued metformin treatment. The primary outcome was the change in GV as measured by a continuous glucose monitoring system (CGMS) from baseline to 16 weeks. RESULTS: At 16 weeks, both the Exenatide and BIAsp30 groups effectively decreased mean glucose (MG), but neither group changed the mean amplitude of glycemic excursion (MAGE), largest amplitude of glycemic excursion (LAGE), mean of daily difference (MODD), or standard deviation of blood glucose (SDBG). The decrease in 2-h post-breakfast glucose excursions was greater in the Exenatide group compared to the BIAsp30 group, with a least square (LS) mean difference [95% CI] of (1.58 [0.53, 2.63]). Exenatide also significantly reduced 2-h post-lunch glucose excursion compared to BIAsp30 (LS mean difference [95% CI], 1.19 [0.18, 2.20]). The Exenatide group had significantly reduced body weight and body mass index (BMI), while the BIAsp30 group had increased weight and had no change in BMI. Both treatments were well tolerated with no serious hypoglycemic events and with fewer identified hypoglycemic events in the Exenatide group than in the BIAsp30 group (5.77% vs. 17.31%, P < 0.01). CONCLUSION: Although there was no difference in change of GV between Exenatide and BIAsp30, exenatide provided more improvement in postprandial glucose excursion and weight control, without increasing the risk of hypoglycemia in Chinese patients with T2DM whose blood glucose was inadequately controlled with metformin. These findings may provide new options for patients who choose further hypoglycemic treatment, especially in patients with obesity who have large postprandial plasma glucose excursions. TRIAL REGISTRATION: ClinicalTrials.gov indentifier: NCT02449603.

The Effect of Recovery Warm-up Time Following Cold Storage on the Dynamic Glucose-stimulated Insulin Secretion of Isolated Human Islets.

Standardized islet characterization assays that can provide results in a timely manner are essential for successful islet cell transplantation. A critical component of islet cell quality is ß-cell function, and perifusion-based assessments of dynamic glucose-stimulated insulin secretion (GSIS) are the most informative method to assess this, as they provide the most complex in vitro evaluation of GSIS. However, protocols used vary considerably among centers and investigators as they often use different low- and high-glucose concentrations, exposure-times, flow-rates, oxygen concentrations, islet numbers, analytical methods, measurement units, and instruments, which result in different readouts and make comparisons across platforms difficult. Additionally, the conditions of islet storage and shipment prior to assessment may also affect islet function. Establishing improved standardized protocols for perifusion GSIS assays should be an integral part of the ongoing effort to increase the rigor of human islet studies. Here, we performed detailed evaluation of GSIS of human islets using a fully automated multichannel perifusion instrument following various warm-up recovery times after cold storage that corresponds to current shipping conditions (8°C). We found that recovery times shorter than 18 h (overnight) resulted in impaired insulin secretion. While the effects were relatively moderate on second-phase insulin secretion, first-phase peaks were restored only following 18-h incubation. Hence, the biphasic profile of dynamic GSIS was considerably affected when islets were not allowed to recover for a sufficient time after being maintained in cold. Accordingly, while cold storage might improve islet cell survival during shipment and prolong the length of culture, functional assessments should be performed only after allowing for at least overnight recovery at physiological temperatures.

Comparative evaluation of biphasic insulin with metformin and triple oral hypoglycemic agents (OHA) in type 2 diabetes patients.

INTRODUCTION: The prevalence of secondary failure to oral hypoglycemic agents among type 2 diabetes mellitus (T2DM) patients ranges from 30 to 60%. The alternative approaches to overcome this issue are either switching to triple oral hypoglycemic agents (OHA) or intensifying the regimen by adding insulin. OBJECTIVE: To compare the glycemic control achieved with biphasic insulin plus metformin and triple OHA in T2DM patients who were not adequately controlled with two OHA regimen. METHODS: A qualitative prospective study was conducted at Asir diabetes center, Abha, KSA. Poorly controlled T2DM patients with two OHA for at least 1 year with glycated hemoglobin (HbA1c) >7.0% were included. Subjects were divided into group I (a third OHA was added to the existing two OHA regimen) and group II (switched over to Biphasic insulin and metformin). At baseline and 3-month intervals, level of HbA1C, Fasting Plasma Glucose (FPG), Postprandial Plasma Glucose (PPG), Blood Pressure (BP), lipid profile and hypoglycemic episodes were obtained and evaluated for one year. RESULTS: 41.1% of patients were in group I and 58.9% were in group II. At the end of the study, there was a significant reduction in HbA1c in group II subjects comparing to group I (8.18 ± 1.32 vs 8.79 ± 1.81, p = 0.0238). FPG and PPG were improved also in group II. The mean body weight increased from baseline in group II is +4.48 kg and decreased from baseline in group I (-0.46 kg). 11.3% from group I and 23.7% from group II reported hypoglycaemic incidences. CONCLUSION: Biphasic insulin and metformin regimen could be an appropriate therapeutic option for achieving good glycemic control compared with triple OHA in patients with two OHA failure.

Efficacy and safety of insulin degludec/insulin aspart versus biphasic insulin aspart 30 in Chinese adults with type 2 diabetes: A phase III, open-label, 2:1 randomized, treat-to-target trial.

AIMS: To assess the efficacy and safety of twice-daily insulin degludec/insulin aspart (IDegAsp) versus biphasic insulin aspart 30 (BIAsp 30) twice daily, both ± metformin, in Chinese adults (N = 543) with type 2 diabetes (T2D) inadequately controlled on premixed/self-mixed or basal insulin ± metformin. MATERIALS AND METHODS: We conducted a 26-week, phase III, open-label, treat-to-target, 2:1 randomized trial. Hierarchical testing was used with non-inferiority of glycated haemoglobin (HbA1c) change from baseline to week 26 as the primary endpoint and superiority for the confirmatory secondary endpoints which were as follows: change from baseline in fasting plasma glucose (FPG); nocturnal confirmed hypoglycaemic episodes (12:01-5:59 am, inclusive); total confirmed hypoglycaemic episodes (severe or plasma glucose <3.1 mmol/L with/without symptoms); body weight; and percentage of responders (HbA1c <53 mmol/mol [<7.0%]) without confirmed hypoglycaemic episodes. RESULTS: Non-inferiority for change from baseline to week 26 in HbA1c and superiority of IDegAsp twice daily versus BIAsp 30 twice daily for change in FPG, nocturnal confirmed and total confirmed hypoglycaemic episodes, was demonstrated. Estimated rates of nocturnal confirmed and total confirmed hypoglycaemic episodes were 47% and 43% lower, respectively, with IDegAsp twice daily versus BIAsp 30 twice daily. Superiority for change in body weight was not confirmed. Participants were more likely to reach the HbA1c goal of <53 mmol/mol (<7.0%) without confirmed hypoglycaemia with IDegAsp twice daily versus BIAsp 30 twice daily by trial end. No new safety signals were identified. CONCLUSIONS: The efficacy and safety of IDegAsp in Chinese patients with T2D was demonstrated, confirming results from international trials.

Comparison of a twice daily injection of insulin aspart 50 with insulin aspart 30 in patients with poorly controlled type 2 diabetes.

OBJECTIVE: To compare the efficacy and safety of a twice daily injection of insulin aspart (BIAsp) 30 and BIAsp50 in patients with type 2 diabetes mellitus (T2DM) poorly controlled with oral hypoglycemic agents (OHAs). METHODS: In this 12 week prospective, randomized, parallel trial, a total of 80 T2DM patients, 59 ± 10 years old with a disease duration of 9.3 ± 6.6 years and HbA1c >7% despite large doses of metformin and sulfonylurea administration, were randomized to receive BIAsp30 (n = 40) or BIAsp50 (n = 40). The primary endpoint was a change in HbA1c at week 12. RESULTS: The changes in HbA1c from baseline were -2.5% ± 1.0% in the BIAsp50 group and -2.5% ± 1.2% in the BIAsp30 group (p = .897). No difference was observed in the rate of HbA1c target achievement (<7.0%) between BIAsp50 (42.5%) and BIAsp30 (32.5%) (p = .495). The change in fasting plasma glucose (FPG) in the BIAsp50 group was lower than that in the BIAsp30 group (p < .001), while the change in two-hour postprandial blood glucose (2hPBG) was higher and blood glucose excursion was lower in the BIAsp50 group than that in the BIAsp30 group (p < .001, p < .001). A significant improvement in HbA1c was observed with BIAsp50 in subgroups with baseline blood glucose excursion >7.8 mmol/L or 2hPBG >17.6 mmol/L compared with BIAsp30. There were no differences in hypoglycemia or body weight between groups. CONCLUSIONS: Compared with BIAsp30, BIAsp50 showed greater efficacy in patients with baseline BG excursion >7.8 mmol/L or 2hPBG >17.6 mmol/L as well as good safety for hypoglycemia. CLINICAL TRIAL REGISTRATION: ChiCTR-IIR-16008958.

Original paper: Efficacy and safety analysis of insulin degludec/insulin aspart compared with biphasic insulin aspart 30: A phase 3, multicentre, international, open-label, randomised, treat-to-target trial in patients with type 2 diabetes fasting during Ramadan.

AIMS: To compare the efficacy and safety of insulin degludec/insulin aspart (IDegAsp) and biphasic insulin aspart 30 (BIAsp 30) before, during and after Ramadan in patients with type 2 diabetes mellitus (T2DM) who fasted during Ramadan. METHODS: In this multinational, randomised, treat-to-target trial, patients with T2DM who intended to fast and were on basal, pre- or self-mixed insulin ±â€¯oral antidiabetic drugs for ≥90 days were randomised (1:1) to IDegAsp twice daily (BID) or BIAsp 30 BID. Treatment period included pre-Ramadan treatment initiation (with insulin titration for 8-20 weeks), Ramadan (4 weeks) and post-Ramadan (4 weeks). Insulin doses were reduced by 30-50% for the pre-dawn meal (suhur) on the first day of Ramadan, and readjusted to the pre-Ramadan levels at the end of Ramadan. Hypoglycaemia was analysed as overall (severe or plasma glucose <3.1 mmol/L [56 mg/dL]), nocturnal (00:01-05:59) or severe (requiring assistance of another person). RESULTS: During the treatment period, IDegAsp (n = 131) had significantly lower overall and nocturnal hypoglycaemia rates with similar glycaemic efficacy, versus BIAsp 30 (n = 132). During Ramadan, despite achieving significantly lower pre-iftar (meal at sunset) self-measured plasma glucose (estimated treatment difference: -0.54 mmol/L [-1.02; -0.07]95% CI, p = .0247; post hoc) with similar overall glycaemic efficacy, IDegAsp showed significantly lower overall and nocturnal hypoglycaemia rates versus BIAsp 30. CONCLUSIONS: IDegAsp is a suitable therapeutic agent for patients who need insulin for sustained glucose control before, during and after Ramadan fasting, with a significantly lower risk of hypoglycaemia, versus BIAsp 30, an existing premixed insulin analogue.

Use of 50/50 Premixed Insulin Analogs in Type 2 Diabetes: Systematic Review and Clinical Recommendations.

INTRODUCTION: Premixed insulin analogs represent an alternative to basal or basal-bolus insulin regimens for the treatment of type 2 diabetes (T2D). "Low-mix" formulations with a low rapid-acting to long-acting analog ratio (e.g., 25/75) are commonly used, but 50/50 formulations (Mix50) may be more appropriate for some patients. We conducted a systematic literature review to assess the efficacy and safety of Mix50, compared with low-mix, basal, or basal-bolus therapy, for insulin initiation and intensification. METHODS: MEDLINE, EMBASE, Cochrane Database of Systematic Reviews, ClinicalTrials.gov, LillyTrials.com, and NovoNordisk-trials.com were searched (11 or 13 Dec 2016) using terms for T2D, premixed insulin analogs, and/or Mix50. Studies (randomized, nonrandomized, or observational; English only) comparing Mix50 with other insulins (except human) and reporting key efficacy [glycated hemoglobin (HbA1c), fasting and postprandial glucose] and/or safety (hypoglycemia, weight gain) outcomes were eligible for inclusion. Narrative reviews, letters, editorials, and conference abstracts were excluded. Risk of bias in randomized trials was assessed using the Cochrane tool. RESULTS: MEDLINE and EMBASE searches identified 716 unique studies, of which 32 met inclusion criteria. An additional three studies were identified in the other databases. All 19 randomized trials except one were open label; risk of other biases was generally low. Although not conclusive, the evidence suggests that Mix50 may provide better glycemic control (HbA1c reduction) and, particularly, postprandial glucose reduction in certain patients, such as those with high carbohydrate diets and Asian patients, than low-mix and basal therapy. Based on this evidence and our experience, we provide clinical guidance on factors to consider when deciding whether Mix50 is appropriate for individual patients. CONCLUSIONS: Mix50 may be more suitable than low-mix therapy for certain patients. Clinicians should consider not only efficacy and safety but also patient characteristics and preferences when tailoring insulin treatment to individuals with T2D. FUNDING: Eli Lilly.

A crossover study of the combination therapy of metformin and exenatide or biphasic insulin aspart 30 in overweight or obese patients newly diagnosed with type 2 diabetes mellitus.

The aim of the present study was to explore the effects of various combinations of exenatide, metformin (MET) and biphasic insulin aspart 30 (BIA30) on type 2 diabetes mellitus (T2DM). Two hundred overweight or obese patients newly diagnosed with T2DM were evenly randomized into two groups: A (twice daily for all: Phase I, 5 µg exenatide + 0.5 g MET for 4 weeks, then 10 µg exenatide + 0.5 g MET for 8 weeks; Phase II, 0.5 g MET for 12 weeks; Phase III, 0.3-0.4 U/kg/day BIA30 + 0.5 g MET for 12 weeks) and B (Phases I, II, III matched the phases III, II and I in group A). In groups A and B a significant decrease and increase, respectively, in glycated hemoglobin (HbAlc) and body mass index (BMI) was noted during Phase I. A 3.2±0.4-kg decrease in body weight in group A and a 2.6±0.3-kg increase in group B was observed. In Phase II, HbAlc was significantly increased in both groups (P<0.05). In Phase III, the BMI was increased in group A and reduced in group B (P<0.05). There was a 3.8±0.4-kg weight decrease in group B and 4.2±0.5-kg increase in group A (P<0.05). The combination of exenatide and MET promoted weight loss, glycemic control, ß-cell function index, C peptide and adiponectin levels. These results suggested that the combination of exenatide and MET is better than the combination of BIA and MET for the therapy of overweight or obese patients newly diagnosed with T2DM.

Mechanisms of the amplifying pathway of insulin secretion in the ß cell.

Pancreatic islet ß cells secrete insulin in response to nutrient secretagogues, like glucose, dependent on calcium influx and nutrient metabolism. One of the most intriguing qualities of ß cells is their ability to use metabolism to amplify the amount of secreted insulin independent of further alterations in intracellular calcium. Many years studying this amplifying process have shaped our current understanding of ß cell stimulus-secretion coupling; yet, the exact mechanisms of amplification have been elusive. Recent studies utilizing metabolomics, computational modeling, and animal models have progressed our understanding of the metabolic amplifying pathway of insulin secretion from the ß cell. New approaches will be discussed which offer in-roads to a more complete model of ß cell function. The development of ß cell therapeutics may be aided by such a model, facilitating the targeting of aspects of the metabolic amplifying pathway which are unique to the ß cell.

An RCT Investigating Patient-Driven Versus Physician-Driven Titration of BIAsp 30 in Patients with Type 2 Diabetes Uncontrolled Using NPH Insulin.

INTRODUCTION: The aim of this study was to confirm the efficacy of patient-driven titration of BIAsp 30 in terms of glycemic control, by comparing it to physician-driven titration of BIAsp 30, in patients with type 2 diabetes in North Africa, the Middle East, and Asia. METHODS: A 20-week, open-label, randomized, two-armed, parallel-group, multicenter study in Egypt, Indonesia, Morocco, Saudi Arabia, and Vietnam. Patients (n = 155) with type 2 diabetes inadequately controlled using neutral protamine Hagedorn (NPH) insulin were randomized to either patient-driven or physician-driven BIAsp 30 titration. RESULTS: The noninferiority of patient-driven compared to physician-driven titration with respect to the reduction in HbA1c was confirmed. The estimated mean change in HbA1c from baseline to week 20 was -1.27% in the patient-driven arm and -1.04% in the physician-driven arm, with an estimated treatment difference of -0.23% (95% confidence interval: -0.54; 0.08). After 20 weeks of treatment, the proportions of patients achieving the target of HbA1c <7.5% were similar between titration arms; the proportions of patients achieving the target of ≤6.5% were also similar. Both titration algorithms were well tolerated, and hypoglycemic episode rates were similar in both arms. CONCLUSION: Patient-driven titration of BIAsp 30 can be as effective and safe as physician-driven titration in non-Western populations. Overall, the switch from NPH insulin to BIAsp 30 was well tolerated in both titration arms and led to improved glycemic control. A limitation of the study was the relatively small number of patients recruited in each country. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov NCT01589653. FUNDING: Novo Nordisk A/S, Denmark.

TREATMENT OF TYPE 2 DIABETES WITH BIPHASIC INSULIN ANALOGUES.

The majority of patients with Type 2 diabetes require insulin therapy for treating hyperglycaemia. There are several regimens available for insulin initiation and maintenance. Insulin analogues have been developed to mimic normal physiology as closely as possible. Biphasic analogues can target both fasting and postprandial hyperglycaemia, with the added advantage of being premixed and thus convenient for the patient. A practical and feasible option is to initiate insulin with one or more biphasic preparations at mealtimes, thus providing both basal and prandial coverage. Individual titration of dose and frequency of daily injections with biphasic insulin preparations has the potential for improving glycaemic control with a high degree of patient acceptance. Drawbacks include a more rigid regimen, a relative lack of flexibility, and a somewhat higher degree of glycaemic variability and hypoglycaemia when compared to multiple daily basal-bolus injections. Awareness of the advantages and limitations of biphasic insulin analogues can assist clinicians in their appropriate use for the treatment of patients with Type 2 diabetes.

Management of postprandial glucose: Recommended targets and treatment with biphasic insulin.

Increases in glycaemia, particularly following meals, have been independently associated with diabetes complications, most notably cardiovascular disease. Control of postprandial plasma glucose (PPG) therefore plays an important role in diabetes management. International diabetes guidelines acknowledge the value of PPG monitoring yet place relatively little emphasis on PPG control. This article considers the impact of suboptimal PPG control and current recommendations with regard to management of PPG. Specific consideration is given to the role of biphasic insulins, one of the treatment options recognised by the International Diabetes Federation as preferentially lowering PPG levels.