Glucose metabolism after bariatric surgery: implications for T2DM remission and hypoglycaemia

Abstract

Although promising therapeutics are in the pipeline, bariatric surgery (also known as metabolic surgery) remains our most effective strategy for the treatment of obesity and type 2 diabetes mellitus (T2DM). Of the many available options, Roux-en-Y gastric bypass (RYGB) and vertical sleeve gastrectomy (VSG) are currently the most widely used procedures. RYGB and VSG have very different anatomical restructuring but both surgeries are effective, to varying degrees, at inducing weight loss and T2DM remission. Both weight loss-dependent and weight loss-independent alterations in multiple tissues (such as the intestine, liver, pancreas, adipose tissue and skeletal muscle) yield net improvements in insulin resistance, insulin secretion and insulin-independent glucose metabolism. In a subset of patients, post-bariatric hypoglycaemia can develop months to years after surgery, potentially reflecting the extreme effects of potent glucose reduction after surgery. This Review addresses the effects of bariatric surgery on glucose regulation and the potential mechanisms responsible for both the resolution of T2DM and the induction of hypoglycaemia.

Fig. 1 ∣. Weight loss-dependent and weight loss-independent mechanisms of bariatric surgery on glucose metabolism.

Bariatric surgery has important weight loss-dependent and weight loss-independent mechanisms for driving improvements in glucose homeostasis. In itself, weight loss improves whole-body and specifically muscle and adipose insulin sensitivity. By contrast, the liver seems to be more susceptible to weight loss-independent effects on improving hepatic insulin sensitivity. Weight loss-independent effects also include changes in postprandial glucose and insulin dynamics, with high peaks and rapid returns towards baseline. Bariatric surgery leads to increases in postprandial levels of multiple gut peptides, bile acids and fibroblast growth factor 19 (FGF19; FGF15 in rodents). Changes in the nutrient profile and increases in bile acid signalling contribute to increases in intestinal cell proliferation (Roux-en-Y gastric bypass (RYGB)) and differentiation towards the enteroendocrine cell (EEC) lineages (both RYGB and vertical sleeve gastrectomy (VSG)). There are probably combined weight loss-dependent and weight loss-independent effects on hepatic levels of triglycerides. GLP1, glucagon-like peptide 1; PYY, peptide YY.

Fig. 2 ∣. Bariatric surgery-induced changes in bile acid dynamics induce alterations in glucose metabolism.

Plasma levels of bile acids increase after bariatric surgery via alterations in the enterohepatic circulation. Increased expression of the intestinal bile acid transporter ASBT increases the resorption of bile acids from the intestinal lumen into the portal vein. Decreases in hepatic bile acid transporters (NTCP, OATP2 and OATP4) reduce the reuptake of bile acids into the liver, which leaves increased levels of bile acids in the circulation. Within the intestine and adipose tissue, bile acids can activate Takeda G protein receptor 5 (TGR5); although the data are conflicting with VSG, this might be one mechanism by which luminal bile acids stimulate glucagon-like peptide 1 (GLP1) and consequently impact glucose metabolism and food intake. Also within the intestine, bile acids activate farnesoid X receptor (FXR), which increases expression and plasma levels of fibroblast growth factor 19 (FGF19; FGF15 in rodents). In the liver, FXR is also activated and the combination of these signalling pathways leads to reductions in bile acid synthesis and decreased gluconeogenesis and lipogenesis, and could also impact aspects of energy homeostasis. Dashed outline around the stomach indicates that it has undergone bariatric surgery. iFXR, intestinal FXR; hFXR, hepatic FXR.

Fig. 3 ∣. Target organ responses to RYGB and VSG.

In the gastrointestinal tract, changes in nutrient entry and intestinal adaptations occur after bariatric surgery. Key changes in other target organs, including the brain, liver, pancreas, skeletal and adipose tissue, are summarized. LPS, lipopolysaccharide; RYGB, Roux-en-Y gastric bypass; VSG, vertical sleeve gastrectomy.

Fig. 4 ∣. An example of a daily pattern of glucose in a patient with post-bariatric hypoglycaemia.

This figure represents a typical pattern of plasma levels of glucose throughout the day in a patient with post-bariatric hypoglycaemia. Nocturnal hypoglycaemia is rarely observed. After a meal, sharp increases occur in plasma levels of glucose, followed by rapid drops that often lead to hypoglycaemia.

Fig. 5 ∣. Timeline of physiological changes occurring after bariatric surgery.

Shown are key changes occurring during the early postoperative recovery, during the phase of rapid weight loss, during the phase where weight loss slows and during the weight loss maintenance phase. FGF19, fibroblast growth factor 19.

Fig. 6 ∣. Changes in glucose regulation after bariatric surgery that hwave been linked to post-bariatric hypoglycaemia.

After bariatric surgery (Roux-en-Y gastric bypass (RYGB) or vertical sleeve gastrectomy (VSG)), nutrients are delivered rapidly to the foregut after a meal, which leads to an early and increased peak in blood levels of glucose and increased postprandial levels of glucagon-like peptide 1 (GLP1). Post-bariatric hypoglycaemia is thought to be caused by insulin-dependent mechanisms (increased insulin levels) or insulin-independent mechanisms (decreased counterregulatory hormones and changes in glucose production and uptake). FGF19, fibroblast growth factor 19; FXR, farnesoid X receptor.