Unit V: Current Research
Causes of Diabetes
Current research involves the search for the causative factors in the development of diabetes mellitus – both DMT1 and DMT2. Evidence to support the multi-factor theory for the development of DMT1 has been gathered over the years. The absolute lack of insulin which develops in DMT1 is believed to be the result of genetic and environmental influences that culminate in an auto-immune response that destroys the insulin-producing function of the islet cells in the pancreas. The resulting loss of function is the root cause of the development of DMT1.
Causative factors for DMT2 are believed to be genetic as well, though the underlying defects have not yet been determined conclusively. Whatever the causative factors, insulin resistance is the culprit in the ultimate development of this disorder, not the absence of insulin.
Current research about DMT1 can be reviewed by accessing Type 1 Diabetes TrialNet at the following site: http://www.diabetestrialnet.org/index.htm. This site reports about studies performed by an international network of researchers who are looking into ways to prevent, delay, and/or reverse the progression of DMT1.This site reports about studies performed by an international network of researchers who are looking into ways to prevent, delay, and/or reverse the progression of DMT1.
TrialNet was established in response to the Surgeon General's Report Healthy People 2010. This report identified diabetes as a national health objective for the Nation. In response to the report, Congress created the Diabetes Research Working Group (DRWG) to develop a plan for diabetes research. One recommendation of the DRWG was to conduct additional research studies (clinical trials) to prevent type 1 diabetes. TrialNet is conducting clinical trials with researchers from 18 Clinical Centers in the United States, Canada, Finland, United Kingdom, Italy, Germany, Australia and New Zealand. In addition, more than 150 medical centers and physician offices are participating in the TrialNet network. Studies are available for people newly diagnosed with type 1 diabetes, as well as for relatives of people with type 1 diabetes who are at greater risk of developing the disease.
Preventing diabetes is a much sought-after goal. But first, a way to identify susceptible individuals (those at risk for DMT1) had to be determined. Accordingly, research efforts in part have focused on discovering predictive markers - immunologic abnormalities that can be detected in the blood of those who eventually develop DMT1 – and other factors that can be used to predict the eventual development of DMT1. Such predictive markers would serve as warnings of impending or ongoing autoimmune destruction in advance of actual symptoms of the disease (Ziegler, Herskowitz, Jackson, Soeldner, & Eisenbarth, 1990).
Through The Diabetes Prevention Trial – Type 1 (DPT-1), one such marker was identified: islet cell autoantibodies (ICA) among first-degree relatives of individuals with DMT1. Another, immunologically based marker identified was insulin autoantibodies. A third predictor, a first-phase insulin release after intravenous glucose of less than the 1st percentile, was also identified (Riley et al., 1990).
Once predictive markers were identified, studies were implemented to test theories about ways to prevent the development of DMT1. One study examined whether the administration of insulin to relatives of individuals with DMT1 who were at risk for developing DMT1 could delay or prevent the development thereof. The study results indicated that insulin (in the dosage used in the study) neither delayed nor prevented the development of DMT1 in individuals at risk for developing the disorder. Note: In this study, low-dose subcutaneous Ultralente insulin was administered twice daily at a total dose of 0.25 unit per kilogram of body weight per day. In addition, subjects underwent four days of continuous intravenous infusions of insulin, annually. Median follow-up of subjects was 3.7 years. The diagnosis of DMT1 was the primary end point of the study (The Diabetes Prevention Trial – Type 1 Study Group, 2002).
Another study examined whether oral insulin administration could prevent or delay the development of DMT1 in relatives of individuals with the disorder. The conclusion? While it was possible to identify individuals at risk for DMT1, based on the detection of islet cell autoantibodies, exposure to oral insulin neither delayed nor prevented DMT1. Further studies of similar individuals with higher levels of insulin autoantibodies were recommended (The Diabetes Prevention Trial – Type 1 Study Group, 2005).
Other studies have continued to refine the clues that predict the development of DMT1:
Abundant evidence indicates that type 1 diabetes occurs as a result of chronic, immunologically mediated destruction of pancreatic B-cells. Support for type 1 diabetes' pathogenetic chronicity includes the presence of islet cell autoantibodies well before the onset of type 1 diabetes... Metabolic abnormalities that include a deficient first-phase insulin response … and impaired glucose tolerance … have also been found to be present before type 1 diabetes occurs. However, the pattern of metabolic evolution to type 1 diabetes has not been characterized as yet (Sosenko et al., 2006, p. 643).
Another study, "The Natural History Study of the Development of Type 1 Diabetes," examined individuals who were at the greatest risk of developing DMT1 to further the understanding of how DMT1 occurs. Because relatives of people with DMT1 are at significantly greater risk of developing the disease than are people with no family history, subjects included12,636 blood relatives of people with DMT1. Nearly 5% of the subjects were found to have one or more antibodies associated with DMT1. More can be learned about this study at https://www.ncbi.nlm.nih.gov/pubmed/18823409 where a synopsis of the study is reported, and where the full citation for further reading can be found.
While the information in the following two paragraphs was provided previously in this self-study, its significance warrants repeating:
There are an estimated 25.8 million people of all ages in the United States (8.3% of the population) who have all types of diabetes. Approximately 18.8 million of these know it; the rest -- 7.0 million -- are unaware (National Diabetes Information Clearinghouse (NDIC), 2011). Seven million people in this country have diabetes but remain undiagnosed. To add to these dismal facts, the Centers for Disease Control and Prevention (CDC) has indicated that approximately 57 million Americans have pre-diabetes (FBG 100-125 mg/dL or A1C of 5.7% - 6.4% on two separate days) (Centers for Disease Control and Prevention, 2011), a condition which, if left untreated will likely lead to diabetes. These are alarming facts with serious health and economic consequences, and the numbers are rising every day.
Over the past thirty years, obesity rates among children in the United States have tripled (Ogden et al., 2006). No doubt, the reasons for what has been called an epidemic of childhood obesity could comprise a long list including increased time in sedentary activities – using the computer or watching television, or playing video games -- rather than actively playing. Other factors relate to the increase in marketing and advertising directed at children. Violence in the streets may have caused parents to prefer to keep their children inside where they are perceived to be safe, rather than outside, playing and at risk. No doubt, there are many reasons, but they all boil down to one problem: More energy is consumed than is used (Sacheck, 2008).
In the past, DMT2 occurred mainly in adults who were overweight and older than 40 years. Now, as more children and adolescents in the United States become overweight, obese and inactive, type 2 diabetes is occurring more often in young people. There is a direct correlation between the rise in the incidence of DMT2 among the nation’s youth and the rise in obesity in this population.The American Diabetes Association now recommends screening for DMT2 or pre-diabetes in children and adolescents who are overweight/obese and have one or more risk factors (2018).
The National Institutes of Health implemented a study (the Diabetes Prevention Program) (DPP) in 1998 (with recruitment of subjects ending in 1999) to determine whether reducing blood glucose levels in persons with impaired glucose tolerance (IGT) – a condition often noted as a precursor of DMT2 - could help to prevent or delay development of DMT2. The DPP was a major clinical trial involving 3,234 overweight people with impaired glucose tolerance. The study compared (1) intensive lifestyle changes consisting of diet and exercise; (2) treatment with the oral diabetes drug metformin (850 mg twice a day); and (3) placebo (a control group that took placebo pills in place of metformin). The second and third groups also received standard information on diet and exercise.
On the advice of the DPP's data monitoring board, the trial ended a year early because the data had clearly answered the main research questions: Diet and exercise dramatically delayed the development of DMT2, as did the medication, metformin, with diet and exercise demonstrating the more powerful influence (Diabetes Prevention Program Research Group, 2002).
The American Diabetes Association (2018) recommends the use of metformin for the prevention of type 2 diabetes for patients with pre-diabetes who are at the highest risk – multiple risk factors – and particularly if they demonstrate progression of hyperglycemia (e.g., A1C ≥ 6.0%) despite lifestyle interventions.
Effective Control and New Ways of Administering Insulin
Research also involves the attempt to discover the correlates of effective control. In other words, what factors provide for a healthy, satisfying life and prevent complications at the same time? One theory that has been supported in research is that tighter control of the blood glucose simulates normal body function. Tight control has been shown to prevent or delay complications in persons with type 1 diabetes (Reichard, Nilsson, & Rosenqvist, 1993), as well as in those with type 2 diabetes (United Kingdom Prospective Diabetes Study Group, 1998). These citations refer to the Diabetes Control and Complications Trial (DCCT) and the United Kingdom Prospective Diabetes Study (UKPDS) respectively.
Methods of more frequent insulin administration have been developed with the usefulness of tight blood glucose control in mind. The insulin pump provides for continuous exogenous insulin infusion (basal infusion) as well as intermittent patient-controlled/pump calculated bolus insulin administration (bolus infusion). The pump can be used for treatment of both DMT1 and DMT2. It has both advantages and disadvantages with regard to diabetes control.
The insulin pump was designed to administer ultra rapid-acting or regular insulin, only. As such, it provides the above infusion types (basal and bolus), and allows for more continuous blood sugar control than any other regimen or type of insulin can provide. As such, this is a powerful advantage of insulin pump therapy. Because of the ability to set different rates based on different times of the day, the insulin pump's efficacy exceeds that of the peakless insulins now available.
However, when an individual who uses a pump needs or wants to go without the pump for an extended period of time (pump malfunction or spending all day at a water park), she/he must appreciate that there is NO INSULIN when the pump is detached. At such times, one of the peakless insulins (insulin glargine or insulin detemir ) can be used. For this reason, the peakless insulins are often referred to as "The Pumper's Holiday" insulins!
A distinct disadvantage of pump therapy is the cost – upfront, recurrent, and hidden costs. The tables below are used for reference, only (since they were published in 2002) and may not reflect current facts:
Initial Costs Associated with Insulin Pump Use
Initial Estimated Costs of Pump and Supplies
(Kanakis, Watts, & Leichter, 2002, p. 214-215)
*Please recognize the publication date of this information and appreciate that the estimated costs have probably increased over the years.
**Information accessed 05/28/18 at: https://www.adwdiabetes.com/product/20274/minimed-paradigm-revel-723-pump-link-software-blue
Estimated Annual Costs Associated with Available Insulin Delivery Technologies
Annual Cost of Supplies**
(Kanakis, Watts, & Leichter, 2002, p. 214-215)
*Annual insulin cost was based on the administration of 50 units of rapid-acting insulin per day, or a monthly consumption of 1,500 units. Prices were based on retail figures accumulated in Seattle, WA during the time period defined in the report.
**Annual costs of supplies reflects monthy use of 100 syringes or 100 pen needle tips or the estimated monthly cost of insulin pump infusion sets (Kanakis, Watts, & Leichter, 2002, p. 215).
The above two tables are included in this self-study simply as a way to emphasize the economic factors related to insulin therapy. The figures are quite dated and, since they reflect data obtained from a limited area (one city in the US).
Recognize that the above tables do not address the cost of the increased number of daily self-blood glucose assessments warranted when an individual is using pump therapy. While this is a completely patient-initiated action, and can be increased or decreased in number according to the patient, individuals on pump therapy are advised to test their blood glucose at least four times each day.
Fortunately, Medicare and Medicaid plans, as well as most health insurance companies' plans, will cover the cost of pump therapy after the necessary approvals and verifications of need have been obtained. However, those individuals who, because of their insurance benefit plans, must share part of the cost, the total upfront and recurrent out-of-pocket expenses can be significant.
Other (hidden) costs are incurred in terms of financial issues for health care providers who prescribe insulin pump therapy. Office personnel must be educated about it so that they can teach proper pump use. More frequent office visits are initially necessary to provide for adjustment of insulin rates and doses.
In addition to the pump-user's commitment to regular and frequent self-blood glucose determinations, he/she must learn and religiously use the technique of carbohydrate (gram) counting for dietary control.
Medtronic Diabetes: http://www.medtronicdiabetes.com/home
Comparison of insulin pumps that are commercially available: http://www.diabetesnet.com/diabetes_technology/insulin_pump_models.php
A New Way to Take Insulin
Research on alternative methods of insulin administration has explored inhalable routes. A new form of insulin administered by the inhalation route was found to control postmeal glycemia with minimal weight gain - Afrezza®, an inhalable insulin powder, was approved by the Food and Drug Administration in 2014. It is prescribed to be taken immediately before meals, much the way short-acting or rapid-acting insulin would be prescribed pre-prandial. In those with type 1 diabetes, inhalable insulin must be used in conjunction with long-acting, basal insulin.
Noninvasive and Continuous Blood Glucose Monitors
In the early decade of the 21st century, devices to provide noninvasive measurements of blood glucose (the GlucoWatch® and the Pendra®) were developed and marketed. Unfortunately, they proved themselves less than desirable for one reason or another. No such devices are currently on the market.
Continuous blood glucose monitoring has been the focal point of research over the past several years. As a result, manufacturers have produced the technology and equipment to achieve that goal AND to allow the information to be communicated directly to the insulin pump. One example is the continuous glucose monitoring system offered by Medtronic.
This technology is especially useful for people who do not recognize when their blood sugar is dangerously low (hypoglycemia unawareness) or high, or is changing rapidly. Low and high alerts can be set to alarm when the blood glucose has reached the predetermined limits. Rate of Change alarms (sounds and vibrations) occur when blood glucose levels are changing rapidly so that the individual can alter insulin dosage and/or treat hypoglycemia earlier than ever before. The technology in continuous blood glucose monitoring is moving toward a completely closed system.
New device prototypes for providing continuous blood glucose monitoring are being developed. Randomized controlled studies comparing glucose control among men and non-pregnant women with DMT1 using self-monitoring of blood glucose (SMBG) or continuous glucose monitoring (CGM) concluded that CGM was associated with significantly greater A1c reductions than SMBG. In addition, experiences with hypoglycemia were less frequent with the CGM group (Pickup, Freeman, & Sutton, 2011). These findings provide significant application to healthcare providers' understanding of ways to enhance blood glucose control for some people with diabetes. Medtronic’s Minimed Paradigm Revel® is a pump that includes a built-in continuous blood glucose monitor.
Transplantations: Pancrease and Islet Cells
The American Diabetes Association's Position Statement, "Pancreas and Islet Transplantation in Type 1 Diabetes," was published in 2006 in Diabetes Care. Successful pancreas transplantation has been shown to significantly improve the quality of life of people with DMT1. However, pancreas transplantation has historically been considered as a therapeutic option only for those individuals with DMT1 who have imminent or established end-stage renal disease.
Foster et al. (2018) implemented a study of individuals with type 1 diabetes who underwent islet cell transplantation and followed them for two years. Statistically significant findings were documented with regard to normalization of A1c and freedom from severe hypoglycemic reactions as well as quality of life.
In the past, the American Diabetes Association Position Statement advised that a pancreas-only transplant was recommended only when the patient suffered from frequent, severe metabolic complications (e.g. diabetic ketoacidosis, hypoglycemia, and/or significant hyperglycemia) that required medical intervention, had difficulties associated with the administration of insulin that were incapacitating, or the patient's insulin regimen had failed to prevent acute complications (American Diabetes Association, 2006).
For some time, simultaneous pancreas-kidney transplantation has been considered the treatment of choice for people with DMT1 and kidney dysfunction (Weiss, Smits, & Wiseman, 2009). However, with improvements in all aspects of pancreas transplantation, the above positions may be debated. Patient survival rates after pancreas transplantation reported in 2013 were > 95% at one year and > 88% at five years. Similarly, survival of grafts was nearly 85% at one year and more than 60% at five years (Gruessner & Gruessner, 2013, p. 555). "Pancreas transplants should be more frequently offered to nonuraemic patients with brittle diabetes mellitus to prevent the development of secondary diabetic complications and to avoid the need for a kidney transplant" (p. 1).
The first human pancreas transplant procedure was performed in 1966 at the University of Minnesota. By mid-1994 more than 6,500 pancreas transplants had been reported to the International Pancreas Transplant Registry (then housed at the University of Arizona in Tucson).
In 2008, data collected worldwide showed that patients with diabetes mellitus received the largest percentage of pancreas transplants (96.6%). Unfortunately, not every institution's reports are forthcoming, so these data reflect only those transplants performed in the United States (Gruessner, Sutherland, & Gruessner, 2010).
For many individuals with DMT1 (and some with DMT2), a pancreas transplant is the only treatment that provides the opportunity to achieve normal blood glucose without significant hypoglycemia, provided the transplant is successful. In addition, the normalization of the underlying glycemic problems can lead to stopping, preventing, or reversing the complications of diabetes (Gruessner & Gruessner, 2013, p. 555).
The islets of Langerhans (cells in the pancreas that produce insulin) represent another avenue of transplantation research in terms of interventions for people with DMT1. Exogenous insulin independence has been achieved through islet cell transplant worldwide (Berman et al., 2009), but "islet recipients rarely maintain long-term insulin independence" (Gruessner & Gruessner, 2013, p. 556). One reference noted only 80% of islet cell transplant recipients were "insulin independent" at one year post-transplant (Gaba, Garcia-Roca, & Oberholzer, 2013). No statistics were included on status of recipients at two or more years post-islet cell transplantation, however. The procedure for transplantation of islet cells has been to obtain the islets from cadaver donors and to implant them in the recipient's liver. While effective in achieving the goal of insulin independence (at least temporarily), intrahepatic transplantation has many disadvantages (Berman et al., 2009).
Consequently, new avenues of transplantation of islet cells are the focus of current research. Studies have been implemented to determine other ways to transplant islet cells. One study examined a novel approach to islet cell transplantation in diabetic monkeys. For reasons outlined in the study, the greater omentum (a transparent extension of the peritoneum that covers the large and small intestines in humans and other primates) was selected from which to construct a pouch to receive islet cell transplants. The results of the study suggested that the greater omentum pouch technique has potential to serve as another site for islet cell transplantation (Berman et al., 2009).
Use of Aspirin as a Prevention Strategy for Cardiovascular Disease
The American Diabetes Association has also researched the various recommendations relative to the use of aspirin as a primary or secondary prevention strategy for cardiovascular disease (CVD), and has published a position statement, "Anti-Platelet Agents – Recommendations." The recommendations are daily aspirin at a dosage of 75-162 mg should be taken by men and women with diabetes who have a history of atherosclerotic cardiovascular disease (CVD) (or a comparable dose of clopidogrel for those who are allergic to aspirin). Others who should received 75-162 mg per day of aspirin are diabetic men over 50 years of age and diabetic women over 60 years of age who have at least one additional major risk factor e.g. hypertension, a family history of CVD, dyslipidemia or albuminuria, or who smoke (American Diabetes Association, 2018, p. S95).
American Diabetes Association at: http://www.diabetes.org
Joslin Diabetes Center: https://joslinresearch.org/clinical-research