MODULE 4
Evidence-based intervention for prediabetes and diabetes type 2 remission and reversal
OBJECTIVES:
- Review the current definitions of remission and reversal
- Identify the lifestyle factors that contribute to diabetes reversal
- Discuss the physiologic changes that restore insulin sensitivity
- Describe the essential components of an intensive lifestyle intervention that will maximize diabetes remission rates
Diabetes Remission and Reversal Definition
To build upon a statement and subsequent publications in the context of more recent experience, the American Diabetes Association convened an international, multidisciplinary expert group. Representatives from the American Diabetes Association, European Association for the Study of Diabetes, Diabetes UK, the Endocrine Society, and the Diabetes Surgery Summit were included. From another perspective, an oncologist was also part of the expert group. This group met three times in person and conducted additional electronic exchanges between February 2019 and September 2020.
Based on the consensus reached by the authors, it proposes suitable definitions of terms and ways to assess glycemic measurements to facilitate the collection and analysis of data that may lead to future clinical guidance. The choice of terminology has implications for clinical practice and policy decisions. Several terms have been proposed for people who have become free of a previously diagnosed disease state.
In type 2 diabetes, the terms resolution, reversal, remission, and cure have been used to describe a favorable outcome of interventions resulting in a disease-free status. In agreement with the prior consensus group’s conclusions, this expert panel concluded that diabetes remission is the most appropriate term. It strikes an appropriate balance, noting that diabetes may not always be active and progressive yet implying that a notable improvement may not be permanent.
It is consistent with the view that a person may require ongoing support to forestall relapse and regular monitoring to allow intervention should hyperglycemia recur. A common tendency is to equate remission with “no evidence of disease,” allowing a binary choice of diagnosis. However, diabetes is defined by hyperglycemia, which exists on a continuum. The consensus group concluded that “no evidence of diabetes” was not an appropriate term to apply to type 2 diabetes.
The underlying pathophysiology of Type 2 diabetes, including deficiencies of insulin and resistance to insulin’s actions, as well as other abnormalities, is rarely completely normalized by interventions. In addition, any criterion for identifying a remission of diabetes will necessarily be arbitrary, a point on a continuum of glycemic levels. Although the previous consensus statement suggested dividing diabetes remission into partial and complete categories, using different glycemic thresholds, this distinction could introduce ambiguity affecting policy decisions related to insurance premiums, reimbursements, and coding of medical encounters.
The prior statement’s suggestion that a prolonged remission, longer than five years, be considered separately did not have an objective basis. The present group doubted that this distinction would assist clinical decisions or processes, at least until more objective information about the frequency of long-term remissions and the medical outcomes associated with them is available. A single definition of remission based on glycemic measurements was thought more likely to be helpful.
Consensus Group Conclusion
Research based on the terminology and definitions outlined in the present statement is needed to determine the frequency, duration, and effects on short- and long-term medical outcomes of remissions of Type 2 diabetes using available interventions.
Multi-Factorial Disease
There’s epigenetic inherited susceptibility that is manifested through environmental exposures and lifestyle, where lies the challenge of remission and reversal. It’s the activation of this epigenetic sensitivity through diet, exercise, stress, and habits. It’s also impacted by the environmental changes around the individual that include alterations in the microbiome, medications, culture, and even relationships.
Case Study
Mechanism of Insulin Resistance
Over time there is a peripheral resistance that develops through inflammatory cytokines, oxidative stress, alterations in the metabolism of the liver through reactive oxygen species, and inflammatory cytokines that begin to create insulin resistance at the level of the liver.
Resulting in increased glucose production at the same time, there is a development of insulin resistance in the skeletal muscle due to intramyocellular lipid accumulation and disruption of insulin signaling. And as individuals gain weight, the adipocytes begin to increase their production of inflammatory cytokines, also creating a problem with insulin resistance levels. It’s a multisite issue that stems from lifestyle choices and genetic susceptibility.
The intramyocellular lipids are green substances accumulated within the skeletal muscle, which is a distinctive feature of insulin resistance as seen under the microscope. This also represents disrupted insulin signaling, which is also associated with elevated leptin levels. This is observed in chronic inflammation with chronically elevated leptin and its association with obesity, over-eating, and chronic inflammatory diseases like metabolic syndrome and cardiovascular disease. This shows a multi-level disruption of not just internal insulin signaling within skeletal muscle but alterations of more systemic hormonal balance, including leptin.
Intramyocellular Lipids
Intramyocellular lipid is important because as it accumulates, it begins to modulate insulin sensitivity via the disruption of intracellular signaling mechanisms through the production of inflammatory cytokines, the alteration of extracellular matrix proteins, it’s disrupted through increasing local Free fatty acid concentration and involved in the regulation of perilipin five gene expression related to insulin resistance.
Looking at the normal insulin signaling and sensitivity, we can see that insulin binds to the insulin receptor and opens the channel for glucose to enter the cell with a very small amount of intramyocellular lipid. The glucose four transporters are activated and open up to allow glucose to enter. The glucose four transporters are also activated through exercise independent of insulin, which becomes an important mechanism in the regulation of insulin sensitivity.
A multi-site disruption resulting in a lack of insulin sensitivity and progressive insulin resistance. There are disruptions by the intramyocellular lipid on the insulin receptors and the mechanisms leading to the opening of the glucose transporters and the entrance of glucose in the cell. This only highlights a multi-site, multi-factorial challenge that comes as a result of intramyocellular lipids.
Insulin resistance is activated through inflammatory cytokines and saturated fatty acids that come directly from dietary contributions, and the adipocytes. There are disruptions from hyperglycemia leading to endoplasmic reticulum stress and the alterations of the inflammatory pathways. This interacts with the insulin receptor substrate, the IRS 1 and 2, which are critical regulators of insulin signaling.
It has also been shown in studies that the IRS 1 and 2 are important in endothelial cell function and have been related to diseases like cardiovascular disease, dementia, and retinopathy. This disruption through saturated fatty acids, cytokines, hyperglycemia, hyperlipidemia have significant impact on IRS 1 and 2 signaling molecules and contributes to some of the secondary disease processes associated with type 2 diabetes.
Secondarily, this whole inflammatory cascade, including NF kappa Beta is upregulated, and this is related to the activation of 400 different genes in the inflammatory cascade. Once the switches have been turned on, there is a progression of inflammation that is related to insulin resistance. Some of the basic physiologic changes that are manifested after the activation of these biochemical changes, we can see a global effect of insulin resistance.
Remission and Reversal
It’s important to recognize that diabetes type 2 is a multifactorial challenge, so it often takes a multi-modal intervention to maximize the potential of improving insulin sensitivity and reversing insulin resistance. It is primarily diet and lifestyle. However, there is a need to address other important components of successful lifestyle intervention. A need to address the environmental challenges, stress, relationship, sleep, and habit that would play into the full solution and help to create a sustainable lifestyle.
The dietary interventional trials discussed in this course are primarily looking at important components like food and exercise. But there should always be an emphasis on other components of a sustainable lifestyle change.
To build upon a statement and subsequent publications in the context of more recent experience, the American Diabetes Association convened an international, multidisciplinary expert group. Representatives from the American Diabetes Association, European Association for the Study of Diabetes, Diabetes UK, the Endocrine Society, and the Diabetes Surgery Summit were included. From another perspective, an oncologist was also part of the expert group. This group met three times in person and conducted additional electronic exchanges between February 2019 and September 2020.
Based on the consensus reached by the authors, it proposes suitable definitions of terms and ways to assess glycemic measurements to facilitate the collection and analysis of data that may lead to future clinical guidance. The choice of terminology has implications for clinical practice and policy decisions. Several terms have been proposed for people who have become free of a previously diagnosed disease state.
In type 2 diabetes, the terms resolution, reversal, remission, and cure have been used to describe a favorable outcome of interventions resulting in a disease-free status. In agreement with the prior consensus group’s conclusions, this expert panel concluded that diabetes remission is the most appropriate term. It strikes an appropriate balance, noting that diabetes may not always be active and progressive yet implying that a notable improvement may not be permanent.
It is consistent with the view that a person may require ongoing support to forestall relapse and regular monitoring to allow intervention should hyperglycemia recur. A common tendency is to equate remission with “no evidence of disease,” allowing a binary choice of diagnosis. However, diabetes is defined by hyperglycemia, which exists on a continuum. The consensus group concluded that “no evidence of diabetes” was not an appropriate term to apply to type 2 diabetes.
The underlying pathophysiology of Type 2 diabetes, including deficiencies of insulin and resistance to insulin’s actions, as well as other abnormalities, is rarely completely normalized by interventions. In addition, any criterion for identifying a remission of diabetes will necessarily be arbitrary, a point on a continuum of glycemic levels. Although the previous consensus statement suggested dividing diabetes remission into partial and complete categories, using different glycemic thresholds, this distinction could introduce ambiguity affecting policy decisions related to insurance premiums, reimbursements, and coding of medical encounters.
The prior statement’s suggestion that a prolonged remission, longer than five years, be considered separately did not have an objective basis. The present group doubted that this distinction would assist clinical decisions or processes, at least until more objective information about the frequency of long-term remissions and the medical outcomes associated with them is available. A single definition of remission based on glycemic measurements was thought more likely to be helpful.
Consensus Group Conclusion
- A return to normal or nearly normal glucose levels in patients with typical type 2 diabetes can sometimes be attained by using current and emerging forms of medical or lifestyle interventions or metabolic surgery.
- The frequency of sustained metabolic improvement in this setting, its likely duration, and its effect on subsequent medical outcomes remain unclear.
- To facilitate clinical decisions, data collection, and research regarding outcomes, more clear terminology describing such improvement is needed.
- The term used to describe a sustained metabolic improvement in Type 2 Diabetes to nearly normal levels should be remission of diabetes.
- Remission should be defined as a return of HbA1c to less than 6.5% that occurs spontaneously or following an intervention, and that persists for at least three months in the absence of usual glucose-lowering pharmacotherapy.
- When HbA1c is determined to be an unreliable marker of chronic glycemic control, fasting plasma glucose of less than 126 mg/dl or estimated A1C of less than 6.5% calculated from continuous glucose monitoring values can be used as alternate criteria.
- Testing of HbA1c to document a remission should be performed just prior to an intervention and no sooner than three months after initiation of the intervention and withdrawal of any glucose-lowering pharmacotherapy.
- Subsequent testing to determine long-term maintenance of remission should be done at least yearly thereafter, together with the testing routinely recommended for potential complications of diabetes.
Research based on the terminology and definitions outlined in the present statement is needed to determine the frequency, duration, and effects on short- and long-term medical outcomes of remissions of Type 2 diabetes using available interventions.
Multi-Factorial Disease
There’s epigenetic inherited susceptibility that is manifested through environmental exposures and lifestyle, where lies the challenge of remission and reversal. It’s the activation of this epigenetic sensitivity through diet, exercise, stress, and habits. It’s also impacted by the environmental changes around the individual that include alterations in the microbiome, medications, culture, and even relationships.
Case Study
- 57-year-old male patient with a 10-year history of type 2 diabetes and a 2-year history of painful diabetic neuropathy.
- Neuropathic and low back pain disrupts his sleep and limits his walking or exercise.
- Prescribed metformin and gabapentin with limited benefit and morning drowsiness.
- Patient was frustrated and hopeless.
- Previous attempts at weight loss have failed, and he is considering gastric bypass surgery. The patient is willing to try a whole food plant-based diet.
- An intensive therapeutic lifestyle change program was initiated, and after two weeks, metformin was reduced. After four weeks, metformin and gabapentin were discontinued with a resolution of pain and improved numbness.
- After eight weeks, he began walking and lost 20 pounds, and today the patient is free of medication, at a normal weight, and is able to do hiking.
Mechanism of Insulin Resistance
Over time there is a peripheral resistance that develops through inflammatory cytokines, oxidative stress, alterations in the metabolism of the liver through reactive oxygen species, and inflammatory cytokines that begin to create insulin resistance at the level of the liver.
Resulting in increased glucose production at the same time, there is a development of insulin resistance in the skeletal muscle due to intramyocellular lipid accumulation and disruption of insulin signaling. And as individuals gain weight, the adipocytes begin to increase their production of inflammatory cytokines, also creating a problem with insulin resistance levels. It’s a multisite issue that stems from lifestyle choices and genetic susceptibility.
The intramyocellular lipids are green substances accumulated within the skeletal muscle, which is a distinctive feature of insulin resistance as seen under the microscope. This also represents disrupted insulin signaling, which is also associated with elevated leptin levels. This is observed in chronic inflammation with chronically elevated leptin and its association with obesity, over-eating, and chronic inflammatory diseases like metabolic syndrome and cardiovascular disease. This shows a multi-level disruption of not just internal insulin signaling within skeletal muscle but alterations of more systemic hormonal balance, including leptin.
Intramyocellular Lipids
Intramyocellular lipid is important because as it accumulates, it begins to modulate insulin sensitivity via the disruption of intracellular signaling mechanisms through the production of inflammatory cytokines, the alteration of extracellular matrix proteins, it’s disrupted through increasing local Free fatty acid concentration and involved in the regulation of perilipin five gene expression related to insulin resistance.
Looking at the normal insulin signaling and sensitivity, we can see that insulin binds to the insulin receptor and opens the channel for glucose to enter the cell with a very small amount of intramyocellular lipid. The glucose four transporters are activated and open up to allow glucose to enter. The glucose four transporters are also activated through exercise independent of insulin, which becomes an important mechanism in the regulation of insulin sensitivity.
A multi-site disruption resulting in a lack of insulin sensitivity and progressive insulin resistance. There are disruptions by the intramyocellular lipid on the insulin receptors and the mechanisms leading to the opening of the glucose transporters and the entrance of glucose in the cell. This only highlights a multi-site, multi-factorial challenge that comes as a result of intramyocellular lipids.
Insulin resistance is activated through inflammatory cytokines and saturated fatty acids that come directly from dietary contributions, and the adipocytes. There are disruptions from hyperglycemia leading to endoplasmic reticulum stress and the alterations of the inflammatory pathways. This interacts with the insulin receptor substrate, the IRS 1 and 2, which are critical regulators of insulin signaling.
It has also been shown in studies that the IRS 1 and 2 are important in endothelial cell function and have been related to diseases like cardiovascular disease, dementia, and retinopathy. This disruption through saturated fatty acids, cytokines, hyperglycemia, hyperlipidemia have significant impact on IRS 1 and 2 signaling molecules and contributes to some of the secondary disease processes associated with type 2 diabetes.
Secondarily, this whole inflammatory cascade, including NF kappa Beta is upregulated, and this is related to the activation of 400 different genes in the inflammatory cascade. Once the switches have been turned on, there is a progression of inflammation that is related to insulin resistance. Some of the basic physiologic changes that are manifested after the activation of these biochemical changes, we can see a global effect of insulin resistance.
Remission and Reversal
- When talking about remission and reversal, clinicians should be looking at normalization of Hemoglobin A1c and normalization of insulin sensitivity through an intervention that normalizes all those biochemical changes.
- Clinicians would essentially see a reduced intramyocellular lipid, hepatic lipid count, reduction of oxidative stress, normalization of the endoplasmic reticulum, reduced inflammation, and improved mitochondrial function.
It’s important to recognize that diabetes type 2 is a multifactorial challenge, so it often takes a multi-modal intervention to maximize the potential of improving insulin sensitivity and reversing insulin resistance. It is primarily diet and lifestyle. However, there is a need to address other important components of successful lifestyle intervention. A need to address the environmental challenges, stress, relationship, sleep, and habit that would play into the full solution and help to create a sustainable lifestyle.
The dietary interventional trials discussed in this course are primarily looking at important components like food and exercise. But there should always be an emphasis on other components of a sustainable lifestyle change.
SELF-PACED ARTICLE REVIEW
Interventional Trials in Type 2 Diabetes
Play the audio lecture video below.
SELF-PACED ARTICLE REVIEW
MODULE 4 TASK |
REFLECTIVE WRITING Download the articles cited in Module 4. Review the articles and create your reflective journal with the title "Characteristics of Lifestyle Medicine Treatment for Remission and Reversal of Insulin Resistance and Type 2 Diabetes." Note: The task needs thorough review of evidences and not simply writing an essay just to comply with the course requirements. You may always take your time to read on the literature provided. PATIENT ENCOUNTER Select at least 10 diabetic patients that you see in your clinical practice and begin to prepare the conduct of your 12-session Shared Medical Appointment (SMA) for Type 2 Diabetes. Submit your proposed SMA plan, including details on your registration, information session and the first three (3) SMA sessions that should cover the contents you had from Modules 1-4. Note: Shared medical appointment is applied by all Lifestyle Medicine physicians and professionals. If you have no experience on SMA, kindly go back to the Lifestyle Medicine competency Course for review or watch the provided videos below. VIRTUAL DISCUSSION What particular topic you are most interested about in this module? Make a brief discussion on why do you think that topic is important in this subject (use the comment section below). Pick one of comments posted that you are interested about and make a brief discussion on your thoughts about his/her inputs. |
SHARED MEDICAL APPOINTMENT - VIDEO REVIEW
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ADVANCE TO MODULE 5
VIRTUAL DISCUSSION
