Introduction Of Human Insulin Research Articles

Insulin in America: A Right or a Privilege?

Even as a medical student, I was interested in the history of insulin. As an endocrine fellow, I read The Discovery of Insulin by Michael Bliss (1). It is a book anyone interested in diabetes should read, as life before insulin is difficult to appreciate by today’s standard of care, at least in the United States. Amazing stories of what people did to obtain insulin are plentiful, perhaps none more dramatic than Eva Saxl’s story, with her husband making insulin in Shanghai, China, for the more than 200 Jews who escaped Nazi persecution during World War II (2). But in the United States, access to insulin had never been a problem. As a medication required for survival by 10% of those with diabetes, it was always available, although for decades quite crude by today’s standards. The insulin patent from the University of Toronto was sold for $1 with the understanding that cheap insulin would become available (3). Through the years, insulin remained affordable. Even with the introduction of human insulin in 1982 ($14 per vial) and then insulin analogs in 1996 ($24 per vial), the increases in insulin pricing did not seem to be a concern. At least in the United States, the vast majority of patients requiring insulin had access to all of the insulin analogs as they were developed. As the years passed, the cost of insulin continued to increase. In 2004, I was asked to write a review of insulin analogs, which was published in early 2005 (4). Just before publication, one of the reviewers asked me to publish the costs of the insulin products. In those days, we used the Web site drugstore.com to compare prices, and, in general, vials of insulin analogs cost ∼$60 each. Although this represented a substantial price increase since the …

Multimeric disintegrin protein polymer fusions that target tumor vasculature.

Recombinant protein therapeutics have increased in number and frequency since the introduction of human insulin, 25 years ago. Presently, proteins and peptides are commonly used in the clinic. However, the incorporation of peptides into clinically approved nanomedicines has been limited. Reasons for this include the challenges of decorating pharmaceutical-grade nanoparticles with proteins by a process that is robust, scalable, and cost-effective. As an alternative to covalent bioconjugation between a protein and nanoparticle, we report that biologically active proteins may themselves mediate the formation of small multimers through steric stabilization by large protein polymers. Unlike multistep purification and bioconjugation, this approach is completed during biosynthesis. As proof-of-principle, the disintegrin protein called vicrostatin (VCN) was fused to an elastin-like polypeptide (A192). A significant fraction of fusion proteins self-assembled into multimers with a hydrodynamic radius of 15.9 nm. The A192-VCN fusion proteins compete specifically for cell-surface integrins on human umbilical vein endothelial cells (HUVECs) and two breast cancer cell lines, MDA-MB-231 and MDA-MB-435. Confocal microscopy revealed that, unlike linear RGD-containing protein polymers, the disintegrin fusion protein undergoes rapid cellular internalization. To explore their potential clinical applications, fusion proteins were characterized using small animal positron emission tomography (microPET). Passive tumor accumulation was observed for control protein polymers; however, the tumor accumulation of A192-VCN was saturable, which is consistent with integrin-mediated binding. The fusion of a protein polymer and disintegrin results in a higher intratumoral contrast compared to free VCN or A192 alone. Given the diversity of disintegrin proteins with specificity for various cell-surface integrins, disintegrin fusions are a new source of biomaterials with potential diagnostic and therapeutic applications.

L’allergie à l’insuline : mise au point

Allergic reactions to insulin became rare since introduction of human insulin. In this review the diagnostic step, allergologic test and the therapeutic options of allergic reactions to insulin are described.

Animal insulin therapy induces a biased insulin antibody response that persists for years after introduction of human insulin

Administration of exogenous insulin for the treatment of diabetes is often accompanied by the development of insulin antibodies (IA). These antibodies may affect the patient's requirement for insulin by acting as an insulin binding reservoir. The improvement of insulin purification in the 1970s and the development of human recombinant insulin both reduced the incidence of IA and their binding levels. This study investigates the parameters affecting IA frequency and binding levels in a cohort of type 1 diabetes (T1D) patients. All patients were treated with human recombinant insulin. About half of the patients had received animal insulin prior to the introduction of human recombinant insulin. We tested the IA frequency and binding level for all serum samples. IA were further analyzed for their epitope specificity comparing human and porcine insulin binding. We found that T1D patients who received animal insulin in the past show significantly higher IA binding levels as compared to patients treated exclusively with human recombinant insulin (IA binding level of 0.9 and 0.25 index, respectively, P = 0.005). T1D patients who received animal insulin in the past showed a relative bias towards porcine insulin, as compared to T1D patients who were treated with human recombinant insulin exclusively (P < 0.0001). We conclude that IA binding level and epitope specificity are biased by treatment with animal insulin. This bias remains for over 20 years after animal insulin treatment is terminated.

Sudden Death and Human Insulin: Is There a Link?

Case reports from the United Kingdom (UK) in 1989 have suggested that the introduction of human insulin in 1985 was associated with an increased risk of sudden death in insulin-treated diabetic patients. If human insulin increases the risk of sudden death, the number of these should have increased during the period where human insulin was introduced. We therefore identified all cases of sudden death in Denmark in younger insulin-treated diabetic patients, age at death below 50 years. During this period the consumption of human insulin went from 0.2% to 70% of the total consumption in Denmark. The total number of cases fulfilling the inclusion criteria was 226, and the annual number of sudden deaths did not change during the study period (p = 0.14). The number of deaths due to hypoglycaemia and cases with unexplained cause of death also remained constant (test for trend: p = 0.44). Chronic alcohol abuse or acute alcohol intoxication was found in 50% of the 135 patients dying from hypoglycaemia, ketoacidosis or unknown cause of death (including found dead in bed), while this was the case in only 16% of the remaining 91 cases dying from other natural causes. We conclude that introduction of human insulin in Denmark was not followed by an increase in sudden deaths among younger insulin-treated diabetic patients.

Human insulin and awareness of acute hypoglycaemic symptoms in insulin-dependent diabetes

Some insulin-dependent diabetic patients who have clear symptoms of hypoglycaemia during animal insulin treatment have reported loss of these symptoms when human insulin preparations are introduced. A survey of Mersey Region, UK, identified eleven patients whose awareness of hypoglycaemia was lost after introduction of human insulin but returned with animal insulin treatment; seven took part in the study. Acute hypoglycaemia was induced in these patients on two occasions by intravenous infusion of porcine or human soluble insulin (2·5 mU. kg -1, min -1) in random order. There was no significant difference between porcine and soluble insulin in the plasma glucose profile; mean (SEM) plasma glucose fell from 7·1 (0·4) mmol/l to a nadir of 1·5 (0·1) mmol/l with porcine insulin and from 7·1 (0·5) mmol/l to 1·6 (0·2) mmol/l with human insulin. An acute autonomic reaction occurred in all seven patients, at a similar plasma glucose concentration (1·9 [0·1] mmol/l with porcine insulin; 2·0 [0·2] mmol/l with human insulin). There were no significant differences in the frequency of symptoms or signs of hypoglycaemia between the two insulin species, nor any consistent differences in plasma glucagon, cortisol, growth hormone, adrenaline, or noradrenaline responses to hypoglycaemia. Symptomatic and hormonal responses to acute hypoglycaemia induced by porcine and human soluble insulins therefore seem to be almost indistinguishable, even in patients carefully selected for their apparent loss of hypoglycaemia awareness with human insulin.