Treatment of type 2 diabetes mellitus: Could surgery be the best treatment option?

By: Keletso Wandile John Mahlangu

Abstract

Diabetes mellitus has become a disease of international concern, with diabetes mellitus type 2 being the most prevalent type accounting for about 90% of cases¹. As governments attempt to minimize the burdens of the illness, statistics continue to reveal increasing disease incidence and prevalence. Many health facilities offer conservative treatment as mainstay treatment however, advancements in surgery have revealed better outcomes which are often overlooked. One of the surgery disciplines which have shown promising results is Bariatric surgery. This article aims to review the efficacy and efficiency of using Bariatric metabolic surgery in the treatment of type 2 diabetes mellitus in comparison to conservative treatment.

Introduction: an overview of diabetes mellitus

Diabetes mellitus is one of the most common metabolic diseases worldwide, a chronic disorder that can be defined as abnormal metabolism of carbohydrates (in the form of glucose) leading to persistent hyperglycemia¹. This chronic hyperglycaemia is known to cause detrimental complications affecting all organ systems, causing both microvascular and macrovascular complications¹. The pathognomonic features of diabetes mellitus are hence related to the increasing prevalence of other comorbid conditions such as hypertension, heart disease, neuropathies, and others. The global prevalence of diabetes mellitus was estimated to be around 463 million people in 2019, a number expected to increase sharply to 578 million people by the year 2030². Diabetes mellitus is a disease of epidemic status with increasing incidence closely related to increased body mass index ­­­­­– a product of unhealthy diets and sedentary behaviours. Several types of diabetes mellitus exist as listed below however, the most prevalent is type 2 diabetes mellitus accounting for an estimated 90% of all cases¹.

Aetiology and pathophysiology

Type 1 diabetes mellitus

Type 1 diabetes mellitus (T1DM) can be described as a disorder characterized by the autoimmune destruction of beta cells of the islets of Langerhans in the pancreas¹. This leads to inadequate insulin production, a hormone responsible for glucose storage, hence the manifestation of diabetes mellitus. T1DM is heavily linked to genetic susceptibility along with environmental factors (dietary factors, obesity, infections particularly viral, and toxins) commonly identified as the precursor for autoimmunity. Due to its strong link to genetics, it is often identified during the early stages of life hence in children and adolescents¹.

Type 2 diabetes mellitus

Type 2 diabetes mellitus (T2DM) can be described as a diabetic condition whose pathognomonic features include deficient insulin secretion, tissue insulin resistance, or inadequate compensation to insulin secretion leading to a hyperglycaemic state³. T2DM does indeed have a genetic component linked to primary insulin deficiency but is strongly associated with lifestyle factors (obesity, physical inactivity, and an unhealthy diet)¹.

Contributions of nutrition and obesity in the pathology of type 2 Diabetes Mellitus

Type 2 Diabetes Mellitus is associated with carbohydrate and fat-rich diets. Such diets are linked to increased blood glucose levels, very low-density lipoproteins, and chylomicrons³. The above-mentioned lead to inflammation in the body due to oxidative stress resulting from reactive oxygen species, products of the metabolism of these substances³. Very high levels of glucose and lipids hence cause oxidative stress, a precursor to β-cell dysfunction.

Of the mentioned modifiable risk factors, the strongest risk factor has been identified to be obesity³. No distinct pathological mechanism has been identified to describe the pathology of obesity in T2DM but numerous factors have been identified. Obesity is known to cause insulin resistance which results in the onset of persistent hyperglycaemia eventually leading to T2DM. Insulin resistance is thought to be caused by accumulated adipose tissue which promotes inflammatory processes including adipokine deregulation and an increase in free fatty acids³.

 

 

 

 

 

 

 

Figure 1(12): Risk factors of type 2 diabetes

Current methods of treatment of Type 2 Diabetes Mellitus

The goal of treating diabetes mellitus is to achieve remission, the definition of which differs according to the literature being used. However, in this paper complete remission is to be defined as normoglycemia (HbA1c<6,5%) for at least a year without the use of medication meant to reduce blood glucose levels⁴

Conservative treatment of type 2 diabetes mellitus

Conservative treatment refers to treatment with the avoidance of surgical intervention. It focuses primarily on addressing risk factors with an eventual progression to pharmacological treatment.

Diet and nutrition

Type 2 diabetes mellitus has been termed to be a lifestyle disease; A disease linked to physical inactivity, improper diet, and obesity. The mainstay treatment of this condition is diet and exercise². Exercise and diet not only serve to manage but prevent the onset of both Type 1 and Type 2 diabetes Mellitus. Western diets bear the most risk as they are highly fat and carbohydrate-saturated³. A diet low in saturated fats, monosaturated fats, refined carbohydrates, and high fibre is to be encouraged in prediabetic and diabetic patients². It is recommended to add whole grains, fruits, vegetables, nuts and legumes to the diet, and reduce intake of red processed meats, refined grains and soft drinks¹⁵. It is advised to limit alcohol intake in prediabetic and diabetic patients. Excess alcohol consumption is associated with an increased risk of weight gain, hypoglycemia, coronary heart disease and mortality¹⁵.

Physical activity

Exercise is a major factor in managing type 2 diabetes. It is a key factor in combating a sedentary lifestyle, a risk factor for the onset of diabetes mellitus. Physical activity is used to combat body fat accumulation, thereby preventing the overweight state and obesity in patients. Aerobic exercise done regularly has been liked to improvements in HbA1c levels in diabetic patients through various mechanisms involving blood vessel compliance, improvement in insulin sensitivity, and enhancing both cardiovascular and pulmonary function⁵. The direct effect of physical activity on type 2 diabetes has several mechanisms.

Physical inactivity is linked to increased release of inflammatory markers including interleukin 6, C-reactive protein, Tumour necrosis factor-alpha, and Interleukin 1 among others³. Interleukin 1 contributes to an autoimmune response to B-cells of the pancreas leading to malfunctions in B-cell functioning eventually causing cell death³. This can cause the onset of type 2 diabetes mellitus. Regular physical activity has been identified to lead to the release of anti-inflammatory cytokines including Interleukin 1 receptor antagonists as well as the release of irisin, a hormone that improves glucose tolerance³. Hence, physical activity can combat factors leading to type 2 diabetes mellitus. Physical activity also leads to the production of antioxidants which reduce oxidative stress³.

Pharmacological treatment

Type 2 diabetes mellitus is a heterogeneous disease with varying contributing factors across patients. Its heterogenic nature leads to variation in patient response to pharmacological treatment¹⁰. Hence there is no uniform pathway in the pharmacological treatment of diabetes mellitus. A good indicator used in monitoring diabetes mellitus is Haemoglobin A1c(HbA1c), a glycated haemoglobin that binds glucose in blood¹¹.HbA1c levels can be used to measure glycaemic control over three months. HbA1c levels below 5,7% reveal a controlled glycaemic state. Levels of 5,7% – 6.4% are an indicator of prediabetes. Levels of 6,5% and above indicate diabetes mellitus¹¹. Primary treatment usually aims to reduce HbA1c to levels below 7,0%.

A majority of countries’ medical guidelines have taken a patient-centered approach to treat type 2 diabetes¹⁰. Many of these involve metformin as the primary drug introduced in diabetic treatment¹⁰. Metformin is used as monotherapy to attempt to control diabetes. Failure to achieve glycaemic control in a set period on monotherapy usually indicates the need to upgrade to drug combination treatment which is catered according to the needs and concerns of the patient. Drug combination treatment ranges from dual to complex with the addition of oral agents such as gliclazide MR, DPP-4 inhibitor, pioglitazone as well as injectable agents such as GLP-1 RA or basal insulin¹⁰. Mechanisms are indicated in figure 2.

Pharmacological treatment prompting weight loss effect

Metformin has been proven to be an appetite suppresant¹⁴. This has been associated mainly with the drug’s gastrointestinal side, central acting effect and insulin-sensitizing effect¹⁴. The literature surrounding the impact of metformin on weight loss has been disenchanting with several studies indicating that it results in minimal weight loss of less than 3,2% of initial weight¹⁴.

Another diabetic drug class that results in reduced weight is α-glucosidase inhibitors. These drugs reduce carbohydrate absorption by inhibiting the enzymatic cleavage of complex carbohydrates into simple sugars limiting the intestinal absorption of glucose¹⁴. This leads to decreased post-prandial blood glucose and has been associated with an average weight loss of about 0,3- 0,4kg in a 1 year follow up study for the treatment of type 2 diabetes¹⁴.

Sodium-glucose cotransporters proteins 1 and 2(SLGT 1&2) are transporter proteins regulating glucose reabsorption in the proximal renal tubule of the kidneys. SGLT-2 is responsible for 90 percent of reabsorption and SLGT-1 for 10%¹⁴. When SGLT inhibitors are used, glucose excretion from the renal tubules increases by about 50-100 grams per day. SLGT 2 inhibitors especially are associated with increased lipid mobilization as they increase glucose /insulin ratios¹⁴. Hence adipose is reduced within the bloodstream. Weight loss is highly dependent on the dosage of these drugs as well as on the combinations with other antidiabetic drugs.

Glucagon-like peptide- 1(GLP-1) and glucose-dependent insulinotropic peptides (GIP) are incretins produced in the GIT. These hormones stimulate glucose dependent insulin secretions which lower blood glucose levels¹⁴.Insulin secretion is associated with early satiety as insulin release suppresses appetite¹⁴. GLP-1 and GIP agonists reduce food intake in the above mentioned manner leading to weight loss. Of the above-mentioned drugs, terzipatide a GLP-1 receptor agonist as been identified to be the most effective in weight loss therapy¹⁴.

Figure 2(10): Drug methods of action of hypoglycaemic drugs used to treat type 2 diabetes mellitus.

Challenges experienced in pharmacological treatment

Pharmaceutical treatment of type 2 diabetes comes with its challenges. As mentioned in the table, many of the drugs have potential side effects. Treatment with metformin has been associated with the onset of vitamin B₁₂ deficiency and is reputable for causing lactic acidosis, placing patients at risk of developing renal disfunction^5,10. Hence administration of this medicine should be heavily evaluated in patients with renal and cardiovascular conditions. SGTL2 inhibitors, a drug used in combination therapy tends to cause glycosuria as it blocks glucose reabsorption⁵. This leads to genitourinary tract infections along with subsequent hypotension due to extracellular fluid loss¹⁰. Several other studies have linked SGTL2 inhibitors to diabetic ketoacidosis and pancreatitis⁵. GLP-1 agonists have shown similar side effects to those of SGTL2⁵. These drugs are some of the most used in pharmacological treatment, hence treatment is patient-centred care is required to avoid adverse effects.

More challenges appear beyond the treatment itself. Patients with uncontrolled glycemia can end up requiring injected insulin therapy. Treatment adherence is greatly reduced when treatment methods are not favoured by the patient. Treatment also relies greatly on lifestyle interventions which when coupled with the medical expenses can be expensive to maintain⁵.

Surgical methods of treatment: Bariatric surgery

Overview

Bariatric surgery refers to surgeries done to induce malabsorption and/or gastric restriction in the gastrointestinal tract to induce weight loss. It has been identified in several studies to be the best surgical intervention in treating obesity, type 2 diabetes as well as the associated co-morbid conditions⁶. Several studies have revealed bariatric surgery to lead to better outcomes in weight loss with average weight loss ranging from 22% – 37% after Roux-en-Y gastric bypass and up to 19% after sleeve gastrectomy, both of which are the two most common procedures done in bariatric surgery⁴.

Although the primary goal of these surgeries is weight loss, bariatric surgery has shown great improvement in patients with metabolic diseases. One greatly affected happens to be type 2 diabetes mellitus, with up to 75% of patients achieving remission in a span of 5 years⁴. Bariatric surgery has produced outcomes of improved glycaemic control, insulin sensitivity as well as control of hyperlipidemia⁶. These have led to great outcomes in type 2 diabetes mellitus as well as its associated co-morbidities such as chronic hypertension, steatosis, and chronic kidney diseases⁶. These surgeries are performed in the majority to treat type 2 diabetes mellitus in patients with a BMI over 35kg/m² and in special cases those with a BMI over 30kg/m² with certain comorbidities⁹.

The two most performed bariatric surgery procedures:

Roux-en-Y gastric bypass surgery

The Roux-en-Y gastric bypass is the most performed form of bariatric surgery accounting for up to 76% of weight loss procedures⁵. The surgical procedure entails a division of the stomach into a small gastric pouch of volume 15-30 mL closer to the lesser curvature o the stomach, leaving a larger portion that can be termed the “gastric remnant”. The gastric pouch is then anastomosed with the jejunum of the small intestines which is excised from the duodenum. A remnant “limb” comprised of the gastric remnant, duodenum, and its biliopancreatic components are then anastomosed about 100-150cm distal to the gastro-jejunal anastomosis⁷. This leads to a mixture of gastric and intestinal restriction as well as malabsorption potentially leading to weight loss. Figure 3 provides a graphical depiction of the procedure.

 

 

 

 

 

 

 

 

 

 

Figure 3: Roux-en-Y gastric bypass (8)

Sleeve gastrectomy

Sleeve gastrectomy, the 2nd most performed procedure in bariatric surgery involves surgical; removal of around 80% of the stomach8. A major part of the antrum and most of the gastric body is resected towards the greater curvature of the stomach7. This leaves the remaining stomach in the shape and size of a banana with a volume in the range of 50 – 150Ml8. A graphical presentation of the surgery has been attached in figure 4. The mechanism of weight loss in this surgery is due to gastric restriction leading to less absorption of nutrients. Hormones signaling hunger such as ghrelin are also greatly reduced due to the decreased stomach surface area8. Leptin on the other hand increases in production due to the decreased stomach volume8. These lead to early satiety and improved glycaemic control.

 

 

 

 

 

 

 

 

 

Figure 4: Sleeve gastrectomy

Mechanisms of glycaemic control after bariatric surgery

Bariatric surgery has various mechanisms associated with positive outcomes in diabetic and prediabetic patients. Glycaemic control is key for achieving remission of type 2 diabetes mellitus. The most obvious is the induction and maintenance of weight loss. Remodelling of the gastrointestinal tract leads to heightened dietary-induced thermogenesis, meaning improved metabolic rate after a meal⁷. Hypothalamic neuronal circuits are altered in a way that favours lesser intake of food as well as early satiety preventing a surfeit of caloric intake. These are associated with altered appetite, taste, and eating patterns⁷. Bariatric surgery has yielded results similar to those in the practice of conservative caloric restriction in the short term (10-20 days)⁷ however, it has additional mechanical and physiological mechanisms that further improve the outcomes.

Insulin resistance is one of the contributors to diabetes mellitus alleviated by multifactorial factors as a result of bariatric surgery⁶. Weight loss has been studied to reveal rapid improvement of insulin sensitivity with weight loss starting from about <10% of weight lost⁷. Since insulin sensitivity has different initiating factors affecting different organ systems in multiple ways, the benefits of bariatric surgery in improving insulin sensitivity are recognized at different periods across the system⁷. Hence it is difficult to identify the direct mechanisms driving the improvement.

The 1^st phase of insulin secretion along with incretin (metabolic hormones involved in amplifying insulin release after a meal) effect are enhanced subsequent to bariatric surgery⁷. Greater improvement is noticed in Roux-en-Y gastric bypass surgery⁷. Bypass surgery involving the stomach and proximal intestines leads to increased incretin secretion, hence the bioavailability of hormones such as Glucose-like peptide-1(GLP-1) and Glucose-dependent-insulinotropic peptide is increased⁷. This perpetuates insulin release from B-cells leading to better glycaemic control. Another hypothesis has been proposed to account for the physical effects of bariatric surgery on incretin secretion. This hypothesis suggests that anti-incretin hormone-secreting cells are produced in the proximal small intestines⁷. From bypassing these cells, incretin production should increase according to the theory. This is yet to be proven. Satiety hormones such as peptide YY are also elevated due to decreased gastric volume leading to early satiety⁷. This is essential in restricting food ingestion, leading to better caloric and diet management.

Another mechanism involved in glycaemic control is the alteration of bile acid composition as well as the metabolism of bile acids after a meal⁷. The direct pathway implicated is yet to be verified. Bariatric surgeries also alter gut microbiota expanding the diversity and cause dysbiosis (imbalance in microbiome)⁶. These in turn lead to alteration in GIT functioning, potentially leading to improved weight loss and glycaemic control.

Bariatric surgery leads to decreased absorption of nutrients along the gastrointestinal tract. Hence there is upregulation of metabolic activity after the nutritional deficiency. Supraclavicular brown adipose tissue remnants in adults who undergo these surgeries tend to experience increased metabolic rates⁷. White adipose tissue conversion to brown adipose tissue also occurs leading to better metabolism and increased weight loss⁷. Studies have revealed that dyslipidaemia is also reversed by metabolic surgeries with mechanisms unclear to researchers⁷.

Challenges experienced in using bariatric surgery as treatment

Bariatric surgeries have advanced from open surgeries to now having a majority of the surgeries done laparascopically⁷. Although this has led to improved outcomes with decreased adverse results, complications still exist. Patients can experience a range of surgical complications from minor pain and bleeds, all the way to wound infections with subsequent systemic sepsis. These complications include leaks in the gastrointestinal tract, inflammation, bleeding, clotting, herniations, and ultimately death^7,13. Common complications that present after the surgery include dumping syndrome (rapid progression of food through the small intestines associated with abdominal pain, sweating, nausea, and vomiting), chronic nutritional deficits, kidney and bladder stones¹³.

Bariatric surgeries also tend to be expensive to perform and care for post-surgery. The financial implications can however be argued in the long term when compared to those of pharmacological treatment⁷. All these factors and more have to be assessed prior to surgery to ensure better treatment outcomes.

Conclusion

Diabetes mellitus continues to profoundly affect individuals across the world. Type 2 diabetes mellitus however offers many entryways for intervention in management. Conservative treatment in the absence of pharmacological intervention remains a major component in the management of risk factors and early disease/ prediabetes.

Further progression to pharmacological treatment is complicated, with multiple considerations involved in determining the best methods and combinations of treatment. Pharmacological treatment remains the preferred option for immediate management of progressing glycemia in comparison to surgery. This is due to the ease of initiation and initial efficiency of pharmacological treatment. Bariatric surgical treatment has however proven to yield far better results in the treatment of type 2 diabetes mellitus. The increased efficacy seems to be due to the mechanisms related to both the anatomical and physiological alterations that result from these surgeries. Surgery does however in return pose a threat in producing complications with greater immediate consequences when compared to pharmacological treatment. Long-term data (over 10 years) is also lacking in research investigating the impact of bariatric surgery on treatment⁷.  It is because of these factors that bariatric surgery is often overlooked as a plausible treatment method. Studies in multimodal treatment consisting of surgical and pharmacological treatment used in conjunction are also lacking⁷.

Diabetic treatment options continue to develop in an attempt to curve the intensifying impact of the disease. More research is required in developing better more efficient and effective treatment options.

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