LEARNING OBJECTIVES
After completing Module 1, the learner should be able to:
1. Name factors which contribute to development of type 1 diabetes (T1D).
2. Describe and differentiate the stages of T1D.
3. Describe how lack of insulin leads to diabetic ketoacidosis (DKA).
4. Compare and contrast type 1 and type 2 diabetes.
Pathophysiology and Natural History of Type 1 Diabetes (T1D)
01 |
Module Authors: Brigitte Frohnert, Marian Rewers
Understanding the Natural History of T1D Autoimmunity
Type 1 diabetes (T1D) results from chronic autoimmune destruction of pancreatic beta-cells (Figure 1). The pathogenesis of T1D results from an interplay of environmental exposures in the context of elevated genetic risk.
Genetics:
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Genetic risk is higher in relatives of individuals with T1D.
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Over 50 genetic regions have been associated with T1D risk.(1)
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The T1D genetic risk score (GRS) aggregates information from multiple risk loci into a single number.
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The GRS is being used by some screening programs to identify high-risk individuals.
Environment: (2)
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Although there are a variety of candidates, the precise environmental exposure which triggers islet autoimmunity is not known.
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Early-childhood respiratory and gastroenteritis infections are associated with onset of IA.
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Exposure to probiotics in early infancy has been associated with decreased risk of IA in high-risk children.
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Vitamin D sufficiency and higher levels of fish-derived fatty acids (EPA, DPA) have been associated with lower risk of IA.
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The constellation of triggers may not be the same in all cases.
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FIGURE 2 Biphasic insulin secretion
Pathogenesis of Insulin Loss
Beta cells can store insulin in secretory granules for rapid release after a glucose stimulus, otherwise known as the first-phase insulin response (Figure 2). Beta cells are also able to ramp up insulin production in response to a meal, producing a lower and slower increase in insulin release, known as the second-phase insulin response. As an individual loses beta cell mass, the remaining beta-cells have decreased capacity to store insulin. For this reason, the first metabolic abnormality in progression to symptomatic T1D is typically the loss of first-phase insulin response. This can eventually result in a higher and more sustained post-prandial glycemic peaks, which can sometimes be seen during oral glucose tolerance testing as impaired glucose tolerance (elevated 2-hour post-prandial glucose levels). Early in progression of islet autoimmunity, glucose elevations are not sustained. Thus, the individual typically does not have symptoms. Over time, glucose abnormalities progress in both the amplitude and persistence of hyperglycemia. It is only when hyperglycemia continues for prolonged periods of time that the person may note the classic symptoms of diabetes: increased urine production and thirst. The pace of progression may depend on a variety of factors, with faster progression in younger children and more pronounced hyperglycemia during times of physiological stress such as febrile illness.
Pathogenesis of
diabetic ketoacidosis
As the beta cell mass is progressively destroyed, insulin levels become very low or absent. Without insulin, the ability to use glucose is greatly diminished. As insulin disappears, glucagon production is no longer inhibited and levels rise. Due to the increased glucagon signaling and relative absence of insulin signaling, the body moves into a catabolic state, despite high glucose levels (Figure 3).
This results in:
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Lipolysis – releasing fatty acids from
adipose tissue -
Ketogenesis from fatty acids
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Protein breakdown – providing substrate
for gluconeogenesis -
Glycogenolysis
While low levels of ketones are a common fasting fuel source for the body, without insulin, ketones rise to abnormal levels and acidosis develops. This state, known as diabetic ketoacidosis (DKA) can quickly spiral to a life-threatening state, particularly in the presence of significant dehydration. DKA can also have significant acute and long-term morbidity including neurologic injury and association with long-term elevation in hemoglobin A1c (A1c).(3, 4)
FIGURE 3
Metabolic changes leading to diabetic ketoacidosis.
The release of insulin inhibition (indicated in red) and the increase in glucagon signaling (indicated in green) lead to further increase in glucose and elevated levels of ketones.
Created with BioRender.com
The 3 Stages of T1D
Islet autoimmunity is marked by the development of autoantibodies against islet autoantigens. These islet autoantibodies (IAb) include insulin autoantibody (IAA), glutamic acid decarboxylase autoantibody (GADA), insulinoma antigen-2 autoantibody (IA-2A), and zinc transporter type 8 autoantibody (ZnT8A). Prospective studies have shown that the confirmed presence of multiple islet autoantibodies (mIA) strongly predicts progression to symptomatic T1D.(5) These observations inform the staging of pre-symptomatic T1D,(5, 6) now incorporated into clinical consensus guidelines of the American Diabetes Association (ADA), the Endocrine Society, and the International Society for Pediatric and Adolescent Diabetes (ISPAD).(6,7,8)
(See Figure 4 and Table 1)
1
FIGURE 4 Timeline and characteristics of the stages of T1D
Stage 1 T1D is defined by the presence of mIAb with 2 or more IAb confirmed on at least two consecutive lab draws. These individuals have normal glucose levels and are asymptomatic. The incidence of developing symptomatic Stage 3 T1D at 5-, 10-, and 15-years is estimated at 48%, 75% and 88%, respectively, with a lifetime risk approaching 100%.(9)
2
3
Stage 2 T1D is defined by one or more IAb in the absence of symptoms but with evidence of dysglycemia, impaired regulation of blood glucose levels, based on OGTT or hemoglobin A1c criteria (see Table 1). While not standard criteria, elevated trends on finger stick glucose monitoring or continuous glucose monitoring (CGM) can support a suspicion of Stage 2 T1D.
Stage 3 T1D is defined when an individual with islet autoimmunity reaches classical diabetes criteria (see Table 1). While typically those meeting Stage 3 criteria are symptomatic, individuals with early-stage T1D who are being monitored can occasionally meet glycemic criteria (Table 1: criteria A–C) before onset of symptoms. In absence of symptoms, hyperglycemia should be confirmed on a separate measure. Most, but not all individuals at Stage 3 T1D will have detectable IAb.
Other considerations for staging T1D
T1D exists on a spectrum, with glycemic presentation impacted by both beta-cell capacity as well as degree of insulin resistance. It is well understood that body size, hormonal milieu and intercurrent illness are among a variety of factors which can cause temporal changes in insulin needs. While beta cell destruction is known to be a progressive process, there is some evidence of transient recovery in insulin production following diagnosis of stage 3 T1D and initiation of insulin therapy (a.k.a. the “honeymoon”).(10) Similarly, OGTT findings in early-stage T1D can often show a waxing and waning course of abnormalities.(11) It is therefore possible for an individual whose glycemic measures previously met a higher stage of T1D to later regress to an earlier stage.
Proposed Refinements to T1D staging nomenclature
Early diagnosis has led to increased appreciation for the spectrum of T1D presentations and additional refinements have been proposed for the stages of T1D, although these are not yet widely adopted:
Stage 2a has been proposed to describe those with one or more positive islet autoantibodies whose glucose levels are marginally abnormal.
Stage 2b includes individuals whose glucose excursions are near the thresholds for stage 3.
An additional subcategorization of Stage 3 has been proposed:
Stage3a: autoantibody positive individuals who meet ADA diagnostic glycemic criteria for stage 3, but who are asymptomatic
Stage 3b: classic onset of stage 3 T1D with overt symptoms, hyperglycemia, and an immediate need for insulin therapy.
Finally, the term Stage 4 T1D has been used to describe those with T1D for many years who have very low or undetectable endogenous insulin production. This population may not have detectable IAb and are more commonly affected by complications of long-standing diabetes. Ongoing work is needed to better define populations of individuals living with T1D and to identify opportunities for intervention and support.
TABLE 1 Type 1 Diabetes — Staging Criteria
NOTES:
For diagnosis of Stage 3 T1D, any criteria A-D may be used; however, in the absence of symptoms, measures A-C must be repeated.
* With laboratory method that is NGSP-certified and standardized to the Diabetes Control and Complications Trial (DCCT) assay.
IFG: impaired fasting glucose
IGT: impaired glucose tolerance
OGTT: oral glucose tolerance test (performed as described by the World Health Organization [1.75 g glucose/kg up to a maximum of 75 g]).
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Identifying the “Silent Phase of T1D” (Early-stage T1D)
Through Islet Autoantibody Testing
Screening for IAb presents the potential for more routine identification of individuals at early-stage T1D. Together with education and monitoring, early identification of individuals at early-stage (or “silent”) T1D is associated with lower rates of DKA at progression to symptomatic diabetes(12,13) (see Module 2).
Additionally, individuals at early-stage T1D may be eligible for intervention, either with FDA-approved teplizumab-mzwv therapy (see Module 9) or intervention clinical research studies (see Module 10).
Type 1 Diabetes vs. Type 2 Diabetes
While T1D is caused by autoimmune destruction of beta cells resulting in the loss of insulin production, a central cause of type 2 diabetes is a defect in insulin action, known as insulin resistance (Figure 5). While both T1D and type 2 diabetes (T2D) can be identified at an early stage, before onset of symptoms, it is important to recognize the difference in both pathophysiology and epidemiology between these two distinct entities (see Table 2).
FIGURE 5 Comparison of pathophysiology of normal insulin signaling vs type 1 vs type 2 diabetes
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