It’s difficult to imagine the existence of a Type 1 diabetic (T1DM) patient in the days before insulin. Most lived extremely short lives marked by chronic wasting and starvation. The treatment available before the discovery of insulin was more of the same: starvation using extremely low-calorie, low-carb diets. This was the only treatment known to prolong the lives of these miserable victims.
It’s also difficult to imagine the excitement and exhilaration upon Frederick Banting and Charles Best’s discovery of insulin and the profound effect it had upon those with T1DM (1). No one witnessing the miraculous turnaround in these patients, who had been languishing for years, could fail to be moved (2). The enormity of this medical breakthrough was so momentous that the Nobel Prize was awarded for the discovery of insulin within a year of its first use (For comparison, 16 years passed between Albert Einstein’s paper on the photoelectric effect and his receipt of the Nobel prize for it).
Since patients with T1DM cannot produce insulin, and since insulin injections appear to reverse patients’ symptoms, it’s easy to understand how the idea took root that insulin — or the lack thereof — is the driving force behind the disease. The notion that insulin is the primary regulator of metabolism and is therefore essential to life is the main dogma of T1DM; its corollary is that insulin replacement therapy should be sufficient to treat T1DM. But as anyone who has treated T1DM patients knows, this treatment is tricky and fraught with problems. Normal, non-diabetic subjects can eat and drink whatever they want, perform heavy exercise, and skip meals, all while maintaining their blood glucose levels within a fairly narrow range. Not so in those with T1DM. The most meticulous attention to exogenous insulin injection schedules, and even the use of insulin pumps, fails to maintain tight blood sugar control (3).
Normal subjects typically maintain HbA1c levels below 4.5%. T1DM patients struggle to stay below 7.5%. With the rarest of exceptions, even those who obsess over taking blood sugar measurements or use continuous glucose monitors have trouble nudging their HbA1c levels below 7.5% using injectable insulin. And when they do succeed, it drops to barely below 7.5%. Meticulous insulin dosing to prevent hyperglycemic swings often produces the opposite problem: hypoglycemia. A graph of blood glucose levels of even the most finely controlled T1DM patients shows glucose excursions all over the place, with many going very high after mealtimes and others going dangerously low, especially after insulin dosing.
Because of the history of insulin use and the belief that insulin is required to manage blood glucose — the insulinocentric dogma — the world of T1DM treatment revolves around the search for ever-cleverer ways of measuring blood glucose levels and for insulins and insulin analogs in all flavors: purer, longer-acting, shorter-acting, medium-acting.
But what if insulin isn’t necessary for life? What if the symptoms of T1DM are not caused by the lack of insulin? What if the insulinocentric dogma of diabetes is false?
Insulin has a counter-regulatory hormone called glucagon (also produced in the pancreas), discovered a year or so after insulin, though never credited early on as much of a factor in T1DM. In fact, glucagon was considered a contaminant in the effort to extract insulin from animal pancreases. Glucagon was so ignored that it took a half-century after its discovery for it to be recognized as a hormone. Since those afflicted with T1DM are unable to produce insulin, and dosing them with injections of insulin treats their symptoms, it makes sense that all the early attention was focused on insulin. Thus, the insulinocentric theory of T1DM took root and is still lodged in the minds of most physicians and researchers as the primary force driving the disease. While glucagon languished in obscurity, Eli Lilly and Company started producing commercial insulin from beef pancreas extracts within a year of the first insulin injection and, along with other pharmaceutical companies, has been producing it and its many analogs since.
But over the last few decades, a number of scientists, most notably Roger Unger of the University of Texas Southwestern Medical Center, have studied the other side of the coin, examining glucagon’s role in T1DM. And, based on many and varied experiments, these researchers have concluded that glucagon, not insulin, is the primary hormone causing the metabolic chaos seen in the disease.
In early studies, Unger and his group created insulin-deficient mice by treating them with streptozotocin (STZ), an agent that destroys the pancreatic beta cells, the cells that produce insulin. These mice suffered severe insulin insufficiency, developed all the symptoms of T1DM, and were dead within a few weeks. When STZ-treated mice were given glucagon suppressors, however, they failed to develop any symptoms of T1DM despite producing no insulin (4).
Inspired by these experiments, Unger et al. used glucagon receptor knockout mice for the next series of studies. When these mice had their beta cells destroyed by STZ, they exhibited no change in activity. They were acting and living as normal mice without insulin and, due to their lack of glucagon receptors, without the ability to use glucagon. When the researchers injected them with adenovirus containing glucagon receptor cDNA, their blood sugars skyrocketed and they became transiently diabetic, demonstrating once again that glucagon and functional glucagon receptors are required for the development of T1DM (5).
One of the stumbling blocks to researchers accepting the idea that unrestrained glucagon is the driving force behind the symptoms of T1DM is that it has been known since the early 1900s that removing the pancreases of animals (and humans) renders them diabetic. Pancreatectomy gets rid of both the glucagon-producing alpha cells and the insulin-producing beta cells, leaving the animals with no insulin and no glucagon, a condition similar to the above studies in which the animals had no insulin and no (or suppressed) glucagon. Yet the pancreatectomized animals quickly developed T1DM, whereas the others didn’t.
The only way the situation made sense was that there were other glucagon-producing cells besides those in the pancreas. Unger and his group undertook a meticulous search and found that there were indeed alpha cells in the stomach that took over and continued to produce glucagon even in animals (and as was subsequently found, in humans) without pancreases (6, 7).
Subjects with no insulin and no glucagon (or no glucagon receptors) seemed to do fine; those with no insulin and active glucagon quickly developed T1DM. Obviously, injected exogenous insulin drives blood glucose down and quells most of the symptoms of T1DM. How does this strange puzzle come together to make sense?
To solve it, Unger and others who had adopted a glucagonocentric view of T1DM looked at the interactions of insulin and glucagon at the cellular level. They found that although insulin does indeed suppress glucagon, it does so only at vastly higher concentrations than could ever be achieved by injected insulin.
The alpha and beta cells that produce glucagon and insulin (respectively) are found scattered throughout the pancreas in discrete groupings of cells called the islets of Langerhans. In these islets, the insulin-producing beta cells are juxtaposed with the glucagon-producing alpha cells (8, 9). The insulin secreted from the beta cells hits the alpha cells at a high concentration of about 2,000 μU/mL, which is enough to suppress the alpha cells’ release of glucagon. As the insulin travels from the pancreas to the liver, its concentration is diluted to around 50 μU/mL, a 40-fold reduction. By the time the insulin reaches the peripheral circulation, its concentration is a mere 5 μU/mL (10).
When the insulin released from the beta cells washes over the adjacent alpha cells and suppresses glucagon release, the resulting insulin-to-glucagon ratio is a little over 7, which is high and sends a signal to the liver to start vacuuming up glucose and converting it to glycogen — which is the normal response after a meal when insulin spikes.
Injected exogenous insulin reaches a concentration of roughly 20 μU/mL in the blood (which is actually much higher than the insulin levels of non-T1DM subjects) and slightly dilutes in reverse fashion from there. Having started at a concentration 100 times weaker than what is needed to suppress glucagon at the cellular level, by the time the injected insulin makes its way to the pancreas, the concentration is many orders of magnitude too low to get the job done.
The resultant very low to non-existent insulin-to-glucagon ratio signals the liver to ratchet up the production and release of glucose, which results in the extreme hyperglycemia of T1DM.
The injected insulin concentration never comes close to the concentration required to shut off the glucagon production at the level of the alpha cells, but it can drive glucose uptake into post-hepatic tissues such as skeletal muscles and adipose tissue. And a little too much injected insulin — especially between meals or after a bout of exercise — can easily cause a hypoglycemic episode. This is why the typical blood glucose profile of a T1DM patient shows an extreme rollercoaster of volatility (10).
Insulinocentric bias has kept most researchers focused on insulin over the past 90 years of T1DM treatment without their ever being able to reliably get and keep patients’ blood glucose levels in the normal ranges. Maybe it’s time to change focus.
Unger’s group has found a way to maintain blood sugars in the normal range in STZ-treated animals that produce no insulin. How? By using a combination of small insulin doses along with glucagon suppressors or blockers (11).
Here’s how it works: As mentioned above, there is a narrow range in which blood sugars fluctuate in those without T1DM. However, in those with the disease, blood sugar makes multiple excursions throughout the day, both above the upper limit of normal and below it. The multiple episodes of hypoglycemia throughout the day — the times blood sugar drops below the lower level of the normal range — are driven by too much exogenous insulin. The large doses of insulin prescribed to most T1DM patients help keep the sugar from going too high but at the price of knocking it too low, especially between meals and after exercise. If the dosages of the insulin injections can be reduced substantially, then blood sugar levels won’t bottom out. The small doses will help drive the excess glucose into skeletal muscle and adipose tissue but not to the extent that it drives levels too low. The excursions out of the upper range of normal, which would be even larger with the small insulin doses, are dealt with by using either glucagon suppressors or blockers. If the excess glucagon secreted by the unrestrained alpha cells has a greatly reduced end effect, then the liver won’t be driven to pump out the copious amounts of glucose and ketones that it would under the typical T1DM barrage.
All the work so far using the insulin-glucagon suppressor combination has been done in animals, but the results have been extremely promising (12). The problem is, these substances are experimental, and thanks to the insulinocentric views of the mainstream, everyone seems to be pursuing insulin pumps and an ever-expanding array of injectable insulins and insulin analogs. If more physicians and scientists would consider the glucagonocentric view of blood sugar management, more time, money, and effort would go into research on glucagon-blocking remedies, which, when made commercially available, would vastly improve the lives of the millions suffering with T1DM.
Additional Reading
Drs. Michael and Mary Dan Eades are the authors of 14 books in the fields of health, nutrition, and exercise, including the bestseller Protein Power.
Dr. Michael Eades was born in Springfield, Missouri, and educated in Missouri, Michigan, and California. He received his undergraduate degree in engineering from California State Polytechnic University and his medical degree from the University of Arkansas. After completing his medical and post-graduate training, he and his wife, Mary Dan, founded Medi-Stat Medical Clinics, a chain of ambulatory out-patient family care clinics in central Arkansas. Since 1986, Dr. Michael Eades has been in the full-time practice of bariatric, nutritional, and metabolic medicine. He and his wife have been in private practice devoting their clinical time exclusively to bariatric and nutritional medicine, gaining first-hand experience treating over 6,000 people suffering from high blood pressure, diabetes, elevated cholesterol and triglycerides, and obesity with their nutritional regimen.
Together, the Eades give numerous lectures to the general public and various lay organizations on their methods of treatment. They have both been guest nutritional experts on over 150 radio and television shows, including national segments for FOX and CBS.
References
- Banting FG, et al. Pancreatic Extracts in the Treatment of Diabetes Mellitus. Can Med Assoc J. 12.3(1922): 141-6.
- Rosenfeld L. Insulin: discovery and controversy. Clin Chem. 48.12(2002): 2270-88.
- Derr R, et al. Is HbA(1c) affected by glycemic instability? Diabetes Care 26.10(2003): 2728-33.
- Lee Y, et al. Metabolic manifestations of insulin deficiency do not occur without glucagon action. Proc Natl Acad Sci USA. 109.37(2012): 14972-6.
- Lee Y, et al. Glucagon receptor knockout prevents insulin-deficient type 1 diabetes in mice. Diabetes 60.2(2011): 391-7.
- Sasaki H, et al. Identification of glucagon in the gastrointestinal tract. J Clin Invest. 56.1(1975): 135-45.
- Blazquez E, et al. Gastric glucagon secretion. Metabolism. 25.11 (1976): 1475-6.
- Bosco D, et al. Unique arrangement of alpha- and beta-cells in human islets of Langerhans. Diabetes 59.5(2010): 1202-10.
- Unger RH and Orci L. Paracrinology of islets and the paracrinopathy of diabetes. Proc Natl Acad Sci USA. 107.37(2010): 16009-12.
- Lee YH, et al. Glucagon is the key factor in the development of diabetes. Diabetologia 59.7(2016): 1372-1375.
- Unger RH and Cherrington AD. Glucagonocentric restructuring of diabetes: a pathophysiologic and therapeutic makeover. J Clin Invest. 122.1(2012): 4-12.
- Pearson MJ, Unger RH, and Holland WL. Clinical Trials, triumphs, and tribulations of glucagon receptor antagonists. Diabetes Care. 39.7(2016): 1075-7.
A Different Perspective on Treatment of Type 1 Diabetes