October 2017 | Issue 32
Decoding diabetes



By Nicole Lim, Senior Assistant Director
Communications & External Relations

Digital tattoos track your blood glucose, while contact lenses scan the nutrients in your meals. Everything is integrated into your smart health-management mobile assistant, which also keeps track of your vital signs, activity and sleep. And if your body’s insulin producing cells fail, then an artificial pancreas is there to help. Could this be the future of diabetes management? Based on track record, it is not inconceivable.

LKCMedicine Professor of Metabolic Medicine Bernhard Boehm said, “The story behind diabetes is all about technology. Advances in technology are what have turned this sometimes deadly disease into a treatable and well manageable chronic condition.”

The first recorded case of diabetes dates back to the ancient Egyptians, but it wasn’t until the late 19th century that the source of the disease was identified – the islets of Langerhans within the pancreas. Since then, 10 Nobel Prizes have been awarded to researchers trying to understand and treat this complex disease.

Despite the many Nobel Prizes, two areas of diabetes have seen little subsequent progress: the classification of the disease beyond insulin-dependent or type 1 diabetes and insulin-resistant or type 2 diabetes, and the need for needles to monitor blood glucose and administer insulin. The former is a key obstacle to delivering treatment at the right time, while the latter leaves many people with the condition reluctant to accept and adhere to treatment.

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Many treatments have existed over the years in an attempt to cure diabetes, but how close are we to that end?

In oncology, a much younger speciality, cancers have been successfully characterised, typed and subtyped, and this data is used to select the best available treatment. Yet for diabetes care, such categorising is not yet possible with many patients still lumped together in a black box called ‘type 2 diabetes’.

The World Health Organisation defines people as having type 2 diabetes when their two-hour post-meal blood glucose level exceeds 11.1mmol/l or their fasting blood glucose level is above 7.0 mmol/l. These levels are thresholds beyond which complications such as diabetic retinopathy arise. A slightly lower range has been determined for people with pre-diabetes, yet, not everyone with pre-diabetes goes on to develop diabetes.

Tan Tock Seng Hospital (TTSH) Senior Consultant with the Department of Endocrinology and LKCMedicine Assistant Professor Rinkoo Dalan said, “These levels, which only look at blood sugar levels, are neither sensitive nor specific enough for optimal patient management.”

She added, “If we could classify patients better, we could treat them better. Right now, we treat everyone equally, and lose out on the opportunity to offer more tailored treatment. That means we are not as effective in the outcomes as we could be.”

At its most fundamental, type 2 diabetes is an imbalance between insulin resistance and insulin sensitivity. The body’s ability to sense rising levels of blood sugar is gradually reduced and its capacity to produce insulin is slowly impaired.

A moment on the lips is a lifetime with a syringe?
With the advent of genomic technologies, diabetes was once again at the forefront of research. Many researchers hoped that studying the genome would help shed light on why some people develop diabetes. In 2007, the Wellcome Trust Case Control Consortium (WTCCC) published data on role of genes in seven common diseases, including diabetes. Back then, this was the largest genome-wide association study ever conducted, involving 14,000 people.

Overall, the more than 40 genetic variants identified by this and other studies only account for a combined total of 10 per cent of the hereditability of type 2 diabetes. Despite the relatively small causal influence on diabetes, they hint at a bigger, much more complex picture.

For example, variations in two genes (TCF7L2 and SLC16A11) associated with diabetes are both inherited from our Neanderthal cousins. Yet Neanderthals themselves were unlikely to have developed diabetes. Our lifestyle, in terms of diet and exercise, became unhealthier with the development of agriculture and later the Industrial Revolution. The pace of change has accelerated over the last century and now far outstrips our genome’s ability to adapt. This leaves many of the genes that helped us survive long periods with little food but much physical activity, working against us.

This evolution is encapsulated in the recent history of the tiny Pacific Ocean island Nauru. The inhabitants of Nauru used to live a very isolated life, eating mainly fish, fruits and vegetables. Today, the island has the highest rate of type 2 diabetes with almost one in two people affected by the disease and almost three in four obese. The cause? A sudden and dramatic shift from a fresh diet to one of imported frozen and canned food, such as Spam.

In addition to these external changes, which manifest in key risk factors such as weight and fitness, other internal body systems including skeletal hormones, the immune system and gut microbiome, have been found to play a role in how the body metabolises glucose and develops insulin resistance.

With so many factors influencing the disease course, scientists are delving deeper into the subtypes that make up this very heterogeneous disease. The closer they look, the more fragmented the picture becomes. Work carried out with the Singapore Phenome Centre, for example, found that the metabolic profile of people who develop diabetes after the age of 65 is different from that of people who develop it in their 40s. Other work points to a hybrid diabetes where a patient carries both the genes for type 1 and type 2 diabetes. These people develop a very gradual type 1 diabetes, called latent autoimmune diabetes of adulthood, or LADA.

Prof Boehm, who is also a senior consultant with TTSH's Department of Endocrinology, said, “There is a cry for specific treatments. Most probably not fully personalised medicine, but at least more individualised to specific profiles. That will be the next breakthrough.”

Irreversible damage of trial and error
While for most people lifestyle and diet modification can prevent this disease, for some, medication may become necessary. But in the absence of detailed characterisation of the disease and its subtypes, treatment approaches are often trial and error. Even with optimal patient compliance that can lead to delays in lowering blood glucose levels. With every delay in this, the window for patients to benefit from the positive legacy effect conferred by prompt blood sugar control gets smaller.

Prof Boehm said, “Some patients never see the positive side of the legacy effect. If blood glucose levels are not controlled early on, patients’ risk of complications can remain high even if they eventually control their blood sugar levels.”

Diabetes is also associated with an increased risk of a whole host of other cardiovascular health problems, up to 15 types of cancer and neurodegenerative mental health conditions, such as Alzheimer’s disease and depression.

“It is a complex disease that doesn’t spare any system in the body,” said Prof Boehm.

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Prof Boehm and Senior Research Fellow Dr Hou Han Wei showcasing their lab-on-a-chip that sorts immune cells by size using just a fingerprick of blood

Technology for better monitoring and treatment
Correcting blood glucose levels is not a one-directional solution. If you go too low, this will also trigger negative side effects. For example, too low a blood sugar and the risk of developing Alzheimer’s disease increases again.

With the technological breakthrough of continuous blood glucose monitors, both closer monitoring and earlier identification have both become possible.

But just as with insulin injections, technology still relies on needles – either a fingerprick or patch with nano needle – to accurately measure blood glucose in real time. While companies have been exploring tears and salivary fluids as a substitute for the invasive blood glucose monitoring, challenges remain.

Asst Prof Rinkoo said, “Even the glucose levels in the interstitial fluid that current continuous blood glucose monitoring systems measure is not the same as those measured directly in blood. There is a 15-minute lag time and with tears the lag will be even longer.”

“While measuring sugar levels in tears or saliva may provide useful long-term data, they would not be helpful to an individual seeking to adjust their insulin dose in response to a meal or activity,” she added.

On the treatment front, insulin has undeniably been a life-saving intervention for people with type 1 diabetes and many with advanced stages of type 2 diabetes. Insulin formulations have become both shorter acting to correct immediate fluctuations and longer acting for stability, yet the administration has remained the same. Once again, new technologies could transform this field.

For example, Prof Boehm is collaborating with NTU School of Materials Science & Engineering Chair Professor Subbu Venkatraman to develop an oral insulin that will not only be more convenient but also mimic the body’s natural physiology more closely. Current insulin injections deliver the hormone straight to the peripheral organ systems such as skeletal muscle and fat tissue. By ingesting insulin, however, it travels via its natural path to the liver and will therefore regulate glucose and metabolism in general much better. 

For the many people who still have beta-cell function, out-of-the-box thinking has resulted in some promising new drug candidates. From a peptide in the Gila monster’s venom, which increases production of insulin and reduces appetite, to a sodium-glucose co-transporter inhibitor that flushes excess blood sugar via urine from the body and at the same time has a positive impact on blood pressure and weight, scientists are searching for new compounds and technologies that will advance and enhance diabetes care.

Finding hope with Goldilocks
Successful management, or even prevention, of diabetes relies on finding the right balance.  Humans need carbohydrates to turn into glucose. Add too much, it becomes toxic. Add to little, and the selfish brain – just 2 per cent of the body’s weight, but consumer of 70 per cent of its glucose - will stop working properly.
With state-of-the-art technologies there is hope that precise calibration and a deeper understanding of the disease can help us reach this balance.

When asked to imagine a world 20 years from now, both Prof Boehm and Asst Prof Rinkoo are optimistic, emphasising that the best outcome will be achieved if all parties and stakeholders come together.
They sketch an environment that taxes sugar and makes healthy meals accessible to all. In their multidisciplinary clinic, they have access to patients’ full genetic profile and clinical phenotype, which enables them to classify patients into specific subtypes.

“At the centre of it all has to be the human being,” stresses Prof Boehm.

Asst Prof Rinkoo, who is one of the investigators of the Health for Life in Singapore (HELIOS) study, also hopes to have a more responsive biomarker panel to assess risk that is communicated in an easy-to-understand single score, where each score comes with specific lifestyle and treatment advice.

Looking into her crystal ball, Asst Prof Rinkoo can envision finding the Goldilocks zone for each and every patient. Leveraging advances in technology, big data analytics, biological systems and pathways including genomics, and novel pharmaceuticals, she believes that personalisation will be possible. “With this in place I can envision a world where no one suffers from complications associated with diabetes, until someone discovers a cure for diabetes,” she concluded.