Mitigation of Type 2 Diabetes in Hypercholesterolemic Patients Undergoing a Partial Ileal Bypass

The partial ileal bypass (PIB) operation is a standard procedure used in the management of hyperlipidmia since 1963. POSCH was the intervention modality in the National Institutes of Health, National Heart Lung and Blood Institute-funded Program on the Surgical Control of the Hyperlipidemias (POSCH) trial. The POSCH study was a secondary trial in patients with a documented prior myocardial infarction. The trial compared the post-dietary lipid therapy changes in 421 PIB-intervention patients to 417 controls, with a lowering of total plasma cholesterol of 24% (P<0.0001), a lowering of low density lipoprotein (LDL)-cholesterol of 38% (P<0.0001), and an elevation of high density lipoprotein (HDL)-cholesterol of 4% (P=0.02). These lipid changes were associated with a 35% (P<0.001) reduction in the intervention group of death due to coronary heart disease and confirmed recurrent myocardial infarction, as well as a 27% (P<0.038) reduction in peripheral vascular disease, and a 54% (P<0.005) diminution in the occurrence of coronary artery surgery or angioplasty. Concurrently with the clinical study, POSCH assessed sequential coronary arteriograms at 0, 3, 5, 7, and 10 years, which showed less disease progression in the surgery group, and even statistically significant plaque regression in the PIB cohort. POSCH PIB patients exhibited a statistically significant increase in life expectancy; this finding persisted at a 25-year follow-up assessment.

In the field of metabolic/bariatric surgery, resolution of type 2 diabetes by gastrointestinal tract manipulations was clearly demonstrated by 1998. In three meta-analyses, the procedures that involved shortening of the ileum (biliopancreatic diversion and duodenal switch) were responsible for the highest percentage of type 2 diabetes resolution. Recently under evaluation are standard metabolic/bariatric and experimental metabolic operations that will engender type 2 diabetes resolution with minimal or no weight loss in non-obese diabetic patients.

The gut-diabetes relationship has often been attributed to an increased elaboration of the hormones glucagon-like peptide-1 (GLP-1) and peptide YY (PYY), both secreted by the L-cells of the intestinal mucosa. These hormones seem to work in concert, either eliciting the same metabolic response or augmenting the actions of the other. With respect to pancreatic endocrine function, GLP-1 and PYY contribute to the incretin effect, counteract the insulin depression action of gastrin stimulating peptide and gastrin-releasing peptide, and stimulate glucose-dependent insulin secretion, preinsulin gene expression, beta-cell proliferation, and antiapoptopic pathways. It has been shown that GLP-1 secretion is reduced in patients with type 2 diabetes. In a recent study of the effects of direct human terminal ileum and cecal contact with a food hydrolysate, significant plasma GLP-1 and PYY elevations were demonstrated, confirming the ability of the cecum, as well as the ileum, to secrete GLP-1 and PYY on stimulation. In the Goto-Kakizaki rat with naturally occurring type 2 diabetes, ileal bypass or excision did not lower GLP-1 production, but interestingly increased it five- to six-fold.

These complementary studies gave rise to the hypothesis that: the PIB operation, in addition to its action on cholesterol metabolism, may aslo prevent and resolve type 2 diabetes.

In our laboratory at the University of Minnesota, the investigators have clearly established the mechanism for the reduction of total cholesterol and LDL-cholesterol by PIB: interference with the cholesterol and bile acid enterohepatic cycles, markedly decreased absorption and reabsorption of cholesterol and bile acids, increased excretion of cholesterol and bile acids, increased turnover of cholesterol to generate bile acids and replenish the cholesterol pool, and the insufficient ability of the body (even in familial hypercholesterolemics) to maintain the miscible (plasma and liver) and less-freely miscible (tissues, including the arteries) body pools, and, thereby, a depletion of the cholesterol content of atherosclerotic plaques. the investigators have now (see above) added to that knowledge that the elimination of the terminal ileum from the intestinal pathway will increase circulating GLP-1 levels, with this incretin probably emanating from the cecum.