The Effect of Standard Versus Longer Intestinal Bypass on GLP-1 Regulation and Glucose Metabolism in Patients With Type 2 Diabetes Undergoing Roux-en-Y Gastric Bypass: The Long-Limb Study.

OBJECTIVE: Roux-en-Y gastric bypass (RYGB) characteristically enhances postprandial levels of glucagon-like peptide 1 (GLP-1), a mechanism that contributes to its profound glucose-lowering effects. This enhancement is thought to be triggered by bypass of food to the distal small intestine with higher densities of neuroendocrine L-cells. We hypothesized that if this is the predominant mechanism behind the enhanced secretion of GLP-1, a longer intestinal bypass would potentiate the postprandial peak in GLP-1, translating into higher insulin secretion and, thus, additional improvements in glucose tolerance. To investigate this, we conducted a mechanistic study comparing two variants of RYGB that differ in the length of intestinal bypass. RESEARCH DESIGN AND METHODS: A total of 53 patients with type 2 diabetes (T2D) and obesity were randomized to either standard limb RYGB (50-cm biliopancreatic limb) or long limb RYGB (150-cm biliopancreatic limb). They underwent measurements of GLP-1 and insulin secretion following a mixed meal and insulin sensitivity using euglycemic hyperinsulinemic clamps at baseline and 2 weeks and at 20% weight loss after surgery. RESULTS: Both groups exhibited enhancement in postprandial GLP-1 secretion and improvements in glycemia compared with baseline. There were no significant differences in postprandial peak concentrations of GLP-1, time to peak, insulin secretion, and insulin sensitivity. CONCLUSIONS: The findings of this study demonstrate that lengthening of the intestinal bypass in RYGB does not affect GLP-1 secretion. Thus, the characteristic enhancement of GLP-1 response after RYGB might not depend on delivery of nutrients to more distal intestinal segments.

The pharmacological treatment and management of obesity.

Obesity is a pandemic with many complications that increase the societal disease burden and cost of health care, and decrease longevity and quality of life. Currently, 1 in 3 adults in the United States is obese. Physicians must therefore regularly confront obesity and its consequent diseases, and develop strategies for effective treatment and management. This article summarizes current lifestyle modifications, pharmacological treatment, and surgical options for the management of obesity and discusses the benefits, limitations, and risks of each. As insights are gained into the pathophysiology of a gut-brain neurochemical feedback axis governing satiety and feeding behavior, targets for new pharmacotherapies are being developed. In particular, gut hormone analogs are an attractive antiobesity therapy because they appear to lack the adverse effects historically associated with central nervous system-acting agents.

Hormonal interactions between gut and brain.

No truly effective drugs exist to treat obesity, which is reaching pandemic proportions. The search for new treatments has led to an interest into the homeostatic system of central appetite regulation. Key components of this system include the hypothalamus and brainstem, the gut, and adipose tissue. It is now recognized that food intake leads to the release of various gut hormones. There are several anorectic (appetite suppressing) gut hormones released, including cholecystokinin, glucagon like peptide-1, oxyntomodulin, peptide tyrosine tyrosine, and pancreatic polypeptide. To date, only one example is known of an orexigenic (appetite stimulating) hormone, ghrelin. These hormones circulate in the blood and signal via vagal nerve afferents to communicate with the hypothalamus and brainstem. This information is integrated and processed in key hypothalamic nuclei. The arcuate nucleus appears to be a central controller of the appetite circuit, integrating both peripheral and central signals. This information is translated into downstream signals affecting body metabolism and food intake. Increased understanding and successful manipulation of this system should enable the design of a successful and much needed anti-obesity treatment.