Diabetes often resolves in patients who have gastric bypass operations well before the patients lose the weight expected to induce metabolic changes, but the process remains somewhat mysterious. Innovative new studies with unique approaches to comparing pre- and post-operative conditions point to a pair of insulinstimulating hormones that could play important roles.
“Exploring the impact this surgery has on digestion could yield new, nonsurgical strategies for treating diabetes and obesity,” says the lead author of one of the studies, Nils Wierup, PhD, associate professor at the Lund University Diabetes Centre in Sweden.
Reported in the May issue of Th e Journal of Clinical Endocrinology and Metabolism, the Lund study examined four obese female patients who had recently undergone Roux-en-Y gastric bypass (RYGB) operations. What made these patients special was that they also had a gastrostomy tube inserted at the time of surgery because they were at risk for complications that might necessitate such exigencies as tube-feeding or emptying the stomach of fluids. So each patient had two feeding routes, orally (and, therefore, via the gastric bypass) or directly into the “old path” of the stomach.
A real-time comparison of different feeding methods about 30 days after surgery avoided the confounding effects that may have plagued other RYGB studies, Wierup says. Most studies have been done so long after surgery that patients have had time to lose large amounts of weight and change their eating habits. After the patients received separate mixed-meal feedings via the two routes, the researchers screened the patients’ blood for approximately 100 hormones and metabolites.
Compared with feeding into the stomach, feeding via the bypass route yielded an almost five-fold increase in plasma insulin, as well as increases in a pair of the hormones called incretins for their stimulation of insulin production: a doubling in glucagon-like peptide 1 (GLP-1) and a 2.5-fold increase in glucose-dependent insulinotropic peptide (GIP, also known as gastric inhibitory peptide). These changes in hormone levels were accompanied by higher branched-chain amino acid levels and lower fatty acid levels. The researchers say that the higher incretin and insulin responses provide “a potential explanation for the rapid remission of type 2 diabetes observed after” RYGB.
In a study published in Diabetes Care in April, researchers at Vanderbilt University mimicked the effects of RYGB in 10 obese patients who had not had any surgery by delivering nutrients directly to the jejunum via a nasal feeding tube. In separate visits to the clinic, the patients received glucose to either the stomach or to the jejunum in random order. As in the Lund study, the jejunal delivery increased peak levels of the incretins GLP-1 and GIP.
The Vanderbilt group also did a similar study in 2011 in nine subjects who had had both RYGB and gastrostomy tubes. That study found an increase in GLP-1 but not GIP when patients were fed via the RYGB route, although GIP peaked much more quickly in the bypass patients.
The findings of increased meal-stimulated insulin and GLP-1 are similar to what has been seen in most before-and-after studies of RYGB, according to Bruce M. Wolfe, MD, professor of surgery at the Oregon Health and Science University in Portland. The GLP-1 effect has been recognized long enough that pharmaceutical companies have marketed incretin mimetics, with a GLP-1 analog — exenatide — on the market for several years. Exenatide helps with modest improvements in blood sugar control, although nothing game-changing. It leads to modest weight loss, in contrast to the weight gain generally associated with insulin use, but requires uncomfortable and too-frequent injections. Drug companies are working to come up with a longer-acting version, Wolfe says.
Randy Seeley, director of the Cincinnati Diabetes and Obesity Center, agrees that the literature is consistent when it comes to the effects of RYGB on GLP-1, but says the finding of increased GIP is more controversial. He says some studies show it is increased and others find it reduced, but that GIP is made in the upper duodenum, “so the general version in the literature is that it is reduced after Roux-en-Y bypass because the nutrients aren’t hitting that part of the intestine that is most responsible for making it.”
How then did these researchers find an increase? The Lund paper suggests that “distal GIP production may be induced to compensate for the loss of proximal GIP production in the intestine.”
Researchers have no clear idea of how big a player GIP is in the diabetes game, but the question of its production leads into an ongoing debate between two competing hypotheses on which aspect of RYGB provides its diabetes benefits: because it bypasses the foregut and, therefore, excludes anti-insulin hormones secreted there or because accelerating the delivery of nutrients to the hindgut increases the secretion of incretins. Seeley and Wierup concur that after years of inconclusive study, the foregut-hindgut debate may have outlived its usefulness, particularly because RYGB by definition delivers both conditions. And another factor confounding this debate is that studies have shown that simple calorie restriction, whether provided by diet or surgery and independent of weight loss, can lead to fast and dramatic improvement in diabetes measures.
Wierup says that the study’s finding that branchedchain amino acids increased after feeding via the bypass route “was unexpected because other researchers have shown, at least a long time after surgery, you get reduced branched-chain amino acids.” He says the finding could be significant because some branched-chain amino acids are direct stimulators of insulin secretion — in vitro experiments with leucine have demonstrated a powerful insulin effect. Wierup notes that despite this effect, branched-chain amino acids have been considered a marker for insulin resistance, and that the new findings call this role into question.
The significance of the changes these researchers identified is still an open question because, as Wolfe says, “There are so many changes occurring after surgery, you can’t measure them all.” And researchers will continue to sort out their importance.
But there is no disputing Wierup’s conclusion: “The take-home message is that the metabolic state is better if you get the food the bypassed way compared to the non-bypassed way.”
— Seaborg is a freelance writer based in Charlottesville, Va., and a regular contributor to Endocrine News.