Why Type 2 Anti-Diabetic Drugs Are Failing, By Mukaila Kareem
As expected by my doctor from the very beginning of the initial diagnosis of diabetes, once the primary and add-on drugs fail, it is assumed that the pancreas is no longer able to secrete insulin and then comes the prescription of insulin injections. The end-stage implication of diabetes as “chronic and progressive” is therefore firmly established…
As a middle age man who undergoes elective total knee or hip replacement, my doctor would expect me to regain pain-free joints and move on with my normal life following some course of physiotherapy. S/he would also expect me to be cured of any acute inflammatory condition, with the possibility of placing me on short term steroids and then slowly weaning me off them to allow my body resume the normal production of this substance.
On the other hand, his/her approach would be entirely different if s/he diagnosed me with type 2 diabetes. Instead of treatment with the goal to cure, as in the two clinical scenarios above, his/her clinical judgement would be to “manage” my blood glucose and not cure the disease. This is consistent with the conventional understanding of diabetes defined by the World Health Organisation as “a chronic, progressive disease characterised by elevated levels of blood glucose”. The management plan may be “coated” with the aim of keeping my blood sugar within normal levels in order to prevent or delay secondary medical conditions such as kidney disease, stroke, heart trouble, blindness, amputation, etc. However, the doctor’s overarching clinical decision is based on the words “chronic” and “progressive”, as he does not expect me to be cured. These two words essentially pre-determine diabetic goals in conventional clinical practice and are being heard and taught in the lecture rooms of Medical Schools all over the world. In other words, type two diabetes is understood to be a life-long and unabating disease that needs to be managed, not cured.
How did this come to be? Well the part about the “…disease [being] characterised by elevated levels of blood glucose” seems to pointedly show and immediate problem that needs to be fixed without worrying about its source. In real life, this glucocentric approach is like frequently mopping a floor wet from a leaking roof, without fixing the leak. It is therefore not surprising that most anti-diabetic drugs act to aggressively lower blood sugar without necessarily targeting the “offending” organs responsible for the abnormal blood glucose level. This approach has been appropriately described as “treating to fail”.
While diets with emphasis on portion control is effective, compliance is poor due to sustained food enticement… Intermittent fasting is however not a diet but it was a way of life… This helps the body to handle fuel substrates efficiently and probably supports why diabetes is not found in hunting and gathering societies.
Pharmacology Burdens Pancreas for Insulin “Harvest”
While my doctor would back off from prescribing long term steroids and hope to cure my acute inflammatory ailment, he expects to sequentially add more glucose lowering drugs as the earlier anti-diabetic medicines begin to lose their effectiveness. Conventionally, the initial oral drug recommended by most guidelines is metformin, an affordable oral medicine belonging to the biguanide class. This medicine is on the list of World Health Organisation’s essential medicines and has been documented for its effect in preventing future heart attacks in people with diabetes. It is also called an insulin sensitiser but its glucose lowering action is mainly on the liver by blocking this organ from the production of (endogenous) glucose. However, as with any off target, its effectiveness is lost once the pancreas is unable to produce more insulin. To further the “pancreascentric” or “glucocentric” approach, the “second-line or add-on treatment” is a class of drugs called sulfonylureas or insulin secretagogues, which principally act on the pancreas to increase insulin secretion but have some additive effect of limiting glucose production in the liver. Sulfonylureas also have the side effects of hypoglycemia and weight gain.
As expected by my doctor from the very beginning of the initial diagnosis of diabetes, once the primary and add-on drugs fail, it is assumed that the pancreas is no longer able to secrete insulin and then comes the prescription of insulin injections. The end-stage implication of diabetes as “chronic and progressive” is therefore firmly established and insulin therapy is set to be a life-long prescription if there is no significant weight loss. While there are newer drug classes in the market, “they are very expensive and unaffordable in developing countries”. Therefore, the current worldwide pharmacology approach puts an increasing burden on the pancreas to “give up” its insulin until it fails. The “destination” insulin therapy from the course of sequential drug treatment is not affordable in most developing countries.
Fat Toxicity Side of Diabetes
While insulin resistance is mostly understood as excessive amounts of glucose in the blood stream (glucotoxicity), due to a lack of sensitivity to insulin, what is not appreciated in diabetes is the presence of high levels of free fatty acids, triglycerides and their carriers (i.e. albumin and cholesterol) in the blood stream. In addition, there is an excessive amount of fats inside individual cells (intracellular fat) and significant amounts of inappropriate fat deposits in various organs in the body. Diabetes is therefore triggered by high blood glucose at the beginning, but it is sustained by excess fats, causing whole body insulin resistance. For instance, insulin resistance in the liver causes this organ to make more fats and produce more glucose while too much fat deposit in the pancreas reduces and eventually stops insulin secretion. Obviously, all people with diabetes are not obese but most people with diabetes are overweight and obese due the body’s poor ability to mobilise the oversupply of fat substrates (lipotoxity).
If you have diabetes, work with your physician; intermittent fasting works: It depletes the fat stores. Without doubt, glucose lowering drugs are efficacious, but they need to be short termed; therefore, physicians work with your patients to wean them off these and not add to them. As with most medicines, more is not better.
Lifestyle Management of Diabetes Protects the Pancreas
Multiple studies have shown that weight loss in people with diabetes improves blood glucose and reduces the need for multiple glucose lowering drugs. It is therefore surprising that no guidelines recommend supervised fasting, given that fasting allows the body to efficiently handle excess fats to restore the competency of the pancreas and reduce production of glucose by the liver. Recent works have established that very low-calorie diets facilitate the “mopping” of the excess fats in “fat soaked” skeletal, liver and pancreas cells on the short term and improves whole-body insulin sensitivity and diabetic remission on the long term. High fat diets, such as ketogenic and low carbohydrate diets, have been found to be protective of the pancreas as fat consumption barely provokes insulin secretion.
While diets with emphasis on portion control is effective, compliance is poor due to sustained food enticement and the encouragement of “healthy snacks for diabetics”. Intermittent fasting is however not a diet but it was a way of life in ancient or indigenous environments where people ate, between several hours, only when they had food. This helps the body to handle fuel substrates efficiently and probably supports why diabetes is not found in hunting and gathering societies. Given its efficacy in diabetic remission, intermittent fasting under medical supervision is cheap and should be included as part of conventional care, especially in developing countries.
I am not a handy person and you would never find me trying to fix stuff. However, I was in an uncomfortable situation a few years ago when I thought I could add oil to my lawn mower. As you might have predicted, I poured more oil than recommended and I had to start searching the internet for the implication(s) of what I had done. Unfortunately, I failed to note the name of the author of the best advice I got but here is the anonymous mechanic quote: “If you ran too much oil for too long, you have trashed your engine!” Sounds like the lipotoxity side of diabetes? Sure! If you have diabetes, work with your physician; intermittent fasting works: It depletes the fat stores. Without doubt, glucose lowering drugs are efficacious, but they need to be short termed; therefore, physicians work with your patients to wean them off these and not add to them. As with most medicines, more is not better.
Mukaila Kareem, a doctor of physiotherapy and physical activity advocate, writes for the USA and can be reached through firstname.lastname@example.org.