Discovery of Insulin and Its Effect on Diabetes Mellituster’s choice

Discovery of Insulin and Its Effect on Diabetes Mellitus choice
Insulin is a protein hormone synthesized from the beta-cells of the pancreas. The hormone was discovered in 1921 by Banting and Best. Insulin is secreted in response to increased blood glucose levels. Deficiency of insulin leads to type-1 diabetes mellitus. The present article focused on the role of insulin and newer approaches of delivering insulin in achieving blood sugar control in type-1 diabetic individuals. The present article indicated that insulin in its natural or synthetic form is equally effective in achieving blood glucose control in individuals affected with type-1 diabetes mellitus. The newer approaches and preparations for delivering insulin are also effective in achieving tight control of blood glucose. Dual-hormone therapies are effective in controlling nocturnal blood glucose in children. Newer approaches of delivering insulin were comparable to conventional administration of insulin (through subcutaneous therapy or pre-prandial insulin administration) for short term management of blood glucose. Recombinant insulin and recombinant insulin-like growth factors are effective in achieving blood glucose control. The article also indicated that insulin analogues (insulin glargine and insulin aspartate) were effective in achieving glycemic control in individuals suffering from type-1 diabetes mellitus. Hence, different formulations of insulin should be appropriately combined for achieving stringent blood glucose control in individuals suffering from type-1 or type-2 diabetes mellitus.

Dietary restrictions and engaging in regular physical activity is important for achieving stringent blood glucose control.
Keywords: “Insulin” “Recombinant Insulin” “Insulin Analogues” “Type-1 diabetes mellitus” “Typpe-2 diabetes mellitus”
Discovery of Insulin and Its Effect on Diabetes Mellitus
Introduction
Insulin is a protein hormone that is synthesized and secreted from the beta-cells of the pancreas. The beta-cells are found in the Islets of Langerhans within the pancreas. Insulin was discovered in 1921 by Banting and Best. Insulin is a natural hormone of our body and is secreted in response to increased blood glucose levels. Blood glucose enters the beta-cells and stimulates insulin. Upon entering the beta-cells glucose triggers release of insulin through two mechanisms. In the first mechanism glucose stimulates the release of insulin from the beta-cells into the blood. This step is referred as fast release of insulin. In the second mechanism glucose stimulates long term release of insulin. This step is referred as slow release of insulin. Deficiency of insulin leads to a metabolic disease known as diabetes mellitus. Diabetes mellitus is disease which is featured by sustained elevated blood sugar levels. If the blood sugar levels are transiently elevated it is referred as hyperglycemia. Sustained hyperglycemia leads to diabetes mellitus. Hence, diabetes mellitus refers to sustained hyperglycemia beyond 130mg/dl during fasting condition (Moses et al., 1996). The present article would focus on the role of insulin in managing diabetes mellitus. The article also ventured the usefulness of newer approaches of delivering insulin in achieving blood sugar control in type-1 diabetic individuals. Moreover, the article would also elucidate the effect of genetically engineered insulin in managing diabetes mellitus. The present article is based on a systematic review of existing literature.
Background
Diabetes mellitus is broadly classified into two types. The two types of diabetes mellitus are referred as type-1 and type-2 diabetes mellitus. Type-1 diabetes mellitus is caused due to a deficiency in insulin production and secretion from the pancreatic beta-cells. Type -1 diabetes mellitus is also referred as juvenile onset diabetes. The most common cause of type-1 diabetes mellitus is destruction of pancreatic beta-cells. On the other hand, type-2 diabetes mellitus is caused due to a failure in insulin actions. Insulin binds to its receptor on the plasma membrane of target cells. Such binding facilitates entry of glucose from the blood to the cells (Moses et al., 1996).
In diabetes mellitus, glucose fails to enter the tissues and cells of our body. As a result, cells and tissues cannot utilize glucose for generating ATP. This leads to breakdown of proteins and fats. Hence, diabetes mellitus is featured by increased breakdown of fatty acids and increased protein metabolism. This results in decreased body mass index, reduction in body weight and malnutrition. Malnutrition is one of the predisposing risk factors for decreased immunity. Hence, diabetic individuals are immune-deficient. As a result, diabetes is featured by increased risk of life-threatening infections and delayed wound healing.
The clinical symptoms of diabetes mellitus include sweating, diuresis (increased frequency of urination), fatigue, increased prevalence and persistence of infections. Hence, diabetes mellitus should be appropriately managed by various pharmacological and non-pharmacological interventions (Haidar, 2015). Insulin in its natural form or in its synthetic form is used for managing diabetes mellitus. Specifically, insulin is used to manage type-1 diabetes mellitus. However, the present guidelines suggest that insulin should be also used as an adjunct for the management of type-2 diabetes mellitus.
Different predisposing factors increase the risk of diabetes mellitus. Sedentary lifestyle, genetics, lack of adequate physical activity and dietary habits are the major predisposing risk factors for diabetes mellitus. Dietary habits include increased consumption of carbohydrates. Cereals and sugars are the major food items that increase the complications and burden of diabetes mellitus. Consumption of cereals and sugars increases blood sugar level. On the other hand, reduced intake of dietary fibers may potentiate the burden of diabetes mellitus. Reduced physical activity decreases the entry of glucose into the cells. Hence, inadequate physical activity increases the risk of hyperglycemia. On the other hand, some individuals are at increased risk of diabetic mellitus due to hereditary factors. There are various complications of diabetes mellitus. The most popular complication of diabetes mellitus is diabetic coma. Diabetic coma results from the physiological changes associated with diabetes mellitus. In diabetes mellitus, glucose fails to enter the cells and tissues from blood. Presence of increased blood glucose causes excess filtration of glucose in the kidneys. Glucose is an osmotically active particle and withdraws water from cells and tissues from the kidney (while it passes through the Henle’s loop). This leads to increased volume and frequency of urination leading to diuresis and glucosuria. Presence of glucose in the urine suggests hyperglycemia. Increased diuresis leads to reduced blood volume and reduced venous return. Since less blood enters into the heart from circulation, the cardiac output of the heart is also decreased. Inadequate cardiac output leads to decreased blood in the different end organs. When the flow of blood is reduced in the brain it leads to dizziness and even collapse of the concerned individual. This is referred as diabetic coma. On the other hand, reduced blood supply also damages the tissues of the kidneys. Diabetes mellitus is managed by various pharmacological and non-pharmacological agents. Insulin is administered subcutaneously for the management of diabetes mellitus. Oral hypoglycemic are also administered for achieving stringent blood glucose control. Different guidelines have endorsed the importance of engaging in regular physical activity and complying with dietary restrictions.
Materials and Methodology
The present article was based on literature review approach. The literature review was conducted through a key word search strategy. Different keywords were linked through with each other for selecting relevant articles. The keywords and connectors used in the study include “Insulin” or “Genetically Engineered Insulin” AND “Management of Diabetes” or “Comparison to pharmacological therapy” or “Comparison to non-pharmacological therapy” AND “control of diabetes mellitus” or “Prevention of diabetes”. Different websites were visited for selecting the appropriate articles. The websites that were visited include Cochrane database, Medline Plus, OVID online, Pubmed Central and Google Scholar. Google Scholar was used to validate the reliability of different articles that were selected from the other four websites. Pooled statistical analysis was conducted for appraising the findings. The present article explored two research questions. The research questions were evaluated based on statistical hypothesis:
Whether insulin in its synthetic or natural form is effective in reducing blood glucose levels?
The null hypothesis contended that insulin in its synthetic or natural form is not effective in reducing blood glucose levels (p>0.05).
Whether genetically engineered insulin is effective in reducing blood glucose levels compared to pharmacological and non-pharmacological intervention?
The null hypothesis contended that genetically engineered insulin is as effective in reducing blood glucose levels compared to pharmacological and non-pharmacological interventions (p>0.05).
Results
The results of the selected articles are represented in Table1.
Authors Objectives Study Design Methodology Inference
Haider et al.(2015) To evaluate the efficacy of dual hormone (insulin-glucagon) artificial pancreas compared to single hormone (insulin) artificial pancreas and subcutaneous insulin therapy for managing nocturnal blood glucose in children suffering from type-1 diabetic mellitus. Prospective, randomized, three-way cross over trial The study participants were randomly allocated to three arms of the study namely individuals on dual hormone (insulin-glucagon) artificial pancreas, individuals on single hormone (insulin) artificial pancreas and individuals on subcutaneous insulin therapy. The therapy was continued for three consecutive nights. The primary outcome of the study was to evaluate the percentage of time spent by the study participants with blood glucose concentrations > 4mmol/liter during 23.00 hours to 7.00 hours. The authors indicated that the time spent with blood glucose concentrations > 4mmol/liter during 23.00 hours to 7.00 hours for dual hormone (insulin-glucagon) artificial pancreas was 0%, with single hormone (insulin) artificial pancreas was 3.1% and with subcutaneous insulin therapy was 3.4%. The results indicated that dual hormone therapy was more effective compared to single hormone therapies in achieving nocturnal blood glucose control in children (p=0.0048).
Rizza et al. (1980) The authors evaluated closed-loop intravenous infusion of insulin (artificial pancreas), open-loop continuous subcutaneous insulin and pre-prandial conventional insulin therapy in achieving blood glucose control in individuals suffering from type-1 diabetic mellitus. Prospective, randomized, placebo controlled trial Study participants were randomly allocated to closed-loop intravenous infusion of insulin (artificial pancreas), open-loop continuous subcutaneous insulin therapy and pre-prandial conventional insulin therapy. Long acting zinc injections were administered preprandially for inducing diabetes in study participants. The findings indicated that the circadian concentrations of plasma glucose and mean amplitude of glycemic excursions did not significantly differ between the various therapeutic approaches (p>0.05). However, the plasma insulin levels were significantly higher compared to normal individuals
(p<0.01). The authors concluded that for short term management of blood glucose all three approaches was equally effective.
Ye at al. (2016) The authors evaluated an innovative micro-needle (MN) based cell therapy for controlling blood glucose levels Prospective randomized control trial on murine model. Micro-needle (MN) patches were introduced for glucose-responsive regulation of insulin secretion from exogenous pancreatic beta-cells (without implantation) in chemically induced type-1 diabetic mice. The authors concluded that Micro-needle (MN) patches are effective in reducing blood glucose levels in chemically induced type-1 diabetic mice. Moreover, such patches have the potential to control blood glucose for a period of 10 hours compared to experimental controls (p<0.001).
Vajo, Fawcett & Duckworth (2001) To evaluate the efficacy of insulin analogs manufactured by recombinant DNA technology Prospective randomized placebo controlled trial Two insulin analogues (insulin glargine and insulin aspartate) were prepared by changing the chemical structure of native insulin for achieving sustained hyperglycemia. The authors concluded that the two insulin analogues (insulin glargine and insulin aspartate) were effective in achieving glycemic control in individuals suffering from type-1 diabetes mellitus
Moses et al. (1996) The authors evaluated the role of recombinant human insulin-like growth factor 1 on insulin sensitivity and glycemic control in patients suffering from type-2 diabetes mellitus. Prospective randomized placebo controlled trial Recombinant human insulin-like growth factor 1 was administered in 12 patients for 6 weeks. The dose of recombinant human insulin-like growth factor 1 was 100 microgram/kg administered twice per day. The mean plasma glucose concentrations, glycosylated hemoglobin levels and the mean insulin concentrations were significantly reduced after administration of recombinant human insulin-like growth factor 1. The authors concluded that recombinant human insulin-like growth factor 1 significantly improved insulin sensitivity and glycemic control in patients suffering from type-2 diabetes mellitus (p<0.001).
Analysis
The present article indicated that insulin in its natural or synthetic form is equally effective in achieving blood glucose control in individuals affected with type-1 diabetes mellitus. The newer approaches and preparations for delivering insulin are also effective in achieving tight control of blood glucose. Dual-hormone therapies have the potential to stringently control nocturnal blood glucose in children. Such therapies may provide the balance between compartmentalization of glucose within the blood and the cells/tissues. Minimum amount of blood glucose is required for stimulating insulin release. Hence, insulin-glucagon therapy may be an appropriate option for achieving blood glucose control by potentiating the action of insulin. The pre-requisite of slow pulse of glucose for insulin release was confirmed by Ye et al. (2016) study. On the other hand, newer approaches of delivering insulin might be comparable to conventional administration of insulin (through subcutaneous therapy or pre-prandial insulin administration) for short term management of blood glucose.
Based on the adverse effects of porcine insulin, recombinant insulin or insulin-like growth factors were synthesized. Both recombinant insulin and insulin-like growth factors are effective in achieving blood glucose control. Moreover, insulin-like growth factors are also effective in improving insulin sensitivity in individuals suffering from type-1 diabetic mellitus. Hence, insulin-like growth factors are effective for achieving blood glucose control in tye-1 and type-2 diabetic individuals. Recombinant insulin (Humulin) is prepared by cloning natural human insulin in plasmids of Escherichia coli. Recombinant insulin is both safe and effective compared to porcine insulin. The article also indicated that insulin analogues (insulin glargine and insulin aspartate) were effective in achieving glycemic control in individuals suffering from type-1 diabetes mellitus. These insulin analogues are commercially manufactured through recombinant DNA technology. Hence, recombinant insulin in its natural or synthetic form is also effective in reducing blood glucose in individuals suffering from type-1 diabetes mellitus. Additionally, insulin analogues are also effective in achieving sustained blood glucose control. The article indicated that different formulations of insulin and/or glucagon should be appropriately fixed for achieving stringent blood glucose control.
Discussion and Conclusion
Diabetes mellitus is a life-threatening indication. Hence, stringent control of blood glucose is highly mandatory. Insulin either in its natural or synthetic form should be administered for achieving stringent blood glucose control. Different approaches and formulations of insulin should be administered for achieving tight glycemic control. However, the different formulations should be appropriately titrated for achieving blood glucose control and at the same time preventing the episodes of hypoglycemia. Future research should be conducted on improving insulin sensitivity in individuals affected with type-2 diabetes mellitus. Research should also be conducted to identify the cause-and-effect relationships for the genesis of type-2 diabetes mellitus. Although insulin and insulin-based approaches are used to manage diabetes mellitus; the role of dietary restrictions and regular physical activity should not be undermined. In fact, different guidelines have endorsed that non-pharmacological interventions should be coupled with pharmacological interventions for managing the burden of diabetes mellitus. Blood glucose should be stringently regulated for reducing the complications of diabetes mellitus.
References
Haidar A.(2015). Outpatient overnight glucose control with dual-hormone artificial pancreas, single-hormone artificial pancreas, or conventional insulin pump therapy in children and adolescents with type 1 diabetes: an open-label, randomised controlled trial, The Lancet, 3(8), 595-604
Moses AC, Young SC, Morrow LA, O’Brien M, Clemmons DR. (1996) Recombinant human insulin-like growth factor I increases insulin sensitivity and improves glycemic control in type II diabetes Diabetes.  45(1),91-100
Rizza, R., Gerich, J., Haymond, M, E. Westland, R, . Hall, &. Clemens, A (1980). Control of Blood Sugar in Insulin-Dependent Diabetes: Comparison of an Artificial Endocrine Pancreas, Continuous Subcutaneous Insulin Infusion, and Intensified Conventional Insulin Therapy N Engl J Med 303, 1313-1318
Vajo Z, Fawcett J, & Duckworth W (2001). Recombinant DNA technology in the treatment of diabetes: insulin analogs Endocr Rev.  22(5),706-717
Ye, Y,Yu, J, Wang, C, Nguyen, Y, Walker, G, Buse, J & Gu, Z (2016) Gu. Microneedles Integrated with Pancreatic Cells and Synthetic Glucose-Signal Amplifiers for Smart Insulin Delivery. Advanced Materials, 12-15