**3. Early research**

Allen, who was born in Iowa, studied medicine at the University of California. He attended Harvard Medical School between 1909 and 1912, and thanks to his father's financing, he also published *Studies on Diabetes and Glycosuria* in 1913.

Insulin receptors were thoroughly studied mostly by Kahn [8], **Figure 8**. He spent most of his career investigating the role of insulin sensitivity in obesity and diabetes.

Kahn currently works as the Chief Academic Officer and Head of Joslin's Section on Integrative Physiology and Metabolism at the Joslin Diabetes Center.

He thoroughly investigated how cells are affected by insulin and the reason behind why only a particular group of cells develops insulin resistance, which is one of the main causes of type 2 diabetes.

**Figure 8.** Carl Ronald Kahn (born January 14, 1944) (Source: [8]).

**Figure 7.** Frederick Madison Allen (1879–1964) (Source: [7]).

**Figure 6.** Elliott Proctor Joslin, MD (June 6, 1869–January 28, 1962) (Source: [6]).

6 Ultimate Guide to Insulin

Kahn through his excellence in diabetes study became Research Director of Joslin and Associate Professor of Medicine at Harvard Medical School in 1981 and 1984. He was the first to discover the importance of the role of insulin actions in the brain and the causation of metabolic diseases by fat cells.

Collip took up the job of purifying the extract within a period of 2 weeks, and it was again administered to Thompson. During the second time, the insulin extract stabilised Thompson's

Collip took up the job of purifying the extract within a period of 2 weeks, and it was again administered to Thompson. During the second time, the insulin extract stabilised Thompson's

Pancreatic diabetes was discovered by Minkowski [11], **Figure 11**. Minkowski studied at the University of Konigsberg before becoming a professor in Strasburg in 1888. Minkowski was a

White [12] was the pioneer of research into diabetic woman during pregnancy; it led to the White classification which is being used to assess diabetes during pregnancy (**Figure 12**).

This classification is still used today to differentiate between existing diabetes before pregnancy and gestational diabetes. The White classification established her in the diabetes history. The secretion of insulin is an energy requiring process which involves the microtubule-microfilament system in beta cells of the islets of Langerhans. Varied numbers of mediators have

The level of glucose in the interstitial fluid regulates the activity of the beta cells. A sharp increase of 8–10 in the secretion of insulin usually occurs in response to an increase in plasma glucose from 70 to 150 mg/dl. During the same phase, a simultaneous decrease in the secretion of glucagon from A cell occurs. There is a greater B-cell response observed following oral

Of major importance, defects in the below-stated portions of the hormone's properties and journey in the body have been correlated and are most often related to hypertension, insulin

Introductory Chapter: Historical Perspective and Brief Overview of Insulin

Introductory Chapter: Historical Perspective and Brief Overview of Insulin

http://dx.doi.org/10.5772/intechopen.81183

http://dx.doi.org/10.5772/intechopen.81183

9

9

Pancreatic diabetes was discovered by Minkowski [11], **Figure 11**. Minkowski studied at the University of Konigsberg before becoming a professor in Strasburg in 1888. Minkowski was a

White [12] was the pioneer of research into diabetic woman during pregnancy; it led to the White classification which is being used to assess diabetes during pregnancy (**Figure 12**).

This classification is still used today to differentiate between existing diabetes before pregnancy and gestational diabetes. The White classification established her in the diabetes history. The secretion of insulin is an energy requiring process which involves the microtubule-microfilament system in beta cells of the islets of Langerhans. Varied numbers of mediators have

The level of glucose in the interstitial fluid regulates the activity of the beta cells. A sharp increase of 8–10 in the secretion of insulin usually occurs in response to an increase in plasma glucose from 70 to 150 mg/dl. During the same phase, a simultaneous decrease in the secretion of glucagon from A cell occurs. There is a greater B-cell response observed following oral

Of major importance, defects in the below-stated portions of the hormone's properties and journey in the body have been correlated and are most often related to hypertension, insulin

as opposed to intravenous glucose administration. This is known as 'incretin' effect.

**Figure 10.** James Bertram Collip, CBE, FRS, FRSC, FRCP, FRCPC (November 20, 1892–June 19, 1965) (Source: [10]).

**Figure 10.** James Bertram Collip, CBE, FRS, FRSC, FRCP, FRCPC (November 20, 1892–June 19, 1965) (Source: [10]).

as opposed to intravenous glucose administration. This is known as 'incretin' effect.

blood glucose levels, which saved his life.

blood glucose levels, which saved his life.

been implicated in the release of insulin.

been implicated in the release of insulin.

resistance and type 2 diabetes [13–19].

resistance and type 2 diabetes [13–19].

pioneer in the procedure of pancreatectomy in dogs.

pioneer in the procedure of pancreatectomy in dogs.

Bouchardat [9], **Figure 9**, is considered as the founder of diabetology, who helped in the treatment of diabetic patients before the creation of insulin in 1922. He was the first clinician who educated patients of diabetology to become aware of the disease. He also stressed the importance of exercise and urine glucose self-monitoring in the treatment of diabetes. He was the pioneer of advising against taking of sugars and starchy food to reduce glycosuria. He was also the first to hypothesise the location of diabetes in the pancreas.

Bouchardat wrote and published a number of books on diabetes, amongst them is his most well-known work 'De la Glycosurie ou diabète sucré, son traitement hygénigue'.

It was Collip [10], **Figure 10**, a biochemist, who played an important role in the production of the first insulin dose that was found to be appropriate for injection into humans.

The credit for the discovery of insulin goes to Banting and Best, but their extract was raw and failed to produce beneficial effects after being administered to Leonard Thompson, the first human to receive it.

**Figure 9.** Apollinaire Bouchardat (July 23, 1809 – April 7, 1886), a French pharmacist and hygienist born in L'Isle-sur-Serein (Source: [9]).

Collip took up the job of purifying the extract within a period of 2 weeks, and it was again administered to Thompson. During the second time, the insulin extract stabilised Thompson's blood glucose levels, which saved his life.

Pancreatic diabetes was discovered by Minkowski [11], **Figure 11**. Minkowski studied at the University of Konigsberg before becoming a professor in Strasburg in 1888. Minkowski was a pioneer in the procedure of pancreatectomy in dogs.

White [12] was the pioneer of research into diabetic woman during pregnancy; it led to the White classification which is being used to assess diabetes during pregnancy (**Figure 12**).

This classification is still used today to differentiate between existing diabetes before pregnancy and gestational diabetes. The White classification established her in the diabetes history.

The secretion of insulin is an energy requiring process which involves the microtubule-microfilament system in beta cells of the islets of Langerhans. Varied numbers of mediators have been implicated in the release of insulin.

The level of glucose in the interstitial fluid regulates the activity of the beta cells. A sharp increase of 8–10 in the secretion of insulin usually occurs in response to an increase in plasma glucose from 70 to 150 mg/dl. During the same phase, a simultaneous decrease in the secretion of glucagon from A cell occurs. There is a greater B-cell response observed following oral as opposed to intravenous glucose administration. This is known as 'incretin' effect.

Of major importance, defects in the below-stated portions of the hormone's properties and journey in the body have been correlated and are most often related to hypertension, insulin resistance and type 2 diabetes [13–19].

**Figure 10.** James Bertram Collip, CBE, FRS, FRSC, FRCP, FRCPC (November 20, 1892–June 19, 1965) (Source: [10]).

The journey of insulin can be divided into five stages, which can be related to insulin resis-

Introductory Chapter: Historical Perspective and Brief Overview of Insulin

http://dx.doi.org/10.5772/intechopen.81183

11

• Defect in the vasoactive properties of insulin during insulin resistance, which includes cap-

• The GLUT4 translocation to the muscle membrane is diminished in humans [14, 22, 30–36].

Most of it is routed to the lysosome for degradation. But most of the degradation of the circulating hormone remaining after second pass through the liver continues in the kidney.

[1] Best CH, Banting FG. https://southcoastherald.co.za/184174/canada-pioneers-diabetes-

[2] Banting FG. https://www.diabetes.co.uk/pioneers/frederick-banting.html [3] Banting W. https://www.diabetes.co.uk/pioneers/william-banting.html [4] Best CH. https://www.diabetes.co.uk/pioneers/charles-herbert-best.html

[5] Thompson L. https://www.diabetes.co.uk/pioneers/leonard-thompson.html [6] Joslin EP. https://www.diabetes.co.uk/pioneers/dr-elliott-proctor-joslin.html

[8] Kahn CR. https://www.diabetes.co.uk/pioneers/ronald-kahn.html

[10] Collip JB. https://www.diabetes.co.uk/pioneers/james-collip.html

[7] Allen FM. https://www.diabetes.co.uk/pioneers/frederick-madison-allen.html

[9] Kahn CR. https://www.diabetes.co.uk/pioneers/apollinaire-bouchardat.html

• Decreased hepatic clearance of insulin [37] and CEACAM1 expression [38] in obesity.

• There is compromised glomerular function in obese people [22, 39–41].

tance and type 2 diabetes:

**Author details**

**References**

treatment/

Gaffar Sarwar Zaman

illary recruitment [22, 26–29].

• Diabetic cell having defective insulin exocytosis [20–25].

Address all correspondence to: gffrzaman@gmail.com

King Khalid University, Abha, Kingdom of Saudi Arabia

**Figure 11.** Oskar Minkowski (January 13, 1858–July 18, 1931) (Source: [11]).

**Figure 12.** Priscilla White (March 17, 1900–December 16, 1989) (Source: [12]).

The journey of insulin can be divided into five stages, which can be related to insulin resistance and type 2 diabetes:


Most of it is routed to the lysosome for degradation. But most of the degradation of the circulating hormone remaining after second pass through the liver continues in the kidney.

#### **Author details**

Gaffar Sarwar Zaman

Address all correspondence to: gffrzaman@gmail.com

King Khalid University, Abha, Kingdom of Saudi Arabia

#### **References**

**Figure 12.** Priscilla White (March 17, 1900–December 16, 1989) (Source: [12]).

**Figure 11.** Oskar Minkowski (January 13, 1858–July 18, 1931) (Source: [11]).

10 Ultimate Guide to Insulin


American Journal of Physiology. Endocrinology and Metabolism. 2000;**279**:E520-E528.

Introductory Chapter: Historical Perspective and Brief Overview of Insulin

http://dx.doi.org/10.5772/intechopen.81183

13

[26] de Jongh RT, Serné EH, IJzerman RG, de Vries G, Stehouwer CDA. Impaired microvascular function in obesity: Implications for obesity-associated microangiopathy, hypertension, and insulin resistance. Circulation. 2004;**109**:2529-2535. DOI: 10.1161/01.

[27] Clerk LH, Vincent MA, Jahn LA, Liu Z, Lindner JR, Barrett EJ. Obesity blunts insulinmediated microvascular recruitment in human forearm muscle. Diabetes. 2006;**55**:1436-

[28] Keske MA, Clerk LH, Price WJ, Jahn LA, Barrett EJ. Obesity blunts microvascular recruitment in human forearm muscle after a mixed meal. Diabetes Care. 2009;**32**:1672-1677.

[29] Broussard JL, Castro AVB, Iyer M, Paszkiewicz RL, Bediako IA, Szczepaniak LS, et al. Insulin access to skeletal muscle is impaired during the early stages of diet-induced

[30] Klip A, Ramlal T, Bilan PJ, Cartee GD, Gulve EA, Holloszy JO. Recruitment of GLUT-4 glucose transporters by insulin in diabetic rat skeletal muscle. Biochemical and Biophysical

Research Communications. 1990;**172**:728-736. DOI: 10.1016/0006-291X(90)90735-6 [31] Zierath JR, He L, Gumà A, Odegoard Wahlström E, Klip A, Wallberg-Henriksson H. Insulin action on glucose transport and plasma membrane GLUT4 content in skeletal muscle from patients with NIDDM. Diabetologia. 1996;**39**:1180-1189. DOI: 10.1007/

[32] Garvey WT, Maianu L, Zhu JH, Brechtel-Hook G, Wallace P, Baron AD. Evidence for defects in the trafficking and translocation of GLUT4 glucose transporters in skeletal muscle as a cause of human insulin resistance. The Journal of Clinical Investigation.

[33] Sylow L, Jensen TE, Kleinert M, Højlund K, Kiens B, Wojtaszewski J, et al. Rac1 signaling is required for insulin-stimulated glucose uptake and is dysregulated in insulinresistant murine and human skeletal muscle. Diabetes. 2013;**62**:1865-1875. DOI: 10.2337/

[34] Aslamy A, Thurmond DC. Exocytosis proteins as novel targets for diabetes prevention and/or remediation? American Journal of Physiology. Regulatory, Integrative and

[36] Samuel VT, Shulman GI. Mechanisms for insulin resistance: Common threads and miss-

[37] Jung S-H, Jung C-H, Reaven GM, Kim SH. Adapting to insulin resistance in obesity: Role

ing links. Cell. 2012;**148**:852-871. DOI: 10.1016/j.cell.2012.02.017

of insulin secretion and clearance. Diabetologia. 2018;**61**:681-687

Comparative Physiology. 2017;**312**:R739-R752. DOI: 10.1152/ajpregu.00002.2017 [35] Foley K, Boguslavsky S, Klip A. Endocytosis, recycling, and regulated exocytosis of glucose transporter 4. Biochemistry. 2011;**50**:3048-3061. DOI: 10.1021/bi2000356

obesity. Obesity (Silver Spring). 2016;**24**:1922-1928. DOI: 10.1002/oby.21562

DOI: 10.1152/ajpendo.2000.279.3.E52e

CIR.0000129772.26647

DOI: 10.2337/dc09-0206

BF02658504

db12-1148

1998;**101**:2377-2386. DOI: 10.1172/JCI1557

1442. DOI: 10.2337/db05-1373


American Journal of Physiology. Endocrinology and Metabolism. 2000;**279**:E520-E528. DOI: 10.1152/ajpendo.2000.279.3.E52e

[26] de Jongh RT, Serné EH, IJzerman RG, de Vries G, Stehouwer CDA. Impaired microvascular function in obesity: Implications for obesity-associated microangiopathy, hypertension, and insulin resistance. Circulation. 2004;**109**:2529-2535. DOI: 10.1161/01. CIR.0000129772.26647

[11] Minkowski O. https://www.diabetes.co.uk/pioneers/oskar-minkowski.html

[13] Taniguchi CM, Emanuelli B, Kahn CR. Critical nodes in signalling pathways: Insights into insulin action. Nature Reviews. Molecular Cell Biology. 2006;**7**:85-96. DOI: 10.1038/

[14] Hoehn KL, Hohnen-Behrens C, Cederberg A, Wu LE, Turner N, Yuasa T, et al. IRS1 independent defects define major nodes of insulin resistance. Cell Metabolism. 2008;

[15] Odegaard JI, Chawla A. Pleiotropic actions of insulin resistance and inflammation in metabolic homeostasis. Science. 2013;**339**:172-177. DOI: 10.1126/science.1230721

[16] Boucher J, Kleinridders A, Kahn CR. Insulin receptor signaling in normal and insulinresistant states. Cold Spring Harbor Perspectives in Biology. 2014;**6**:a009191. DOI: 10.1101/

[17] DeFronzo RA, Ferrannini E, Groop L, Henry RR, Herman WH, Holst JJ, et al. Type 2 diabetes mellitus. Nature Reviews Disease Primers. 2015;**1**:15019. DOI: 10.1038/nrdp.2015.19

[18] Samuel VT, Shulman GI. The pathogenesis of insulin resistance: Integrating signaling pathways and substrate flux. The Journal of Clinical Investigation. 2016;**126**:12-22. DOI:

[19] Haeusler RA, McGraw TE, Accili D. Biochemical and cellular properties of insulin receptor signalling. Nature Reviews. Molecular Cell Biology. 2018;**19**:31-44. DOI: 10.1038/

[20] Ferdaoussi M, MacDonald PE. Toward connecting metabolism to the exocytotic site.

[21] Gandasi NR, Yin P, Riz M, Chibalina MV, Cortese G, Lund P-E, et al. Ca2+ channel clustering with insulin-containing granules is disturbed in type 2 diabetes. The Journal of

[22] Tokarz VL, MacDonald PE, Klip A. The cell biology of systemic insulin function. The Journal of Cell Biology. 2018. DOI: 10.1083/jcb.201802095. http://jcb.rupress.org/content/

[23] Lang DA, Matthews DR, Burnett M, Turner RC. Brief, irregular oscillations of basal plasma insulin and glucose concentrations in diabetic man. Diabetes. 1981;**30**:435-439.

[24] Hollingdal M, Juhl CB, Pincus SM, Sturis J, Veldhuis JD, Polonsky KS, et al. Failure of physiological plasma glucose excursions to entrain high-frequency pulsatile insulin secretion in type 2 diabetes. Diabetes. 2000;**49**:1334-1340. DOI: 10.2337/diabetes.49.8.1334

[25] Laedtke T, Kjems L, Pørksen N, Schmitz O, Veldhuis J, Kao PC, et al. Overnight inhibition of insulin secretion restores pulsatility and proinsulin/insulin ratio in type 2 diabetes.

Trends in Cell Biology. 2017;**27**:163-171. DOI: 10.1016/j.tcb.2016.10.003

Clinical Investigation. 2017;**127**:2353-2364. DOI: 10.1172/JCI88491

early/2018/04/04/jcb.201802095/tab-article-info

DOI: 10.2337/diab.30.5.435

[12] White P. https://www.diabetes.co.uk/pioneers/priscilla-white.html

**7**:421-433. DOI: 10.1016/j.cmet.2008.04.005

nrm1837

12 Ultimate Guide to Insulin

cshperspect.a009191

10.1172/JCI77812

nrm.2017.89


[38] Lee W. The CEACAM1 expression is decreased in the liver of severely obese patients with or without diabetes. Diagnostic Pathology. 2011;**6**:40. DOI: 10.1186/1746-1596-6-40

**Chapter 2**

**Provisional chapter**

**Insulin – Overview, Infections and Benefits of**

**Insulin – Overview, Infections and Benefits of** 

DOI: 10.5772/intechopen.81346

From the time the earliest description of diabetes appeared around 552 BC in the *Ebers Papyrus*, people have been searching for a cure for it. The term 'diabetes' was introduced by Aretaeus of Cappadocia, a Greek physician, (129–199 AD). Before the availability of insulin, any child who had diabetes had a very poor life expectancy, and the prognosis was also poor for any adult having the disease. In 1921, Canadian physician Frederick Banting and medical student Charles H. Best discovered the hormone insulin in the pancreatic extracts of dogs. Earlier, several injections of insulin were required daily; in the 1930s, H.C. Hagedorn, a chemist in Denmark, added protamine to the preparation and found that it prolonged the action of insulin. It was not until 1978 that the first recombinant DNA human insulin was prepared by combining the insulin A- and B-chains. Credit goes to David Goeddel and his colleagues (of Genentech) for this. Some innate (cytokines, complement) humoral immune functions are decreased and some remain the same in patients with diabetes mellitus (DM) compared to those without DM. We all know why diabetics are more prone to infections by this point. The science keeps the mind going but what keeps the heart going? Probably a big size chocolate bar for a diabetic with a blood sugar of. But no! Resistance is a key. If we are not going to resist that candy bar, nor are the bacteria or other organisms causing infection going to. There is not a lot we can do after this point, but there is quite a lot that could be done before—immunisation. Diabetes is an uphill battle for those that suffer from it; but the new health insurance schemes offered by the government should ease a little bit of the pressure. Insulin is not a definitive cure for diabetes but is definitely a form of life support. As of now, there is no complete cure for diabetes, but there may be one to wipe it out in the future due to the

> © 2016 The Author(s). Licensee InTech. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

© 2018 The Author(s). Licensee IntechOpen. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use,

distribution, and reproduction in any medium, provided the original work is properly cited.

**Immunization and Insurance**

**Immunization and Insurance**

Additional information is available at the end of the chapter

Additional information is available at the end of the chapter

advancing technologies in the field of science.

**Keywords:** diabetes, insulin, immunisation, insurance

http://dx.doi.org/10.5772/intechopen.81346

Ashish Chauhan

Ashish Chauhan

**Abstract**


#### **Chapter 2 Provisional chapter**

#### **Insulin – Overview, Infections and Benefits of Immunization and Insurance Insulin – Overview, Infections and Benefits of Immunization and Insurance**

DOI: 10.5772/intechopen.81346

#### Ashish Chauhan Ashish Chauhan

[38] Lee W. The CEACAM1 expression is decreased in the liver of severely obese patients with or without diabetes. Diagnostic Pathology. 2011;**6**:40. DOI: 10.1186/1746-1596-6-40

[39] Kanasaki K, Kitada M, Kanasaki M, Koya D. The biological consequence of obesity on the kidney. Nephrology, Dialysis, Transplantation. 2013;**28**(Suppl. 4):iv1-iv7. DOI:

[40] Spoto B, Pisano A, Zoccali C. Insulin resistance in chronic kidney disease: A systematic review. American Journal of Physiology. Renal Physiology. 2016;**311**:F1087-F1108. DOI:

[41] Robbins DC, Shoelson SE, Tager HS, Mead PM, Gaynor DH. Products of therapeutic insulins in the blood of insulin-dependent (type I) diabetic patients. Diabetes. 1985;**34**:510-

10.1093/ndt/gft098

14 Ultimate Guide to Insulin

10.1152/ajprenal.00340.2016

519. DOI: 10.2337/diab.34.5.510

Additional information is available at the end of the chapter Additional information is available at the end of the chapter

http://dx.doi.org/10.5772/intechopen.81346

#### **Abstract**

From the time the earliest description of diabetes appeared around 552 BC in the *Ebers Papyrus*, people have been searching for a cure for it. The term 'diabetes' was introduced by Aretaeus of Cappadocia, a Greek physician, (129–199 AD). Before the availability of insulin, any child who had diabetes had a very poor life expectancy, and the prognosis was also poor for any adult having the disease. In 1921, Canadian physician Frederick Banting and medical student Charles H. Best discovered the hormone insulin in the pancreatic extracts of dogs. Earlier, several injections of insulin were required daily; in the 1930s, H.C. Hagedorn, a chemist in Denmark, added protamine to the preparation and found that it prolonged the action of insulin. It was not until 1978 that the first recombinant DNA human insulin was prepared by combining the insulin A- and B-chains. Credit goes to David Goeddel and his colleagues (of Genentech) for this. Some innate (cytokines, complement) humoral immune functions are decreased and some remain the same in patients with diabetes mellitus (DM) compared to those without DM. We all know why diabetics are more prone to infections by this point. The science keeps the mind going but what keeps the heart going? Probably a big size chocolate bar for a diabetic with a blood sugar of. But no! Resistance is a key. If we are not going to resist that candy bar, nor are the bacteria or other organisms causing infection going to. There is not a lot we can do after this point, but there is quite a lot that could be done before—immunisation. Diabetes is an uphill battle for those that suffer from it; but the new health insurance schemes offered by the government should ease a little bit of the pressure. Insulin is not a definitive cure for diabetes but is definitely a form of life support. As of now, there is no complete cure for diabetes, but there may be one to wipe it out in the future due to the advancing technologies in the field of science.

**Keywords:** diabetes, insulin, immunisation, insurance

© 2016 The Author(s). Licensee InTech. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. © 2018 The Author(s). Licensee IntechOpen. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
