Insulin Analogues Research Articles

P-23 Insulin autoimmune syndrome possibly induced by Alpha-Lipoic acid

Abstract Introduction Insulin autoimmune syndrome (IAS) is a relative rare cause of hypoglycemia due to the presence of extremely high circulating insulin levels and elevated serum concentrations of autoantibodies to human insulin despite no prior exposure to exogenous insulin, insulin analogues or oral hypoglycemic agents. It is characterized by repeated fasting hypoglycemia or episodes of hypoglycemia late after meals in non-diabetic, non-acutely ill patients. Increasing the titer of insulin autoantibodies and immune reactive insulin occurs owing to both genetic influences and environmental triggers such as medication, genetic instability and other factors. It is associated with the use of drugs comprising sulfhydryl groups, such as methimazole, clopidogrel and alpha lipoic acid, mostly. Insulin autoantibodies appear a few weeks after the exposure of sulfhydryl radicals. Here, we summarize the case of IAS caused by drug administration. Clinical Case A 60-year-old female patient who has a history of migraine for 30 years was referred to our hospital for feeling of hunger, dizziness, sweating, tremor, and palpitations for 1 month. These symptoms had commenced episodically, soon after starting 600 mg/day of alpha lipoic acid. She was diagnosed with hypoglycemia based on a plasma glucose concentration of 31 mg/dL. There was no personal or family history of diabetes mellitus, or previous use of oral hypoglycemic drugs such as sulfonylureas or exogenous insulin. No abnormality was detected in the systemic examination. She had no smoking and alcohol abuse. Her regular medication was tricyclic antidepressant (amitriptyline). Laboratory results are presented in Table 1. On our evalution, the serum levels of insulin, C-peptide, and anti-insulin antibody titers were inappropriately elevated in the presence of hypoglycemia, confirming the diagnosis of hyperinsulinemic hypoglycemia. Thyroid function, human growth hormone, insulin growth factor-1 (IGF-1), and cortisol result were within normal limits. Screening for antinuclear factor, serum protein electrophoresis, serology for viral hepatitis, and other autoimmune diseases were negative. Insulinoma was excluded with computed tomography. In light of the above results, a diagnosis of IAS was made with possible alpha lipoic acid. Because, alpha lipoic acid was the only medication being taken associated with a sulfhydryl group. The patient was prescribed oral methylprednisolone (32 mg once daily), alpha lipoic acid was withdrawn. Hypoglycemia did not occur after methylprednisolone treatment of follow-up. Methylprednisolone treatment was tapered to 4 mg once daily within 2 months. The insulin, and anti-insulin antibody titers had decreased. Conclusion We report a rare case of IAS. Sulfhydryl group containing drugs such as alpha lipoic acid might induce or exacerbate hypoglycemia in patients with a history of IAS. For this reason, the use of alpha lipoic acid should be questioned in patients with IAS. Table 1. Laboratory test results

User-experience testing of an evidence-to-decision framework for selecting essential medicines.

Essential medicine lists (EMLs) are important medicine prioritization tools used by the World Health Organization (WHO) EML and over 130 countries. The criteria used by WHO's Expert Committee on the Selection and Use of Essential Medicines has parallels to the GRADE Evidence-to-Decision (EtD) frameworks. In this study, we explored the EtD frameworks and a visual abstract as adjunctive tools to strengthen the integrate evidence and improve the transparency of decisions of EML applications. We conducted user-experience testing interviews of key EML stakeholders using Morville's honeycomb model. Interviews explored multifaceted dimensions (e.g., usability) on two EML applications for the 2021 WHO EML-long-acting insulin analogues for diabetes and immune checkpoint inhibitors for lung cancer. Using a pre-determined coding framework and thematic analysis we iteratively improved both the EtD framework and the visual abstract. We coded the transcripts of 17 interviews with 13 respondents in 103 locations of the interview texts across all dimensions of the user-experience honeycomb. Respondents felt the EtD framework and visual abstract presented complementary useful and findable adjuncts to the traditional EML application. They felt this would increase transparency and efficiency in evidence assessed by EML committees. As EtD frameworks are also used in health practice guidelines, including those by the WHO, respondents articulated that the adoption of the EtD by EML applications represents a tangible mechanism to align EMLs and guidelines, decrease duplication of work and improve coordination. Improvements were made to clarify instructions for the EtD and visual abstract, and to refine the design and content included. 'Availability' was added as an additional criterion for EML applications to highlight this criterion in alignment with WHO EML criteria. EtD frameworks and visual abstracts present additional important tools to communicate evidence and support decision-criteria in EML applications, which have global health impact. Access to essential medicines is important for achieving universal health coverage, and the development of essential medicine lists should be as evidence-based and trustworthy as possible.

Mediation effect of serum zinc on insulin secretion inhibited by methyl tert-butyl ether in gas station workers.

Methyl tert-butyl ether (MTBE), a type of gasoline additive, has been found to affect insulin function and glucose homeostasis in animal experiments, but there is still no epidemiological evidence. Zinc (Zn) is a key regulatory element of insulin secretion and function, and Zn homeostasis can be disrupted by MTBE exposure through inducing oxidative stress. Therefore, we suspected that Zn might be involved and play an important role in the process of insulin secretion inhibited by MTBE exposure. In this study, we recruited 201 male subjects including occupational and non-occupational MTBE exposure from Anhui Province, China in 2019. Serum insulin and functional analog fibroblast growth factor 1 (FGF1) and blood MTBE were detected by Elisa and headspace solid-phase microextraction and gas chromatography-high-resolution mass spectrometry. According to MTBE internal exposure level, the workers were divided into low- and high-exposed groups and found that the serum insulin level in the high-exposed group was significantly lower than that in the low-exposed group (p = 0.003) while fasting plasma glucose (FPG) level increased obviously in the high-exposed group compared to the low-exposed group (p = 0.001). Further analysis showed that MTBE exposure level was positively correlated with FPG level, but negatively correlated with serum insulin level, which suggested that the FPG level increase might be related to the decrease of serum insulin level induced by MTBE exposure. The results of further mediation effect analysis showed that changes in serum zinc levels played a major intermediary role in the process of insulin secretion inhibition and blood glucose elevation caused by MTBE exposure. In addition, a significant negative correlation was found between MTBE exposure and serum Zn level, which might play a strong mediating effect on the inhibition of insulin secretion induced by MTBE exposure. In conclusion, our study provided evidence that MTBE could inhibit insulin secretion and interfere with Zn metabolism in gas station workers for the first time, and found that Zn might play an important mediation effect during the process of inhibiting insulin secretion and interfering with glucose metabolism induced by MTBE exposure.

Human serum albumin as a potential drug delivery system for N-methylated hot spot insulin analogs inhibiting hormone aggregation

The purpose of this study was to investigate whether Human Serum Albumin (HSA) can bind N-methylated analogs of hot spots of native insulin. Three N-methylated derivatives of the A13–A19 fragment of native insulin were used: L(N-Me)YQLENY (1), LYQ(N-Me)LENY (2), and L(N-Me)YQ(N-Me)LENY (3). The studied N-methylated insulin fragments possess inhibiting potential against hormone aggregation. A variety of research techniques, including spectroscopic methods and microscopy assays, were used to study the interaction of HSA with the N-methylated insulin fragments. Based on spectroscopic measurements with Congo Red and Thioflavin T, all the analyzed N-methylated peptides were able to interact with the HSA surface. The CD spectrum registered for HSA in the presence of L(N-Me)YQLENY showed the smallest content of α-helix conformation, indicating the most compact HSA structure. Based on the results of MST, the dissociation constants (Kd) for complexes of HSA and peptides 1–3 were 19.2 nM (complex 1), 15.6 nM (complex 2), and 8.07 nM (complex 3). Microscopy assays, dynamic light scattering measurements as well as computer simulation of protein–ligand interaction also confirmed the possibility of docking the N-methylated inhibitors within HSA.

Improvement of blood glucose control and reduction of hypoglycemia, body weight, and C-reactive protein in type 1 diabetic patients treated with intensive insulin therapy with insulin analogs

Background/Aim. Good metabolic control can delay the onset and progression of chronic complications of diabetes mellitus (DM). Intensified insulin therapy (IIT) is the cornerstone of good metabolic control in the treatment of type 1 DM (T1DM) while avoiding hypoglycemia and body weight (BW) gain in those patients. The aim of the study was to assess the effects of IIT with insulin analogs (aspart and glargine) in T1DM patients. Methods. This prospective clinical study included 49 patients with at least one year of T1DM duration, who were on IIT with human insulin at that moment. They commenced therapy with insulin aspart for three months, followed by insulin glargine for another three months. An analysis of blood glucose (BG) control (glycated hemoglobin ? HbA1c, mean BG, fasting BG, postprandial BG, and glycemic variability) and analysis of BW, hypoglycemia, and C-reactive protein (CRP) levels were performed. Results. The HbA1c level decreased slightly (non-significantly) after three months of insulin aspart therapy (from 9.28% to 8.83%) and decreased significantly after the aspart/glargine combination (to 8.08%; p < 0.001). After the first three months with aspart therapy, a significant reduction in postprandial BG was noted after all three main meals. The mean postprandial rise of BG was significantly reduced. The variability of daily BG was significantly reduced (standard deviation of BG fell from 2.28 mmol/L to 1.90 mmol/L; p < 0.05). The mean BG value in the profiles decreased (from 9.11 mmol/L to 8.31 mmol/L; p < 0.05). All BG values in the profiles after six months were statistically significantly lower compared to the initial values, as well as the mean BG (6.88 mmol/L; p < 0.001) and the variability of daily BG (1.49 mmol/L; p < 0.01). Our results showed a significant reduction in the number of hypoglycemias after three months, especially after the introduction of insulin glargine therapy (significant reduction in the number of symptomatic, asymptomatic, and nocturnal hypoglycemias). The results showed a discrete but significant reduction in BW and a significant reduction in CRP levels (from 3.43 mg/L to 2.25 mg/L; p < 0.001). Conclusion. Treatment of patients with T1DM with insulin analogs (insulin aspart and insulin glargine) in IIT leads to improved BG control with a reduction in the number of hypoglycemia, BW, and CRP levels.

Identification of PK-PD Insulin Models using Experimental GIR Data

We present a method to estimate parameters in pharmacokinetic (PK) and pharmacodynamic (PD) models for glucose insulin dynamics in humans. The method combines 1) experimental glucose infusion rate (GIR) data from glucose clamp studies and 2) a PK-PD model to estimate parameters such that the model fits the data. Assuming that the glucose clamp is perfect, we do not need to know the details of the controller in the clamp, and the GIR can be computed directly from the PK-PD model. To illustrate the procedure, we use the glucoregulatory model developed by Hovorka and modify it to have a smooth non-negative endogeneous glucose production (EGP) term. We estimate PK-PD parameters for rapid-acting insulin analogs (Fiasp and NovoRapid). We use these PK-PD parameters to illustrate GIR for insulin analogs with 30% and 50% faster absorption time than currently available rapid-acting insulin analogs. We discuss the role of system identification using GIR data from glucose clamp studies and how such identified models can be used in automated insulin dosing (AID) systems with ultra rapid-acting insulin.

The role of superfast insulin analogues in diabetes mellitus

In recent decades, significant advances in sugar therapy have been associated with the introduction of human insulin analogues. Superfast human insulin analogues have become an important tool for achieving optimal glycemic control and improving the quality of life of patients. Due to its unique pharmacokinetics, this group of insulin preparations provides a faster and more predictable onset of action, which allows its profile to be as close as possible to the secretion of endogenous insulin. A number of clinical trials have confirmed the advantage of superfast insulin analogues in the control of postprandial hyperglycemia compared with insulin preparations of the previous generation.

Iodine Promotes Glucose Uptake through Akt Phosphorylation and Glut-4 in Adipocytes, but Higher Doses Induce Cytotoxic Effects in Pancreatic Beta Cells.

Epidemiological clinical reports have shown an association between iodine excess with diabetes mellitus type 2 and higher blood glucose. However, the relationship between iodine, the pancreas, adipose tissue, and glucose transport is unclear. The goal of this study was to analyze the effect of iodine concentrations (in Lugol solution) on glucose transport, insulin secretion, and its cytotoxic effects in mature 3T3-L1 adipocytes and pancreatic beta-TC-6 cells. Fibroblast 3T3-L1, mature adipocytes, and pancreatic beta-TC-6 cells were treated with 1 to 1000 µM of Lugol (molecular iodine dissolved in potassium iodide) for 30 min to 24 h for an MTT proliferation assay. Then, glucose uptake was measured with the fluorescent analog 2-NBDG, insulin receptor, Akt protein, p-Akt (ser-473), PPAR-gamma, and Glut4 by immunoblot; furthermore, insulin, alpha-amylase, oxidative stress, and caspase-3 activation were measured by colorimetric methods and the expression of markers of the apoptotic pathway at the RNAm level by real-time PCR. Low concentrations of Lugol significantly induce insulin secretion and glucose uptake in pancreatic beta-TC-6 cells, and in adipose cells, iodine-induced glucose uptake depends on the serine-473 phosphorylation of Akt (p-Akt) and Glut4. Higher doses of Lugol lead to cell growth inhibition, oxidative stress, and cellular apoptosis dependent on PPAR-gamma, Bax mRNA expression, and caspase-3 activation in pancreatic beta-TC-6 cells. Iodine could influence glucose metabolism in mature adipocytes and insulin secretion in pancreatic beta cells, but excessive levels may cause cytotoxic damage to pancreatic beta cells.

In T2DM requiring insulin initiation, icodec titrated with an app safely reduced HbA1c vs. daily basal insulin analogues at 52 wk.

Bajaj HS, Aberle J, Davies M, et al. Once-weekly insulin icodec with dosing guide app versus once-daily basal insulin analogues in insulin-naive type 2 diabetes (ONWARDS 5): a randomized trial. Ann Intern Med. 2023;176:1476-1485. 37748181.

Toward once-monthly insulin therapy via synergy in two pharmacokinetic protractors: Fc-conjugation and fatty acid acylation.

Pharmacokinetic properties and duration of therapeutic action of a pharmaceutical agent can be significantly extended through the combination of two distinct strategies aimed at increasing plasma half-life: fatty acid acylation and Fc-conjugation. Using insulin as a case study, we demonstrate that a doubly protracted insulin analog produces a substantial prolongation of pharmacodynamic effect to lower blood glucose in STZ-treated mice when compared to the Fc-only counterparts. This enhancement is further corroborated by direct pharmacokinetic measurements in rat and dog models, demonstrating the potential for once-monthly insulin therapy. The results suggest that this approach might have broad application across a diverse spectrum of peptide- and protein-based therapeutics.

Availability, price and affordability of insulin, delivery devices and self-monitoring blood glucose devices in Indonesia.

Insulin is essential for the survival of people with type 1 diabetes and for better management of people with type 2 diabetes. People with diabetes using insulin also require self-monitoring blood glucose (SMBG) devices (e.g., meters, strips, continuous monitoring systems) for day-to-day management. It is essential to ensure that insulin and these devices are available and affordable. This study aimed to evaluate the availability, price, and affordability of insulin and SMBG devices in Indonesia using an adaptation of the World Health Organization/Health Action International (WHO/HAI) price survey. A total of 34 public health facilities (hospitals, primary healthcare centres/Puskesmas) and 37 private pharmacies were sampled. Information from three major online marketplaces was also collected. Prices were expressed as median patient prices (US$). Affordability was defined as the number of days' wages needed by the lowest paid unskilled government worker (LPGW) to purchase 30 days' supply of insulin, delivery devices and SMBGs. Availability of analogue insulin was slightly higher in public facilities (63.6%) than in the private sector (43.2%), with no human insulin available in both sectors. Conversely, better availability was observed in private facilities for SMBG devices as public sector facilities did not supply devices for self-testing. Median prices for 1000IU analogues varied between the public sector (US$ 5.26) and the private sector (US$11.24). The highest median price of analogues was seen in online marketplaces (US$ 28.65). The least costly median price of SMBG devices were observed in online platforms (meter: US$ 18.37, test strip: US$ 0.27, lancet: US$ 0.02). A low-income person had to work 2-3 days to buy 1000IU of analogues. It required 5-7 days' and 4-5 day's wages to purchase a meter and a month's supply of test strips, respectively. The availability and affordability of insulin and SMBG devices remain important issues in Indonesia requiring holistic approaches for further improvement.

Once-weekly Insulin Icodec Versus Once-daily Long-acting Insulin for Type II Diabetes: A Meta-analysis of Randomized Controlled Trials.

Insulin icodec is a novel basal insulin analog with once-weekly subcutaneous administration. We aim to estimate the efficacy and safety of insulin icodec vs long-acting insulin (insulin glargine and degludec) in type II diabetic patients. We conducted a systematic review and meta-analysis synthesizing randomized controlled trials (RCTs), which were retrieved by systematically searching PubMed, Web of Science, SCOPUS, and Cochrane through May 29, 2023. We used RevMan V. 5.4 to pool dichotomous data using risk ratio (RR) and continuous data using mean difference (MD) with a 95% confidence interval (CI). Our primary outcome was glycated hemoglobin (HbA1C) change. We included 7 RCTs with a total of 3183 patients. Insulin icodec was associated with significantly decreased HbA1C (MD: -0.15 with 95% CI [-0.24, -0.06], P = .002) and increased percentage of time with glucose in range (TIR) (MD: 4.06 with 95% CI [2.06, 6.06], P = .0001). However, insulin icodec was associated with increased body weight (MD: 0.57 with 95% CI [0.45, 0.70], P = .00001). Also, there was no difference regarding any serious adverse events (AEs) (RR: 0.96 with 95% CI [0.76, 1.20], P = .7) or AEs leading to withdrawal (RR: 1.54 with 95% CI [0.84, 2.82], P = .16). However, insulin icodec was associated with increased any AEs incidence (RR: 1.06 with 95% CI [1.01, 1.12], P = .02). Insulin icodec was associated with decreased HbA1C, increased TIR, with similar hypoglycemic and serious AEs. However, it was also associated with increased body weight and the incidence of any AEs.

Pharmacokinetics and bioavailability of a new long-acting insulin analog in healthy Chinese volunteers: an open, randomized, single-dose, two-period and two-sequence cross-over study.

Objectives: INS068 is a novel, soluble, and long-acting insulin analog. In this study, we evaluated the pharmacokinetics and relative bioavailability of two formulations of INS068 in healthy Chinese subjects: a reference formulation packaged in vials and administered via syringe (R), and a test formulation packaged and administered via pen injector (T). Methods: A randomized, open-label, two-period, two-sequence crossover study was conducted with 24 healthy Chinese subjects. Subjects were randomized and administered subcutaneously in the abdomen at 0.4 U/kg of test or reference INS068 injection according to an open crossover design. INS068 concentrations in the serum were measured using LC-MS/MS, and the pharmacokinetic parameters of maximum concentration (Cmax) and area under the concentration-time curve (AUC0-t and AUC0-∞) were used to evaluate relative bioavailability. Results: After a single dose at 0.4 U/kg, the median Tmax of INS068 was 12 h for both formulations, and the mean t1/2 for T and R was 13.0 h and 12.6 h, respectively. The geometric means of Cmax and AUC0-∞ were 3.99 nmol/L and 120 h·nmol/L for the T, and 4.05 nmol/L and 117 h·nmol/L for the R, respectively. The geometric mean ratios of Cmax, AUC0-t and AUC0-∞ of T over R were 98.7% (90% CI: 92.7%-105.2%), 102.6% (90% CI: 100.0%-105.3%) and 102.8% (90% CI: 100.1%-105.5%). Conclusion: The overall PK profile of the two formulations of INS068 injection was comparable in healthy subjects, and the pen injector of INS068 had adequate safety and tolerability, supporting it as a new formulation in a phase III study and bridging PK data from early phase clinical trials. Clinical Trial Registration: clinicaltrials.gov, identifier: NCT05336071.

Acetone-induced structural variant of insulin amyloid fibrils

Self-propagating polymorphism of amyloid fibrils is a distinct manifestation of non-equilibrium conditions under which protein aggregation typically occurs. Structural variants of fibrils can often be accessed through physicochemical perturbations of the de novo aggregation process. On the other hand, tiny changes in the amino acid sequence of the parent protein may also result in structurally distinguishable amyloid fibrils. Here, we show that in the presence of acetone, the low-pH fibrillization pathway of bovine insulin (BI) leads to a new type of amyloid with the infrared features (split amide I′ band with the maximum at 1623 cm−1) bearing a striking resemblance to those of the previously reported fibrils from recombinant LysB31-ArgB32 human insulin analog formed in the absence of the co-solvent. Insulin fibrils formed in the presence ([BI-ace]) and absence ([BI]) of acetone cross-seed each other and pass their infrared features to the daughter generations of fibrils. We have used dimethyl sulfoxide (DMSO) coupled to in situ infrared spectroscopy measurements to probe the stability of fibrils against chemical denaturation. While both types of fibrils eventually undergo DMSO-induced disassembly coupled to a β-sheet→coil transition, in the case of [BI-ace] amyloid, the denaturation is preceded by the fibrils transiently acquiring the [BI]-like infrared characteristics. We argue that this effect is caused by DMSO-induced dehydration of [BI-ace]. In support to this hypothesis, we show that, even in the absence of DMSO, the infrared features of [BI-ace] disappear upon drying. We discuss this very peculiar aspect of [BI-ace] fibrils in the context of recently accessed in silico models of plausible structural variants of insulin protofilaments.

Detection of recombinant Pichia pastoris producing glargine

The global prevalence of diabetes continues to rise. Diabetes management involves the administration of insulin to help regulate blood glucose levels. Currently, two main types of insulin are used for diabetes treatment: human insulin and insulin analogs. One such insulin analog is insulin glargine, categorized as a long-acting insulin. Four prominent organisms used for insulin production are Escherichia coli, Pichia pastoris, Saccharomyces cerevisiae, and Hansenula polymorpha. Pichia pastoris was used to produce insulin glargine in this study. The pPICZαA-G plasmid containing the synthetic glargine gene was inserted into Pichia pastoris. Recombinant Pichia pastoris containing the pPICZαA-G plasmid was detected using selection media with Zeocin, Polymerase Chain Reaction (PCR), and DNA sequencing. Through the implementation of selection media containing Zeocin, PCR, and DNA sequencing techniques, it was known that the recombinant Pichia pastoris contained the synthetic glargine gene. Further research will be carried out testing the expression of glargine in recombinant Pichia pastoris.

Undetected Exogenous Insulin Administration in a Child: Assessment of Assay Limitations and Impact on the Practice of Laboratory Medicine

Abstract Introduction/Objective The development of new synthetic insulin analogues over the past few decades has significantly impacted the management of hypoglycemia. However, accurately measuring these analogues presents challenges due to variable cross-reactivity with many insulin assays. Failure to consider cross-reactivity may lead to the misdiagnosis of exogenous insulin administration. Methods/Case Report A 13-year-old female with a history of type 1 DM was presented to an outside hospital emergency department with symptoms indicative of hypoglycemia. Multiple child protective services (CPS) referrals are noted. The patient had experienced several episodes of hypoglycemia over the prior week with blood glucose in the 30-40 mg/dL range. There were no associated symptoms of diarrhea, emesis, or fatigue. The patient was transferred to a pediatric hospital were preliminary investigations indicated abnormally low blood glucose levels with low insulin and C-peptide levels. Further evaluation was initiated to determine the underlying cause of these episodes and to ensure appropriate adjustments in insulin dosing and regimen. Initially, the Elecsys insulin assay (Roche Diagnostics) was utilized to quantify insulin levels which shows a low cross-reactivity for insulin lispro and glargine. To validate the hypothesis of an undetected exogenous insulin overdose, blood samples were sent to another laboratory employing The Advia Centaur insulin assay (Siemens) which exhibits a higher cross-reactivity for insulin lispro and glargine (89%-143%, respectively), indicating a higher recognition and measurement sensitivity for these insulin analogues. The analysis using this assay revealed significantly elevated insulin levels, corroborating the presence of an insulin overdose. The sample at the time of presentation at the outside hospital was confirmed to be 434.1 mU/L. A sample collected 17 hours later had an insulin level of 23.5 mU/L. Results (if a Case Study enter NA) NA Conclusion This case study highlights the critical issue of undetected insulin overdose in a child and emphasizes the limitations of the initial insulin assay employed. Improving assay sensitivity and reliability will enhance patient care and safety. This case study reminds clinicians and laboratory professionals of the need for ongoing quality assurance and vigilance in their practices.

The effect of insulin analogs in people with type 1 diabetes at increased risk of severe hypoglycemia

Type 1 diabetes is characterized by insulin deficiency, and treatment is to supply insulin mimicking the physiological endogenous insulin secretion. Since its discovery, insulin therapy has evolved, and since the 1990s, an increasing number of insulin analogs with various pharmacokinetic and pharmacodynamic profiles have become available. Despite the improvement of insulin therapy, hypoglycemia remains the main side effect and is a daily concern for many people with diabetes and their families. A proportion of people with type 1 diabetes are at increased risk of hypoglycemia and experience recurring episodes. When designing insulin trials, this group of people is most often excluded in order to reduce the risk of adverse study outcomes, even though it may be the group that may benefit the most from treatment with new insulins. The results of the phase III trials, therefore, underestimate the clinical impact and pharmacoeconomic effect of the implementation of new insulins in the broader type 1 diabetes population. This paper reviews the four insulin trials that include people at increased risk of hypoglycemia. In general, the studies confirm the results from phase III trials in terms of similar reduction and maintenance of HbA1c, as well as relative rate reductions of hypoglycemia. However, the absolute treatment differences in the reduction of hypoglycemia are even greater in the trials, including people at high risk of hypoglycemia. This emphasizes the importance of including people at high risk of hypoglycemia to assess the full clinical and pharmacoeconomic benefit of new insulins.

Diselenide-bond replacement of the external disulfide bond of insulin increases its oligomerization leading to sustained activity

Seleno-insulin, a class of artificial insulin analogs, in which one of the three disulfide-bonds (S-S’s) of wild-type insulin (Ins) is replaced by a diselenide-bond (Se-Se), is attracting attention for its unique chemical and physiological properties that differ from those of Ins. Previously, we pioneered the development of a [C7UA,C7UB] analog of bovine pancreatic insulin (SeIns) as the first example, and demonstrated its high resistance against insulin-degrading enzyme (IDE). In this study, the conditions for the synthesis of SeIns via native chain assembly (NCA) were optimized to attain a maximum yield of 72%, which is comparable to the in vitro folding efficiency for single-chain proinsulin. When the resistance of BPIns to IDE was evaluated in the presence of SeIns, the degradation rate of BPIns became significantly slower than that of BPIns alone. Furthermore, the investigation on the intermolecular association properties of SeIns and BPIns using analytical ultracentrifugation suggested that SeIns readily forms oligomers not only with its own but also with BPIns. The hypoglycemic effect of SeIns on diabetic rats was observed at a dose of 150 μg/300 g rat. The strategy of replacing the solvent-exposed S-S with Se-Se provides new guidance for the design of long-acting insulin formulations.

Once-weekly Insulin Icodec as Compared to Once-daily Basal Insulins: A Meta-analysis

BackgroundOnce-weekly basal insulin icodec has been tested in clinical trials for efficacy and safety over currently available glargine-100 and degludec in different clinical settings for type 2 diabetes. We performed this meta-analysis to evaluate its overall safety and efficacy as compared to glargine-100 and degludec (nonicodec), from all available randomized controlled trials. MethodsSeven trials comparing once-daily basal insulin analogs to once-weekly basal insulin icodec were included. Based on available information, outcomes in terms of HbA1c, fasting plasma glucose reduction, and increase in time in range (TIR) were compared. Side-effects were compared for overall hypoglycemia, severe hypoglycemia, and weight gain. The pooled effect size for continuously distributed data was measured as a reduction in “estimated differences in mean (with 95% CI).” For categorical data, the pooled effect size was measured as the Mantel-Haenszel risk ratio (with 95% CI). ResultsAnalyzing against the nonicodec comparators together, the “estimated mean changes” in HbA1c and fasting plasma glucose favoring icodec were −0.22% (−0.35, −0.10) and −1.59 mg% (−9.26, 6.08) respectively. The “estimated mean increment” in weight for icodec was 0.64 kg (0.61, 0.67). The “estimated mean percentage” increment in TIR for icodec was 4.24% (2.99, 5.49). The Mantel-Haenszel risk ratios for all hypoglycemic events and severe hypoglycemia for icodec were 1.24 (1.02, 1.50) (P = .03) and 0.81 (0.31, 2.08) (P is not significant), respectively, suggesting a 24% increased incidence of all hypoglycemia with icodec. ConclusionOnce-weekly basal insulin icodec as compared to once-daily basal insulin analogs had a slight increase in the risk of overall hypoglycemia and weight gain, without any difference in severe hypoglycemia, with similar glycemic control (in terms of fasting plasma glucose, HbA1c, and TIR).

The Role of Ultra-Rapid-Acting Insulin Analogs in Diabetes: An Expert Consensus.

Ultra-rapid-acting insulin analogs (URAA) are a further development and refinement of rapid-acting insulin analogs. Because of their adapted formulation, URAA provide an even faster pharmacokinetics and thus an accelerated onset of insulin action than conventional rapid-acting insulin analogs, allowing for a more physiologic delivery of exogenously applied insulin. Clinical trials have confirmed the superiority of URAA in controlling postprandial glucose excursions, with a safety profile that is comparable to the rapid-acting insulins. Consequently, many individuals with diabetes mellitus may benefit from URAA in terms of prandial glycemic control. Unfortunately, there are only few available recommendations from authoritative sources for use of URAA in clinical practice. Therefore, this expert consensus report aims to define populations of people with diabetes mellitus for whom URAA may be beneficial and to provide health care professionals with concrete, practical recommendations on how best to use URAA in this context.