Research

Research and Innovation in the Medical Field and Diabetes

Red meat eaters face (massive short-term) increased risk of diabetes

Eating red meat comes with a risk according to a new study published in JAMA which correlated an increased risk of Type 2 Diabetes via a 20 year prospective study. Increasing the amount of rea meat consumption by just 0.5 servings per day was associated with a 48% increase in risk.  A related editorial comments

The article by Pan et al1 confirms previous observations that the consumption of so-called red meat is associated with an increased risk of type 2 diabetes mellitus (T2DM). While previous studies have been cross-sectional in nature, the present study demonstrated that a relatively short-term (4-year) increase in red meat consumption is associated with subsequent risk, even in individuals who initially consumed low amounts of red meat. The authors demonstrated that consuming more red meat is also associated with weight gain, and a statistical adjustment for change in body weight attenuates but does not eliminate the risk, indicating that increased weight is not the only cause of a greater risk of T2DM associated with red meat consumption. The data in this article are valuable for those considering strategies to decrease the risk of developing T2DM.

I can see the Chick-vil-a commercial somewhere in all of this.

now.

 

 

Advancement: reproducing human beta cells that make insulin

transplant cell insulin cluster

Research aimed at treating diabetes through beta cells that can be transplanted just took a step forward:

Researchers at Washington University School of Medicine in St. Louis have identified a way to trigger reproduction in the laboratory of clusters of human cells that make insulin, potentially removing a significant obstacle to transplanting the cells as a treatment for patients with type 1 diabetes.

Efforts to make this treatment possible have been limited by a dearth of insulin-producing beta cells that can be removed from donors after death, and by the stubborn refusal of human beta cells to proliferate in the laboratory after harvesting.

They … used a novel conditioned medium expressing Wnt3a, R-spondin-3 and Noggin to engage Wnt signaling at the receptor level in combination with RhoA/ROCK inhibitors, SB-431542 and Y-27632, to significantly enhance adult human β-cell proliferation and maintain β-cell specific gene expression, insulin secretion and content in intact islets.

The new technique uses a cell conditioning solution originally developed to trigger reproduction of cells from the lining of the intestine.

“Until now, there didn’t seem to be a way to reliably make the limited supply of human beta cells proliferate in the laboratory and remain functional,” said Michael McDaniel, PhD, professor of pathology and immunology. “We have not only found a technique to make the cells willing to multiply, we’ve done it in a way that preserves their ability to make insulin.”

The findings are now available online in PLOS ONE. (A Novel Strategy to Increase the Proliferative Potential of Adult Human β-Cells While Maintaining Their Differentiated Phenotype)

The current method for harvesting human islets, which are comprised primarily of the insulin-producing beta cells, makes it necessary to find two or three donors to extract enough cells to produce an adequate supply of insulin to treat a single patient with diabetes.
The idea for the new technique came from an on-campus gathering to share research results. Lead author Haytham Aly, PhD, a postdoctoral research scholar, reported on his work with beta cells and was approached by Thaddeus Stappenbeck, MD, PhD, associate professor of pathology and immunology, who studies autoimmune problems in the gut. Stappenbeck had developed a medium that causes cells from the intestine’s lining to proliferate in test tubes.

“He said, why don’t you try it, and he gave us some samples,” Aly said. “We put the solution in our freezer for a month or so, and when we finally gave it a try, we were amazed at the results: human beta cells in Dr. Stappenbeck’s solution reproduced at a rate that was 20 times higher than beta cells in a solution that contained the sugar glucose.”

The ability to produce large quantities of human beta cells in the laboratory gives the researchers hope that they could one day be transplanted into patients with type 1 diabetes.

The advantage of Stappenbeck’s solution may be that it is designed to activate multiple growth signaling pathways in cells, according to the researchers. Earlier attempts to make beta cells proliferate focused on one or two growth pathways. The solution also activates genes that help prevent beta cells from dying.

Because pancreatic cancers are among the most deadly tumors, the scientists checked to make sure the proliferating beta cells weren’t becoming more like cancer cells. They found that none of the factors known to contribute to pancreatic cancer were active in the laboratory-grown beta cells.

“This is an important concern to keep in mind if we are to expand human beta cells in culture with this medium and subsequently transplant them into patients,” said Aly.
If the new availability of laboratory-grown beta cells makes it possible to treat patients with transplants from one donor instead of multiple donors, McDaniel noted, that might reduce the risk of immune system rejection of the transplants.

“Another benefit in using this novel growth medium to expand isolated human beta cells is that the cells remain healthier and have reduced levels of cell damage or death,” Aly said. “That may also reduce the chances of immune system rejection.”

Source

FDA Wants Artificial Pancreas Approval

An artificial pancreas, as commonly reported, is a medical device that is worn and attached to a person.  It autonomously changes the insulin administered to a person with diabetes in response to glucose measurements, which are measured automatically.

The system has a few basic components that include a continuous glucose monitor (CGM), a continuous subcutaneous insulin pump and a control system that determines the rate of insulin infusion given the measured glucose through time.  An artificial pancreas will also include a display, communication system, overrides, alarms, fail safes, and controls for user input (i.e., for indicating meals, exercise, etc).  However, the fundamental components are the three I mentioned.

Despite decades of research, the three basic components as a whole may not be ready for complete autonomous application.  Insulin pumps are quite reliable and control algorithms have reportedly been developed that effectively achieve a target range while avoiding hypoglycemia.  However, continuous measurement of blood glucose through current subcutaneous sensing technology has proven to be quite challenging .

That said, researchers are now entering what appears to be the final stretch to bring an artificial pancreas (or a system that at least reduces insulin in response to low glucose) to the FDA…. And, we want it:

Teenaged delegates from the Juvenile Diabetes Research Foundation testified on Capitol Hill, urging Congress to accelerate research and review of artificial pancreas systems for managing insulin for patients with type 1 diabetes.

“After participating in clinical research since I was three years old, I can honestly say the closed loop artificial pancreas trial was the most amazing experience of my entire life and holds so much promise for people living with this disease,” said Kerry Morgan, a 17-year-old JDRF Children’s Congress delegate from Glen Allen, Va., who testified before the Senate Committee on Homeland Security and Government Affairs this week.

Would you be surprised to learn that the FDA wants it too:

FDA WANTS APPROVAL, TOO

Charles “Chip” Zimliki, chairman of the U.S. Food and Drug Administration’s Artificial Pancreas Critical Path Initiative, which was created in 2006 to accelerate the availability of an artificial pancreas system, says he is eager to have a system approved.

“The FDA wants the artificial pancreas on the market as much as anyone else does. We just have to operate within U.S. laws to make sure it is safe and effective,” Zimliki said.

Last week, the agency released guidance for how to develop a low glucose suspend system, an automatic shut-off mechanism used with an insulin pump. Medtronic already sells pumps with this the feature in Europe. It safeguards against a dangerous drop in glucose levels by temporarily halting glucose delivery.

By year-end, FDA plans to release detailed guidance on more complicated closed-loop systems, Zimliki said.

“We think of this system, the artificial pancreas, as one unit. There is going to have to be agreement among various companies to determine who is the reporting party for submitting it,” he said.

“That is a relatively new idea with respect to these systems.”

Zimliki, who is a type 1 diabetic, thinks the first approved devices will be ones that deliver insulin only, but he is very encouraged by the system being developed by the team at Boston University and Massachusetts General.

“They have what I call the Cadillac of closed-loop systems,” he said. In addition to delivering insulin, the device also delivers an infusion of glucagon, a hormone released by the pancreas to raise blood sugar levels.

“They are showing some very promising results,” he said.

See the JDRF more more information on this project and the latest FDA guidance.

Diabetes Mine has an interesting post and interview with the principle investigators from Boston University and Massachusetts General Hospital (see the youtube video).

A “Cure” for Type 2 Diabetes

In case you haven’t already heard, researchers are now reporting that Type 2 Diabetes may (possibly) be reversed by a restricted low-calorie diet:

Adhering to the strict 600 calorie-a-day diet causes fat levels in the pancreas to plummet, restoring normal function, found Prof Roy Taylor of Newcastle University.

The discovery, a “radical change” in understanding of the condition, holds out the possibility that sufferers could cure themselves – if they have the willpower.

Until recently received medical wisdom was that Type 2 diabetes was largely irreversible.

But this small-scale study indicates that defeating it could be easier than commonly thought.

Prof Taylor asked 11 volunteers, all recently diagnosed, to go on what he admitted was an “extreme diet” of specially formulated drinks and non-starchy vegetables, for eight weeks.

Hyscience comments:

As the article goes on to point out, the trial study involved only 11 patients that ate a “meal-replacement” milkshake of 150 calories three times a day. This was supplemented with three portions of non-starchy vegetables including cabbage, broccoli, peppers, tomatoes, cucumber and lettuce. After one week, their pre-breakfast blood sugar levels had returned to normal and an MRI scan revealed that the fat levels in the pancreas were also normal, down from around eight per cent to six per cent.

Notes to self:

  • Great news – perhaps (I think)
  • “small-scale study” –  The smaller the study the less likely the results will be supported over time, esp. considering all of the potential influential factors.  Something like 33% of all reported major medical studies is contradicted within five years.
  • Radical change in management – pharma and device companies may need to revisit their strategic roadmap if this research is supported by larger scale studies

 

Low Glucose Suspend – FDA Guidance

While complications of diabetes are understood and have been tied to the cost of providing healthcare, trends indicate the incidence Diabetes Mellitus in the United States and other developing countries is growing at an alarming rate.

There is so much about diabetes that is understood, predicted and recommended and yet management continues to be a challenge.  Could it be that better tools are needed?

To meet the challenge, researchers have been developing technology based tools that will help manage the disease through automation. That is, automatically administering an appropriate amount of insulin in response to a person’s glucose level and carbohydrate intake.

Often called the “artificial pancreas”, such systems combine continuous glucose measurement systems (CGM), insulin pumps (giving continuous subcutaneous insulin infusion) and advanced algorithms to give insulin dosing recommendations and stop infusion when a hypoglycemic event is predicted. The latter is called a “low glucose suspend” (LGS) device and provides benefit as a result of its autonomous action aimed at avoiding low blood sugar (predictively) or reducing the impact of hypoglycemia in a reactive manner.

Yesterday, the FDA release a new guidance document that will help medical device manufacturers submit their artificial pancreas-like product for review. The move is encouraging for a number of reasons. First, the agency is agreeing that automation has a role in the marketplace and is encouraging a path forward. Second, progress has been made and interest expressed to the point that the FDA felt is necessary to invest in guidance.

On the other-hand, there are a number of challenges the agency suggests must be remedied involving CGMs:

  • Using the same CGM to measure success and to make decisions about if and when to turn the pump off will introduce bias. Although the size of the bias may or may not be large, determining the extent of the bias will be impossible without an independent measure.
  • Although CGMs have been successful in improving diabetes management through their tracking and trending functions, these devices have not been shown to be accurate enough to support use for insulin dosing.
  • The glucose meters used to calibrate the CGMs also have inaccuracies that can compound the errors in the glucose values reported by the CGM and are part of the device system.
  • Use of retrospective signal calibration using reference blood glucose values or introducing a reference method to be performed by the patients may be possible solutions if the approach is appropriately validated.
  • CGMs have periods of sensor irregularities and signal drop out. These sensor performance problems arise in addition to sensor accuracy challenges and would need to be resolved and/or mitigated.

But are they effective enough to “pause” an insulin infusion?  Perhaps, but what if users begin to rely on a “pause” as their safety net even though CGMs have the issues listed above?

From an altruistic standpoint, advances in this area will help those suffering from Diabetes and in particular individuals who are unable to properly treat their disease (esp. children). From a business stand-point, a revolutionary product that is intuitive, effective and safe will provide a huge advantage in a market that seems stuck on the stick meter.

 

 

Type 2 Diabetes – an autoimmune disease

Type 2 diabetes is in the process of being redefined as an autoimmune disease rather than just a metabolic disorder.

A recent study, appearing in Nature Magazine, showed that an antibody called anti-CD20, which targets and eliminates mature B cells in the immune system, stopped diabetes type 2 developing in lab mice prone to develop the disease, and restored their blood sugar level to normal:

Chronic inflammation characterized by T cell and macrophage infiltration of visceral adipose tissue (VAT) is a hallmark of obesity-associated insulin resistance and glucose intolerance. Here we show a fundamental pathogenic role for B cells in the development of these metabolic abnormalities. B cells accumulate in VAT in diet-induced obese (DIO) mice, and DIO mice lacking B cells are protected from disease despite weight gain. B cell effects on glucose metabolism are mechanistically linked to the activation of proinflammatory macrophages and T cells and to the production of pathogenic IgG antibodies. Treatment with a B cell–depleting CD20 antibody attenuates disease, whereas transfer of IgG from DIO mice rapidly induces insulin resistance and glucose intolerance. Moreover, insulin resistance in obese humans is associated with a unique profile of IgG autoantibodies. These results establish the importance of B cells and adaptive immunity in insulin resistance and suggest new diagnostic and therapeutic modalities for managing the disease.

One of the many reasons that this is significant is that it could lead to future novel treatments.

Adult Stem Cells Continue to Show Promise for Diabetes Research and Therapy

Stem cell research is a promising component of what we hope will bring about a cure-like therapy for diabetes.  It may also provide models that enable the unraveling of Type 1 Diabetes and the mechanisms that bring about an auto-immune attack on islet cells.

We understand the ethical problems with destroying and harvesting an immature human in support of embryonic stem cell research. In addition, ESCR carries with it other challenges that have signifantly limited practical success including rejection and the potential for unpredictable growth.

Adult stem cells, derived from the same person they will be used to eventually treat, may enable the growth of insulin-producing cells, which could be used to repair the imcomplete pancreas.  Alok Jha, writing for the Observer, has an excellent piece that details the advantage that reprogrammed adult stem cells have:

Key to this is the discovery, in the past few years, of a way to make stem cells that do not require the destruction of embryos. In one move, these induced pluripotent stem (iPS) cells remove the ethical roadblocks faced by embryonic stem cells and, because they are so much easier to make, give scientists an inexhaustible supply of material, bringing them ever closer to those hoped-for treatments.

(…)

In 2007, Shinya Yamanaka at Kyoto University in Japan demonstrated a way of producing ES-like cells without using eggs. He took a skin cell and, using a virus, inserted four specific bits of DNA into the skin cell’s nucleus. The skin cell incorporated the genetic material and was regressed into an ES-like cell – it had been “reprogrammed” using a batch of chemicals in the lab. In a few short experiments, scientists had a near-limitless supply of stem cells that were, seemingly, as good as ES cells for their research.

As I mentioned earlier, one of the key applications for these cells is the development of models to study disease states:

Models using iPS cells have proliferated in a few short years: they are now available for, among other things, motor neurone disease, juvenile diabetes and sickle cell anaemia.

[Read more...]

Closed-Loop Control for Anesthesia Delivery

Earlier today I commented on my optimism concerning closed-loop control for glucose management.  A different application but somewhat analagous system (i.e., closed-loop) has been developed and tested for anesthesia delivery:

We have developed a proportional-integral-derivative controller allowing the closed-loop coadministration of propofol and remifentanil, guided by a Bispectral Index (BIS) monitor, during induction and maintenance of general anesthesia. The controller was compared with manual target-controlled infusion.

The controller allows the automated delivery of propofol and remifentanil and maintains BIS values in predetermined boundaries during general anesthesia better than manual administration.

You can see the system in action below (video uploaded by Medgadget):

Artificial Pancreas and Closed Loop Control – is it really that far off?

For many years academic researchers and device companies alike have investigated, developed and studied that artificial pancreas.   The system isn’t really a pancreas per se but rather a multi-component system that  continuously measures glucose (via a subcutaneous sensor), uses a computerized closed loop controller to determine the proper insulin infusion rate and and then automatically adjusts insulin delivery via a subcutaneous insulin pump.

Many of these automatic feedback control systems are in clinical trials and there has been enthusiasm generated by NIH and JDRF sponsored research in this field.

I don’t think the artificial pancreas is far off at all, although the first generation may not be the fully automated high performing system that we dream about.  Insulin pumps are reliable and sophisticated control systems have been developed that optimize insulin delivery decisions using a personalized predictive model (i.e., determines future glucose response via an adaptive nonlinear PK/PD equation).   The weak link, in my opinion, is the glucose sensing system.  Continuous glucose monitors have improved but may not be at the point were tight glycemic control is possible.  However, some level of autonomous action does seem feasible – today.

 

The Cure – devices, transplants, stem cells and stopping beta cell attackers

I’m a proud techno-geek.  As a result, when I think about diabetes I tend to gravitate to technology oriented device solutions.  An Artificial Pancreas, a non-invasive blood glucose meter and interchangeable/inter-operable pumps and meters.

And, I like data, lots of data.

While technology is very important, the holy grail of diabetes research is not the future medical device with Star Trek capability unless it is able to promote and bring about a cure.

Pancreas and islet transplants have benefit individuals but have not yet provided a treatment that is worth the risk for most individuals.  And, even if the risks were mitigated, the lack of suitable donors is another impediment.

To me, the ideal is the development of implantable islets from adult stem cells take from the same individual who will receive them.  Rejection of the islets would be minimized and the us of immunosuppressive drugs, I would guess, could be minimize.  In short, Autologous Stem Cell Therapy Transplant requiring no immunosuppression

[Read more...]

Here’s your chance – DiabetesMine Design Challenge

DiabetesMine, a leading informational and community web site for people with diabetes, recently announced the kickoff of the 2011 DiabetesMine Design Challenge, a competition that fosters innovation in the creation of new tools designed to improve life with diabetes.

This annual web-based competition, hosted at here, calls for fresh ideas for new devices, web applications, or other instruments designed to help people live better with diabetes. The contest is underwritten by the California HealthCare Foundation (CHCF), an independent philanthropy committed to improving the way healthcare is delivered and financed in California and beyond. It is also supported by the global design and innovation firm IDEO, headquartered in Palo Alto, CA, and endorsed by Medgadget.com, the Internet journal of emerging medical technologies.

 

Read the announcement at DiabetesMine!

Alzheimer’s Disease may actually begin in the liver – not the brain

Although the actual cause of Alzheimer’s Disease continues to escape medical researchers, experts to associated plaques and “tangles” in the brain with the onset of this chronic and debilitating illness.

But where to the plaques come from and what trigger’s their build-up?  I found this article interesting, if not mind-blowing:

A new study has suggested that the plaques associated with Alzheimer’s disease start in the liver and not in the brain—completely altering scientists’ ideas about the disease.

The unexpected results could now potentially simplify the nature of Alzheimer’s prevention and treatment strategies.

Researchers from the Scripps Research Institute and ModGene, L.L.C., used a mouse model for Alzheimer’s disease to identify genes that influence the amount of amyloid that accumulates in the brain.

In other words, a substance has been found that leads to brain plaque, which is associated with Alzheimer’s.  The source of the plaque appears to be in the liver, not the brain.  As a result, the substance potentially could be blocked ….  If the link is ultimately established, a potential treatment has been identified which lowers the production of beta amyloid in neuroblastoma cells.

Recent reports discussed prophylactic use of drugs rather than treatment of therapies of those already suffering from dementia.

Confusion among cancer patients

About a third of cancer patients taking opioid painkillers experience cognitive problems such as confusion, disorientation and forgetfulness, a new study finds.

[Read more...]

Gastric Bypass Surgery Reverses Heart Ailments!

gastric-bypass-surgery.jpgThis is fairly significant news…. gastric bypass does help lose weight and treat diabetes (more here):

Well- who is a candidate for these procedures? Usually patients with a BMI of over 40 or over 35 with health consequences that are obesity related. Does gastric bypass have any effect on diabetes? In a series of 1000 patients, 150 of whom had diabetes, 83% experienced resolution of their diabetes (defined by a normalization of A1c and coming of medications for diabetes) after the surgery

However, there now appears to be additional benefits:

A new report from the Journal of the American College of Cardiology reports that patients who had received gastric bypass surgery not only lost weight but had maintained healthier cardiac health, while also reducing previous cardiac complications spurred by obesity.

Often times when a patient is obese, an increase in the largest portion of the heart, the left ventricle can become larger in mass causing the heart to work harder to pump blood into the body. According to the study, echocardiograms, or ultrasounds of the heart showed a remodeling of the heart structure which included a reduction of left ventricular mass and right ventricular cavity area in patients that had received Gastric Bypass Surgery, a procedure Texas Bariatric Specialists performs.

“Patients now have another reason to add to their check-off list of the benefits of a gastric bypass. Why would anyone severely obese wait any longer when the health risks are too high,” says Texas Bariatric Specialists founder Dr. Nilesh A Patel.
A gastric bypass is a bariatric procedure that is the single largest contributor to these findings and is offered at Texas Bariatric Specialists. In the Laparoscopic gastric bypass surgery procedure, the surgeon makes a small stomach pouch at the top of the stomach, the pouch is later connected to the small intestine bypassing the larger stomach. The gastric bypass can result in complete resolution in type 2 diabetes, hypertension, high blood pressure, sleep apnea, and the loss of 65 percent of excess body fat.

Source: press release

Infection and Early Diabetes Risk

We’ve understood for some time that Type 1 Diabetes is an autoimmune disease in which the beta cells are casualties of a T-cell mediated autoimmune attack. As a result, researchers hypothesized that environmental triggers could play some roll in the onset of the disease. It appears they are one step closer in their understanding, as reported in the British Medical Journal (BMJ 2011; 2011; 342:d35 doi: 10.1136/bmj.d35 (Published 3 February 2011):

There is a clinically significant association between enterovirus infection, detected with molecular methods, and autoimmunity/type 1 diabetes.

First, note that enteroviruses are second only to the “common cold” viruses, the rhinoviruses, as the most common viral infectious with an estimated 10-15 million cases per year in the United States.
Second, the study was a retrospective analysis of published reports. This is a common method and accepted approach although there are limitations due to the difficulty in normalizing results across diverse study protocols.
Third, the study found a clear relationship between the presence of an enterovirus infection and type 1 diabetes. However, causality was not proven — the results provide ‘additional support to the direct evidence of enterovirus infection in pancreatic tissue of individuals with type 1 diabetes’. That is, the two are often observed together.

Mechanisms – Knowing and Curing

By answering the question of how diabetes surgery works, we may be answering the question of how diabetes itself works.
Gastric bypass surgery can lead to diabetes remission independent of weight loss even in subjects who are are not obese, which points to the small bowel as the possible site of critical mechanisms for the development of diabetes.

Do you know diabetes research?

Vaccines cause diabetes? Vaccines are Likely to Cause Insulin Dependent Diabetes in Over 2% of Children With a Strong Family History of Insulin Dependent Diabetes. – more
More Non-invasive hype? Researchers at Baylor University, in Waco, TX, have engineered a thumb-pad sensor that measures glucose levels via electromagnetic waves–no finger pricking required. “The sensor is still in the early stages of development.” – more
Gene DiscoveryThe Children’s Hospital of Philadelphia has developed a large-scale effort to identify the genes responsible for common childhood diseases. The Center for Applied Genomics aims to improve understanding of the genetic causes of the most prevalent diseases of childhood, including ADHD, asthma, allergies, obesity, diabetes and cancer — all of which are thought be caused by the complex interactions of multiple genes within our bodies.more

Beta Cells
treatments for diabetes that will restore of preserve insulin secretion in order to delay or prevent long-term complications from the disease. – more
Prevent Type 1Researchers have begun a clinical study of oral insulin to prevent or delay type 1 diabetes in at-risk peoplemore
Why Low-Carb may be better: A diet low in carbohydrates but high in animal fat and protein doesn’t seem to increase the risk of type 2 diabetes in women, a new study claims. – more
Dexcom Testimonial: not research but looks good!
Embryonic Defects: linked to diabetes.
Exercise can help: A few good workouts might be the first steps toward better diabetes controlmore
Note: except in cases in which research contradicts “conventional wisdom”, no peer review or technical assessments are reported. Why?

Diabetes Fight May Be Helped By New Molecular Target

life-microrna-art-bg.jpgResearchers say that the fight against diabetes could be helped by targeting a newly discovered molecule, a microRNA known as miR124:

The researchers found that miR124 inhibits the production of insulin in the pancreas. It does this by controlling how several genes are expressed in the body’s beta cells, which secrete insulin.
Insulin is the principal hormone that regulates the uptake of glucose and if the body produces insufficient insulin this can cause diabetes.
The researchers believe that if drugs could be developed to suppress the action of miR124, and related microRNAs, in those with diabetes, this could enable more insulin to be produced, helping to combat the condition.
… Synthetic molecules known as antagomirs can inactivate microRNAs and scientists are hopeful that they might one day be able to harness their properties to switch off selected microRNAs, including miR124.

Continue reading …