Treatment of Type 2 Diabetes

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metabolik-cerrahiThe condition that includes obesity, diabetes, high cholesterol and hypertension is called Metabolic Syndrome. The treatment of Metabolic Syndrome by surgical methods is called Metabolic Surgery.
Metabolic Syndrome, including conditions of obesity, type 2 diabetes, hypertension and cholesterol metabolism malfunction, is a significant cause of death, due to the fact that, along with serious organ damage, it causes cardiovascular diseases. Loss of work and significant material loss are also typical features in this long-lasting condition.

The frequency of both obesity and metabolic syndrome is increasing world-wide. It is known that 1.1 Billion of the world population is overweight and that nearly 400 Million are obese (Body Mass Index >30) (1,2). Metabolic diseases like type II diabetes, coronary arterial diseases and hyper-tension can be mentioned among the most important diseases accompanying obesity. Beside this, it is also known that the rate of cancer is higher in obese patients (3-6). Obesity accompanying diseases are indicated in Table 1.

It was determined that there were 150 Million diabetes patients in the world by the year 2004 and estimated that this figure will reach 300 Million in 2025 (7,8). About 90% of all diabetics are diagnosed as type II diabetic patients (9). This increasing disease frequency causes additional illness management costs and health expenditures. Whilst the frequency of obesity and metabolic syndrome have reached an alarming dimension in many developing countries, it is foreseen that the rates in question will increase by 150% in 2030 due to reasons like increasing urbanization, fast-food type nutritional habits and sedentary life styles (6). Though different figures are indicated in different studies, it is known that also in our country about 18% of the adult population is obese and that about 11% of the adult population are type II diabetes patients (10-15). Obesity and metabolic syndrome related chronic diseases constitute a significant portion of medicine associated expenditures in our country. 25% of each $1USD spent on health costs in the world are for obesity, diabetes and health problems related to these (16).

Serious damage of vital functions causes heart attack, paralysis, kidney diseases and kidney insufficiency in diabetic patients. Besides, the occurrence of circulatory disorders may cause vision loss, muscle and bone diseases, decreased libido and organ loss to develop. In many studies it is revealed that 35-55% of diabetic patients are not able to sustain their blood sugar levels in the range recommended by ADA (17). The treatment of type II diabetes requires, along with serious patient adaptation, high hospital costs and long term medicine usage. Theoretically, it is accepted that a type II diabetic patient consumes all the insulin deposits in his/her body within a period of 10-12 years and that he/she becomes an insulin addicted patient after this period. The medicinal and hospital costs of patients further increase after this period and the progression of the disease accelerates. A treatment method that would be able to interrupt this vicious cycle would both have a positive effect on the patient’s survival and quality of life, but also make a significant economic contribution to the health system. Although diabetes frequency is increasing to pandemic ratios no significant difference is provided by the results achieved with the existing treatment modalities and the resolution of the disease doesn’t appear to be possible.

The surgical treatment of type II diabetes was raised for the first time by the Walter Pories’ study with the interesting title ‘Who would have thought it?’, published in Annals of Surgery in 1995 (18). In this study, Pories noted that in the long term (14 years) tracking of bariatric surgery patients an important portion (82,9% of the diabetics and 98,7% of patients with glucose intolerance) had kept their glycaemia levels in normal ranges. It is mentioned in this study that the impulses (incretins) occurring in the small intestine upon closure of the duodenum and the proximal jejunum for food entrance plays an important role for the regulation of blood sugar. That hormonal changes and blood sugar control occurred directly in the following days after the surgery resulted in the idea that diabetes control was actually centred in the entero-insular axis and with the changes in the incretin metabolism than in weight loss due to bariatric intervention. This change due to the duodenum and the proximal small intestine is called the Foregut Theory. Numerous further studies have found their place in the literature in following years, confirming Pories’ results (19-26). Nevertheless, though significant weight losses occurred in gastric by-pass patients, only 75% diabetic resolution could be achieved.

It is possible to foresee which patient would benefit from these processes by the documentation of pathophysiological mechanisms valid in metabolic surgery applications. Patients with a shorter diabetic background and a higher endogenous insulin reserve benefit more from metabolic surgery applications since the surgical treatment increases insulin sensitivity. Diabetic resolution can be achieved by nearly 100% of this group of patients. The patients are able to live for long years without any antibiotic treatment. However, a recovery of the blood sugar levels in patients with a diabetes background of 12 years and more occurs only after months, possibly due to the influence of weight loss. The Foregut Theory hypothesis, emphasizing the effects of small intestine by-pass on diabetes resolution, was supported in following years by the hypothesis titled the Hindgut Theory. The Hindgut Theory is an entity set forth in order to state the effects of the distal small intestine on diabetes resolution and allowed us to understand the responses of our digestive system physiology to the changes in the food industry during recent years. Namely; there have been serious changes in the ingredients of food consumed with the daily diet, particularly in developed countries, in recent years (27-29). A significant part of the food we consume is constituted of refined, even super-refined and saccharified foods. Therefore, the foods are somewhat pre-digested and are then near to fully digested in the duodenum and the proximal small intestine. And more importantly, the majority of the new generation food industry products consist of hyper-caloric foods. Our digestive system has not adapted itself to the reeling changes in the food industry, particularly during the last 20 years. As a result, the chylus arriving in the small intestine gets rather poor in terms of nutrient content and the ileum mucosa attenuates. Also, the effects of the enteric hormones, playing a role in the ileum centred digestion, decrease. This situation constitutes the basic rational of Metabolic Surgery applications.

Put simply, metabolic surgery application either takes the food to the ileum or the ileum to the food. Whilst the food is directed to the ileum with a by-pass of the foregut by Gastric By-Pass (RYGBP), Biliopancreatic Diversion (BPD) and Duodenal Switch (DS) processes, it is provided that the ileum meets the food in earlier stages of the digestion with the Ileal Interposition operations (Table 2). It is emphasized that the documented effects of the surgeries occur due to the small intestine sourced hormones (incretins). The most known incretins are the Glucagon-like Peptide-1 (GLP-1) and the Glucose-dependent Insulinotropic Peptide (GIP). Incretins are released during the digestion function and increase the effect of insulin. Their effect on both insulin and glucagon are glucose-dependent. The stimulation of beta cells and insulin release occurs rather by the orally taken glucose than the intravenous glucose application. And this difference is called the Incretin Effect. Whilst it varies in diabetic patients depending on the grade of the disease, it is different from healthy individuals, and independent from the Incretin Effect on glucose and the insulin release response. This response may be in the form of delay, non achievement of the necessary level and/or extension. This response is important, in as much as the Incretin Effect has a determinant influence on glycaemia after dining. Whilst both incretin derivates have an influence on insulin release and its effects, only GLP-1 enters the glucagon and the partial antagonism and suppresses their effects. Endogenous GIP is in fact released by the K cells, sourced in the lymphocyte located in the duodenum, particularly in relation to oral fat intake. Their levels decrease in hunger situations and increase with food intake. The primary effect of GIP is to stimulate glucose-dependent insulin secretion. And endogenous GLP-1 is released by the L cells in the distal small intestine. It is derived from a wide pro-glucagon molecule, which also encodes glucagon at the same time. Similar to GIP, their levels decrease in hunger situations and increase at satiety.

They have influences on both the insulin release from pancreatic beta cells and gastrointestinal motility (30-32). It is noted that after Metabolic Surgery processes significant increases occur in the incretin levels and that the effects on blood sugar might be conducted via the incretins (33-41). Beside this, it is reported that GLP-1 activation caused a satiety feeling and saturation via the receptors in the brain monitoring this molecule (42). The Exenatide molecule, isolated for the first time from the salivary gland of the Gila monster laboratory animal, is a synthetic GLP-1 analogue. The homology of this analogue with the natural GLP-1 in humans is about 53% (43-44). More importantly, these cannot be catabolised by the GLP-1 catabolising DPP-4 (Dipeptidyl Peptidase 4) enzyme (30,31). Though this, even with combined regimes, in which GLP-1 analogues are used, the goals (HbA1c < 7) determined by the ADA (American Diabetes Association) can only be achieved in 50% of patients (45). In patients to whom Metabolic Surgery is applied, a diabetic resolution can be seen at the 98% level. This situation makes one think that the pathophysiological changes occurring after Metabolic Surgery cannot only be explained with incretin theories. Other pathophysiological mechanisms causing a resolution at such a high level are still waiting to be fully explained. Whilst not all mechanisms providing the high resolution possibility are explained in full, Metabolic Surgery applications provide an efficient and long termed resolution in the treatment of the Metabolic Syndrome and its components (46-52). Furthermore, there are 8 to 30 years tracking results from applied Metabolic Surgery procedures, although these may vary according to the specific surgical technique. Further to this, Metabolic Surgery applications extend the life of obese patients and also influence cancer frequency positively (53-57). Perhaps most importantly these applications can achieve a resolution at ratios varying between 75% and 98% in type II diabetes (58-64). However, not every patient can benefit from these applications to the same degree, and therefore there are some factors to be determined regarding what degree of type II diabetes resolution will be seen in each patient after the surgical application. As the most important among these, the total disease duration before the surgery, the remaining insulin level and other accompanying co-morbidities by the activity of this can be mentioned (65-70). In recent years, along with the increase of our knowledge regarding the digestive physiology, neurohormonal mechanisms controlling hunger, satiety, energy receipt and usage are better understood. The possibly most important point to be emphasized in the light of this knowledge is that metabolic surgery applications change the course of type II diabetes by making changes to intestinally sourced hormonal transmission mechanisms rather than to a mechanical new passage or a non-specific malabsorption. Only a definite portion of type II diabetics comply with these criterions since the surgical indication is restricted to patients with a BMI of above 35 and a co-morbidity, or with a BMI of above 40 without a co-morbidity. But, it should not be forgotten that these indications were made with regard to the patient populations in countries (especially in the USA), in which bariatric surgeries are more commonly performed. Whereby, there are significant deviations in Asian countries and even between the individuals of different races in America (71). The body/muscle ratio of Spaniards and Asian race member individuals are lesser compared with other races and type II diabetes occurs in these persons at lower BMI values (71,72). Therefore, the decisions regarding metabolic surgery applications in each society should be made by considering the facts of the society in question. Along with these, the possibility to treat type II diabetes with surgical methods is still a subject that needs to be questioned and to be explained with other mechanisms. Pre-clinical studies and clinical series indicate that type II diabetes is a disease, potentially capable of being cured by surgical methods. Each society and each country should be able to reveal the appropriate patient profile with well planned clinical studies by considering their own patient characteristics. A better understanding of the issue will also contribute to a better understanding of gastrointestinal physiology, insulin resistance and new anti-diabetic treatment methods.