Mitigation of Type 2 Diabetes by 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.

The investigators have now completed and submitted for publication our study on the incidence
of type 2 diabetes in the POSCH program 25 plus years after formal trial closure (IRB Code
Number: 1408M53283). The title of our paper is "Partial Ileal Bypass Affords Protection from
Onset of Type 2 Diabetes". Of the 66 control patient responders in POSCH, 17 contracted type
2 diabetes (25.8%); of 80 PIB responders, 8 contracted type 2 diabetes (10%). The difference
between groups was significant (P=0.015 by Fisher Exact Test) with an odds ratio of 0.320 for
the PIB group and an over two-fold (2.6) increase in the incidence of type 2 diabetes in the
controls. Including borderline type 2 diabetes (prediabetic) patients, these values were 22
of 66 controls (33.3%) and 10 of 80 PIB patients (12.5%), with an odds ratio of 0.286 and a
P<0.004, and again an over two-fold (2.7) increase in the incidence of type 2 diabetes in the
control patients. Therefore, PIB appeared to afford protection from the onset of type 2
diabetes for over 30 years.

Inclusion Criteria:

- Hyperlipidemia patients referred for partial ileal bypass, who also have type 2
diabetes.

Exclusion Criteria:

- Preoperative C-peptide indicative of non-functioning islet cells.