Reversing Diabetes By Awakening Beta Cells—Nearly There

The potential for achieving remission in newly diagnosed diabetes appears feasible given recent evidence that changes that induce beta cell function may induce disease remission for type 1 diabetes and reverse type 2 diabetes.

With Roy Taylor, MD, Michael Haller, MD, Domenico Accili, MD, and J. Michael Gonzalez-Campoy, MD, PhD

With 1.5 million Americans learning they have diabetes annually, the push to reverse diabetes has taken a promising turn given findings from several recent studies.1-3

Roy Taylor, MD, professor of medicine at the University of Newcastle, UK, continues with research into type 2 diabetes (T2D), further demonstrating that newly diagnosed patients may reverse the disease with substantial weight loss.1,2 In the latest study published in the journal, Cell Metabolism,2  Dr. Taylor and his team introduced new clues regarding how weight loss may be responsible for improving beta cell function in some individuals—and why others who lost substantial amounts of weight were not able to shed their diabetes. 

In a trial focusing on type 1 diabetes (T1D),Michael Haller, MD, professor of medicine and chief of pediatric endocrinology at the University of Florida Diabetes Institute in Gainesville, reported that low-dose anti-thymocyte globulin (ATG) preserved beta cell function and improved hemoglobin A1c (HbA1c) in patients with newly T1D.

In effect, Dr. Taylor told EndocrineWeb, his weight loss program is ready for prime time so it is very important that clinicians are prepared to be more aggressive about stressing weight loss in patients who are newly diagnosed with type 2 diabetes, while Dr. Haller said his approach still requires more research with a longer follow up before any celebrating can begin.

Results of DiRECT: Outcomes of a Primary Care-Led Weight Loss Program

In a trial published in Lancet,4 Dr. Taylor et al reported that nearly half of the patients who were followed with early-onset T2D were able to return to non-diabetic status after substantial weight loss. Since this data was presented, the researchers have gone on to test the hypothesis that weight loss of more than 10 kg (22 lbs) would normalize liver fat and reduce pancreatic fat stores, such that a reversal in diabetes status seemed wholly dependent upon the ability of individual patient's beta cells to recover after achieving dramatic changes in body weight.1

Reversing type 2 diabetes is possible when weight loss is achieved after initial diagnosis.

Our work,1,2,4 Dr. Taylor said, “challenges the long-held belief that beta cell function is irreversibly lost in patients with type 2 diabetes.” In effect, beta cell activity can be rescued, he said, based on their research examining potentially relevant metabolic factors, such as liver fat content, pancreatic fat levels, triglycerides, and beta cell function in a subset of 64 patients from the earlier study.

In the intervention group,1 liver fat content decreased from 16% to 3.1% (P = 0.0001).2 Among the patients on a very low-calorie eating plan, plasma triglycerides and pancreas fat decreased regardless of their glucose activity.

In addition, in both those who responded and those who did not, the reduction in the metabolic factors was similar but only responders demonstrated early and sustained improvements in beta cell function.1,2

The most striking difference was the first-phase insulin response,according to Dr. Taylor, as it increased in responders but not non-responders.1 Recovery of first-phase insulin response (0.04 to 0.11 nmol.min/m2,  P = 0.0001) defined those who returned to non-diabetic status and was durable at 12 months. Also important—Good responders overall had a shorter diabetes duration (2.7 years vs. 3.8 years, P = 0.02).

"As you would expect, people had a different length of the window as to when they remained reversible [with regard to their diabetes]," Dr. Taylor told EndocrineWeb. For example, one patient had been diagnosed with diabetes for 24 years, he said, and went back to normal insulin function.

'It appears that this person had beta cells susceptible to being switched off by the fat accumulation that was not absolutely kaput by the fat." While this patient may be an outlier, "for others, even three years [after diagnosis] was too late," he said.

These study results advance our understanding of the onset of type 2 diabetes, moving the clinical field closer to the possibility of a cure, at least in some people,1 said Dr. Taylor.

"T2D is simply the result of too much fat overloading the liver and pancreas in people who happen to be susceptible to the fat-induced damage," he said. One limitation of the study, however, is that the population sample was 98% Caucasian, so similar research is essential in other populations, as is more follow-up, and this is underway.

Time for Action Plan in Clinical Practice

Even though many questions remain, Dr. Taylor expressed certainty of that the timing is right for endocrinologists and primary care practitioners to take a more aggressive approach with regard to weight managed in their patients—more urgently in those who are newly diagnosed with type 2—to emphasize the urgency to lose the excess weight immediately.

While about half of his patients were content to take anti-diabetes medicine to manage their blood sugar despite the well-known complications of diabetes, Dr. Taylor said, many others were ''horrified'' at receiving a diagnosis of diabetes, and appeared highly motivated to address the condition.

Clinicians should find reassurance from the relief that patients expressed when learning that a change in lifestyle might be enough to reverse the course of their disease.  

“Health care providers can learn this [weight loss] protocol with just eight hours of training,” said Dr. Taylor. However, he voiced caution to physicians to select patients wisely as his recommended approach to weight control is “not for the faint of heart: The three-month initial weight loss stage is a liquid diet—four shakes a day, 200 calories each.”

After the weight loss phase, patients are transitioned back to regular meals, by replacing one shake at a time to gradually restore solid meals as the patient receives individualized instructions on how to eat to maintain the lost weight.Participants were seen once a month to receive individualized weight maintenance guidance, including instruction to eat about 30% less than their estimated intake at the start of the study.4

Another key aspect of Dr. Taylor’s protocol was to work with patients who successfully achieved desired weight loss to phase in exercise as an important element of the weight maintenance phase. "Quite a few people took up a sport they used to play," he said. Or in many cases just began with daily walking.

Even so, "the average weight tended to creep up'' among many of the participants,”4 he said, speculating that the difficulty in keeping lost weight off may depend on personal ''fat thresholds." In effect, it may be that when the fat weight begins to rise in patients who had successfully reversed their diagnosis of diabetes, keeping an eye on liver fat levels may offer a key to future treatment strategies in these patients, said Dr. Taylor.

One explanation for the development of type 2 diabetes may be that people with a so-called healthy body mass index might be carrying more adipose fat than their body is able to cope with to prevent diabetes, Dr. Taylor said.

Reversing the Natural History of Type 1 Diabetes, Too

In research focusing on T1D,3 Michael J. Haller, MD, professor and chief of pediatric endocrinology at the University of Florida, Gainesville, and colleagues, found that treating patients newly diagnosed with type 1 diabetes with low-dose anti-thymocyte globulin (ATG) slowed the decline of C-peptide and reduces hemoglobin A1c (HbA1c).

"We were using FDA-approved drugs and repurposing them for use in T1D," Dr. Haller told EndocrineWeb, until now, ATG primarily has been used to treat kidney transplant patients.

According to their findings published in the journal Diabetes Care,3 the investigators focused on the understanding that type 1 diabetes is a T-cell mediated process marked by autoimmune destruction of β-cells, he said. While several agents targeting T- and β-lymphocytes have shown promise, no single agent yet has demonstrated long-term or sustained success in preserving C-peptide or reducing HbA1c, which are two critical markers of disease reversal.

His team randomly assigned 89 patients, with an average age of 17 years, who were diagnosed with type 1 diabetes for less than 100 days, to one of three groups:3

  • A single course of ATG (2.5 mg/kg)
  • A single course of ATGATG plus pegylated granulocyte colony stimulating factor (GCSF)
  • Placebo doses of both ATB and GCSF

The one-year mean C-peptide measurement (as assessed by plasma drug concentration-time under the curve) was significantly higher in those in the first group: treated with ATG (0.646 nmol/L) versus placebo (0.406 nmol/L, P = 0.0003), but not in those treated with the combination (0.528 nmol/L) versus placebo (P = 0.031).3 Both ATG alone, and combination ATG and GCSF achieved a reduction in A1C at one year.

"Of course, longer follow-up is necessary to see if the findings hold," Dr. Haller said, "and it will be critical to evaluate the efficacy of maintenance therapy." While he wouldn’t yet propose that physicians try the treatment with patients at this point, he said that the findings offer reasonable promise that type 1 diabetes might be reversed or even prevented on a large scale.

Closing In On Biological Mechanisms of Beta Cell Action

Those in the diabetes community ''have been talking for some time about the understanding that in diabetes, primarily for type 2, the insulin-producing cells are not dead but simply inactive," said Domenico Accili, MD, chief of the division of endocrinology, and the Russell Berrie Foundation Professor of Diabetes at the Columbia University College of Physicians and Surgeons, New York; he was not involved in either study but reviewed the findings for EndocrineWeb.

"The [Taylor] study is very important to the extent that it provides the clinical correlation for basic cellular and biological activities and at the same time provides a rationale for what is happening in these patients whose diabetes does or does not respond to weight loss," Dr. Accili said.

In effect, the new research echoes what we have known for a while, Dr. Accili said, so "if you put patients with diabetes on a diet [to promote weight loss], it will have a positive impact on their beta cells." To reiterate Dr. Taylor’s sentiment, “the message for patients is to change your lifestyle when you get a type 2 diabetes diagnosis,” he said.

With this recent research, "what we are learning now is, maybe there is more room for lifestyle modification than we thought, and with a much more significant impact," Dr. Accili told EndocrineWeb.

Likewise, he said, “the Haller study goes in that direction, suggesting that intervention in the early phases of type 1 diabetes might also make a difference.” Dr. Accili agreed, that ''this is not at the clinical stage yet" for type 1 diabetes but worth following.

Insights from Experts in Obesity Management 

“Both studies are of significant interest,” in furthering our understanding of the interrelationship between obesity and diabetes, said J. Michael Gonzalez-Campoy, MD, PhD, FACE, medical director and CEO of the Minnesota Center for Obesity, Metabolism.

"First, we know that with increasing fat mass may develop adipose tissue dysfunction (ie, adiposopathy).  Changes in adipose hormones—specifically a rise in leptin and a drop in adiponectin, and the development of insulin resistance whereby insulin cannot activate its receptor in target tissues—will have a negative impact on beta cells. In particular, as insulin resistance develops so too does the inability to move triglycerides into cells, causing the body to recirculate free fatty acids, which directly impair beta cell function. This process sets up a vicious cycle, with decreasing insulin release leading to further decline in insulin activity which then leads to a further rise in circulating triglycerides,” said Dr. Gonzalez-Campoy.

"With regard to weight loss, it’s evident that some patients are more responsive and able to restore their insulin production while others are not able to recover. It could be that responders were able to re-establish the first phase of insulin release to increase insulin production but the mechanism of action for this difference was not captured in this paper. Although triglycerides fell in both groups, there were differences in VLDL-triglyceride levels, and this offer at least a partial explanation,” he said.

"However, the [Taylor] paper on type 2 diabetes did not measure adipokines or gut-hormone levels,” Dr. Gonzalez-Campoy told EndocrineWeb. As such, there are other mechanisms at play that need to be considered in diabetes management.

In adiposopathy, for example, the ratio of leptin to adiponectin rises (leptin increases and adiponectin decreases); there are also elevations in markers of inflammation, since adiposopathy includes the infiltration of adipose tissue by macrophages when adipose tissues exceeds is vascular supply and ischemia develops, he said, so that an increased leptin to adiponectin ratio and elevated cytokines each may lead to impaired GLP-1 release, he said.

“Although not measured in this study, it seems likely that responders had better resolution of the adiposopathy than non-responders, which would suggest that it is not the drop in poundage (response of adiposity), but rather a return of adipose tissue and intestinal endocrine function to normal that helps explain the authors’ observations. Hence, the need for further studies to clarify the mechanisms of action in restoring beta cell function," said Dr. Gonzalez-Campoy.

“As for the type 1 study,3 it is known that ''something triggers an immune system response that leads to the development of antibodies against pancreatic beta cells. The trigger or triggers have not been identified, however, it seems clear that a population of lymphocytes capable of making antibodies against the beta cells is involved,” he said, adding, “The concept that we can fight this immunological response is not new; there are now many monoclonal antibodies incorporated into mainstream of medical practice.”

 “What’s new is that the TRIAL NET investigators were able to demonstrate that anti-thymocyte globulin (ATG) decreased the rate of beta cell loss in patients with T1D while the addition of GCSF did not enhance the protective effect of ATG,”3 said Dr. Gonzalez-Campoy, “Thus, an immunological attack that destroys insulin-producing beta cells has proven to be a viable treatment but it needs refinement.”

“Although we buy patients some time without the need for full insulin replacement, we are still not able to stop the destruction of beta cells,” he said. “As the authors conclude, more studies will be needed to see if combination therapy using ATG and other immune modulators may be able to stop the attack on the beta cells.”

Lifestyle Strategies To Help Motivate Patients

Nutrition experts have long stated that a varied diet would be the route to better health but a more honest appraisal of the Western diet may just put that axiom on its head. According to an American Heart Association science advisory published in Circulation, the clearest insight regarding the rising rates of obesity and diabetes can be attributed to the overwhelming variety of food products available to American consumers.5

According to Marcia C. Oliveira Otto, PhD, assistant professor at the University of Texas Health Science Center in Houston, for the researchers who conducted an analysis of diet studies, “The longstanding American public health recommendation to ‘eat a variety of foods’ was introduced last century in response to widespread nutrient deficiencies, particularly in low-income countries with limited access to nutritious foods,” said Otto. However, “recent evidence suggests this approach may not help improve people’s eating habits, nor prevent obesity in places where processed, unhealthy food options are very common, wide-ranging and relatively inexpensive.” 

They concluded that in the present day, eating a wide range of food products has resulted in a scenario in which the American diet, consisting of so many highly processed products and fast foods has resulted in a 40% rise in overconsumption and poor choices.5

It’s evident that the more options there are, the more people eat. For examples, its become second nature for many to sit down to a meal consisting of French fries with ketchup and a shake or soft drink to go along with the cheeseburger on a white bun. Adding insult to injury, when faced with a spread of inexpensive food, the usual course is to finish every last bit so the concept of satiety has been lost. In effect, faced with aisles of choices has made it nearly impossible for the majority of Americans to make healthy food choices.

In another timely statement released by Houston Methodist Leading Medicine, Kristen Kizer, RD, a licensed clinical dietitian, said, “we live in a society that believes lower calorie food means more weight loss and ultimately better health. While this is true in some respects, to be successful at both losing weight and keeping it off, it’s [more] important to focus on the nutritional value, not just the caloric value, of your food.”

When faced with a patient newly diagnosed with diabetes, clinicians might call on these rationale understandings to initiate a conversation about diet and weight management. To offer concrete strategies in response to the “what do I do now,” here are some strategies to offer (with links to direct your patients for further reading):

There are no relevant financial disclosures for any of these professionals except. Dr. Accili who is the co-founder of a biotech firm, Forkhead Bio Therapeutics, involved in developing diabetes treatments.

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