History of Diabetes
English physiologist Sir Edward Albert Sharpey-Schafer's further studying of the pancreas, leads him to the discovery of a substance that would normally be produced in non-diabetics: insulin. The name comes from the Latin insula, meaning island, referencing the insulin-producing islets of Langerhans in the pancreas.
Elliott Joslin, MD, publishes the first edition of The Treatment of Diabetes Mellitus. A clinician and educator, Joslin is renowned throughout the world as one of the most influential voices in diabetes care.
Frederick Banting, MD, and his then student assistant, Charles Best, MD, extract insulin from dog pancreases. They inject the insulin into dogs whose pancreases have been removed, and the animals’ blood sugar levels go down. James Collip purifies the extract so that it can be used in humans.
Eli Lilly and Company begin commercial production of insulin. In the decades that follow, manufacturers develop a variety of slower-acting insulins, the first being protamine insulin introduced by Novo Nordisk Pharmaceuticals, Inc., in 1936.
At a time when less than half of all babies born to mothers with diabetes survive, Priscilla White, MD, starts the Joslin Pregnancy Clinic. Fifty years later, Dr. White achieves a 90 percent survival rate among babies born to her patients.
The American Diabetes Association is founded to address the increasing incidence of diabetes and the complications developing from the disease.
Rachmiel Levine, MD, discovers that insulin works like a key, transporting glucose into cells.
Becton Dickinson and Company begins production of a standardized insulin syringe designed and approved by the ADA.
The American Dietetic Association, and the U.S. Public Health Service devise a meal planner that divides foods into six groups, or “exchanges”, based on the calories, carbohydrate, protein, and fat in each serving of food.
Tablets for testing urine glucose become widely available, and urine test strips appear over the next few years. These options are simpler than using Benedict’s solution, which must be mixed with urine and heated over boiling water.
The first successful kidney transplant is performed at the Peter Bent Brigham Hospital in Boston.
Sulfonylureas, oral medications that stimulate the pancreas to release more insulin, are available. New, more potent forms of these drugs will become available later.
Using radioimmunoassay technology developed by Solomon Berson, MD and Rosalyn Yalow, PhD measure insulin in the blood. They notice that some people with diabetes still make their own insulin, and they identify “insulin-dependent” (type 1) and “non-insulin-dependent” (type 2) diabetes.
Glucagon, an injectable treatment for severe hypoglycemia, is introduced by Eli Lilly and Company.
Rosalyn Yalow PhD, receives the ADA Outstanding Scientific Achievement Award for her 1959 discovery of measuring insulin in the blood using radioimmunoassay technology. The ADA presents this award each year to an individual researcher under age 45 who has made an outstanding contribution to diabetes research that demonstrates both originality and independence of thought.
The Ames Company introduces, the first strips for testing blood glucose by color code.
The first successful pancreas transplant is performed at the University of Minnesota Hospital.
Development of the Biostator enabled continuous glucose monitoring and closed loop insulin infusion.
Laser eye treatment becomes an effective therapy for certain types of retinopathy. By the end of this decade, a treatment known as vitrectomy becomes widely used to restore sight.
The Ames Company devices the first glucose meter.
The relationship between blood vessel disease and hyperglycemia is reported, thanks to research showing evidence of capillary basement membrane thickening in people with diabetes. Further research showed that this thickening can be reduced in certain circumstances with medications.
U100 insulin is introduced. With the availability of this single concentration and with insulin syringes marked with only a U100 scale, it is hoped that the frequency of dosing errors is reduced.
Glucagon is shown to be a mechanism for increasing the immediate supply of fuel to the body.
Tumor angiogenesis factor is found to cause abnormal growth of new blood vessels in the eye.
Progress is made in obtaining islets from normal pancreases. Beta cells can be grown in test tubes and can respond to glucose by producing insulin.
The National Diabetes Research and Education Act, the first diabetes law in U.S. history, requires the government to coordinate national research on diabetes and distribute diabetes information.
Researchers in Edinburgh, Scotland, and London, UK, detect antibodies to islet cells in people with type 1 diabetes, adding weight to the argument that type 1 diabetes is caused by an immune system attack on pancreatic islet cells.
Human Leukocyte Antigens (HLAs) are discovered on cell surfaces. People with type 1 diabetes have specific patterns of HLA that are associated with varying levels of risk for diabetes. Patel 1975.
Exchange Lists are revised to reflect a new understanding of nutrition and diabetes, thanks to studies that show the need to reduce fat in the diet and that carbohydrates need not be disproportionately restricted. Note: The lists are revised again in 1986 and 1995. Thompson 1974; Philips 1975; Berkson 1975; Fernandes 1979; Wolfe 1979; Gray 1980; Bantle 1983; Chen 1984; Klandorf 1986; Surwit 1989; Georgopolous 1992; Staprans 1993; Lovejoy 1993; Hellerstein 1994; Air 1999; Hu 1999; Havel 1999; Gannon 1999, 2003.
Scientists discover patients with type 1 diabetes who have a form of insulin molecule with a genetic defect. Understanding how defective insulin interacts with healthy insulin helps scientists to better understand how healthy insulin functions.
Pancreas and islet cell transplantation meet with some success in animals. Transplantations in humans are less successful. Dickerman 1979; Najarian 1979; Kyriakides 1979; Simmons 1979; Brown 1979; Lum 1979.
Insulin receptors are discovered on cell membranes. This discovery raises the possibility that missing or defective insulin receptors may prevent glucose from entering the cells, thus contributing to the insulin resistance of type 2 diabetes. Archer 1974.
Rosalyn Yalow, PhD is awarded the Nobel Prize in Physiology and Medicine. Together with Dr. Solomon Berson, they develop a sensitive radioimmunoassay technique used in determining the amount of insulin in biological materials.
Boston researchers develop a test to measure glycosylated hemoglobin (A1C).
Researchers at the City of Hope National Medical Center in Duarte, California, and Genentech, Inc., in San Francisco, induce E. coli bacteria to produce insulin identical to human insulin.
Portable insulin pumps are introduced and researchers achieve normal blood sugar levels in patients using them. But, due to their large size, they are impractical at this time. Philip Felig 1970, 1974; Service 1975; Tamborlane, Jr. 1979.
The National Diabetes Information Clearinghouse is created by the federal government to gather and document all diabetes literature.
The National Diabetes Data Group develops a new diabetes classification system: 1) insulin-dependent or type 1 diabetes, 2) non-insulin-dependent or type 2 diabetes, 3) gestational diabetes, and 4) diabetes associated with other syndromes or conditions.
The hyperinsulinemic-euglycemic clamp technique is introduced allowing the precise measure of insulin sensitivity of muscle and liver. The ‘clamp’ technique becomes the gold standard for measure of insulin sensitivity.
Researchers surmount the cross-species barrier in the transplantation of beta cells. Sutherland 1973, 1983; Archer 1980.
A new animal model of type 1 diabetes, the non-obese diabetic (NOD) strain of mouse is described in Japan.
Introduction of the basal-bolus concept essentially simultaneously with insulin pumps enabled "intensive insulin therapy" to be used in the clinic to effectively treat people with type 1 diabetes.
Researchers use the immunosuppressive drug cyclosporine to treat those with type 1 diabetes (a significant number of patients are able to reduce or eliminate the amount of insulin used) and prevent type 1 diabetes in those at risk.
Islets are microencapsulated and implanted. Although promising, this technology must still be perfected and does not cure diabetes in humans.
The FDA approves human insulin produced by genetically altered bacteria.
Aldose reductase inhibitor is shown to improve diabetic neuropathy in rats. The compounds in humans have shown little effect.
A 64K autoantibody is discovered and is found to be associated with type 1 diabetes.
An antigen known as HLA-DR is found to potentially trigger rejection of transplanted human islets. Because the antigen is located on the walls of the blood vessels in the implanted cells scientists predict that removing the blood vessels from the implant prior to transplantation should help prevent rejection.
A link between hypoglycemia and brain metabolism is established. Crane 1981; Reichlin 1981.
Second-generation sulfonylureas enter the market allowing patients to take smaller doses and potentially reduce side effects.
Immunotoxins are found to kill cells that may trigger a reaction to transplanted islets.
Insulin molecule is identified to be a target of autoimmune response in individuals with type 1 diabetes.
Islet Cell Antibodies (ICAs) are known to attach themselves to beta cells. Researchers are not yet sure what these ICAs do, but they begin to test the potential of ICA screening to identify people whose beta cells are in the process of being destroyed.
Scientists discover a relationship between pregnancy and the worsening of diabetic retinopathy.
A National Eye Institute study conclusively proves that can be successfully treated with laser photocoagulation.
A series of small studies indicate that tight control of blood glucose can prevent or delay the onset of diabetes complications. These studies will lead to the development of the Diabetes Control and Complications Trial (DCCT).
The National Diabetes Data Group reports that type 2 diabetes is more common among African Americans, Mexican Americans, and Native Americans than among Caucasians. Fifty percent of all Pima Indians in Arizona over the age of 35 have diabetes – the highest rate in the world.
The 64K autoantibody originally discovered in 1982 is found to be predictive of type 1 diabetes. This protein, GAD, or glutamate decarboxylase, is an important enzyme involved in cellular communication in the brain and pancreas. The immune system’s attack on GAD triggers a progressive autoimmune response that leads to diabetes.
Researchers can now calculate type 1 diabetes risk based on heredity.
Aminoguanide is developed. This compound prevents “sticky” glucose from narrowing or blocking blood vessels.
Researchers determine that tight control of glucose levels during pregnancy is important for the health of the baby, and continue to study how diabetes increases the risk for birth defects. Bleicher 1975; Shank 1979; Braunstein 1981; Katyal 1985; Kleigman 1986.
A specific genetic abnormality is discovered in 96% of studied patients with type 1 diabetes. Their results indicate that there is more than a 100-fold risk of developing diabetes with this particular genetic abnormality. Trucco 1986.
Massimo Trucco, MD at the University of Pittsburgh, working with John A. Todd, PhD, uncovered a genetic abnormality leading to type 1 diabetes. Ninety-six percent of the patients in their study with diabetes were not carrying an aspartic acid in codon 57 of their HLA-DQ beta-chain. Their results indicate that there is more than a 100-fold risk of developing diabetes with this particular genetic abnormality. This was a large step in discovering the predisposition to type 1 diabetes.
Studies show that medications known as angiotensin converting enzyme (ACE) inhibitors not only lower blood pressure but also slow progression of kidney disease. Wilkes 1986.
Clinical trials of metformin performed in the U.S. show beneficial results in treating type 2 diabetes. This drug was available since the 1950’s in Europe.
Researchers develop a glucose-sensing device that offers hope of being implantable.
A new anti-rejection drug, FK506, is used in transplant patients.
Glucose is discovered to be distributed into muscle and fat cells via a transporter known as GLUT-4. Understanding how glucose is transported from the bloodstream into cells to be used as fuel is important to locating different drug targets that can improve insulin sensitivity.
GAD is identified as the 64K autoantigen. In mice, it is initially targeted as the body’s immune system attacks and destroys beta cells.
Insulin receptor substrate-1 (IRS-1) is discovered. IRS-1 plays a role in intracellular signaling when insulin is present. This discovery opens the door to understanding insulin signaling.
Researchers are able to prevent the destruction of beta cells in mice by specifically neutralizing the immune cells that would have attacked GAD. This therapy prevented the autoimmune process from the beginning, thereby preventing the mice from developing diabetes.
Daniel Kauffman, PhD, Mark Atkinson, PhD, and Noel MacLaren, MD identified the protein that is initially targeted as the body’s immune system attacks and destroys the beta cells that manufacture insulin in the pancreas. This protein, GAD, or glutamate decarboxylase, is an important enzyme involved in cellular communication in the brain and pancreas. The immune system’s attack on GAD triggers a progressive autoimmune response that leads to diabetes. After the researchers pinpointed the cause of the onset of diabetes, they were able to prevent the destruction of the beta cells in the mice by specifically neutralizing the immune cells that would have attacked GAD. This therapy prevented the autoimmune process from the beginning, thereby preventing the mice from developing diabetes.
The showed that keeping blood glucose levels as close to normal as possible slows the onset and progression of eye, kidney, and nerve diseases caused by diabetes. In fact, it demonstrated that any sustained lowering of blood glucose helps, even if the person has a history of poor control.
An initiative to develop a resource consisting of comprehensive data and genetic material of type 2 diabetes families, GENNID (Genetics of Non-Insulin Dependent Diabetes), is begun. This material is made available to the scientific community for genetic studies of type 2 diabetes. Since 1993, DNA and data for over 6,100 individuals in over 1,800 families has been collected.
Captopril is FDA approved to treat end-stage renal disease.
The Diabetes Prevention Trial – Type 1 (DPT-1) is started based on evidence in mice and a small study in humans. The study will determine whether or not injecting insulin or ingesting insulin tablets can prevent or mitigate the immune system attack on the beta cells that make insulin. Atkinson; Eisenbarth.
Leptin, the fat cell hormone that modulates feeding behavior and hormone secretion, is cloned. The Scandinavian Simvistatin Survival Study (4S) showed that cholesterol lowering with statins markedly reduced the risk of myocardial infarction, stroke or death. The effect was greatest in individuals with diabetes.
The incretin hormone GLP-1 is discovered. Incretin hormones are secreted from the gut in response to food, and encourage the body to produce insulin. Discovery of GLP-1 will later lead to a new class of diabetes drugs that can increase insulin secretion in response to glucose, and even increase the amount of beta cells in the pancreas. Habener 1987; Weir G 1988.
PPAR gamma is cloned. PPAR gamma is a key regulator of fat cell differentiation and fat metabolism.
In addition to IDDM1 and IDDM2, researchers find 18 different chromosome regions which show some positive evidence of linkage to diabetes. However, there are probably no genes with large effects aside from IDDM1.
The hormone adiponectin is discovered by American and Japanese investigators.
The drug metformin becomes available in the U.S.. Metformin is a biguanide that prevents glucose production in the liver.
Researchers discover different subsets of T helper cells in type 1 diabetes. T helper 1-like cells actively promote diabetes, while T helper 2-like cells invade the islets but do not prevent or promote disease.
The carbohydrate-counting approach to meal planning, based on the idea that carbohydrate is the main nutrient affecting glucose levels, becomes a popular option.
The drug acarbose, brand name Precose (Bayer Corporation) becomes available in the U.S. Acarbose is an alpha-glucosidase inhibitor that slows digestion of some carbohydrates.
Lispro (a lysine-proline analog) is introduced by Eli Lilly and Company as the world’s fastest acting insulin.
Mutation in the gene HNF4 is shown to cause maturity onset diabetes of the young (MODY). Subsequently, mutations in an additional 5 genes are discovered to be associated with -cell dysfunction leading to MODY.
The Diabetes Prevention Trial – Type 2 (DPT-2) begins. This study will determine whether or not diet, exercise, and medications can prevent type 2 diabetes from developing in those with impaired glucose tolerance.
A noninvasive blood glucose meter (the Diasensor 1000, by Biocontrol Technology, Inc.) is submitted to the FDA for the first time. The application for approval is rejected and research continues.
Troglitazone, brand name Rezulin (Parke-Davis), is approved by the FDA. It is the first in a class of drugs known as thiazolidinediones, and it improves insulin sensitivity in muscle cells. It is eventually removed from the market due to liver toxicity. Rosiglitazone and pioglitazone, also in this drug class, are later developed.
Type 1 and type 2 diabetes are now defined by cause rather than treatment. In addition, the fasting glucose level for diabetes is lowered from 140 mg/dl to 126 mg/dl.
Repaglinide, brand name Prandin (Novo Nordisk) is developed. Repaglinide belongs to a class of drugs known as meglitinides. It stimulates insulin secretion in the presence of glucose.
The United Kingdom Prospective Diabetes Study (UKPDS) proves that people with type 2 diabetes who practice tight control of blood sugar levels and blood pressure levels reduce their risk of complications. The study also suggested that metformin could reduce the risk of cardiovascular deaths. Two small studies indicate that is as effective as injected insulin.
Research shows people with diabetes often have serious heart problems early in life. Aggressive treatment for all risk factors is encouraged.
Researchers at the University of Alberta in Edmonton, Canada report on the success of an islet cell transplant technique known as the Edmonton protocol. This technique can restore long-term insulin production and glucose control in those with type 1 diabetes and unstable control, but insulin independence is usually not sustainable.
The Hyperglycemia and Adverse Pregnancy Outcome Study (HAPO) begins. HAPO is a study to determine whether hyperglycemia in pregnancy is associated with a high risk of poor maternal, fetal and neonatal outcomes. Metzger 2000.
For the first time, investigators evaluate use of an insulin pump in older patients with type 2 diabetes. The study ultimately shows that both the insulin pump and multiple daily injections achieve excellent glycemic control with good safety and patient satisfaction. Raskin 2001; Herman 2001.
2001-2002The Finnish Diabetes Prevention Study showed in 2001 that moderate diet and exercise could reduce the onset of type 2 diabetes in individuals with impaired glucose tolerance by 58%. This is followed in 2002 by the U.S. Diabetes Prevention Program (DPP) which showed identical results and also showed that metformin could reduce the incidence of type 2 diabetes by 31%.
Treatment with the anti-CD3 monoclonal antibody, hOKT3gamma1(Ala-Ala), slows the deterioration of insulin production and improves metabolic control during the first year of type 1 diabetes in the majority of patients.
The American Diabetes Association defines pre-diabetes as impaired fasting glucose (IFG) and/or impaired glucose tolerance (IGT). IFG is defined as a fasting blood glucose of 100-125 mg/dl, and IGT is defined as a glucose level from 140 mg/dl – 199 mg/dl two hours after consuming a glucose-rich drink.
The DPT-1 study showed that neither low-dose insulin injections in people at high risk for developing type 1 diabetes, nor insulin capsules taken orally by people at moderate risk for type 1 diabetes were successful at preventing or delaying diabetes.
Investigators begin to collaborate to develop basic science, clinical and translational research aimed at better understanding or preventing the onset of type 2 diabetes. Hirschhorn 2003; Hollenberg 2005.
The Troglitazone in Prevention of Diabetes (TRIPOD) study treats women at risk of developing type 2 diabetes with TZDs. The results were dramatic: The drugs were apparently effective in preventing the onset of the disease.
Researchers step-up efforts to find alternative sources of insulin producing cells for transplantation. The work of these researchers could lead to procedures that would ultimately restore the body’s ability to produce insulin. Burant 2004; Dong 2004; German 2004; Garfinkel 2004; Inverardi 2004; Robbins 2004; Yoon 2004.
Educational and behavioral clinical outcomes studies begin to support patients with type 2 diabetes in making the decision to choose, initiate and continue insulin therapy. Montori 2004; Rothman 2004.
Research into gaining a better understanding of diabetes during pregnancy and its effects on both mother and baby continues. Sharma 2004; Lernmark 2004; Catalano 2004.
Exenatide, brand name Byetta, is approved in the U.S. as a first-in-class incretin mimetic (GLP-1) drug to treat type 2 diabetes. An injectable drug, exenatide works by increasing insulin production in response to blood glucose levels. Beinborn 2000.
Spurred by the obesity epidemic and increasing rates of type 2 diabetes in children, researchers focus on educational, behavioral, and nutritional outcome studies supporting a better understanding of healthy food choices in children and adolescents. Duffy 2005; Naar-King 2005; Raynor 2005.
Pramlintide, brand name Symlin, is approved in the U.S. as an injectable adjunct treatment for people (with type 1 or type 2 diabetes) who use insulin at mealtimes but still fail to achieve desirable blood glucose levels.
The drug liraglutide enters phase 3 clinical trials. Liraglutide is a form of the natural hormone, GLP-1, that stimulates insulin production in the presence of glucose.
The first inhaled form of insulin to be FDA approved for adults with type 1 or type 2 diabetes, Exubera is found to be just as effective as short-acting insulin injections in controlling blood glucose levels.
Data from the Diabetes Reduction Assessment with Ramipril and Rosiglitazone Medication (DREAM) study were reported at a meeting of the European Association for the Study of Diabetes (EASD). The results suggest that TZD treatment may prevent type 2 diabetes in patients at high risk.
FDA approves JANUVIA (sitagliptin phosphate), the first in a new class of drugs known as DPP-4 inhibitors that enhances the body's own ability to lower elevated blood sugar. DPP-4 is an enzyme that naturally blocks GLP-1 from working, so by inhibiting this enzyme, we are able to keep GLP-1 working in the gut to promote insulin secretion.
For the first time in our history an algorithm is developed for drug treatment of diabetes. This is having enormous implications for treatment, since doctors have a wide-array of treatment options.
A consensus paper is published on treatment of pre-diabetes (lifestyle modification versus drugs, and if the latter, what drug (s).
Using a mathematical model, a "virtual" animal with type 1 diabetes is developed. This virtual animal model allows scientists to study the various ways in which type 1 diabetes develops, the impact of interventions to prevent diabetes, and to study the immunologic similarities/differences between humans and other animals.
Fish oil is found to lower the risk of Type 1 diabetes by 55% due to its' anti-inflammatory properties. Still researchers caution that treating children at risk for diabetes with fish oil is not the answer but does not exclude including it in a healthy diet. Aside from fish, Omega-3 can also be found walnuts, olives, canola oils and other supplements. (Journal of the American Medical Association , September 2007).
Researchers from Cambridge, England, conclude subjects with the highest concentration of vitamin C in their blood are more likely to develop type 2 than participants with lower levels. Fruit and vegetables and other factors commonly associated with a risk for diabetes, do not change the effects of vitamin C but individuals with gum disease, double their chances. (Diabetes Care, July 2008).
An unnamed 55-year-old woman whose pancreas was removed due to chronic pancreatitis, receives another pancreas, transplanted into her forearm. Inslet cells extracted from her pancreas, are implanted into her left forearm, creating a functioning pancreas. (The Methodist Transplant Center, October 2008).
Scientists identify five genetic biomarkers that could lead to improved treatments for Type 2 patients. The implications of this discovery include determining which patients will best respond to certain drug treatments and provides the foundation for personalized medicine, administering medicine to individuals based on their genetic make-up. (Johns Hopkins University School of Medicine in Baltimore, June 2009).
Dr. Stephanie Venn-Watson, a veterinary epidemiologist and director, discovers that dolphins posses the ability to "turn on and off" diabetic symptoms. When food is scarce, dolphins turn on the gene but can turn it off when it is abundant again. Venn-Watson makes the discovery from analyzing blood samples and theorizes that dolphins developed this ability when they evolved from land to sea animals 55 million years ago. She furthers suggests evidence that humans may posses a similar ability but dormant. (New York Daily News, March 2010).
Scientists identify genetic markers affecting a baby's size at birth and the development of diabetes later in life. These findings provide the first strong evidence of a genetic link between diabetes and low birth weight; it also explains why smaller babies have higher rates of diabetes as adults. Pregnant mothers eating habits also play a role. (Nature Genetics, April 6, 2010).
Research shows that bones may play an important role in regulating blood sugar. Resorption, the destruction of old bone to to make way for new bone, is also important for maintaining healthy blood glucose levels. A previous study showed that Osteocalcin, a hormone released by bone regulates glucose and could not function properly until bones begin the resorption process. In addition, the study has implications for people who suffer from osteoporosis as well as diabetics because a common drug treatment for osteoporosis could make a person more likely to develop diabetes and bone may become a viable treatment for type 2 diabetes. (Cell Journal, July 2010).
A small-scale study suggests that adult athletes with type 1 diabetes who drink coffee before exercise may reduce or prevent hypoglycemia. Results of the study were presented at the American Diabetes Association (ADA) 70th Scientific Sessions. On the day that the participants drank coffee, their blood glucose levels stayed up and they did not need glucose. Reversely, when they received placebo, their blood glucose levels fell and they needed glucose. Larger trials need to be done because the dose of caffeine used in the study is not proportionate to coffee intake in the real world. Another study is planned with a lower dose. (Medscape Medical News, July 2010).