In vitro bioactivity of insulin analogues: Lipogenic and anti-lipolytic potency and their interaction with the effect of native insulin (original) (raw)
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Mechanism of action of insulin and insulin analogues
Diabetologia, 1981
A [14C]~glucose tracer infusion method was used to compare the effects of insulin infusion on glucose metabolism with the effects of infusion of three semisynthetic modified insulins and of proinsu= lin. Insulin produced hypoglycaemia in the anaesthetised dog by decreasing hepatic glucose production and increasing peripheral glucose utilisation. Compensatory antihypoglycaemic mechanisms eventually modified these responses. A1, Be9-Diacetyl insulin exerted an hypoglycaemic effect entirely by stimulation of peripheral glucose uptake. A1-B29 crosslinked insulins and proinsulin produced hypoglycaemia almost entirely by decreasing hepatic glucose production and had little effect on tissue uptake. These observations suggest that insulin analogues may have actions in vivo that are qualitatively different from those of native insulin and suggest that certain analogues have a predominant action on the liver. This has important therapeutic implications concerning the development of semisynthetic insulins for clinical use.
Novel insulin analogues and its mitogenic potential
Diabetes, Obesity and Metabolism, 2006
Insulin analogues were developed to modify the structure of the human insulin molecule in order to more accurately approximate the endogenous secretion of insulin. With the help of recombinant technology and sitedirected mutagenesis, the insulin molecule can be modified to either delay or shorten absorption time, providing better insulin treatment options and facilitating the achievement of glycaemic goals. Changing the structure of the insulin molecule, however, may significantly alter both its metabolic and mitogenic activity. Multiple factors such as residence time on the receptor, dissociation rate, rate of receptor internalization and the degree of phosphorylation of signalling proteins can affect the mitogenic potencies of insulin analogues. Changes in the structure of the insulin have raised concern about the safety of the insulin analogues. For example, questions have emerged about the relationship between the use of insulin lispro and insulin glargine and the progression of diabetic retinopathy. Two studies have shown progression of retinopathy with the use of insulin lispro. However, others have not confirmed these results, and causality could not be proven as progression of retinopathy can occur with rapid improvement in glycaemic control, and methods of assessments among studies were not consistent. Therefore, we examine the metabolic and mitogenic characteristics of the three insulin analogues, insulin lispro, insulin aspart and insulin glargine, that are currently on the market, as well as the two insulin analogues, insulin glulisine and insulin detemir, that are soon going to be available for clinical use.
Insulin analogs: Glimpse on contemporary facts and future prospective
Life Sciences, 2019
Insulin remains a predominant life-saving medication for type 1 and type 2 Diabetes Mellites. Natural insulin secretion limits the fluctuation of the narrow and high surge of blood glucose levels. However, imitating the same by external insulin remains a challenge as a variety of insulin analogs (rapid acting, short acting, intermediate acting and long-acting) have different pharmacokinetic (PK) and pharmacodynamic (PD) properties. Inconsistent reduction in overall hyperglycemia level and nocturnal hypoglycemia due to variable absorption time and time action profile predominantly highlights the need of revisiting the PK/PD of insulin analogs as single analog is not yet sufficed to replace internal insulin exogenously. Combination therapy with basal and prandial insulins or intensification of hypoglycemic therapy with premixed insulins are of prime importance in managing diabetes effectively, imitating the natural insulin secretion. Therefore, the knowledge of PK/PD properties might help a practitioner to design, implement and manage insulin replacement therapy effectively and averting adverse events. Present study reports the comparative analysis of PK/PD profile of various insulin analogs based on the concurrent information about clinical aspects. Moreover, study interlinks the major concerns of therapeutic efficacy of insulin analogs with their respective onset of action and duration of effectiveness and reported adverse drug reaction which explore the scope of improvement.
Diabetologia, 1976
Beef insulin, pork proinsulin and four derivatives of beef insulin modified at the A1-B29 site on the molecular surface have been studied. Three derivatives had a synthetic crosslink between the A and B chains. Previous studies with these materials [2, 3 and 5] had demonstrated in vivo bioactivities which were much higher than those displayed in vitro. This paper reports experiments which explain this discrepancy. The analogues were administered at equimolar rates to anaesthetised greyhounds by a priming-dose constant infusion technique and the plasma concentrations achieved were estimated by radioimmunoassay. Proinsulin and the modified insulins were metabolised more slowly than insulin. Biopotency values, which related fall in plasma glucose concentration to the total administered dose of analogue, agreed broadly with published results of conventional in vivo bioassays. On the other hand, calculation of potency in relation to the serum concentration of analogue actually achieved, yielded results which agreed more closely with in vitro assay data. We conclude that for these analogues, reported discrepancies between in vitro and in vivo biopotencies can be largely explained by the different rates at which these materials are metabolised.
In order to provide comprehensive information on the differences in bioactivity between human insulin and insulin analogues, published in vitro comparisons of human insulin and the rapid acting analogues insulin lispro (Humalog ® ), insulin aspart ( NovoRapid ® ), insulin glulisine (Apidra ® ), and the slow acting analogues insulin glargine (Lantus ® ), and insulin detemir (Levemir ® ) were gathered from the past 20 years (except for receptor binding studies). A total of 50 reports were retrieved, with great heterogeneity among study methodology. However, various differences in bioactivity compared to human insulin were obvious (e.g. differences in effects on metabolism, mitogenesis, apoptosis, intracellular signalling, thrombocyte function, protein degradation). Whether or not these differences have clinical bearings (and among which patient populations) remains to be determined.
Characterisation of insulin analogues therapeutically available to patients
PloS one, 2018
The structure and function of clinical dosage insulin and its analogues were assessed. This included 'native insulins' (human recombinant, bovine, porcine), 'fast-acting analogues' (aspart, glulisine, lispro) and 'slow-acting analogues' (glargine, detemir, degludec). Analytical ultracentrifugation, both sedimentation velocity and equilibrium experiments, were employed to yield distributions of both molar mass and sedimentation coefficient of all nine insulins. Size exclusion chromatography, coupled to multi-angle light scattering, was also used to explore the function of these analogues. On ultracentrifugation analysis, the insulins under investigation were found to be in numerous conformational states, however the majority of insulins were present in a primarily hexameric conformation. This was true for all native insulins and two fast-acting analogues. However, glargine was present as a dimer, detemir was a multi-hexameric system, degludec was a dodecamer (...
Effect of insulin analogues on 3t3-l1 adipogenesis and lipolysis
European Journal of Clinical Investigation, 2011
Background Insulin has several biological functions besides glycaemic control. We investigated and compared the effects of six different commercial insulins on adipocyte cell differentiation, the lipolytic activity of differentiated cells, and the expression levels of genes involved in adipogenesis and associated with insulin activity. Materials and methods 3T3-L1 cells were induced to differentiate with six commercial insulins: glargine, lispro, aspart, detemir, NPH and regular recombinant human insulin (used as control). Cell differentiation, lipolysis and gene expression were measured at day 7 (D7) and day 10 (D10) after induction of differentiation in these cells. Results The highest values of cell differentiation and lipolysis were found at D10 for all the insulins used. Preadipocyte differentiation differed at both times depending on the insulin used, with detemir insulin being the least adipogenic. The PPARc mRNA level varied according to the insulin and was a good genetic marker of adipogenesis at D7. Cells treated with glargine insulin showed the highest lipolysis and HSL expression on both days. Gene expression levels of InsR, SREBP-1c and SCD-1 differed depending on the insulin studied. Conclusions Detemir insulin was the least adipogenic of the insulins tested, whereas treatment with glargine insulin tended to produce the highest lipolysis levels. Under these experimental conditions, the modifications made in commercial insulins to improve glycaemic control also affect adipocyte differentiation, the lipolysis level of differentiated cells, and the expression of different genes that can modify metabolic pathways independently of glucose metabolism.