Sugary heart on stethoscope and EKG 2048 x 1365

Some new healthcare companies claim to “reverse diabetes” with a lifestyle intervention that primarily focuses on the blood glucose and hemoglobin A1c level. That claim may be a clever marketing ploy, but it has little to do with the latest science on diabetes.

Although their intervention reduces carbohydrate and sugar intake dramatically and it does lower blood glucose. The problem is that it does not address the core issue in Type 2 diabetes.

The definition of Type 2 diabetes

Type 2 diabetes is defined by a blood glucose of 126 or higher or a hemoglobin A1c of 6.5 or higher. If you introduce sugar and carbohydrate restriction and cause weight loss, the glucose and hemoglobin A1c levels will fall below those numbers and so, by that definition, diabetes is “cured.” The patient no longer meets the criteria for a diabetes diagnosis.

But this premise ignores fundamental and important realities. High glucose levels cause changes in gene expression that persist after the glucose returns to normal causing atherosclerosis and other complications. This well-known phenomenon is called metabolic memory.

Metabolic memory

Metabolic memory is a critical concept that points to the broader reality of people living with Type 2 diabetes. The high glucose levels found in people with the condition are only one part of the complex molecular biology that causes diabetic complications.

The cardiovascular complications of diabetes begin in the fetus and even in the lifestyle choices of prior generations. Overfeeding or underfeeding in the parental generation can produce infants that are too small or too large based on inappropriate activation or inactivation of genes (epigenetics). That inappropriate switching on or off is persistent and many genes are involved causing hypertension, diabetes, and cardiovascular complications in adults.

Patients may themselves switch these genes on or off later in life by gaining weight or smoking. These genes cause diabetes by killing insulin-producing cells in the pancreas and increasing insulin resistance leading to high glucose which further increases oxidative particles and switches on additional genes that cause diabetic complications.

These genes remain switched on even when the glucose is lowered. Therefore, it is very important to continue to take medications that interfere very specifically with the signaling that these genes generate.

Metformin

Promoting the message that cardiometabolic medication should be stopped when the glucose falls below the diabetic level is not in keeping with the latest science and contrary to diabetic guidelines.

The American Diabetes Association (ADA) guidelines recommend metformin use even in prediabetic patients who have a BMI of 35 or greater, have a history of gestational diabetes, or an increasing fasting glucose or hemoglobin A1c. That is because metformin reduces progression to diabetes by about 31%.

Roughly half of prediabetic patients will progress to diabetes despite weight loss. Even patients in the later stages of prediabetes may have lost 70-80% of their insulin-producing function.

These prediabetic patients should not stop metformin when they have lost weight and their glucose improves. There is a tendency for diabetes to reappear with age. Certainly, metformin should not be stopped in patients who already have diabetes regardless of their glucose level.

How metformin works

Metformin reduces diabetic complications by interfering with signaling that has nothing to do with blood glucose levels. It inhibits the same master metabolic switch as the active ingredient in the drug-eluting coronary artery stent.

The increased risk of major cardiovascular events does not disappear with diet and weight loss, however, metformin directly reduces that risk. Type 2 diabetics lose about 10 years of life. If they are on metformin, they live a bit longer than normal people. Metformin is safe and costs only about $4 a month. It is dangerous to recommend “stopping diabetic medications once the glucose is controlled by lifestyle interventions.”

Controlling glucose

Controlling glucose levels has beneficial effects on microvascular events like retinopathy, neuropathy, and kidney damage but it does not reduce the problems that cause most serious cardiovascular complications, death, disability, and costs. Most diabetics die of cardiovascular disease.

Lowering the glucose with lifestyle or any medication approved for the purpose does NOT reduce cardiovascular events. In fact, aggressive glucose lowering with medication and lifestyle caused more people to die.

This is especially important because cardiovascular event incidence and other complications can be dramatically mitigated with a comprehensive solution that brings to bear lifestyle management and medications that interfere with the molecular biology that causes cardiometabolic complications.

Lowering the glucose by any means below the diabetic level, stopping the medication, and expecting complications to fall makes sense, but that idea is not supported by the evidence.

Drugs that block epigenetic signaling

Take a look at the diagram below. Type 2 diabetes occurs mostly in patients with extra abdominal fat caused by poor diet. Increased nutrition and fat switches genes on/off that increase angiotensin II, aldosterone, HMG CoA Reductase, and mTOR activity.

Angiotensin receptor blockers (ARBs), spironolactone, statins, and metformin interfere directly with the molecular signaling cascades that these genes activate. Blocking angiotensin II with an ARB, aldosterone with spironolactone, HMG CoA reductase with a statin, and mTOR with metformin dramatically reduces cardiovascular events in multiple settings. The genes involved are switched on before diabetes develops.

In fact, these elements contribute to diabetes development. Increased mTOR activity directly increases insulin resistance. Blocking mTOR with metformin reduces progression to diabetes.

Elevated aldosterone levels make a strong contribution to metabolic syndrome development. Blocking angiotensin II reduces progression to diabetes.

Blocking HMG Co A reductase with a statin actually increases the incidence of diabetes but has a powerful impact on cardiovascular events and other outcomes. Even that can likely be explained by a hard look at the molecular biology. Blocking HMG CoA reductase with a statin does lower LDL cholesterol but it also reduces Coenzyme Q10 production. Coenzyme Q10 is a powerful antioxidant and it is important for mitochondrial function. Impaired mitochondrial function may be important in the modestly increased risk of diabetes in patients who take statins.

Type 2 Diabetes Treatment

The best treatment for type 2 diabetes is not a matter of either lifestyle or medication. Effective treatment requires best practice implementation of lifestyle measures along with medications that interfere with the molecular biology causing disease. For most patients, medical treatment will include metformin, statins, and angiotensin receptor blockers.

It is important to move beyond a medical system focused on risk factors and organ systems.

Related Article:  How to Make Managing Diabetes a Habit

There is a very complex interplay in the molecular biology that causes hypertension, diabetes, high cholesterol, and related complications. Reversing diabetes with weight loss and dietary interventions makes perfect sense but improving cardiovascular outcomes and reducing costs to the fullest extent requires a more comprehensive solution. We can treat chronic disease with precision medicine and molecular biology now.

3 COMMENTS

  1. Thanks for the question. Lifestyle change is essential. Diabetics love carbs and/or sugar. Muscle to fat ratio is important. Resistance exercise helps maintain muscle mass. The number of people going on dialysis increases every year. Partial solutions will only prolong the misery. A comprehensive solution includes lifestyle interventions and best medication practices. It includes new science, new systems, and new payment models. The question is not, which is the best, but rather what combination of interventions is best the have the maximum impact on disease.

  2. Fascinating. I had no idea about metabolic memory and how it gets passed down. So do you not see any influence of lifestyle changes? Or are you saying they don’t play as big in the reversal of diabetes and other chronic diseases because of gene expression?

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