Perspectives in Diabetes
Importance of Small Intestine
in Diabetic Hypercholesterolemia
KENNEiTH R. FEINGOLD
Numerous studies have demonstrated that poor
glycemic control is asssociated with elevated plasma
cholesterol levels in diabetic patients. Experiments
have shown that cholesterol synthesis is increased in
the small intestine of various diabetic animals. This
increase is a generalized phenomenon occurring in all
segments of the small intestine. Insulin therapy that
normalizes blood glucose levels markedly decreases
intestinal cholesterol synthesis in diabetic animals to a
level similar to that observed in control animals.
Studies have suggested that the hyperphagia that
accompanies poorly controlled diabetes is the chief
stimulus for the increase in intestinal cholesterol
synthesis. However, the direct contact of the intestinal
mucosa with nutrients is not the sole trigger for
increasing cholesterol synthesis in the small intestine,
suggesting that circulating and/or neurological factors
play a role. The transport of newly synthesized
cholesterol, most of which is in the chylomicron
lipoprotein fraction, from the intestines to the
circulation is increased in diabetic rats. The sterols
associated with these chylomicrons are rapidly cleared
from the circulation and delivered to the liver. The
increased transport of chylomicrons from the intestine
to the circulation in diabetic patients could potentially
result in several alterations in lipid metabolism that
may increase the risk of atherosclerotic vascular
disease. Diabetes 38:141-45, 1989
M
uch of the morbidity and mortality associated
with diabetes is due to atherosclerosis (for review see ref. 1). In the Framingham study, the
incidence of cardiovascular disease is significantly increased in diabetes, and even with adjustment for
From the Department of Medicine. University of California, and the Metabolism
Section. Medical Service. Veterans Administration Medical Center. San Franc i s , ~ ~California.
.
Address correspondence and reprint requests to Dr. Kenneth R. Feingold.
Veterans Administration Medical Cenler, Metabolism Secl~on(1 1IF). 4150
Clement Street, San Franc~sco.CA 94121
Received for publication 19 August 1988 and accepted in revised form 20
September 1988.
DIABETES, VOL. 38, FEBRUARY 1989
the other known risk factors for atherosclerosis, the risk of
vascular disease is still increased (2). These results indicate
that diabetic patients have an increased risk of vascular
disease that is not simply the result of an increased prevalence of nondiabetic risk factors but rather an independent
risk factor for atherosclerosis. The mechanisms by which
diabetes increases atherosclerosis remain speculative despite intensive investigative efforts (Fig. 1).
However, it is essential to recognize that the interaction of
diabetes with other risk factors, such as hypercholesterolemia, is of major importance. If a 40-yr-old diabetic man
smokes cigarettes, has an increased blood pressure (systolic BP 195 mmHg), and has increased plasma cholesterol
levels (336 mgldl), the probability of his developing cardiovascular disease during the next 8 yr is 46% (2). However,
if these other risk factors are not present, the probability of
developing cardiovascular disease is very small. For example, if the 40-yr-old diabetic man does not smoke, has a BP
of 135 mmHg, and has a plasma cholesterol of 185 mgldl,
the probability of developing cardiovascular disease over
the next 8 yr is only -3%, which is lower than the average
risk in nondiabetic males (2). When risk factors are matched,
the relative risk of cardiovascular disease is greater in diabetic than nondiabetic individuals. However, from the point
of view of diminishing cardiovascular disease, these data
demonstrate that the elimination of the other risk factors is
of paramount importance. These observations are supported
by studies in Third World and Eastern societies, where the
prevalence of risk factors for atherosclerosis is decreased
and vascular disease does not account for a large percentage of deaths in patients with diabetes (3)
INCREASES IN PLASMA
CHOLESTEROL CONCENTRATIONS
Numerous reports have demonstrated that poor glycemic
control is associated with elevated plasma cholesterol levels
in both diabetic humans and diabetic animal models (1). For
example, Sosenko et al. (4) compared plasma cholesterol
levels in insulin-dependent diabetic (IDDM) patients with
varying degrees of metabolic control with plasma cholesterol
concentrations in nondiabetic siblings. In the patients with
excellent glycemic control, plasma cholesterol levels were
similar to those of nondiabetic subjects, whereas in poorly
controlled diabetic patients, the plasma cholesterol levels
were significantly increased. The elevation of plasma cholesterol levels in poorly controlled diabetic patients is due to
increases in very-low-density lipoprotein (VLDL) and lowdensity lipoprotein (LDL) levels (4).
Even more impressive than cross-sectional studies are the
interventional studies that have demonstrated that, in both
non-insulin-dependentdiabetic (NIDDM) and IDDM patients,
improvements in metabolic control result in a decrease in
plasma cholesterol concentrations (1). For example, Dunn
et al. (5) have shown that lowering fasting plasma glucose
levels by continuous insulin infusion is associated with a
decrease in total plasma cholesterol levels from 232 to 182
mgldl. The decrease in plasma cholesterol levels are due
to a decrease in both VLDL and LDL levels. The reduction
in plasma cholesterol levels is greatest in the individuals who
initially had the poorest glycemic control (5). Similarly, in
NIDDM patients, Pfeifer et al. (6) demonstrated that there is
a direct correlation between the decrease in glycosylated
hemoglobin and the decrease in plasma cholesterol levels.
Thus, there is substantial evidence from both epidemiological and interventional studies demonstrating that poor glycemic control is associated with increased plasma cholesterol levels. The increase in plasma cholesterol levels
associated with poor glycemic control is relatively modest
(20-50 mgldl), but based on epidemiological studies in diabetic patients (2,3) and therapeutic trials in nondiabetic
subjects (7), these modest elevations could have harmful
consequences. For example, data from the Framingham study
show that in a 40-yr-old diabetic man who does not smoke
and has a systolic blood pressure of 120 mmHg, increasing
the plasma cholesterol level from 185 to 235 mg/dl increases
the risk of cardiovascular disease by 70%.
SMALL INTESTINAL CHOLESTEROL SYNTHESIS
Despite extensive investigation, the mechanism by which
diabetes produces hypercholesterolemia is unknown. We
describe studies from our laboratory and others suggesting
that the intestine may play an important role in the diabetesinduced increase in plasma cholesterol levels (Fig. 1).
In intact rats, de novo cholesterol synthesis is increased
POOR GLYCEMIC CONTROL
1
INCREASED FOOD INTAKE
1
SMALL INTESTINAL HYPERTROPHY
INCREASED SMALL INTESTINAL CHOLESTEROL AND TRIGLYCERIDE SYNTHESIS
INCREASED CHOLESTEROL ABSORPTION
1
INCREASED TRANSPORT OF CHOLESTEROL AND TRIGLYCERIDE
FROM INTESTINE TO CIRCULATION
INCREASED DELIVERY OF
CHOLESTEROL AND TRIGLYCERIDE
INCREASED
PRODUCTION
VLDL
INCREASED UPTAKE OF
CHOLESTEROL BY VESSELS
DECREASEIN
HEPATIC LDL RECEPTOR
NUMBER
FIG. 1. Potentlal mechanism by which diabetes leads to
plasma c h o l e s t e r o l levels. See text f o r detalls.
Increases
In
two- to threefold in the gut of rats with streptozocin-induced
diabetes (8). This increase in cholesterogenesis occurs in
both the small and large intestine, but quantitatively, the
small intestine is responsible for most of the observed increase (8). The enhancement of small intestinal cholesterol
synthesis occurs soon after the onset of diabetes and persists for at least 5 wk. Most significant, insulin therapy that
normalizes blood glucose levels markedly decreases intestinal cholesterol synthesis in diabetic rats to a level similar
to that of control rats (8). Diabetes did not lead to an increase
in cholesterol synthesis in other organs, including the liver
(8). Other laboratories have shown that hydroxymethylglutaryl (HMG)-CoA reductase activity, the rate-limiting enzyme
in cholesterol synthesis, is increased in the small intestine
of diabetic rats (9-1 1). In the liver, HMG-CoA reductase
activity is normal in moderately diabetic rats, but with worsening of glycemic control, hepatic HMG-CoA reductase activity decreases (12).
Studies of spontaneously diabetic chinese hamsters (13),
diabetic dbldb mice (13), spontaneously diabetic BBIW rats
(14), and alloxan-induced diabetic rabbits (15) have also
demonstrated that cholesterol synthesis is increased in the
small intestine of diabetic animals. These observations suggest that in diabetic animals, an enhancement of intestinal
cholesterol synthesis may be a general phenomenon. In obese
insulin-resistant animal models of diabetes, we have also
observed an increase in hepatic cholesterol synthesis (13).
LOCALIZATION AND REGULATION OF CHOLESTEROL
SYNTHESIS IN INTESTINE OF DIABETIC ANIMALS
Diabetes leads to an increase in the size of the intestines.
In animals with diabetes of relatively short duration the small
intestine is hypertrophied only slightly, and small intestinal
cholesterol synthesis is increased both on a per-total-organ
basis and on a per-gram basis (16). In animals with diabetes
for an extended duration the small intestine is markedly hypertrophied, and cholesterol synthesis on a per-total-organ
basis is increased; on a per-gram basis, it can be increased,
the same, or decreased (16). These observations indicate
that soon after the onset of diabetes, an increased rate of
cholesterol synthesis per unit mass is responsible for the
increase in total small intestinal cholesterol synthesis. In contrast, after a longer period of diabetes, the increase in total
small intestinal cholesterol synthesis is primarily due to an
increase in intestinal mass.
Studies have further demonstrated that the increase in
cholesterol synthesis in the small intestine of diabetic animals
is a generalized phenomenon occurring in all segments along
the longitudinal axis of the intestine (duodenum to ileum)
(16). Diabetes enhances cholesterol synthesis in the distal
segments of the small intestine to a greater degree than in
the proximal segments (16). In the distal small intestine,
cholesterol synthesis is increased in all cell fractions along
the villus crypt axis, but the increase is greatest in the upper
villus cells (17). In contrast, in the proximal small intestine
the increase in cholesterol synthesis is chiefly due to an
increase in the crypt cell fraction (17). These results demonstrate that, although cholesterol synthesis is increased in
all segments along the duodenoileum axis, the cells responsible for this increase differ in the proximal and distal
small intestine.
DIABETES, VOL. 38, FEBRUARY 1989
Various factors regulate cholesterol synthesis in the small
intestine of diabetic animals. Cholesterol feeding decreases,
whereas procedures that reduce bile acid pool size stimulate
cholesterol synthesis in the small intestine (18). Pharmacologically lowering plasma cholesterol levels with 4-aminopyrazolo(3,4-d)pyrimidine stimulates small intestinal cholesterol synthesis in diabetic animals (19). The response to
these experimental manipulations in diabetic animals is similar to that observed in control animals and indicates that the
regulation of small intestinal cholesterol synthesis is not altered by the diabetic state.
ROLE OF HYPERPHAGIA IN INCREASING INTESTINAL
CHOLESTEROL SYNTHESIS
The mechanism by which diabetes stimulates small intestinal
cholesterol synthesis may be related to the increased food
intake that accompanies poorly controlled d~abetes.Experiments have indicated that limiting food intake by pair feeding
can prevent the increase in small intestinal cholesterol synthesis seen in diabetes (16,20). Moreover,studies have demonstrated that other conditions that result in an increase in
food int,eke also enhance small intestinal cholesterol synthesis (21). Specifically, in 3rd-trimester pregnant rats, 21-day
lactating rats, obese rats, and animals infused intragastrically with 16 vs. 8 g glucose/day, cholesterol synthesis is
increased in the small intestine (21). Thus, in four hyperphagic models, increased food intake is associated with
increases in small intestinal cholesterol synthesis. These
findings suggest that the hyperphagia that accompanies
poorly controlled diabetes is the chief stimulus for the increase in intestinal cholesterol synthesis. Moreover, in other
physiological or pathological conditions associated with increased food intake, small intestinal cholesterol synthesis
may also be increased, a phenomenon that could potentially
lead to detrimental effects on total-body cholesterol homeostasis.
We next examined whether the stimulation of intestinal
cholesterol synthesis by increased food intake is due to an
increased bulk of food or is related to caloric content (21).
In both control and diabetic animals, when 50% Alphacel
(nonnutritive bulk; ICN Biomedicals) is added to the diet, the
quantity of food intake approximately doubled, whereas the
caloric intake remained constant (21). Despite the marked
increase in ingested food bulk, intestinal cholesterol synthesis in both control and diabetic animals was unchanged by
the addition of Alphacel (21). These experiments demonstrate that increasing the bulk of food ingested is not a stimulus to increasing cholesterol synthesis in the intestine. In
contrast, feeding glucose or fructose alone is sufficient to
stimulate intestinal cholesterol synthesis in diabetic animals
(22). In diabetic animals fed a 15% glucose solution as the
sole source of calories, cholesterol synthesis in the intestine
is increased greater than fourfold (22). Thus, the increase
in cholesterol synthesis in the intestines of hyperphagic diabetic rats occurs in response to a single caloric source,
indicating that dietary fiber, complex carbohydrates, protein,
and lipids are not required for this phenomenon.
The increase in small intestinal cholesterol synthesis induced by increased food intake does not require the direct
contact of the intestinal mucosa with nutrients (21). In dia-
DIABETEiS, VOL. 38, FEBRUARY 1989
betic animals in which either the proximal or midintestine is
excluded from contact with nutrients, we observed an approximately twofold increase in cholesterol synthesis in the
bypassed segment (21,23). In another model of hyperphagia, i.e., lactating animals, we have also observed that
cholesterol synthesis is increased in segments of the small
intestine that have been excluded from contact with ingested
nutrients (23). These results indicate that the direct contact
of the intestinal mucosa with nutrients is not the sole trigger
for increasing cholesterol synthesis in the intestine of hyperphagic animals, suggesting that circulating hormones
and/or neurological factors play a role.
Very recently we observed that the characteristic increase
in small intestinal cholesterol synthesis in diabetic animals
is prevented by total gastrectomy (see Feingold et al., this
issue, p. 219). Diabetic animals with total gastrectomies still
have increased food intake and a hypertrophied small intestine, yet intestinal cholesterol synthesis is similar in gastrectomized diabetic and normal animals. The mechanism
by which total gastrectomy prevents the characteristic increase in intestinal cholesterol synthesis in diabetic animals
is unknown. Vagotomy and selective removal of either the
antrum or the fundus of the stomach did not prevent the
increase, indicating that the inhibition requires the removal
of the entire stomach. The stomach possibly produces a
circulating andlor luminal substance that is required for the
diabetes-induced increase in intestinal cholesterol synthesis.
FATE OF CHOLESTEROL SYNTHESIZED IN INTESTINE OF
DIABETIC ANIMALS
Cholesterol synthesized in the small intestine has three main
fates: it can be transported via the lymphatics to the bloodstream and contribute to the extraintestinal cholesterol pool,
it can be utilized in the formation of cellular membranes in
the intestines, or it can be excreted into the intestinal lumen.
Studies from our laboratory with control and diabetic animals
whose thoracic ducts have been cannulated demonstrated
that the rate of transport of newly synthesized cholesterol
from the intestine to the circulation is increased fourfold In
diabetic rats (24). Additionally, the percentage of newly synthesized cholesterol transported via the lymphatics to the
bloodstream is greater in the diabetic animals. Thus, the
increased quantity of labeled cholesterol transported in the
lymph of diabetic rats is accounted for by two factors, an
enhancement of intestinal cholesterol synthesis and an Increased percentage transport of newly synthesized cholesterol from the intestines to the circulation. In both control and
diabetic rats, most (-80%) of the newly synthesized cholesterol was transported in the chylomicron lipoprotein fraction (24). Employing entirely different methods, Young et al.
(25) also showed that cholesterol synthesized in the small
intestine is transported to the circulation to a greater extent
in diabetic animals than in control animals. In addition to the
increased synthesis and transport of endogenous cholesterol, studies have demonstrated that the absorption of exogenous dietary cholesterol is also enhanced in diabetic
animals (26-28). Thus, diabetes induces an increase in the
transport of both endogenous and exogenous cholesterol
from the small intestine to the circulation.
143
METABOLISM OF CHYLOMICRONS IN DIABETIC ANIMALS
Studies have demonstrated that the sterol component of chylomicrons obtained from diabetic animals is rapidly cleared
from the circulation when administered to either control or
diabetic animals (29). If the rate of disappearance of either
[3H]vitamin A- or [14C]cholesterol-labeled normal chylomicrons administered to control animals is compared with that
of labeled diabetic chylomicrons administered to diabetic
animals, the half-times are almost identical (vitamin A t,,,:
control, 3.6 min; diabetic, 3.5 min; cholesterol t,,,: control,
5.7 min; diabetic, 4.4 min) (29). The rapid disappearance of
labeled chylomicrons from the circulation in diabetic animals
is accompanied by a parallel increase in label in the liver,
with >85% of the ['4C]cholesterol present in the liver 15 min
after chylomicron administration. These results demonstrate
that the sterols associated with chylomicrons are rapidly
cleared from the circulation of diabetic animals and that most
of the intestinally derived sterols are delivered to the liver.
POTENTIAL ADVERSE CONSEQUENCES OF
INCREASED TRANSPORT OF CHYLOMICRONS FROM
INTESTINE TO CIRCULATION
The increased transport of chylomicrons from the intestine
to the circulation in diabetic patients could result in adverse
consequences. First, it has been postulated by Zilversmit
(30) that an increased flux of cholesterol in chylomicrons is
atherogenic. If this is so, then the increased transport of
cholesterol in chylomicrons and chylomicron remnants in
diabetes could be a potential mechanism by which diabetes
increases the risk of atherosclerosis independent of serum
lipid levels. Second, the cholesterol carried in the chylomicrons is rapidly transported to the liver, where it could lead
to an increase in hepatic cholesterol content. Some but not
all studies have reported that the concentration of cholesterol
in the liver is increased in diabetic animals (26,31,32). Increases in hepatic cholesterol content result in a decrease
in the number of hepatic LDL receptors (33). Thus, the increased transport of cholesterol from the intestine to the liver
in diabetic animals could decrease the number of hepatic
LDL receptors. This effect is superimposed on other factors
affecting LDL-receptor number in diabetes. Insulin increases
the number of LDL receptors on fibroblasts grown in tissue
culture, and insulin infusions stimulate LDLcatabolism in vivo
in humans (34,35). These observations suggest that insulin
deficiency might also lead to a decrease in hepatic LDLreceptor number. Hepatic LDL receptors play a crucial role
in regulating serum LDL levels by affecting both the catabolism of LDL and the rate of LDL formation from VLDL (33).
Decreases in the number of hepatic LDL receptors are accompanied by increased serum LDL cholesterol levels (33).
Finally, small intestinal triglyceride synthesis is increased
in diabetic animals, which is accompanied by the increased
transport in the lymph of triglycerides from the small intestine
to circulation (36). This probably results in the increased
delivery of triglyceride to the liver, which could stimulate
hepatic VLDL secretion (37) and contribute to the increased
serum VLDL levels that frequently accompany poorly controlled diabetes. Because VLDL is the precursor of LDL,
increases in VLDL levels can indirectly contribute to an increase in serum LDL. In summary, the increased transport
of lipids from the iniestine to the circulation in poorly con-
trolled diabetes could potentially result in alterations in lipid
metabolism that may increase the risk of atherosclerosis.
ACKNOWLEDGMENTS
I acknowledge the excellent secretarial assistance of Pam
Herranz and Maggie Joe and greatly appreciate the helpful
comments of Drs. Marvin D.Siperstein and Carl Grunfeld.
This work was supported by the Research Service of the
Veterans Administration.
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