Metabolic Memory and Epigenetics: The Most Important New Science to Inform Chronic Disease Management
No, You Can’t Reverse Diabetes
Definition: Metabolic memory is a term used to describe beneficial effects of immediate intensive treatment of high blood sugar and the observation that they are maintained for many years, regardless of the blood sugar level in the later course of diabetes.
In other words, early aggressive treatment of diabetes reduces complications years later compared with patients who receive usual care—the care that most of us receive. This difference in results persists for years even when all participants in the study go back to usual care and sugar control is the same. Multiple landmark clinical trials have proven this point beyond any doubt.
We have known about metabolic memory for forty years. The landmark Diabetes Control and Complications Trial (DCCT) proved that intensive blood sugar control in individuals with type 1 diabetes significantly delays or prevents eye and kidney damage by about half compared with usual care. The profound benefits of intensive therapy led to the early termination of the Diabetes Control and Complications Trial, and all participants were put on intensive insulin treatment and followed long-term. This long-term study was called the Epidemiology of Diabetes Interventions and Complications (EDIC) study. Even though everyone went on intensive insulin treatment after the DCCT trial was stopped and sugar levels were the same in both groups, the major difference in the development of eye, kidney, and nerve damage persisted over 18 years of observation. Aggressive treatment of diabetes early provides protection from bad outcomes. Aggressive treatment later will not bring an equal level of protection. This effect is called metabolic memory and it has been confirmed in numerous scientific studies of diabetes. Early aggressive treatment has a powerful and enduring effect to protect cells and organs. “The protection initiated by intensive treatment appears to outlast the intensive treatment itself, although the duration of the effect remains to determined.” Patients with type 1 diabetes need aggressive glucose control early.
Another study in type 1 diabetes over 25 years showed that individuals free of advanced complications were characterized by a lower cholesterol, lower blood pressure , and considerably lower sugar levels. The UK Prospective Diabetes Study (UKPDS) from England on type 2 diabetes is the one that got me much more interested in diabetes. It showed that patients on metformin had 40% fewer heart attacks than individuals who achieved the same blood sugar by another means. It convinced me that I needed to learn much more about diabetes. There were 5 years of additional follow-up after the study, and even though patients returned to usual care and their risk factor control was no different, more aggressive early treatment showed persistent benefit. Patients with more aggressive early treatment with metformin showed significant risk reductions for any diabetes-related complication of 21%, myocardial infarction of 33%, , and death from any cause of 27% 5 years after the study ended and everyone received the same treatment. Once again, early aggressive treatment provided protection years later when there was no difference in management.
The most impressive impact of metabolic memory comes from a study done in Denmark. The Steno 2 trial identified patients with an average age of 55 who had type 2 diabetes complicated by small amounts of protein in the urine (microalbuminuria.) These are very high-risk patients. They already have chronic kidney disease, but most of them don’t live to go on dialysis because they die of heart attacks and strokes. This trial tested aggressive care vs usual care—the care that most people receive. It was an optimal medical therapy trial. Because of their high risk, lower targets for blood pressure, cholesterol, and sugar control were used. They all received low-dose aspirin. Clinicians worked to help them stop smoking. They used lisinopril or losartan for blood pressure lowering and kidney protection, atorvastatin for cholesterol, and metformin for patients who were overweight and diabetic. The differences in results were astounding.
After 8 years of comparing intensive treatment with usual care, patients receiving intensive therapy had a significantly lower risk of severe complications. They were half as likely to have a heart attack or a stroke, forty percent as likely to have progression of their kidney disease, and about forty percent as likely to have serious eye damage. Due to the striking difference in these results, it was considered unethical to continue with the usual care group and they were also placed on intensive treatment. From this point onwards, all patients were on intensive treatment, but there continued to be a huge difference in results. Five years later, the patients in usual care for the first eight years, had 4 times as many heart attacks, 5 times as many strokes, and 6 times as many people progressed to dialysis after 13 total years of follow-up. Once again, early intensive management continued to provide additional protection even when all are on intensive management later. Go to figure 3 in the link above. You can see that the risk of death, heart attack, and stroke continues to widen between patients who were on intensive management vs those who were in usual care even though everyone goes on the same intensive treatment. Remarkably, there are now 21 years of follow-up in this study and the differences in results persist. For example, patients who received intensive management early have a 70% reduction in hospital admissions for congestive heart failure.
If you want to stay healthier longer, this is critical information for you. The existence of metabolic memory means that there is no such thing as reversing diabetes or other related conditions like heart artery disease or high blood pressure no matter how well you manage diet and exercise. You have switched on genes that stay switched on.
The risks of metabolic memory begin when we are children. The lifestyle choices made by a teenager have a huge impact on how long they will be healthy. On average, one of the greatest increases in risk occurs in the late teens when many people start smoking and become more independent in their eating choices. When a teenager has increased belly fat, high blood pressure, high cholesterol, elevated sugar, smoking cigarettes, inactivity, or poor diet they are much more likely to die early, have a heart attack or stroke, or have multiple chronic illnesses. Research has shown that people who don’t have these risk factors from adolescence onward live longer, healthier lives free of multiple chronic. Young people who avoid these risk factors have a lower risk of developing heart attacks and strokes in adulthood and very low mortality rates into their 50s. “In fact, if everyone controlled these risk factors in late adolescence or young adulthood, the vast majority of heart attacks and strokes would be avoided.” That is a reason that family food and smoking culture is so important.
The better we understand disease, the easier and more effective treatment becomes. New science provides strong clues about how metabolic memory works. Let’s focus on type 2 diabetes. Type 2 diabetes occurs primarily because of environmental factors like fast and processed foods, sugary drinks including juices with added fructose, smoking, and inactivity. These factors in combination lead to increased belly fat and oxidant production. One puff of cigarette smoke contains ten to the fifteenth oxidative particles. Excess oxidants inappropriately switch on normal genes that were essential to fetal and childhood development, become much less active in slender healthy young adults who don’t smoke, and are switched back on inappropriately by excess oxidants from increased belly fat, high glucose levels in the blood, and cigarette smoking. These changes in gene regulation are termed epigenetic. These excess oxidants switch on growth factors which subsequently switch on mTOR and switch off AMPK.
These epigenetic modifications have been observed in various cells and organs under diabetic conditions where the blood sugar is too high. Prior episodes of high blood sugar lead to continued risk of complications even if the blood sugar levels are consistently below diabetic levels later because of diet, weight loss and exercise. You can lower the sugar to a non-diabetic level, but you can’t reduce the risk of serious complications to normal. You can’t reverse diabetes. Once these genes are switched on, they stay switched on to increase inflammation, make the arteries thicker, and the heart bigger. They kill the functional cells in the vital organs like the heart, liver, kidney, brain, and pancreas. Once they are switched on, they remain switched on even after weight loss, stopping smoking, and lowering blood sugar and pressure to normal levels. If these genes are switched on prior to having children, those changes are passed on to the next two generations to increase the risk of diabetes, heart attack, and stroke.
Even though diabetes can be controlled through medications, insulin, and lifestyle modifications, in many with diabetes, prior periods of high blood sugar due to inadequate sugar control can be associated with continued risk of complications long after glucose levels have been normalized. This “metabolic memory” of prior blood sugar control is due to epigenetic changes.
Remember the very first study I reviewed in this piece. It showed that intensive treatment of patients with type 1 diabetes with multiple insulin shots or an insulin pump dramatically reduces complications years later. Ten years after the Diabetes Control and Complications Trial careful analysis showed that patients with more complications had more genes switched on that caused inflammation and vascular disease. They had more epigenetic changes. These differences persisted for as long as 17 years even though glucose control was the equal after the trial. Epigenetic changes explained 68-97% of the correlation between sugar control during the study period and nerve or eye damage later when everyone had the same level of glucose. Taken together, results from experimental models and human studies support the notion that persistent epigenetic changes driven by high blood glucose are a major driving force underlying metabolic memory.
This science of increased oxidant production driving epigenetic changes that lead to increased complications in diabetes leads to much more effective treatments in the real world.
As you can easily see from this diagram, excess belly fat leads to increased levels of angiotensin II, aldosterone, and HMG CoA reductase which increase oxidant production and switch on the EGFR growth factor gene. EGFR in turn switches on mTOR and switches off AMPK. mTOR activation causes the arteries to get thicker, increases inflammation, and kills the critical functional cells in vital organ like the heart, brain, kidney, liver, and pancreas. The medications in the green boxes block oxidant production directly from these inappropriately switched on genes or they directly inhibit mTOR and switch on AMPK as metformin does. Jardiance also switches on AMPK. That is why these medications added to diet and exercise produce dramatically better results compared with the care that most people receive. You can dramatically improve your health in the long term by aggressively treating diabetes and related conditions early and consistently. A better diet, more exercise, and not smoking cigarettes protect your children throughout their lives. You can’t reverse diabetes, but the new science can help you and your family live a longer healthier life now and you can protect generations to come.
This is amazing information. I would imagine - in fact I believe there are studies - showing that strong early intervention often has powerful long-term effects - say in having a great Grade One experience, have lifelong effects. I remember one study of the outcome for children of having a specific Grade One teacher in a low-income low-education environment in Montreal. Children with other Grade One teachers in that school hardly ever went on to university. 40% of the students in her classes went to university. I remember that she taught the children what most teachers would not approach, even about art appreciation, until high school, if then. She treated them as smart and education as wonderful. Clearly i was very impressed by the study (which I read and let go) and the teacher.
Thank you I did hear of a book called "The Diabetes Code". Again treating diabetes with intermittent fasting and improved diet. Lifestyle changes. Excellent article and topic.