How Does Bariatric Surgery Improve Type II Diabetes? The Neglected Importance of the Liver in Clearing Glucose and Insulin from the Portal Blood

Currently, the best treatment method to achieve weight loss in morbid obese persons (BMI ≥ 40) by inducing a negative balance between energy intake (or absorption) and energy expenditure, is the bariatric surgery [8]. The obtained BW loss is primarily due to a mechanical restriction of food intake (e.g., gastric banding) and/or malabsorptive procedures (e.g., gastric bypass). The effectiveness of bariatric surgery in abolishing T2DM ranges from 43% with gastric banding to 98% with Biliopancreatic Diversion (BPD) with/out duodenal switch [9,10]. Little is known of the exact underlying mechanisms of the improvement of insulin sensitivity and glycemia [10], but mechanisms like the ‘‘foregut’’ and the ‘‘hindgut’’ hypotheses have been proposed [11].

Recent publications showed that many patients had lost about one-third of their BWs and an improvement of T2DM acutely post-bariatric operation [6,12]. In addition, the bypass of duodenum and proximal jejunum by nutrients enhanced insulin sensitivity, inhibited lipolysis, and increased insulin clearance in glucose-tolerant and diabetic obese subjects. These results may further our knowledge of the effects of bariatric surgery on both IR and T2DM [13].

Improvement in T2DM is seen in 80-98% of obese diabetic patients who undergo gastric bypass or BPD. This improvement is evident early after the operation before significant weight loss has occurred, though the exact mechanism remains unclear. Studies have focused on changes in the entero-insular axis, which is mediated in part by the interaction of incretin hormones, e.g., the Glucagon-Like Peptide-1 (GIP1) and Glucose-Dependent Insulinotropic Polypeptide (GIP), on the beta islet cells of the pancreas. The responsible mechanisms for the supposed increased GLP1 synthesis are still a matter of debate [14]. Other mechanisms which have been postulated focus on the adipo-insular axis; the actions of adiponectin and leptin seem to have an important role in IR, but their action depends on weight loss [11].

Every year more than 100.000 morbid obese people get different operations for weight loss, however, few studies report long-term follow-up post-operation in cohorts with adequate retention rates. Data from a recently published Cochrane review is based just on 1798 patients (22 trials!) reported, and Yang et al. studied 3-years effects of Laparoscopic Sleeve Gastrectomy (LSG) versus Roux-En-Y Gastric Bypass (RYGP) on T2DM patients (BMI ≥ 28-35 kg/m²) [15]. Interestingly, it was found that 78.6% in the LSG and 85.2% in the RYGB group achieved complete remission of T2DM with HbA1c <6.0% without taking diabetic medications, and 89.3% LSG vs. 92.6% RYGB group gained successful treatment of diabetes with HbA1c ≤ 6.5%. RYGB group had significantly greater BW loss than the LSG group. Serum lipids in each group were also greatly improved [15].

Futhermore, the influence of gender on long-term (5-years) weight loss and comorbidity improvement after LSG and RYGB was investigated. The LSG was more effective in obese male than female patients regards to the percentage of excess BMI lost (%EBMIL), with no difference in comorbidities. However, RYGB procedure elicited similar results in both genders in terms of % EBMIL and comorbidities [16].

In a systemic review about bariatirc surgery of 7371 clinical studies since 1946 performed on patients with a BMI ≥ 35, had >2 years of outcome information, and had follow-up measures for at least 80% of the initial cohort, it was found that for T2DM (HBA1c<6.5% without medication), sample-size-weighted remission rates were 66.7% for RYGP and 28.6% for gastric band. For hyperlipidemia (cholesterol <200 mg/dL, HDL>40 mg/dL, LDL<160 mg/dL, and triglycerides<200 mg/dL), remission rates were 60.4% for RYGP and 22.7% for gastric band. It is conuded that RYGP has better outcomes than gastric band procedures for long-term loss, T2DM control and remission, hypertension, and hyperlipidemia [17].

Importantly, Madsbad et al. reported that with all three of these procedures, remission of diabetes is associated with early increases in insulin sensitivity in the liver and later in peripheral tissues (Figure 1). The LSG and RYBG are also associated with improved insulin secretion and an exaggerated postprandial rise in GLP1 [18].
 

The liver is the major site for insulin clearance as it takes up about 75% of insulin presents in portal blood [13,19]. It has been shown that a direct connection of portal vein with the inferior vena cava- portacaval shunt-, thus bypassing the liver entry; increased of peripheral blood insulin and blood and urinary glucose levels [20]. Insulin clearance is impaired in T2DM and obesity, and severity of the changes of IR has been correlated with the severity of hepatic steatosis [21]. After bariatric surgery there is a sudden decrease of nutrients ingestion. People claim that this is not enough to explain the improvement of the serum glucose level and of the HBA1c.

Bariatric surgery may also reduce lipid deposition in the liver [7]. This effect has not, however, been considered when effects of bariatric surgery on glucose metabolism have been reported, especially as most published studies [17] of bariatric surgery are retrospective. In fact, none of the studies published so far has given information about changes of liver size and/or liver fat content post-bariatric operation. By reporting changes in histology after bariatric surgery, none of the studies published so far has given information about changes of liver size and/or quantitative liver lipid content post-bariatric operation.

A common presentation of pancreatic pathologies is jaundice, which occurs due to the obstruction of the common bile duct and is the classical symptom of pancreatic head malignancies and consequent impaired liver function. In the context of chronic liver disease, markers for common bile-duct obstruction and liver cell damage are associated with the development of IR, metabolic syndrome and T2DM [22]. Remarkably, surgically reversible blood glucose dysregulation diagnosed concomitantly with a (peri-) pancreatic tumor appears secondary to compromised liver function due to tumor compression of the common bile duct and the subsequent increase in IR. It can be categorized as “cholestasis-induced diabetes” and thereby distinguished from other forms of hyperglycemic disorders [23].

Raffaelli et al. studied the changes in the levels of diurnal leptin, insulin and free fatty acid in severely obese (BMI ≥ 40 kg/m²) women before and 6-months after BPD [2]. Amazingly, they reported that BPD, a malabsorptive bariatric operation that drastically reduces circulating lipid levels, improves IR independently of weight loss. They demonstrated that normalization of insulin sensitivity after bariatric surgery was associated with a reduction in 24-h free fatty acid concentrations and changes in the pattern of leptin peaks in plasma. Bariatric surgery improves the metabolic dysfunction of obesity, and this may be through a reduction in circulating free fatty acids and modification of leptin metabolism [2]. Raised FFA levels decrease the ability of insulin to suppress hepatic glucose output and to promote peripheral glucose uptake, which are supposed to be the major features of IR [2]. In contrast, overnight reduction of FFA levels with acipimox, a drug used to treat hypertriglyceridemia, has been reported to improve IR in obese subjects [24].

However, the bariatric surgery-induced weight loss can be explained by reduced consumption of high-fat/ fructose-containing diets and alcohol [25]; the nutrients that cause hepatic steatosis, hepatomegaly, and consequently IR, when consumed in extensive amounts [3,5]. This suggests that the reappearance of the hyperglycemia, insulinemia and IR in patient’s long-time postoperation is due to the accumulation of fats in the liver, which in turn reduces liver’s ability to take up insulin and glucose from the portal blood .This reduction becomes even greater when hepatocellular damage and consequent reduction of liver function occur. This indicates the central role of the liver in glucose and insulin homeostasis.

The prevalence of and predictive markers for NAFLD in 184 morbidly obese patients undergoing bariatric surgery were assessed. It has been found that the prevalence of NAFLD was 84%, and non-invasive markers include the age, waist circumference, serum ALT activity, and serum triglyceride level are efficient for the diagnosis and management of NAFLD in morbidly obese patients [26].

Recently, we reproduced the situation of hyperinsulinemia and hyperglycemia in presence of NAFLD conditions observed in humans by inducing feeding rats with different hypercaloric diets. Rats were reared on chow, Lieber-DeCarli (LDC), LDC+30% kJ ethanol and 30% kJ fructose (L-EF) for 28-days. L-EF diet caused liver dysfunction, hypertriglyceridemia, and low HDL-cholesterol. Furthermore, we [4] found that the mRNA expression of hepatic insulin receptor substrate-1/2 was significantly reduced in the L-EF group, accompanied by hyperglycemia and decreased C-peptide:insulin ratio, pointing to hepatic IR and reduced insulin and glucose clearance (Figure 2). While the effect of metformin on BW may be due to the frequent gastrointestinal side effect with reduction of the introduction of nutrients, GLP-1 may influence the appetite at the brain level.

The current evidence suggests that bariatric surgery for patients with severe obesity decreases the grade of steatosis, hepatic inflammation, and fibrosis. However, further long-term studies are required to confirm the true effects before recommending bariatric surgery as a potential treatment for NASH [7]. Thanos et al. have examined the long-term effects of RYGB on the rat brain's response to the anticipation of palatable high-fat vs. regular diet [27]. They found that RYGB alters brain activity in areas involved in reward expectation and taste processing when anticipating a palatable fatty food. Thus, specific cerebellar regions with altered metabolism following RYGB may help identify novel therapeutic targets for treatment of obesity [27].