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British Journal of Healthcare and Medical Research - Vol. 11, No. 6
Publication Date: December 25, 2024
DOI:10.14738/bjhmr.116.17854.
Tulp, O. L. (2024). Effects of Miglitol on Caloric Efficiency and Lipid Profiles in Obese Male SHR/Ntul//-cp Rats. British Journal of
Healthcare and Medical Research, Vol - 11(6). 49-58.
Services for Science and Education – United Kingdom
Effects of Miglitol on Caloric Efficiency and Lipid Profiles in Obese
Male SHR/Ntul//-cp Rats
Orien L Tulp
University of Science, Arts and Technology,
Montserrat, and Investigator, Einstein Medical
Institute, North Palm Beach, FL USA
ABSTRACT
Elevations in plasma lipid profiles are a common observation in overweight, obese,
hyperinsulinemic, and adult-onset diabetes. The effects of luminal inhibition of
starch digestion on parameters of weight gain and plasma lipid profiles were
determined in groups of adult obese male T2DM SHR/Ntul//-cp rats. Animals were
fed a USDA-formulated, nutritionally complete diet containing 54% sucrose (SUC,
CHO) component (Control) or the same diet containing a pharmacologic α- glucosidase inhibitor (1,5 dideoxy-1,5-[(2-hydroxyethyl) imino]-D glucitol; generic
miglitol), 150 mg/kg diet, ad libitum for up to 8 weeks. Miglitol resulted in modest
decreases in [food intake and net weight gain. At the end of the study. heparinized
bloods were collected for determination of plasma cholesterol, low-density
lipoprotein (LDL) and high-density lipoprotein (HDL) fractions. The miglitol- associated luminal inhibition of glucosidase activity resulted in 20% reduction in
total cholesterol, and in both α- (LDL) and β-lipoprotein (HDL) fractions. These
results indicate that simple inhibition of luminal α-glucosidase activity via miglitol
may be a useful adjunct in the clinical management of hypercholesterolemia in
states of obesity, T2DM and other glucose intolerant states, in addition to
therapeutic applications in enhancing and improving glycemic control in man and
animals.
Keywords: Obesity, Diabetes, T2DM, Cholesterol, Lipid Profiles, Sucrase, a-Glucosidase
Inhibition, Miglitol, Rats.
INTRODUCTION
The current prevalence of obesity, type 2 diabetes and their common pathophysiologic
sequalae are now approaching epidemic proportions in much of Westernized society, with no
clear therapeutic resolution on the horizon.1 Elevations in plasma lipid profiles including total
cholesterol (TC) and LDL Cholesterol (LDL-C) and modest decreases in HDL-Chol are among
the most common observations in Obesity+T2DM, and represent a major contributor to a
myriad of cardiovascular disorders often accompanying the condition.2 The hallmarks of most
treatment regimens include modifying elements of diet, exercise and lifestyle, individually or in
combination, and are often met with limited success. Dietary habits typically include both
familial and cultural dietary practices and may be negatively influenced by economic and
habitual constraints.3 In addition the adequacy and availability of nutritious foods may add an
additional barrier to issues relating to food insecurity. Moreover, the recent influx of high
fructose corn syrup (HFCS) sweeteners into the food supply chain has introduced yet another
confounding constituent, resulting in a five-fold or greater increase in dietary fructose intake,
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British Journal of Healthcare and Medical Research (BJHMR) Vol 11, Issue 06, December-2024
Services for Science and Education – United Kingdom
and resulting in further pathophysiologic divergences in optimal metabolic pathways.4
Introduction of healthful dietary changes are often a challenge to implement, as the
pathophysiologic changes thar may pregess to more serious health issues typically occur
gradually, and are often asymptomatic in the early stages of disease progression. Thus, by the
time their progression becomes physiologically apparent, the magnitude of disease has likely
advanced, and more aggressive therapeutic measures may be necessary to arrest, resolve, or
reverse further progression. Specifically, the process of atherogenesis often has an
asymptomatic onset early in life, and while early stages of atherogenic changes may undergo
reversal, as the disorder progress into adulthood the potential for effective reversal diminishes.
Insulin resistance, a common observation in obese, T2DM states contributes to systemic
inflammation, and to further progression of atherogenesis and its pathophysiologic sequelae.2
The pseudosaccharide compound 1,5 dideoxy-1,5-[(2-hydroxyethyl) imino]-D glucitol;
miglitol; Glyset®)is an established inhibitor of luminal starch digestion, where it binds to brush
border glucosidase enzyme receptor domains, thereby delaying the rate of digestion and
subsequent luminal glucose uptake from the gastrointestinal tract.5,6 Starches normally
undergo rapid digestion into simple sugars in the upper echelons of the small intestine, where
the rate-limiting step in glucose uptake approximates to the rate of glucosidase activity. Diet
composition, especially the presence of dietary fibers, gums and pectins can impede the rate of
luminal brush border digestion, albeit with some gastrointestinal distress when the relative
contributions of the indigestible fibers exceed ideal proportions and/or gastrointestinal
thresholds. As the rates of luminal CHO digestion become decreased, plasma insulin
requirements may also plateau at a lower magnitude, as less insulin would then be required to
facilitate monosaccharide uptake and disposal in peripheral tissues.7 The insulin-lowering
phenomenon may be enhanced, since the haff-life of insulin receptor activity is typically
considerably longer than that of starch digestion and subsequent monosaccharide oxidation.
Thus, dietary supplements or additives that might extend the process of luminal digestion of
starches and luminal absorption of simple carbohydrates pose an interesting prospect in
modulating downstream physiologic plasma insulin activities, including the metabolic effects
of insulin on lipogenic and cholesterol generating parameters. Insulin exerts numerous effects
on multiple key parameters of intermediary metabolism, including modulation of protein
turnover, carbohydrate oxidation and storage, and lipogenesis to cite just a few that are
pertinent to this study. Thus, the purpose of the present investigation was to determine the
effects of partial luminal α-glucosidase inhibition on plasma lipid profiles with miglitol, and
were conducted in an animal model where early onset obesity, hyperinsulinemia, insulin
resistance and T2DM occurs during early stages of adolescence and remains present
thereafter.8-10 The obesity and progression to T2DM occurs via expression of an autosomal
recessive epigenetic trait, accompanied soon afterward with the commonly observed
progression of pathophysiologic sequelae including derangements in plasma cholesterol and
lipid profiles.8,9
The SHR/Ntul//-cp rat model was developed in the small animal genetics unit at the NIH by
Hansen by incorporating the -cp trait from the Koletsky rat into a longevity-prone NIH (N)
strain of unknown origin.8,11 This was followed by crossing the N-cp strain with the
spontaneously hypertensive rat (SHR), and completing 12 or more cycles of backcrossing
sufficient to establish congenic status while preserving the SHR and -cp traits. The hypertensive
trait was preserved only in the lean phenotype while the T2DM developed soon after weaning
in the obese phenotype, and the newly developed SHR/N-cp strain preserved the albino coat of
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Tulp, O. L. (2024). Effects of Miglitol on Caloric Efficiency and Lipid Profiles in Obese Male SHR/Ntul//-cp Rats. British Journal of Healthcare and
Medical Research, Vol - 11(6). 49-58.
URL: http://dx.doi.org/10.14738/bjhmr.116.17854.
the SHR strain. Both phenotypes exhibit a significantly decreased lifespan due to complications
of T2DM compared to their longevity-prone NIH (N) heritage.9
MATERIALS AND METHODS
Groups of congenic obese male SHR/Ntul//-cp rats (n= 8 rats/group) housed under standard
laboratory conditions of temperature (21-22 degrees C/ 50% RH) on a reverse light cycle (dark
0800-2000 daily) in adjacent hanging steel cages with individual occupancy. Animals were fed
Purina Chow and house water ad libitum from weaning to 8 weeks of age, at which time early
stages of obesity and T2DM were clearly established and glycosuria and T2DM confirmed. At 8
weeks of age, rats were switched to a semi-purified control diet developed at the Carbohydrate
Nutrition Laboratories of the USDA that contained 54% carbohydrate as sucrose, 20% protein
as equal parts casein and lactalbumin, 5.9 % cellulose, 16% fats as equal parts beef tallow, lard,
corn oil, and hydrogenated coconut oil, 3.1% AIN vitamin salt mix, and 1% Teklad vitamin
fortification mix (Control diet).
10 The energy content of the diet was computed to provide 48.2
% of calories from CHO, 33.3 % of calories from fats, and 18.5% of calories from protein
respectively as described elsewhere (ref). The semi purified diet was fed ad libitum for up to 8
weeks. In addition, additional quantities of the control diet were fortified with 150 mg of the α- glucosidase inhibitor per kg diet (equal to ~ 2.5 mg of miglitol/rat/day), and also fed to the α- glucosidase inhibitor treatment group for up to 8 weeks duration. Body weights were
monitored periodically throughout as an indicator of wellness. At the end of the study, rats were
fasted overnight and blood obtained via tail bleeding in heparinized tubes for plasma lipid
analysis. Plasma cholesterol and the α- lipoprotein and β-lipoprotein fractions corresponding
to the LDL and HDL fractions respectively were determined spectrophotometrically following
affinity chromatographic separation via the procedure of Bucolo and David.12 Data were
analyzed via standard statistical procedures including application of Pages ‘L’ test for trend
analysis where statistical significance via the ‘t’ test was suggestive but not confirmatory.13,14
The study was approved by the Institutional Animal care and Use Committee.
RESULTS
Initial and final Body weights and net weight gain of rats over 7 weeks of observations are
depicted in Figure 1 and indicate that initial weights were similar in both treatment groups
(263±11 g. vs. 263±12 g). The a-glucosidase inhibitor miglitol resulted in modestly (~13%)
lower rates of weight gain and in similarly lower final body weights during the 7 weeks of
observation of the study. (Control vs. Drug FBW: p. = < 0.05 via trend analysis; Control vs Net
Gain: p=<0.05 via trend analysis.)
The effects of luminal α-glucoside inhibition on plasma total cholesterol are depicted in Figure
2, and indicate that α-glucosidase inhibition resulted in an approximate 20% decrease in total
plasma cholesterol concentrations after <8 weeks of the dietary and pharmacologic treatment.
In addition, the final concentrations of both the LDL and the HDL lipoprotein fractions were
both decreased by an average of ~18-20% following the α-glucosidase treatment, and the
effects were nearly evenly distributed across both LDL and HDL fractions. In addition, the
lipoprotein ratios are depicted in Figure 3 and further indicate evidence that the pharmacologic
treatment of luminal α-glucosidase activity with miglitol was without significant effect on
lipoprotein ratios, thereby indicating that the effects of the anti-glucosidase agent were equally
distributed across all lipoprotein fractions, consistent with a predicted global effect of
improvements in insulin actions on lipid biosynthesis and metabolism.