Title : Diabetes Mantra - Glucotoxicity - DT2 11
link : Diabetes Mantra - Glucotoxicity - DT2 11
Diabetes Mantra - Glucotoxicity - DT2 11
For all the years I've been in medicine, the mantra of diabetes care can be summarized in the strict glycemic control . The head endocrinologist would bark "Get the blood sugars in the normal range at all costs, soldier!"
"Sir! Yes, sir!" Was the appropriate response. This is based on the recognition that diabetes is characterized by high blood sugar levels, although this was not the underlying cause of the disease. high blood glucose levels are a symptom of the disease, not the disease itself real. In type 1 diabetes, lack of insulin was the primary cause of the disease, so clearly the replacement of insulin is a cornerstone of treatment.
In T2D however, high insulin resistance is the primary cause of the disease. Therefore, logic dictates that the treatment should be directed to reverse the insulin resistance rather than the symptoms of high levels of blood sugar. Moreover, being predominantly a disease of the diet, it would appear only rational that the cure is the diet pharmaceutical place. However, the nexus of type 1 and 2 diabetes was the appearance of high blood sugar levels. Therefore, borrowing heavily from the playbook of type 1, insulin is used increasingly for type 2 diabetes also. During the last decade the number of patients using insulin increased 50%, and nearly a third of patients with diabetes in general in the United States use insuli n. This is slightly horrible, considering that 90-95% of diabetes in the United States is the DT2, where the use of insulin is highly questionable for the reasons stated above. In 2011, according to the CDC, 85.3% of patients were using drugs or insulin for diabetes.
large-scale trials had shown that tight blood sugar control was largely useless in preventing cardiovascular disease . After all, it not just makes sense to give more insulin to a patient with a disease that has too much insulin already. That's something like washing clothes, putting them in water and dry clothes ... also put them in water. DM1 and DM2 are kind of opposites as once has very little insulin and the other has too. How on earth that awaits us should be treated exactly the same? Are we idiots?
Until the mid-1990s, it was not clear that high blood glucose levels were dangerous. In the short term, low-sugar levels are much more dangerous. Severe hypoglycaemia is strongly associated with a wide range of adverse outcomes, including heart disease and death. A study JAMA 2014 in Internal Medicine observed incidence of hypoglycemia. About 100,000 visits to the emergency room and 30,000 hospital admissions are directly related to hypoglycemia. Over 5 years, the estimated cost of this care is $ 600 million. Older patients generally have a higher risk. From 1999-2011, an estimated 404,000 patients were hospitalized for hypoglycemia compared to an estimated 280,000 hospitalized for high blood sugar levels. The consequences can be serious -. Seizures, loss of consciousness and even death 
Things changed in 1993 with the publication of DCCT (Diabetes Control and Complications Trial ) in NEJM. 1441 patients with type 1 diabetes were randomized to tight control of glucose (3-4 daily injections) or conventional control (1-2 daily injections). The higher dose of insulin successfully reduced the average blood sugar. A1C was about 7% in the strict control group and about 9% in the conventional group. By the standards of today, an A1C or 9% is considered well out of control. The incidence of hypoglycemia, as expected was 3 times higher in the intensive control group.
over 6.5 years of follow up, the incidence of retinopathy was reduced by 76%. Diabetic nephropathy (kidney disease) decreased by 50%, and nerve damage reduced by 60%. The trial was more than enough time to evaluate the effects of strict glycemic control in macro vascular disease (heart attacks and strokes). There was no beneficial effect at the end of the test, but if any benefit would come from a longer follow-up was unknown.
Therefore, these patients were followed for longer in the EDIC (Epidemiology of Diabetes Interventions and Complications) essay published in 2005 in the NEJM. This followed the same group of patients to an average of 17 years. These groups were not actively treated, but only followed, so that both groups had control blood glucose same years from 6.5 to 17. The mean A1c was 7.8 to 7.9%. This was underpowered to detect any changes in CVD time, which was reduced by approximately 50%. 
This clearly established the paradigm of Glucotoxicity in DM1. Remember that T1D is characterized by a lack of insulin. Giving enough insulin to control sugar levels in this disease provided significant reductions in complications of diabetes. This meant that much of the toxicity DM1 could be attributed to the effect of blood sugar.
had a cost, however. hypoglycemic episodes were not increased as noted above. In addition, the incidence of substantial weight gain was significantly higher in the intensive treatment group. Almost 30% of subjects in the higher dose group developed insulin 'significant weight gain', well above what was seen in the conventional group. However, it could not be denied benefits.
However, in the late 1990s, there was some evidence of concern among some physicians about excessive weight gain. The group with the highest weight gain (defined by the first quartile, or top 25% of weight gainers) increased their body mass index from 24 to 31 during the treatment period. In other words, it went from normal weight to obesity in an effort to reduce blood sugar. Blood pressure and blood cholesterol were also affected adversely. The other problem was that the weight gain tended to be in the abdominal area. The combination of the central adiposity, hypertension and dyslipidaemia is a feature of the metabolic syndrome which is more typical of type 2 diabetes, which is characterized by excess insulin. This could not be good news. But the worst was yet to come.
Regarding the EDIC study investigators again questioned whether this excessive weight gain had detrimental effects . Subjects in the EDIC study, after 17 years of insulin treatment had their coronary artery calcification (CAC) and scores the intima-media thickness of the carotid (ITTA) measured. Both they are also accepted measures of atherosclerosis - the buildup of plaque in the artery leading to heart attacks and strokes. High levels of calcification of blood vessels and thickened walls were a sign of bad things to come. CIMT was measured in years 1 and 6. CAC was measured at 8 years of EDIC or 11-20 years after the start of the test.
With the longest follow the EDIC study, patients continued to gain weight, continued to increase their waist circumference, and continued to require increasingly higher doses of insulin. Those who gained more weight also had worse blood pressure and lipid parameters. Even more disturbing, the CIMT scores and CAC scores also increased in this group excessive weight gain. What this means is that we can show reduced toxicity of glucose in type 1 diabetes with intensive treatment, but there is a good chance that we are seeing, in the long term toxicity of treatment with insulin as well.
The insulin well known to cause weight gain propensity is not a trivial problem of trying to fit into your swimsuit. It has harmful consequences. Insulin causes obesity. Along with obesity, metabolic syndrome (lipid problems, central obesity, and high blood pressure) is obtained. What's worse, you start seeing subclinical atherosclerosis markers (CAC and CIMT).
So there are actually two types of toxicity here. Not the toxicity of high levels of blood sugar, but also long-term toxicity of high doses of insulin leads to obesity. In type 1 diabetes, starting with very low insulin so the key problem in the short term (<10 years) is the glucose toxicity. However, as you take high doses of insulin more time, you start seeing some of the same problems you get with T2D -. A problem of excess insulin
The problem was that this problem of toxicity of insulin has not been considered until recently. The DCCT / EDIC trial only seemed to confirm the Glucotoxicity and that's what doctors focused on. All the bad effects of diabetes both type 1 and 2 were considered as a result of high blood sugar. Under this paradigm, then, blood sugar should be lowered at all costs - even if it means sledgehammering someone with hundreds of units of insulin. Large manufacturers of insulin, of course, were more than willing to fund this research.
If this applies to type 2 diabetes was a good question. DM2 is a disease of too much insulin resistance leading to high blood sugar levels. It is immediately apparent that the hammering someone with more insulin is a great idea. After all, patients with type 2 diabetes are high, not low insulin.
But the prevailing mantra was lowering sugar levels. The UKPDS begin to shed some light .
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