Redefining Diabetes: Can We Reverse Type 1 DM?
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For those who don’t know, I’ve returned to school to fill in my many knowledge gaps regarding health and disease. As I learn, I hope to share the nuances of health and disease emerging in the literature that can’t yet be standardized and taught in school.
I believe in personalized medicine with all my heart. Yes, it’s more complex and doesn’t allow for the liberal use of algorithms. Instead, it forces the clinician to view every patient as a unique and complex organism. It forces critical thinking, creativity, and a desire to keep learning and challenging the various dogmas in medicine. It requires the clinician to draw on past experiences to blend the science and art of medicine instead of pushing every patient down a singular path.
This is a presentation I gave to my clinical nutrition class from which I thought the Medgeeks community could benefit. The objectives for this article/presentation are:
Traditional definition of the disease
Challenges with age, weight, and autoimmunity
Diabetes classifications
Pathophysiology
Preproinsulin, proinsulin, insulin, and c-peptide
Incretins: GIP and GLP-1
GABA - more than a neurotransmitter
How little we truly know
Traditional Definition
Prediabetes is defined by:
Fasting glucose levels between 100 mg/dL to 125 mg/dL or
HbA1C between 5.7% to 6.4% or
2-hour OGTT of 140 to 199 mg/dL
Diabetes is defined by:
Fasting glucose levels over 125 mg/dL or
HbA1C over 6.5% or
2-hour OGTT over 200 mg/dL or
Random glucose over 200 mg/dL with classic symptoms
Most patients are screened for diabetes during their yearly physical with fasting glucose. But as you will see, dysfunction occurs long before we see elevations in fasting glucose levels. The earlier we can start lifestyle interventions, the better the outcome for the patient.
The challenge with age, weight, and autoimmunity
It was once believed that type 1 diabetics are always thin and young, while type 2 diabetics are always older and overweight. Unfortunately, due to poor lifestyle factors adopted early in life, we can no longer use age to aid in the diagnosis.
According to the CDC, 60% of adults in the United States have at least one chronic disease, 40% have at least two or more chronic diseases, and 70% of all deaths are secondary to a chronic disease. It's estimated that 80% of chronic diseases and premature deaths could potentially be prevented. According to the National Council on Aging, nearly 95% of adults 60 and older have at least one chronic condition, while almost 80% have two or more.
Finally, the CDC states that 40% of school-aged children in the United States are living with at least one chronic disease; that percentage jumps to 60% if we include behavioral mental health disorders.
As it stands, 60% of adults and 60% of school-aged children all have at least one chronic disease.
According to 2017–2018 data from the National Health and Nutrition Examination Survey (NHANES), it’s estimated that 82% of adults in the United States are overweight or obese with the following breakdown:
Overweight: 30.7%
Obese: 42.4%
Severe obesity: 9.2%
The National Health and Nutrition Examination Survey also estimates that 41.5% of children are overweight or obese, with the following breakdown:
Overweight: 16.1%
Obese: 19.3%
Severe obesity: 6.1%
According to the Autoimmune Association, 50 million people (15% of the population) have an autoimmune disease, and an additional 8 million (2.5% of the population) have autoantibodies that don’t yet meet a disease requirement. Autoantibodies can be present for years before the patient fits the official criteria for an autoimmune disease. Autoimmune disease prevalence doubled from 10.4% in 2010 to 20.8% in 2018 in pediatrics. It’s also important to note that 25% of patients with one autoimmune disease develop a second autoimmune disease.
Diabetes Classifications
The classifications have expanded significantly since the initial grouping of type 1 and type 2 diabetes mellitus:
Type 1 diabetes subtypes:
Type 1A
Type 1B/idiopathic
Latent autoimmune diabetes in adults (LADA)
Type 2 diabetes subtypes
Classic type 2 diabetes
Gestational diabetes
Monogenic diabetes
Genetic defects in mitochondrial DNA
Diseases of the exocrine pancreas
Endocrinopathies
Drug/chemical induced.
Viral infections
Uncommon forms of immune-mediated diabetes
Other genetic syndromes
Alternatively, the following has been proposed as an alternative classification system (but isn’t currently used in practice):
Severe autoimmune diabetes
Severe insulin-deficient diabetes (SIDD)
Severe insulin-resistant diabetes (SIRD)
Mild obesity-related diabetes (MOD)
Mild age-related diabetes (MARD)
Interestingly, each subtype is based on testing parameters that aren’t routinely employed. In practice, the clinician categorizes the patient based on age and weight. As you can see from the data, both children and adults have multiple risk factors for type 1 diabetes and type 2 diabetes. This, coupled with the fact that 82% of Americans are overweight or obese, makes it challenging to use these factors to help guide the diagnosis.
Diabetes pathophysiology
Things are further complicated by the discovery of latent autoimmune diabetes in adults, which is a slower autoimmune destruction of the pancreatic beta cells that occurs in adults. There is also emerging evidence that type 2 diabetes may be mediated, at least in part, by an autoimmune process.
The cell danger response is a theory proposed by Dr. Naviaux that illustrates how the mitochondria lie at the heart of chronic disease secondary to the production of chronic low-grade inflammation (an appropriate defense mechanism against an insult that fails to self-terminate).
It’s been noted that immune system (macrophage, b-cells, t-cells, inflammatory cytokines, etc.) dysregulation is seen years before insulin resistance and contributes to the acceleration of beta-cell dysfunction.
It may not be autoimmunity in the traditional sense, with specific autoantibodies we’ve identified previously, although it’s possible we haven’t discovered the corresponding autoantibodies (our technology limits us). Still, the immune system is a potent mediator for this chronic disease.
As a general rule, type 1 diabetes is traditionally considered to be autoimmune, while type 2 diabetes is traditionally characterized by insulin resistance and impaired insulin secretion. Classically, in type 1 DM, there will be various autoantibodies:
Islet cell
Glutamic acid decarboxylase
Insulin
Insulinoma-associated protein 2
Zinc transporter ZnT8
It’s important to note that antibodies are not required to develop type 1 diabetes; T cells also influence pancreatic beta-cell destruction.
Both type 1 and type 2 diabetes result from a complex interplay between genetics, various environmental factors (perinatal factors, infection, diet, etc.), and dysregulation of the immune system (that may or may not involve autoantibodies). The pathogenesis (regardless of type) results in beta-cell dysfunction, insulin resistance, and hyperglycemia.
Beta-cell dysfunction is believed to occur early in type 2 DM, independent of insulin resistance. It’s also been recognized that insulin resistance occurs in type 1 DM.
In other words, every subtype of diabetes shares characteristics we once believed to be isolated to specific subtypes. I hope this makes you realize that diabetes, like all chronic diseases, likely exists on a continuum. If you don’t know what I’m referring to, check out the lecture, The Health Disease Continuum.
Preproinsulin, proinsulin, insulin, and c-peptide
We should discuss beta-cell dysfunction since this is the first measurable portion of the diabetes continuum. The endoplasmic reticulum inside the pancreatic beta cells produces preproinsulin. This is then converted to proinsulin and sent to the Golgi apparatus to be packaged inside secretory vesicles. Here, proinsulin has been cleaved of c-peptide and two pairs of amino acids from each end; the final result is the conversion to the active form of insulin.
Typically, pancreatic beta cells secrete roughly 15% proinsulin and 85% insulin. Patients with beta-cell dysfunction secrete up to 40% as proinsulin (inactive form). Because more inactive insulin is being secreted, the overall effectiveness of insulin decreases, and the pancreas is forced to secrete more. The increase in proinsulin could be secondary to inefficient processing (proinsulin to insulin) or premature release (before proinsulin can be converted to insulin) due to the increased requirements.
Identifying beta-cell dysfunction as early as possible is crucial to patient outcomes. Unfortunately, we can’t simply look at the ratio of proinsulin to insulin when looking for dysfunction. This is because patients with insulin resistance also have decreased hepatic clearance of insulin, resulting in elevated insulin levels; this throws off the proportions between the two, giving an artificially low proinsulin percentage appearance.
But, the c-peptide level isn’t affected by insulin resistance, so the proinsulin to c-peptide ratio is the preferred marker of beta cell dysfunction. It’s essential to recognize that patients are asymptomatic during the initial phases of beta cell dysfunction.
It was previously believed that insulin resistance was a defining feature of type 2 DM, and autoimmune beta cell destruction was a defining feature of type 1 DM. But this is no longer the case.
New research shows that patients diagnosed with type 1 DM still secrete proinsulin, regardless of their c-peptide level.
In other words, it may look like the pancreas isn’t producing insulin due to a low c-peptide and low insulin. However, proinsulin may still be elevated and signifies a functioning pancreas. When was the last time you checked a c-peptide, let alone proinsulin?
When we see a low c-peptide/insulin, we traditionally assume the pancreas may no longer work and insulin is required indefinitely. But that might not be the case. Instead, we might have a problem converting proinsulin to insulin (at least initially).
Would increasing this conversion reverse what we traditionally view as type 1 DM? Interesting to think about. I want to discuss a couple more essential mechanisms regarding glucose homeostasis.
Incretins: GIP and GLP-1
After we consume a meal, glucose in the small intestine stimulates the release of incretins (GIP and GLP-1). Incretins communicate to the pancreatic beta cells to prime themselves to secrete the performed insulin, known as the first phase of insulin response. The first phase lasts only 10-15 minutes and declines. After that, the second phase of insulin response takes over and continues until the patient is euglycemic. Insulin release is, therefore, biphasic.
GLP-1 also increases insulin sensitivity, suppresses glucagon secretion, reduces macrophage infiltration in blood vessels, and reduces the production of pro-inflammatory cytokines (IL-6, IL-1β, TNF-α, and CRP). This also shows how immune dysregulation is closely tied to glucose homeostasis.
A new way to look at diabetes
Instead of looking at diabetes as something binary (you either have diabetes or you don’t), I prefer to view this metabolic derangement on a continuum:
Immune dysregulation ↔ Insulin resistance/beta cell dysfunction ↔ pre-diabetes ↔ diabetes.
Many think of prediabetes as the initial stages of diabetes. However, we must realize this is not the beginning of dysfunction. This is only the abnormal lab we chose to look for that appears right before the arbitrary cutoff of 125 mg/dL; other abnormalities occur long before we see an elevated fasting glucose.
Before an elevation in fasting glucose, we'll see elevated postprandial glucose and elevations in fasting and postprandial insulin (same with c-peptide and proinsulin levels). We'll even see immune dysregulation before there are signs of insulin resistance and beta cell dysfunction.
In other words, immune dysregulation leads to insulin resistance and beta cell dysfunction, which leads to prediabetes, which leads to diabetes. It's thought that insulin resistance precedes diabetes by 10-20 years, but prediabetes can turn into diabetes in just one year. The person with a fasting glucose of 120 mg/dL isn't much better off than the person with a glucose of 126 mg/dL, seeing how they both had elevated insulin levels for at least one decade.
Although immune dysregulation is the first step in this process, it’s not specific to the progression of diabetes because it will be the first step in every chronic disease.
So, what is the first measurable marker specific to diabetes? Alterations in proinsulin and c-peptide (increased ratio) will precede any glucose abnormalities by years. Early on, we’ll also see a diminished first-phase insulin response, which can be estimated with an oral glucose tolerance test coupled with proinsulin, insulin, and c-peptide measurements.
Instead, we wait until there are abnormalities in fasting glucose to begin the conversation with a patient. Alternatively, we might use the HbA1C to diagnose and monitor management.
However, focusing on a patient’s HA1c doesn’t address the root cause of the dysfunction and can be misleading:
Episodic bouts of hyperglycemia and hypoglycemia average out to a normal HA1c.
The HA1c depends on healthy RBCs that live their entire lifespan, which many diabetic patients lack.
We must also remember that hyperglycemia is the last stage of the diabetic disease continuum.
Immune dysregulation ↔ Insulin resistance/beta cell dysfunction ↔ pre-diabetes ↔ diabetes.
Focusing only on the patient’s glucose is a losing battle. Although this is important, it shouldn’t stop at achieving glycemic control. We also want to go upstream as much as possible (root cause) because once this is corrected, all the various downstream effects (symptoms and glucose intolerance) will be allowed to heal.
Of course, we must acknowledge that specific problems may be irreversible and largely dependent on the time it takes to address cellular dysfunction. The longer we wait to address the imbalance, the bigger it will grow and the more it will transverse to other body parts.
Clinicians often like to give things time to unravel, but that strategy will inevitably lead to poorer outcomes. Fixing a leaking faucet is easier and cheaper than fixing a broken pipe. If you hold off on addressing the simple problem, the pipe could burst, potentially leading to irreversible damage. The body is no different.
GABA - More than a neurotransmitter
Let’s revisit our discussion of insulin. We discussed how it’s produced, packed, and released and commented on the biphasic response. But what happens after it’s released into the bloodstream? What are the various ways in which insulin lowers glucose mechanistically? Just because we know a few mechanisms doesn’t necessarily mean we know every mechanism.
As we know, the beta cells secrete insulin, and the alpha cells secrete glucagon. When insulin is secreted, GLUT4 transporters move to the cells’ surface. These receptors allow the uptake of glucose from serum into the cell. After insulin levels drop, the levels of GLUT4 transporters on the cell membrane also diminish. There are also GLUT 1,2,3 and 5 and SGLT1 and SGLT2 transporters, but they all allow glucose transport independent of insulin.
Insulin also binds to receptors on the alpha cells inside the pancreas, causing chloride channels to translocate to the cell membrane. The beta cells also release GABA, which binds to the chloride channels, allowing chloride to enter the cell. This hyperpolarizes the cell, stopping the secretion of glucagon. GABA also binds to receptors on the beta cell, signaling to secrete more insulin. GABA has been shown to delay diabetes onset, restore normal blood glucose, decrease inflammatory cytokine expression that participates in the pathogenesis of type 1 DM, and enhance β-cell function and growth.
It’s been postulated that GABA and its effects on glucagon may be a more significant player in glucose homeostasis than insulin.
In 2011, a study published in the Journal of Diabetes showed that injections of GABA prevented mice from developing type 1 diabetes and reversed the disease in mice that already had it.
In 2022, Nature published the trial, A randomized trial of oral gamma-aminobutyric acid (GABA) or the combination of GABA with glutamic acid decarboxylase (GAD) on pancreatic islet endocrine function in children with newly diagnosed type 1 diabetes. This was the first human clinical trial regarding GABA and GAD conducted in newly diagnosed type 1 DM patients. Because it was the first human trial, patients were given low doses to confirm the safety and tolerability of oral GABA. Although it didn’t achieve its primary outcome of conserving beta cell function, they did notice a significant decrease in fasting and nutrient-stimulated glucagon secretion. The next step is to increase the doses used.
How little we truly know
Insulin was discovered in 1921 by Sir Frederick G Banting, Charles H Best, and JJR Macleod at the University of Toronto. It’s amazing that after 100 years, we are still learning about this hormone. It makes me wonder how much we truly know about many things we consider facts.
We only have answers to the questions we know to ask, and current technology ultimately limits our findings.
Keep curiosity alive and continue asking questions!
If you haven’t already done so, check out my last lecture, The Health Disease Continuum.
References
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Autoimmune Association. (n.d.). About Autoimmunity. Retrieved from https://autoimmune.org/resource-center/about-autoimmunity/
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