February 2024 issue, BioElectRx Business Report
February 29, 2024 | The potential market for treating diabetes has proven to be an elusive, though alluring target for bioelectronic medicine vendors. The dearth of effective therapies for advanced type 2 diabetes represents one of the greatest unmet medical needs of our generation.
Several bioelectronic medicine startups, including MetaCure, Cyberonics (now LivaNova), EnteroMedics (now ReShape LifeSciences), Intrapace, Beta-Stim, Transneuronix, Leptos Biomedical, and EndoVx have tried neuromodulation of abdominal branches of the vagus nerve in an effort to control appetite and gastric/duodenal motility. All of these approaches eventually failed, although ReShape has continued research on its Diabetes Bloc-Stim Neuromodulation device.
Bioelectronic medicine research teams and commercial firms interested in pursuing the diabetes indication would be wise to consider some of the experiences that vendors of insulin pumps encountered in the development of that product category. Although insulin pumps aren’t neuromodulation devices in the traditional sense, they can be considered crude bioelectronic medicine devices in one way of thinking. The devices modulate carbohydrate and fat metabolism at a systemic level—by controlling blood insulin—rather than at the level of the relevant organ, the pancreas. In theory, the pancreas can be controlled by autonomic nerves to switch its hormone production at appropriate times: insulin while eating; glucagon while fasting. With that in mind, let’s explore a dark side of systemic insulin therapy by pumps.
Insulin therapy dates back about 100 years; the first diabetic patient was injected with insulin in 1922. Large-scale production of insulin in the U.S. started a year later, in 1923. Both type 1 and type 2 diabetics were initially injected with a short-acting form of insulin during food consumption, so blood glucose could be quickly converted to fat (triglycerides) and stored in the muscles and adipose tissue. The main risk of short-acting insulin injections was that inducing a rapid drop in blood glucose limited its physiological availability for powering brain activity and occasionally resulted in a loss of consciousness (or even coma). Fortunately, the risk was not great when patients were awake, as they could readily feel an approaching hypoglycemia as lightheadedness and compensate by consuming something sweet.
The dark side of systemic insulin therapy first emerged when Novo Nordisk introduced a long-acting insulin in 1936. For type 1 diabetics, long-acting insulin was a great improvement over short-acting insulin, as it reduced the risk of hypoglycemia. For type 2 diabetics, however, the long term presence of insulin in the bloodstream was rather bad. Many patients already suffered from excessive insulin levels in the blood, and adding more insulin meant that more fat was created and stored inside the body. In type 2 diabetics, these widespread fat deposits slowly accumulate in all arteries as plaque and cause a variety of atherosclerotic diseases, such as a heart attack, stroke, diabetic neuropathy, diabetic nephropathy, diabetic retinopathy, and any combination of these.
One might argue that the harmful effects of long-acting insulin on fat accumulation could be compensated by dietary changes, specifically by avoiding saturated fats, which are particularly harmful in creating plaques. The largest (5,000+ patients), longest (10 years), and most expensive ($200 million) randomized controlled clinical trial Look AHEAD evaluated the effect of low-fat diet on atherosclerotic diseases in type 2 diabetics. Despite consuming 30% less fat, losing 7% of their weight, and keeping that low weight for several years, these diabetics had no improvements in incidences of stroke, myocardial infarction, heart failure, angina, and diabetic neuropathy. Worse still, despite all their dieting efforts, their blood level of “bad” LDL cholesterol stayed higher than in diabetics who were on a normal diet. Since the diabetics in both groups continued to take long-acting insulin, its harmful effect on fat accumulation outweighed any possible benefit of a low-fat diet.
In recent years, there has been a lot of research toward creating closed-loop algorithms for insulin pumps. Unfortunately, no matter how clever these algorithms may become, they cannot compensate for the systemic spread of insulin and its prolonged action in the bloodstream, both of which contribute to widespread fat accumulation in the arteries. Clinicians have created the somewhat ambiguous medical term “insulin-resistant” to describe people with advanced type 2 diabetes and it essentially means “with excessive insulin.” As such, it should be obvious why advanced disease cannot be treated by pumping more insulin.
Looking to the future, perhaps the modulation of a smaller vagal branch that directly innervates the pancreas could allow its production of glucagon during fasting and only briefly switch to production of insulin during eating. As the neural interfaces for small vagal branches are being developed, let’s hope for more appetite in pursuing neuromodulation therapies for type 2 diabetes.
