scholarly journals Molecular and pharmacological characterization of insulin icodec: a new basal insulin analog designed for once-weekly dosing

2021 ◽  
Vol 9 (1) ◽  
pp. e002301
Author(s):  
Erica Nishimura ◽  
Lone Pridal ◽  
Tine Glendorf ◽  
Bo Falk Hansen ◽  
František Hubálek ◽  
...  
Keyword(s):  
Type 2 Diabetes ◽  
Half Life ◽  
Intracellular Signaling ◽  
Basal Insulin ◽  
Subcutaneous Administration ◽  
Insulin Analog ◽  
Pharmacological Properties ◽  
Molecular Stability

IntroductionInsulin icodec is a novel, long-acting insulin analog designed to cover basal insulin requirements with once-weekly subcutaneous administration. Here we describe the molecular engineering and the biological and pharmacological properties of insulin icodec.Research design and methodsA number of in vitro assays measuring receptor binding, intracellular signaling as well as cellular metabolic and mitogenic responses were used to characterize the biological properties of insulin icodec. To evaluate the pharmacological properties of insulin icodec in individuals with type 2 diabetes, a randomized, double-blind, double-dummy, active-controlled, multiple-dose, dose escalation trial was conducted.ResultsThe long half-life of insulin icodec was achieved by introducing modifications to the insulin molecule aiming to obtain a safe, albumin-bound circulating depot of insulin icodec, providing protracted insulin action and clearance. Addition of a C20 fatty diacid-containing side chain imparts strong, reversible albumin binding, while three amino acid substitutions (A14E, B16H and B25H) provide molecular stability and contribute to attenuating insulin receptor (IR) binding and clearance, further prolonging the half-life. In vitro cell-based studies showed that insulin icodec activates the same dose-dependent IR-mediated signaling and metabolic responses as native human insulin (HI). The affinity of insulin icodec for the insulin-like growth factor-1 receptor was proportionately lower than its binding to the IR, and the in vitro mitogenic effect of insulin icodec in various human cells was low relative to HI. The clinical pharmacology trial in people with type 2 diabetes showed that insulin icodec was well tolerated and has pharmacokinetic/pharmacodynamic properties that are suited for once-weekly dosing, with a mean half-life of 196 hours and close to even distribution of glucose-lowering effect over the entire dosing interval of 1 week.ConclusionsThe molecular modifications introduced into insulin icodec provide a novel basal insulin with biological and pharmacokinetic/pharmacodynamic properties suitable for once-weekly dosing.Trial registration numberNCT02964104.

scholarly journals Combined use of basal insulin analog and acarbose reduces postprandial glucose in patients with uncontrolled type 2 diabetes

2014 ◽  
Vol 6 (2) ◽  
pp. 219-226 ◽  
Author(s):  
Ji‐Hyun Kim ◽  
Ji‐Hyun Ahn ◽  
Soo‐Kyung Kim ◽  
Dae‐Ho Lee ◽  
Hye‐Soon Kim ◽  
...  
Keyword(s):  
Type 2 Diabetes ◽  
Basal Insulin ◽  
Postprandial Glucose ◽  
Insulin Analog ◽  
Combined Use

Insulin Detemir—A New Basal Insulin Analog

2005 ◽  
Vol 39 (3) ◽  
pp. 502-507 ◽  
Author(s):  
Jennifer D Goldman-Levine ◽  
Karen W Lee
Keyword(s):  
Type 2 Diabetes ◽  
Basal Insulin ◽  
Insulin Detemir ◽  
Data Extraction ◽  
Safety Data ◽  
Clinical Trial Data ◽  
Insulin Analog ◽  
Study Selection

OBJECTIVE: To review the pharmacology, pharmacokinetics, clinical trial data, adverse effects, and role in therapy of insulin detemir. DATA SOURCES: Articles and meeting abstracts were identified through searches of MEDLINE (1996–June 2004), EMBASE (1980–June 2004), and International Pharmaceutical Abstracts (1970–June 2004) databases, and unpublished information was provided by the manufacturer. STUDY SELECTION AND DATA EXTRACTION: All available studies relating to insulin detemir's pharmacology were selected. Only human studies were used for pharmacokinetic, drug interaction, efficacy, and safety data. DATA SYNTHESIS: Insulin detemir is a basal insulin analog that has been shown to improve glycemic control in patients with type 1 and type 2 diabetes. CONCLUSIONS: Insulin detemir offers some benefits over NPH for use as basal insulin in patients with type 1 and type 2 diabetes.

scholarly journals Oral GLP-1 Analogue Ameliorates Obesity-Induced Diabetes In Db/Db Mouse

2021 ◽  
Author(s):  
Hanlin Zhang ◽  
Meng Dong ◽  
Wanzhu Jin
Keyword(s):  
Type 2 Diabetes ◽  
Lactococcus Lactis ◽  
Delivery System ◽  
Half Life ◽  
Oral Drug Delivery ◽  
Single Amino Acid ◽  
Oral Drug ◽  
Oral Drug Delivery System

Abstract Type 2 diabetes is currently experiencing an outbreak worldwide. GLP-1 effectively lowers blood glucose level as an emerging target for the treatment of type 2 diabetes. However, the application of GLP-1 is limited by short half-life and too expensive cost in clinic. In this study we employed the food-grade probiotics as delivery system to express human GLP-1 and its analogue. Recombinant lactococcus lactis could express GLP-1 and analogue in vitro and modified GLP-1 analogue was more resistant to DPP-4 degradation. Oral administration of GLP-1 analogue could reduce the fat mass. More importantly, GLP-1 analogue improved hyperglycemia and insulin resistance in Db/Db mouse although the insulin secretion is not observed in vitro. Our study demonstrates that lactococcus lactis genetically modified with single amino acid mutation could prolong half-life of GLP-1 and increase insulin sensitivity in Db/Db mouse model as an oral drug delivery system driving the development and innovation of drug therapy for type 2 diabetes.

scholarly journals Effects of Basal Insulin Analog and Metformin on Glycaemia Control and Weight as Risk Factors for Endothelial Dysfunction

2008 ◽  
Vol 8 (4) ◽  
pp. 309-312 ◽  
Author(s):  
Belma Aščić – Buturović ◽  
Mirsad Kacila
Keyword(s):  
Type 2 Diabetes ◽  
Cardiovascular Diseases ◽  
Endothelial Dysfunction ◽  
Weight Reduction ◽  
Basal Insulin ◽  
Lifestyle Modification ◽  
Insulin Analog ◽  
Glycaemia Control ◽  
Fasting Glycaemia

Obese patients with type 2 diabetes and impaired glucose tolerance are at increased risk of development of cardiovascular diseases. Endothelial dysfunction may be a reason for development of atherosclerosis and cardiovascular diseases. Lifestyle modification, increased physical activity, weight reduction, energy restricted diet and good glycaemia control can be useful for the endothelial function improvement and may decrease the risk of cardiovascular diseases. The aim of this study was to evaluate the effects of basal insulin analog and metformin on glycaemia control and weight as risk factors of endothelial dysfunction. Total of 15 patients (9 male and 6 female) with type 2 diabetes were studied. The patients were monitored over six months period. Glycated hemoglobin (HbA1c), fasting plasma glucose (FPG), postprandial plasma glucose (PPG), and body mass index (BMI) were observed. Mean age of the subjects was 53,4 ± 6,27 years. Mean diabetes duration was 3,71 ± 1,89 years. At the end of the study mean body mass index decreased from 27,5 ± 1,45 kg/m2 to 25,7 ±1,22 kg/m2. In this study we included diabetic patients with fasting glycaemia over 7 mmol/ dm3, postmeal glycaemia over 7,8 mmol/dm3 and glycated hemoglobin over 7%. Prior to the study, the patients were treated with premix insulin divided in two daily doses and metformin after the lunch, which did not result in sufficient regulation of glycaemia. We started treatment with one daily insulin basal analog and three daily doses of metformin and monitored the above mentioned parameters. We advised patients to change their lifestyle, to practice energy restricted diet and to increase their daily physical activity. Insulin doses were titrated separately for each patient (0,7-1 IU/kg). Weight reduction was recorded after the study. Mean fasting glycaemia decreased from 8,6±0,49 mmol/dm3 to 7,04±0,19 mmol/dm3 (p < 0,05). Mean postmeal glycaemia decreased from 9,74 ± 0,79 mmol/dm3 to 7,6 ± 0,43 mmol/dm3 (p<0,05). Mean HbA1c decreased from 8,80 ± 0,59 % to 7,11 ± 0,22 % (p<0,05).Treatment with one daily doses of basal insulin analog and three daily doses of metformin with lifestyle modification and weight reduction, in obese patients with type 2 diabetes can be useful for the endothelial function improvement and may decrease the risk of cardiovascular diseases.

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