β-Cell Function After Weight-Loss Induced by Bariatric Surgery

The study of diabetes in humans has been hampered to some extent by the relative inaccessibility of a key organ in the pathogenesis of this disease: the islet of Langerhans and, more importantly, the insulin secretory machinery that are β-cells (4, 16). This has resulted in a relative dearth of knowledge in regard to key aspects of its pathogenesis. In vivo studies have demonstrated that insulin secretion is delayed and defective in people with Type 2 diabetes (1). Moreover, these defects interact with obesity and with defective suppression of glucagon to exacerbate postprandial hyperglycemia (25). However, there remain key gaps in our knowledge of the numbers, lifespan, and turnover of β-cells in people with diabetes. These gaps are exacerbated by an inability to reliably image islets and β-cells in vivo. As such, there is often an unfortunate conflation of β-cell mass and function that further confuses the existing literature.

Obesity is without doubt a risk factor for diabetes. However, a body mass index (BMI) of ≥40 kg/m² does not invariably imply the presence of diabetes in affected individuals; for example, in a large multi-ethnic cohort, although individuals with a BMI of 40.0–49.9 kg/m² had a relative risk of 9.8 (95%; CI: 9.5–1.1) for Type 2 diabetes compared with age-matched controls, only 12% had Type 2 diabetes (14). Type 2 diabetes arises from a relative insulin deficiency for the prevailing defect in insulin action, and present understanding suggests that, for a given degree of glucose tolerance, there is a hyperbolic relationship between insulin secretion and action such that for a small decrease in insulin action there is a compensatory increase in insulin secretion (6). Diabetes ensues when insulin secretion can no longer compensate for defects in insulin action. Cross-sectional data suggest that the decline in secretion occurs in concert with a decline in insulin resistance across the spectrum of prediabetes but does not identify why subjects with severe obesity vary in their risk of diabetes (21).

With this in mind, Bariatric surgery has been the subject of renewed interest given its effects on glucose metabolism in Type 2 diabetes, with retrospective reviews suggesting a high rate of remission from Type 2 diabetes (2). However, it is important to appreciate that remission of diabetes after bariatric surgery is variably defined and characterized purely in terms of glucose concentrations (3). How the morphology and function of islets is changed–if at all–remains an area of great uncertainty. Likewise, it is unknown whether the frequency and amplitude of insulin pulsatility–key markers of β-cell health–are changed by weight-loss surgery (17, 20). Bariatric surgery is reported to rapidly improve glucose concentrations and insulin action (at least when measured qualitatively) independent of a significant change in weight (28). However, these changes are also observed in response to significant caloric restriction (600–800 kcal daily), suggesting that such improvement is not unique to bariatric surgery (13). More recently, Jackness et al. showed comparable effects of similar caloric restriction and Roux-en-Y Gastric Bypass (RYGB) on β-cell function in patients with Type 2 diabetes over the first 3 wk after intervention (10). Caloric restriction per se likely explains an important part of the favorable metabolic changes observed early after bariatric surgery.

That being said, the measurement of insulin secretion and β-cell function in vivo is complex and suffers from a lack of standardization as well as a failure to distinguish between physiological and nonphysiological stimuli. One particular limitation that is unique to surgeries that bypass the capacitive function of the stomach is the development of a symptom complex often referred to as “Dumping” that is elicited by the rapid delivery of osmotically and calorically dense carbohydrates, usually in liquid form to the jejunum/proximal ileum. This automatically limits the ability to use the oral glucose tolerance test, which is usually the standard oral challenge to test β-cell function in response to a physiological challenge. Moreover, rapid gastrointestinal transit and consequent rapid absorption of nutrients after RYGB produces large excursions of glucose, which elicit an insulin response that is more dependent on the dynamic component of β-cell responsivity to glucose that reflects release of preformed insulin secretory granules rather than the static component that reflects synthesis and secretion of insulin in response to a sustained glucose challenge (24). Supraphysiologic stimuli such as hyperglycemic clamps typically utilize sustained intravenous delivery of glucose and other insulin secretagogues. These tests may not reflect normal physiology and, given intravenous delivery of the stimulus, avoid potential influences of the incretin system on glucose metabolism (5).

Increased delivery of calories to the jejunum/ileum increases enteroendocrine secretion, most notably that of glucagon-like peptide-1 (GLP-1) (15). Although GLP-1 increases insulin secretion and suppresses glucagon secretion, making it a natural candidate to explain the anti-diabetogenic effect of bariatric surgery, competitive inhibition at its cognate receptor by Exendin-9,39 has relatively small effects on insulin secretion in response to an oral challenge after RYGB (11, 12, 24). Does bariatric surgery benefit functional β-cell mass? There is a dearth of data available to directly answer this question. At present, there have been three prospective, randomized, nonblinded studies examining the effect of bariatric surgery compared with medical therapy alone in achieving glycemic control (9, 19, 22). The remission rates reported are significantly lower than those previously reported by retrospective review. For example, in the study by Shauer et al., 12% of patients receiving medical therapy achieved an HbA_1c of <6.0% in contrast to 42% undergoing RYGB (22). Similar results were reported by Ikramuddin et al. (9). Although this is a significant difference in favor of RYGB compared with intensive therapy, less than half achieved the current definition of remission from Type 2 diabetes (3). Coincidentally, attempts at predicting remission of diabetes after bariatric surgery have concluded that insulin use for the treatment of diabetes before surgery is a powerful negative predictor of a favorable metabolic response to intervention (26). The insulin secretory response to intravenous GLP-1, arginine, and glucose-dependent insulinotropic polypeptide (GIP) seem to be unchanged 1 wk and 3 mo after bariatric surgery (8).

A more recent development is the description of postprandial hypoglycemia after RYGB, which is ameliorated by partial pancreatectomy (23). Such patients were identified by the documentation of postprandial hypoglycemia in response to a (nonstandardized) oral challenge, imaging studies that do not document a focal islet-cell tumor, and selective arterial calcium stimulation testing (SACST) with abnormal responses to intra-arterial calcium in one or more vascular territories. Abnormal islet morphology was reported in these subjects, a finding that to some extent has been disputed compared with alternative control specimen (18). The criteria for an abnormal SACST may also be somewhat arbitrary, given that normal insulin pulses have amplitudes that are often threefold higher than baseline values (20). Although gut hormones were quickly blamed for the islet morphology seen after RYGB, this is far from settled and requires further study (7, 27).

To conclude, the role of bariatric surgery in the management of medically complicated obesity–especially that complicated by Type 2 diabetes–perfectly crystallizes what is known about β-cell biology in vivo. Glucose control usually improves to the point where a significant proportion of affected patients will experience remission of diabetes. However, it remains uncertain whether this is associated with an amelioration of cellular health and function in the endocrine pancreas. Better understanding of what happens in the aftermath of significant weight loss might become the window that illuminates measurement or assessment of islet function and mass.