Over 100 Years of Diabetes Research

Robert Russell Bensley

There is a rich history of diabetes-related research at the University of Chicago. In 1907, working in the Hull Laboratory of Anatomy at the University of Chicago, Robert Russell Bensley together with his student M. A. Lane, devised histological staining techniques that enabled a better visualization of the anatomy of the pancreas, including endocrine islets of Langerhans that were found to contain at least two different “granular cell types”, alpha- and beta-cells [1].

First Biological Indication of the Existence of Insulin

Later, these were found to be glucagon and insulin producing cells respectively. Bensley further developed these histological studies on the pancreas and in 1911 published a seminal work describing the anatomy of the pancreas in great detail [2]. Here he calculated the islet cell mass of the pancreas quite accurately. He was also able to document an extensive ductal network in the pancreas and that the origin of islets came from short branches of larger ducts – often referred to as islet neogenesis today. Bensley extended his innovative histological techniques to examine other organs and later became interested in isolating cells organelles, especially mitochondria, to study their structure and function. Today, the American Association of Anatomists honors the life and work of Robert Russell Bensley by its annual R.R. Bensley Award. This recognizes a cell biologist who has made a distinguished contribution to the advancement of anatomy through discovery, ingenuity, and publications in the field of cell biology.

The Hull Laboratories of Physiology and Biochemistry at the University of Chicago were also very active in the diabetes research arena at this time (1910-1912), which of course was prior to the discovery of insulin. Following the findings of Josef von Mering and Oskar Minkowski in Strassburg (1890) there was an investment made to study diabetes in pancreatectomized dogs. Between 1910-1911 Ernest Lyman Scott (pictured below as a Major in the American Expeditionary Force (AEF) during World War 1 (circa 1918)) was experimenting with acid and alcohol extractions of the pancreas to see if a glucose-lowering substance could be found. Indeed, in 1911 he published an article indicating that injection of extracts of pancreas could transiently lower gluosuria in total pancreatectomized dogs [3]. This was a first biological indication of the existence of insulin (then referred to as an ‘internal secretion’). However, Scott and his colleagues were rather cautious in interpreting their results at the time, since several of the dogs had a slight increase in body temperature and could not rule out a toxic side effect. Nonetheless, there were three key aspects about this work. First, the pancreatic duct was ligated that so that the exocrine pancreas atrophied over the endocrine pancreas. Second, was the use of acid and alcohol to make the extract. Third, was the method of measuring glucose in the urine relative to nitrogen content, an assay that Scott standardized. These were all key to the approach that Banting and Best later took to purify insulin in Toronto in 1921.

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Anton J. (Ajax) Carlson

Around the same time that Scott was working in Hull Physiological Laboratory, Fred Drennan, at the urging of Anton J. (Ajax) Carlson – soon to be the charismatic and long standing Chairman of the Physiology Department (1916-1940), conducted an experiment to indicate that the ‘internal secretion’ of the pancreas (i.e.insulin) was circulating in the blood. Essentially, Drennan carried out a blood transfusion on a pancreatectomized diabetic dog with blood from a normal dog and showed that this transiently lowered the glucosuria in the diabetic animal [4]. Carlson himself also conducted studies in partially pancreatectomized dogs, finding that if the pancreatic remnant was too small there was no recovery of the glucosuria, especially if there was “overstrain” by carbohydrate feeding [5]. Others in the Physiology Department at the beginning of Carlson’s tenure of Chair were also encouraged in diabetes research. Arno Luckhardt examined mechanisms of polyphagia in diabetes [6]. Soon after the discovery of insulin, N.F. Fisher sought to improve insulin preparations from bovine pancreas and optimize their administration in the treatment of diabetes [7].

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Somastatin-producing Cells

In 1930, working in the neighboring Hull Laboratory of Anatomy, William Bloom in developing the histological methodology of Bensley discovered a third “granular cell type” in the islets of Langerhans named D-cells [8], which were later found to be the somatostatin producing cells. A modern day immunofluorescent image below depicts the glucagon producing alpha, insulin producing beta and somatostatin producing delta cells of a mouse islet of Langerhans.

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McLean-Hastings Equation

In 1934, Franklin McLean (the architect of the School of Medicine at the University of Chicago) together with A. Baird Hastings in the Physiology Department devised a method for measuring calcium in blood and other biological samples that also developed the ‘McLean-Hastings Equation’ for estimating free calcium ion concentrations. This work showed that free ionic [Ca2+] is the biological active form of calcium [9]. Relevant to diabetes research, we now know that increasing calcium ion influx into the beta-cell from the circulation is key to triggering insulin secretion in vivo.

Baird Hastings also made some fundamental contributions to our current understanding of metabolism that were initiated while at the University of Chicago, particularly with pyruvate oxidative metabolism [10]. He later refined this interest at Harvard University using radioactive carbon tracing techniques for his metabolic studies to examine the effect of diet and insulin on liver metabolism under both normal and diabetic circumstances.

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Konrad Bloch : Insulin Regulates Fatty Acid Synthesis

The 1940s and 1950s were an active time for metabolic research related to diabetes and obesity at the University of Chicago. In the Departments of Biochemistry and Surgery, Albert L. Lehninger was examining mitochondrial oxidation of fatty acids and other fuels [11]. Konrad Bloch was on the University of Chicago faculty between 1946-1954 in the Department of Biochemistry using radioactive carbon incorporation techniques to examine the fatty acid and cholesterol biosynthesis [12]. Here he showed that insulin regulated fatty acid synthesis. Bloch also investigated the biosynthesis of glutathione and formation of ketone bodies at this time. He would eventually win the Noble prize in 1964 for his work on the mechanism and regulation of the cholesterol and fatty acid metabolism.

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Insulin Stimulates the Transport of Glucose

From 1936 – 1960 Rachmiel Levine M.D. was working at the Michael Reese Hospital in Chicago, and also had a research appointment in the Department of Physiology at the University of Chicago. His early work with Samuel Soskin introduced the theory that the greater the amount of glucose present in the blood, the greater the amount that is used by the body. Soon after Levine’s research work progressed and led him to propose that insulin served as the key regulatory factor for stimulating the transport of glucose into the cells [13]. This was quite a heretical idea at the time, since it was then believed that glucose passively passed through the cell membrane. However, it was eventually accepted that insulin stimulates the transport of glucose from blood to fat/muscle cells and thus lowers blood glucose level.

In the late 1950s, early 1960s Ira Wool, also in the Department of Physiology at the University of Chicago first showed that insulin could stimulate protein synthesis in muscle and other tissues, independently of glucose or amino acid transport, in a series of elegant studies using radioactive amino acid incorporation techniques [14].

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Donald Steiner : The Discovery of Proinsulin

In 1965 in the Department of Biochemistry, Dr. Donald Steiner made the breakthrough discovery that insulin was not synthesized as two separate A- and B-chains, but as a single polypeptide chain precursor molecule, proinsulin [15]. A portion of the proinsulin molecule (known as C-peptide) is cleaved out after its biosynthesis resulting in the A- and B-chains correctly aligned and insulin in its appropriate structure. Soon after Steiner found that proinsulin itself was synthesized as a precursor molecule, preproinsulin, where an extension ‘pre-peptide’ (also known as a signal peptide) enables newly synthesized proinsulin to get into a compartment in the beta-cell where it can be readily processed and secreted. The discovery of proinsulin was a landmark, being the first “pro-hormone”, and opened up a whole new field as to how secretory proteins are manufactured and processed in cells. Indeed, it was also a key finding for the manufacture of synthetic human insulin used therapeutically today.

The discovery of proinsulin and its processing to insulin and C-peptide also led to the first radioimmunoassay for C-peptide developed by Drs. Arthur Rubenstein and Donald Steiner, which has been a useful analytical tool in the clinic and research lab to treat and study diabetes [16]. Drs. Rubenstein and Steiner, together with Dr. Howard Tager, were key members of a team at the University of Chicago that discovered that a variety of rare mutations in the coding sequence of the preproinsulin gene could cause diabetes [17].

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The Genetics of Diabetes

Dr. Graeme Bell was a key member of the team that cloned the human insulin gene and the insulin receptor. At the University of Chicago, together with Drs. Nancy Cox and Kenneth Polonsky, since 1991 Bell has identified four out of the six known genes associated with Maturity Onset Diabetes of Youth (MODY) and found functional mutations in these [18], which, in turn, has given valuable insight into the pathogenesis of diabetes. In addition, more recently Drs. Bell, Steiner and Lou Philipson have been a significant part of an international team that has discovered major genes that cause Neonatal Diabetes including mutations in the insulin gene itself that lead to a loss of biological activity insulin [19].

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The Diabetes Prevention Program

The Diabetes Prevention Program (DPP) was a major multicenter clinical research study aimed at discovering whether modest weight loss through dietary changes and increased physical activity or treatment with the oral diabetes drug metformin (Glucophage) could prevent or delay the onset of type 2 diabetes in study participants. At the University of Chicago, the study was led by David Ehrmann, MD. At the beginning of the DPP, participants were all overweight and had blood glucose, also called blood sugar, levels higher than normal, but not high enough for a diagnosis of diabetes — a condition called pre-diabetes.

The DPP found that participants who lost a modest amount of weight through dietary changes and increased physical activity sharply reduced their chances of developing diabetes. Taking metformin also reduced risk, although less dramatically. The DPP resolved its research questions earlier than projected and, following the recommendation of an external monitoring board, the study was halted a year early. The researchers published their findings in the February 7, 2002, issue of the New England Journal of Medicine.

The DPP’s results indicate that millions of high-risk people can delay or avoid developing type 2 diabetes by losing weight through regular physical activity and a diet low in fat and calories. Weight loss and physical activity lower the risk of diabetes by improving the body’s ability to use insulin and process glucose. The DPP also suggests that metformin can help delay the onset of diabetes.

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Lou Philipson — Lilly Jaffe

Lilly Jaffe, of Chicago, was diagnosed with type 1 diabetes more than six years ago, at the tender age of one month.

In 2006, her parents, Laurie and Mike, longtime JDRF volunteers, had attended the annual meeting of JDRF’s Illinois Chapter, where Dr. Louis Philipson, of the University of Chicago, presented. He mentioned a study out of the U.K. that showed that some children diagnosed with diabetes in their first six months of life actually don’t have type 1 autoimmune diabetes, but instead have diabetes characterized by a rare genetic mutation that can be treated with a common oral medication.

Mike approached Dr. Philipson and told him about Lilly, who had been on a pump for years by then. Since she fit the profile with her early diagnosis, he was given a simple, saliva DNA test. The results came back in a few days: Lilly was positive for one of these rare mutations. A month after that, Lilly was admitted to the University of Chicago’s Clinical Research Center to begin a week-long program to see if the oral treatment could work for her. She began a small dose of the medicine, and her insulin dose was cut in half. Over the course of the week, her oral medication was increased each day, and her insulin dose was decreased. After a week, tests began showing that, indeed, Lilly had begun to produce insulin on her own — for the first time in her six and a half years of life!

The Jaffes left the hospital that night — with Lilly still on a pump, but using dramatically less insulin. About five days later, the pump came off, and Lilly had taken the last insulin shot she would ever need.

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Rob Sargis: Molecular Mechanisms Affected by Pollution

In the Section of Endocrinology, Diabetes, and Metabolism, Robert Sargis is currently studying the effects of synthetic chemicals released into the environment on the development of obesity and diabetes. Research regarding the effects of these endocrine-disrupting chemicals (EDCs) on reproduction and the thyroid is quite popular and recent. Less is known about their effects on metabolism. Sargis’s research is devoted to studying the molecular mechanisms by which environmental pollution affects fat cell function in order to understand how such chemicals may be contributing to the obesity and diabetes epidemics.

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Siri Greeley: MonogenicDiabetes.org

Through basic and clinical research, Dr. Greeley hopes to shed light on the full spectrum of childhood diabetes. His research focuses on how best to classify the diabetes type of each individual patient. Dr. Greeley is particularly interested in monogenic diabetes, which is caused by single gene mutations and is often unrecognized, even though this group of disorders may represent as much as 2 to 3 percent of all diabetes cases. Dr. Greeley, a Lewis-Sebring Fellow, recently designed and implemented the first national Web-based registry of patients with neonatal diabetes, who are more likely to have an underlying monogenic cause.

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Chris Rhodes: The Research Continues

Research at the Kovler Diabetes Center tries to uncover novel hidden factors behind diabetes. Here are a few examples of exciting ongoing research:

•   A new map directly linking a small region of the brain (the hypothalamus) to
pancreatic islets for fine control of insulin and glucagon secretion has been recently
defined (Chris Rhodes lab).

•   A novel gene, BNIP3, has been discovered that may clear a dysfunctional fatty liver
in obesity (Kay Macleod lab).

•   Not all fat is equal. New insight into different kinds of white fat and function of
brown fat to alleviated symptoms of obesity and type 2 diabetes has been
found (Matthew Brady lab).

•   Super-secreting mice that show the importance in timing and efficiency of insulin
secretion to treat type 2 diabetes driven by the PKA gene have been studied
(Barton Wicksteed lab).

•   Novel insight into promoting beta-cell survival and well-being by control of a
beta-cell gene (IRS-2) may lead to new treatments for diabetes (Chris Rhodes lab).

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References

  1. Lane, M.A. The Cytological Characters of the Areas of Langerhans. (1907)  Am. J. Anat. 7: 409-422.
  2. Bensley, R.R. Studies on the Pancreas of the Guinea Pig. (1911)  Am. J. Anat. 12: 297-388; and Structure and Relationships of the Islets of Langerhans (1914-15) The Harvey Lectures 10: 250-289.
  3. Scott E.L. On the Influence of Intravenous Injections of an Extract of the Pancreas on Experimental Pancreatic Diabetes (1911) Am. J. Physiol. 29: 306-310; and in ‘Great Scott’ by Scott A.E. Library of Congress, Catalog Number 72-80201 (Copyright 1971 by the Scott Publishing Company, Bogota, NJ, USA).
  4. Drennan F.M. The Presence of the Internal Secretion of the Pancreas in the Blood. (1911) Am. J. Physiol. 28: 396-402.
  5. Jensen V.W. & Carlson A.J. The Apparent Influence of a Diet of Carbohydrates on the Pancreas Remnant of Partially Pancreatectomized Dogs. (1920) Am. J. Physiol. 51: 423-429.
  6. Luckhardt A.B. Contributions to the Physiologu of the Stomach. The Cause of the Polyphagia in Pancreatic Diabetes. (1917) Am. J. Physiol. 33: 313-323.
  7. Fisher N.F Preparation of Insulin. (1923) Am J. Phsiol. 67: 57-64; and Attempts to Maintain the Life of Totally Pancreatectomized Dogs Indefinitely by Insulin (1923) Am. J. Physiol. 67: 634-642.
  8. Bloom W. A New Type of Granular Cell in the Islets of Langerhans of Man. (1931) Anat. Rec. 49: 363-371.
  9. McLean F.C. & Hastings B. A Biological Method for the Estimation of Calcium Ion Concentration. (1934) J. Biol. Chem. 107: 337-350; The State of Calcium in the Fluids of the Body. The Conditions Affecting the Ionization of Calcium. (1935) J. Biol. Chem. 108: 285 – 321.
  10. Guzman Barron ES & Hastings AB Studies on Biological Oxidations. II. The Oxidation of Lactic Acid by a-Hydroxyoxidase, and its Mechanism (1933) J. Biol. Chem. 100: 155 – 182; and Guzman Barron ES & Hastings AB Studies on Biological Oxidations. III. The Oxidation-Reduction Potential of the System Lactate-Enzyme-Pyruvate (1934) J. Biol. Chem. 107: 567 – 578.
  11. Lehninger A.L. A Quantitative Study of the Products of Fatty Acid Oxidation in Liver Suspensions. (1946) J. Biol. Chem.162: 291-306; and Kennedy EP & Lehninger A.L. The Products of Fatty Acid Oxidation in Isolated Rat Liver Mitochondria (1950) 185: 275-285.
  12. Bloch K, Clark LC, & Isaac Harary I. Utilization of Branched Chain Acids in Cholesterol Synthesis (1954) J. Biol. Chem. 211: 687-699; Johnston RB & Bloch K. Enzymatic Synthesis of Glutathione (1951) J. Biol. Chem., 188: 221-240; Bloch K & Kramer W. The Effect of Pyruvate and Insulin on Fatty Acid Synthesis In Vitro (1948) J. Biol. Chem. 173: 811 – 812. Zabin I & Bloch K. The Formation of Ketone Bodies from Isovaleric Acid (1950) J. Biol. Chem., 185: 117-129.
  13. Soskin S. & Levine R. A Relationship Between the Blood Sugar Level and the Rate of Sugar Utilization, Affecting the Theories of Diabetes (1937) Am. J. Physiol. 120: 761 – 770; Soskin S. & Levine R. On the Mode of Action of Insulin. (1940) Am. J. Physiol. 128: 782-786.
  14. Wool I.G. & Krahl M.E. Incorporation of C14-Amino Acids into Protein of Isolated Diaphragms: an Effect of Insulin Independent of Glucose Entry. (1959) Am. J. Physiol. 196: 961-964; Wool I.G. & Krahl M.E. An Effect of Insulin on Peptide Synthesis Independent of Glucose or Amino-Acid Transport. (1959) Nature 183: 1399-1400; Wool I.G. & Manchester K.L. Insulin and Incorporation of Amino-Acids into Protein of Rat Tissues. (1962) Nature 193: 345-346.
  15. Steiner D.F. & Oyer P.E. The Biosynthesis of Insulin and a Probable Precursor of Insulin by a Human Islet Cell Adenoma. (1967) Proc. Natl. Acad. Sci. U. S. A. 57: 473-480; Steiner D.F. Cunningham D. Spigelman L. & Aten B. Insulin Biosynthesis: Evidence for a Precursor. (1967) Science 157: 697-700.
  16. Melani F, Rubenstein A.H. Oyer P.E. & Steiner D.F. Identification of Proinsulin and C-peptide in Human Serum by a Specific Immunoassay. (1970) Proc. Natl. Acad. Sci. U. S. A. 67: 148-55.
  17. Kwok S.C. Steiner D.F. Rubenstein A.H. & Tager H.S. Identification of a Point Mutation in the Human Insulin Gene Giving Rise to a Structurally Abnormal Insulin (Insulin Chicago). (1983) Diabetes 32: 872-875.
  18. Bell G.I. & Polonsky K.S. Diabetes Mellitus and Genetically Programmed Defects in Beta-Cell Function. (2001) Nature 414: 788-791.
  19. Støy J, Edghill EL, Flanagan SE, Ye H, Paz VP, Pluzhnikov A, Below JE, Hayes MG, Cox NJ, Lipkind GM, Lipton RB, Greeley SA, Patch AM, Ellard S, Steiner DF, Hattersley AT, Philipson LH, Bell GI; Neonatal Diabetes International Collaborative Group. Insulin gene mutations as a cause of permanent neonatal diabetes. Proc. Natl. Acad. Sci. USA (2007) 104:15040-15044.
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