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Hypoglycemic effect of Lupinus mutabilis in healthy volunteers and subjects with dysglycemia

  • Instituto Nacional de Investigaciones Agropecuarias, INIAP

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Metabolic syndrome and type-2 diabetes are increasing health problems that negatively affect health care systems worldwide. There is a constant urge to develop new therapies with better effects, lower side effects at lower prices to treat these diseases. Lupinus species and their derivates are good candidates to be used as hypoglycaemic agents. A phase II clinical trial was conducted to assess the role of raw Lupinus mutabilis on blood glucose and insulin in normoglycemic and dysglycemic subjects. Results show that consumption of L. mutabilis by normal weight healthy young individuals did not change importantly blood glucose and insulin levels. On the other hand, consumption of similar doses of lupinus by dysglycemic individuals (fasting glucose > 100 mg/dL) decreased significantly blood glucose. Lupinus effects were greater in those subjects with higher basal glucose levels. Glucose lowering effects of lupinus were not observed after soy intake that was used as control. A statistically significant reduction in insulin levels was also observed in the lupinus group compared with the soy group after 60 minutes of treatment. Furthermore, only treatment with lupinus improved insulin resistance in dysglycemic subjects. These data demonstrate that lupinus consumption could be a feasible and low cost alternative to treat chronic hyperglycemic diseases.
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Nutr Hosp. 2012;27(2):425-433
S.V.R. 318
Hypoglycemic effect of Lupinus mutabilis in healthy volunteers
and subjects with dysglycemia
M. Fornasini1, J. Castro2, E. Villacrés3, L. Narváez1, M.ª P. Villamar1y M. E. Baldeón1
1Colegio de Ciencias de la Salud. Universidad San Francisco de Quito. 2Servicio de Diabetología. Unidad Municipal de Salud
Norte Patronato San José. 3Instituto Nacional Autónomo de Investigaciones Agropecuarias, INIAP. Quito. Ecuador.
La diabetes tipo 2 y el síndrome metabólico son proble-
mas de salud en crecimiento que afectan a los sistemas de
salud en todo el mundo. Hay una necesidad urgente de
desarrollar terapias nuevas con mejores efectos, con
menos efectos adversos y de bajo costo para tratar estas
patologías. Las especies de Lupinus y sus derivados son
buenos candidatos para ser utilizados como agentes hipo-
glicemiantes. Se realizó un estudio clínico de fase II para
analizar el efecto de Lupinus mutabilis crudo sobre los
niveles de glucosa e insulina en la sangre de sujetos nor-
males y con disglicemia. Los resultados del estudio
demuestran que el consumo de L mutabilis por sujetos
sanos, jóvenes de peso normal, no altera importante-
mente los niveles sanguíneos de glucosa o insulina. Por
otro lado, la ingesta de dosis similares por individuos con
disglicemia (glucosa en ayunas > 100 mg/dL) disminuyó
significativamente los niveles de glucosa. Los efectos del
lupinus fueron más evidentes en aquellos sujetos con los
niveles basales de glucosa más altos. Los efectos hipoglice-
miantes de lupinus no se observaron después del consumo
de soya que se utilizó como control. Se observó también
una disminución estadísticamente significativa en los
niveles de insulina sanguínea luego de 60 minutos en el
grupo de voluntarios que consumió lupinus pero no en
aquellos que consumieron soya. Además solamente el tra-
tamiento con lupinus mejoró la resistencia a la insulina en
los sujetos con disglicemia. Estos datos demuestran que el
consumo de lupinus podría ser una alternativa factible y
de bajo costo para el tratamiento de enfermedades cróni-
cas con hiperglicemia.
(Nutr Hosp. 2012;27:425-433)
Palabras clave: Lupinus mutabilis. Hipoglicemia. Diabe-
tes. Ecuador. Alcaloides.
Metabolic syndrome and type-2 diabetes are increasing
health problems that negatively affect health care systems
worldwide. There is a constant urge to develop new thera-
pies with better effects, lower side effects at lower prices
to treat these diseases. Lupinus species and their derivates
are good candidates to be used as hypoglycaemic agents. A
phase II clinical trial was conducted to assess the role of raw
Lupinus mutabilis on blood glucose and insulin in normo-
glycemic and dysglycemic subjects. Results show that
consumption of L. mutabilis by normal weight healthy
young individuals did not change importantly blood glucose
and insulin levels. On the other hand, consumption of
similar doses of lupinus by dysglycemic individuals (fasting
glucose > 100 mg/dL) decreased significantly blood
glucose. Lupinus effects were greater in those subjects
with higher basal glucose levels. Glucose lowering effects
of lupinus were not observed after soy intake that was
used as control. A statistically significant reduction in
insulin levels was also observed in the lupinus group
compared with the soy group after 60 minutes of treat-
ment. Furthermore, only treatment with lupinus
improved insulin resistance in dysglycemic subjects.
These data demonstrate that lupinus consumption could
be a feasible and low cost alternative to treat chronic
hyperglycemic diseases.
(Nutr Hosp. 2012;27:425-433)
Key words: Lupinus mutabilis. Hypoglycemia. Diabetes.
Ecuador. Alkaloids.
Correspondence: Manuel E. Baldeón.
Colegio de Ciencias de la Salud.
Universidad San Francisco de Quito.
Hospital de los Valles.
Edificio de Consultorios Médicos.
Planta Baja.
Vía Interoceánica, km. 12 1/2 y Av. Florencia.
Sector La Primavera, Cumbayá.
Quito. Ecuador.
Recibido: 2-VIII-2011.
Aceptado: 27-IX-2011.
Type-2 diabetes is a highly prevalent disease around
the world. It was reported that 135 million people were
affected in 2005 and it has been estimated that approxi-
mately 217 million will be affected with the disease by
2030.1Unfortunately, most of the new cases are
expected to come from developing countries.2For
instance, diabetes was the first cause of death in
Ecuador in 2009.3Treatment of diabetes is expensive,
for the year 2000 the total cost to treat the disease was
$132 billion. Considering the limited resources dedi-
cated for heath care in developing countries most
people will not be able to afford current treatments. It is
estimated that approximately 30% of hospital bed-days
in Latin America are used for diabetes related condi-
tions whose cost are an important burden for health
care.2Although there are several drugs that improve the
hyperglycaemic state characteristic of the disease,
there is a constant urge to develop new therapies with
higher efficacy, lower side effects at lower prices to
treat diabetes.4
Lupinus mutabilis a sweet fabaceae is an endemic
legume species of South America. In the Andean
region L. mutabilis beans are known as “chochos”,
“tarwi” or Andean lupin; in Spain the beans are
called “altramuz”. The beans are a traditional food in
Ecuador, Perú and Bolivia. Lupinus mutabilis is rich
in quinolizidine alkaloids and require cooking and
removal of these alkaloids before consumption. The
alkaloid fraction from L.mutabilis has more than 20
different quinolizidine alkaloids and lupanine, 13-
hydroxylupanine, 4-hydroxylupanine, sparteine and
tetrahydrorhombifoline are the most abundant.5
Proteins and alkaloids from lupin are good candi-
dates to be used as hypoglycaemic agents.6,7 Admin-
istration of conglutin-γ, a lupin seed protein, to rats
subjected to glucose overload produces a significant
reduction of plasma glucose with respect to control.6
In vitro studies demonstrate that quinolizidine alka-
loids from lupinus have secretagogue effects in
pancreatic isolated rat islets. Also, studies in vivo in
streptozotocin-induced diabetic rats demonstrated
that 2-thiionospartine a quinolizidine alkaloid from
lupinus lowered plasma glucose concentrations.8
Furthermore, the intravenous administration of the
alkaloid sparteine to non-insulin dependent diabetic
subjects decreased plasma glucose concentrations
and increased insulin concentrations.9Taken
together these data demonstrate that alkaloids from
lupinus could be used as hypoglycaemic agents to
treat type-2 diabetes.
One of the main problems with the use of alkaloids
from lupinus spp is their toxicity. The main side
effects after a toxic dose of alkaloid consumptions
are neurologic such as loss of motor coordination and
muscle control. The lethal dose of lupinus spp alka-
loids in humans is approximately 30 mg/kg of body
weight.10 There are limited data regarding the toxic
dose of these alkaloids in humans. However, in the
study by Paolisso et al., described above the authors
used a dose of 240 mg of sparteine sulphate in moder-
ately overweight individuals without apparent acute
toxicity.9The therapeutic dose for sparteine sulfate
ranges from 75 to 600 mg/day.11 Secondary data indi-
cate that toxic doses of quinolizidinic alkaloids for
human adults start at 25 mg/kg of body weight.12
Considering the hypoglycaemic effects of lupinus
from alkaloids as well as their potential toxicity
shown in previous work, the objective of the present
study was to evaluate the effect of raw Lupinus muta-
bilis consumption on plasma glucose and insulin
concentrations in healthy volunteers as well as in
dysglycemic individuals.
Subjects and methods
The Human Subjects Protection Committee at the
Universidad San Francisco de Quito, Quito Ecuador,
approved this study. Each participant signed an
Informed Consent form after receiving explanation of
the study and its possible consequences.
Subjects and study design
A phase II clinical trial was conducted in two
different populations. Young healthy normal weight
individuals constituted the first group (group-one).
Most participants in group-one were third year medical
students. The second group was formed by volunteers
with a glucose level at initial screening greater than 100
mg/dL (group-two). Most of the volunteers in group-
two were either first-degree relatives of patients with
type-2 diabetes or overweight/obese subjects. Most
participants in group-two were recruited at the
Endocrinology Unit in a health care center (Unidad
Municipal de Salud del Norte). Within each of the indi-
cated populations a control group that received raw soy
was conformed for comparison. Eligible subjects were
randomly assigned to the groups in a proportion of
three (lupinus) to one (soy).
Source of Lupinus mutabilis and Soy
Lupinus mutabilis is the most abundant variety of
lupinus and a popular legume consumed in Ecuador.
Lupinus mutabilis line 450 was harvested between
September and October of 2007 from Cotopaxi, which
is an Andean province of Ecuador.12 The L. mutabilis
was hand harvested when the beans had approximately
17% of humidity. Beans were then dried over a cement
platform for approximately 48 hours until the beans
were 13% water. The dried beans were then placed in
sacs and stored in dry environment at room tempera-
ture 17-20º C. After milling to a 300 micron powder
426 M. Fornasini et al.
Nutr Hosp. 2012;27(2):425-433
(done on site at CC laboratory plant, Ambato Ecuador)
L. mutabilis was encapsulated in gelatin capsules by
CC-laboratories. No fillers or binders were added to the
lupinus powder. Dry soybeans were purchased in a
local supermarket and were processed in a similar
fashion than L. mutabilis beans.
Dose of Lupinus mutabilis
Raw L. mutabilis or soy was administered in
gelatin capsules containing 400 mg of lupine powder
seeds or milled soy. Capsules were identical in
appearance and were kindly prepared by (CC-Labo-
ratorios, Quito- Ecuador). Similar amounts of L.
mutabilis or soy per kilogram of body weight were
administered to volunteers. To estimate the dose of L.
mutabilis, the therapeutic (75 to 600 mg/day) and the
toxic (25 mg/kg) doses of alkaloids present in L.
mutabilis were consi dered.11,10 Thus, it was estimated
that 3.1 mg/kg of body weight was safe to carryout
the trial. The amount of grain containing 3.125 mg of
alkaloid was 98.4 mg.
The amount of alkaloid present in raw L. mutabilis
was measured as previously described and is indicated
in table I.13
Anthropometric measurements
A standardized clinic weight scale was used to deter-
mine both height and weight of each participant.
Weight and height were taken with light clothing on,
but shoes off.14
Glucose, insulin and homeostasis model assessment-
estimatedinsulin resistance (HOMA) determinations
Serum glucose was measured using a glucose
oxidase method (Roche-Diagnostics) using a Hitachi
Roche-917 full-automated analyzer system.
Serum insulin was determined using an electro-
chemiluminicense immunoassay (ECLIA) following
the manufacturer’s instructions (Roche/Hitachi,
Quito-Ecuador) and chemiluminescent emission
was measured using a fully automated analyzer
system ELECSYS 2010 (Roche Diagnostics, Quito-
Both glucose and insulin determinations were
carried out in NetLab Laboratory. NetLab maintains an
internal and external quality control system (College of
American Pathologists, Brazilian Society of Clinical
Pathologists, SBOC).
The HOMA 2 values were calculated using a modi-
fied formula of Wallace et al, fasting plasma glucose
(mg/dL) multiplied by fasting serum insulin (mU/ml)
and divided by 405.15 The same calculation was done
using serum glucose and insulin at 60 and 90 minutes
after lupinus or soy intake.
Blood samples
Qualified personnel took blood samples in the
morning between 8 am and 10 am after 12 hours of
fasting. Samples were centrifuged within 2 hours
and processed immediately. Two additional samples
were collected at 60 and 90 minutes after treat-
ments. Hypoglycemic effects of lupine alkaloids
have been observed within two hours of alkaloid
Based on the reported toxic doses of L mutabilis
alkaloids (25 mg/kg) a dose of 3.1 mg/kg of body
weight was considered safe and consequently was used
in this study. Control group received soy in an amount
that matched L mutabilis intake.
Descriptive statistics such as means and standard
deviation and percentages were calculated. Due to the
nature of the data non-parametric statistics were used.
Kruskal Wallis was used to test statistical significance
for difference between groups. Paired Wilcoxon
Signed Ranks Test was used to test for differences
within treatment groups.
Demographics and general
characteristics of volunteers
Data indicate that there were not statistically signifi-
cant differences within normoglycemic and dysg-
lycemic groups in the demographic/anthropometric
variables. However, there were statistically significant
Hypoglycemic effect of Lupinus
mutabilis in human volunteers
427Nutr Hosp. 2012;27(2):425-433
Table I
Alkaloid content of Lupinus mutabilis
Type of sample Alkaloid content
Raw grain with skin 3.26 ± 0.135 Content in
percentage (% W/W*)
Cooked grain with skin 0.75 ± 0.02
Cooked grain without skin 0.3034 ± 0.008
Water used to cook raw grain 2.09 (% V/V**)
*W/W: Weight/weight.
** V/V: Volume/volume.
differences between normoglycemic and dysglycemic
individuals in all the variables indicated in table II.
Effect of lupinus mutabilis on blood glucose
and insulin in healthy volunteers
Twenty-one healthy volunteers were randomly
assigned to consume lupinus (N = 16) or soy (N = 5).
Subjects were admitted at Hospital de los Valles after
an overnight fasting. After a short interview and
anthropometric measurements, a blood sample was
drawn from volunteers. Subsequently, a calculated
dose (refer to subjects and methods) of L mutabilis or
soy was administered to each participant. After treat-
ments two blood samples at 60 and 90 minutes were
obtained. Blood was processed as indicated before and
serum glucose and insulin were measured. Table III
shows the mean concentrations of these parameters
before and after treatment with L mutabilis or soy. Data
in table III indicates that consumption of L mutabilis or
soy did not induced statistical significant changes in
blood glucose and insulin after 60 and 90 minutes
neither within nor between treatment groups of healthy
Subsequently, the potential hypoglycemic effects of
L mutabilis were evaluated in volunteers with
increased concentrations of fasting glucose that were
not receiving any hypoglycemic treatment.
Effect of Lupinus mutabilis on blood glucose
and insulin in dysglycemic volunteers
Volunteers for this phase of the study were first-
degree relatives of patients with type-2 diabetes or
overweight/obese subjects without a previous diag-
nosis of diabetes. Most participants in this group were
recruited in an outpatient endocrinology unit. Twenty-
four volunteers were randomly allocated to consume L
mutabilis (N = 17) or soy (N = 7) and were treated simi-
larly than the healthy volunteer group that was normo-
glycemic described above.
Comparisons within groups indicate that consump-
tion of L mutabilis decreased blood glucose concentra-
tions after 60 minutes of ingestion but the decrease was
not statistically significant table IV. However, L muta-
bilis ingestion produced a statistical significant
decrease of serum insulin after 90 minutes of treatment.
No other statistical significant changes were observed
after L mutabilis treatment. On the other hand soy
intake did not cause statistical significant changes in
either glucose or insulin during the study table IV.
A close analysis of the data indicated that the greatest
variability in glucose and insulin concentrations was
observed in individuals that consumed L mutabilis and
whose basal glucose concentration was greater than 100
mg/dL. The statistical analysis of the variations in blood
glucose and insulin in subjects with basal glucose
greater than 100 mg/dL is shown in table V.
428 M. Fornasini et al.
Nutr Hosp. 2012;27(2):425-433
Table II
Demographics compared by group
Age Gender Weight Height BMI WC
Treatments (years) Female
U ± SD
U ± SD
U ± SD
U ± SD
(%) (kg) (m) (cm)
Normoglycemic L. mutabilis 21.8 ± 2,6 4/16 (25) 64.8 ± 11.2 1.71 ± 0.1 22.1 ± 2.9 77.5 ± 8.1
Soy 23.8 ± 0.8 2/5 (40) 68.2 ± 21.0 1.73 ± 0.1 22.5 ± 4.4 79 ± 14.6
Dysglycemic L. mutabilis 55.8 ± 12.0 12/17 (70.6) 74.9 ± 17 1.54 ± 0.01 31.5 ± 6.2 98 ± 13
Soy 58.4 ± 4.9 5/7 (71.4) 87.3 ± 17 1.56 ± 0.01 36.1 ± 6.5 111.2 ± 18.4
Table III
Comparison of blood glucose and insulin concentrations in normoglycemic volunteers treated with lupinus mutabilis or soy
Glucose Glucose Glucose
0 min 60 min 90 min P-value P-value
Treatments μ± SD μ± SD μ± SD 0 vs. 60 min 0 vs. 90 min
(mg/dL) (mg/dL) (mg/dL)
Lupinus (N = 16) 82.8 ± 6.2 81.3 ± 6.6 80.3 ± 5.2 0.36 0.08
Soy (N = 5) 83.4 ± 5.8 80.0 ± 9.3 81.4 ± 9.7 0.35 0.89
Insulin Insulin Insulin
0 min 60 min 90 min P-value P-value
μU ± SD μU ± SD μU ± SD 0 vs. 60 min 0 vs. 90 min
(mg/dL) (mg/dL) (mg/dL)
Lupinus (N = 16) 7.3 ± 3.7 7.8 ± 3.6 6.5 ± 4 0.44 0.37
Soy (N = 5) 10.4 ± 9.7 10.5 ± 9.6 6.8 ± 6.8 1.00 0.14
Table V shows that in subjects with basal glucose
100 mg/dL that consumed L mutabilis had statisti-
cally significant lower concentrations of glucose after
60 and 90 minutes after treatment. In addition, insulin
concentrations were also significantly lower than basal
levels after 90 minutes of L mutabilis intake. On the
other hand, consumption of soy did not result in signifi-
cant changes in either, glucose or insulin levels over
the study time figure 1 panels C and D.
Differences between treatment groups
Comparison between treatment groups that consumed
L mutabilis with those that consumed soy showed that
there were not statistically significant differences in the
levels of blood glucose before and after treatments.
However, it is notorious that in severe disglycemic indi-
viduals that consumed L mutabilis there were statistically
significant decreases in glucose levels which lasted up to
90 minutes figure 1 panel A whereas in the group that
consumed soy there were not statistically significant
decreases in blood glucose figure 1 panel C.
Regarding insulin concentrations, data show that
after 60 minutes of treatments there was a statistically
significant decrease in insulin concentration in the L
mutabilis compared with the soy group (p = 0.039),
figure 1 panels B vs. D. Panels B and D also show that
in volunteers with dysglycemia, insulin concentrations
decreased with L mutabilis consumption whereas
insulin concentration in the soy group increased.
Furthermore, there was a progressive inhibitory effect
of L mutabilis in serum insulin that was dependent on
basal glucose concentrations. The higher the basal
blood glucose the greater the L mutabilis inhibitory
effect on insulin level at 60 and 90 minutes post treat-
ment figure 1 panels B vs. D.
In order to assess changes in insulin resistance in
treatment groups the Homeostatic model assessment
(HOMA) was calculated. HOMA indicates the degree
of insulin resistance (IR) based on the levels of fasting
glucose and insulin.15 It is well known that only fasting
glucose and insulin concentrations are used to estimate
HOMA. However, in order to evaluate the potential
effect of L mutabilis consumption on insulin resistance
the HOMA-IR was also calculated at 60 and 90
Hypoglycemic effect of Lupinus
mutabilis in human volunteers
429Nutr Hosp. 2012;27(2):425-433
Table IV
Comparison of blood glucose and insulin concentrations in dysglycemic volunteers treated with lupinus mutabilis or soy
Glucose Glucose Glucose
0 min 60 min 90 min P-value P-value
Treatments μ± DE μ± DE μ± DE 0 vs. 60 min 0 vs. 90 min
(mg/dL) (mg/dL) (mg/dL)
Lupinus (N = 17) 107.5 ± 14.4 103.4 ± 7.2 105.3 ± 6.8 0.08 0.51
Soy (N = 7) 102.3 ± 6.4 100.6 ± 4.8 102.9 ± 7.0 0.35 0.92
Insulin Insulin Insulin
0 min 60 min 90 min P-value P-value
μU ± DE μU ± DE μU ± DE 0 vs. 60 min 0 vs. 90 min
(mg/dL) (mg/dL) (mg/dL)
Lupinus (N = 17) 13.3 ± 16.0 9.9 ± 8.4 9.3 ± 7.7 0.12 0.00
Soy (N = 7) 15.7 ± 8.9 18.4 ± 9.2 11.7 ± 7.0 0.06 0.18
Table V
Comparison of blood glucose and insulin concentrations in dysglycemic volunteers treated with lupinus mutabilis or soy
with basal glucose levels 100 mg/dL
Glucose Glucose Glucose
0 min 60 min 90 min P-value P-value
Treatments μ± SD μ± SD μ± SD 0 vs. 60 min 0 vs. 90 min
(mg/dL) (mg/dL) (mg/dL)
Lupinus (N = 12) 114.2 ± 11.6 105.4 ± 5.6 107.8 ± 5.6 0.00 0.03
Soy (N = 5) 105.2 ± 5.0 102.4 ± 4.3 104.2 ± 6.7 0.28 0.46
Insulin Insulin Insulin
0 min 60 min 90 min P-value P-value
μU ± SD μU ± SD μU ± SD 0 vs. 60 min 0 vs. 90 min
(mg/dL) (mg/dL) (mg/dL)
Lupinus (N = 14) 15.1 ± 18.6 11.0 ± 9.6 10.0 ± 8.9 0.15 0.00
Soy (N = 5) 12.2 ± 5.5 14.4 ± 5.2 8.4 ± 4.8 0.23 0.23
minutes after treatments. Values of HOMA-IR greater
than 2.5 are abnormal and indicate glucose intolerance
or type-2 diabetes.16,17 Data indicate that in subjects
with normoglycemia the HOMA values were main-
tained in the normal range after L mutabilis or soy
consumption, figure 2 panels A and C. On the other
hand, in individuals with dysglycemia that consumed L
mutabilis there was a decrease in HOMA-IR 60 and 90
min after its intake figure 2 panel B. In the group with
dysglycemia that consume L. mutabilis the mean value
of HOMA-IR went from a frank abnormal basal value
to normal values at 60 and 90 minutes of treatment
figure 2 panel B. Furthermore, subjects with dysg-
lycemia that consumed soy showed initially an
increase after 60 minutes and subsequently a decrease
after 90 minutes in HOMA-IR values figure 2 panel D.
In this last group, HOMA-IR was always maintained in
the abnormal range.
Some patients that received L mutabilis experi-
enced dizziness, hypotension and blurred vision. Ten
out of 33 subjects that consumed L mutabilis reported
transitory dizziness, 2 were part of group with
normoglycemia and 8 were subjects from the group
with dysglycemia. None of the volunteers that
consumed soy reported any side effects. Two of the
individuals with dysglycemia that reported dizziness
also had hypotension and one of them had also
blurred vision.
Present data show that consumption of L mutabilis
by normal weight healthy young individuals did not
significantly change blood glucose and insulin levels.
However, consumption of similar doses of L mutabilis
by individuals with dysglycemia (fasting glucose > 100
mg/dL) decreased significantly blood glucose and
insulin levels. L mutabilis effect was greater in those
subjects with higher basal glucose levels. Glucose
lowering effects of L mutabilis were not observed in a
control group receiving soy. In addition, a statistically
significant reduction in insulin levels was observed in
the L mutabilis group compared with the soy group after
60 minutes of treatment. Furthermore, only treatment
with L mutabilis improved insulin resistance in subjects
with dysglycemia whereas soy treatment did not. These
data demonstrate that L mutabilis consumption has
important metabolic effects.
Previous in vitro and in vivo work indicates that
conglutin-γand alkaloids from lupinus spp cause
important metabolic effects, which are in agreement
430 M. Fornasini et al.
Nutr Hosp. 2012;27(2):425-433
Fig. 1.—Levels of blood glucose and insulin in volunteers treated with lupinus mutabilis or soy. Panel A glucose and b insulin, lupinus
group. Panel C glucose and D insulin, soy group. NG = normoglycemic; DG = dysglycemic (do not use color, IR).
DG 100
DG 110
DG 120
DG 100
DG 110
DG 100
DG 110
DG 100
DG 110
DG 120
min min min
min min min
min min min
min min min
with the present report. Conglutin-γ, a protein from
lupinus has shown specific binding to insulin and
hypoglycaemic effects in rats subjected to glucose
overload.6The mechanisms of action of this protein for
its hypoglycaemic effects have not been determined.
Garcia Lopez et al., reported that quinolizidinic alkaloids
from lupinus spp induced insulin release from cultured
pancreatic islets from normal rats.7This secretagogue
effect was greater in islets cultured with high glucose
concentrations than in islets cultured with low glucose.
However, some alkaloids, like 2-thionosparteine,
induced insulin secretion even in those islets cultured
in medium with low glucose. On the other hand, alka-
loids such as lupanine, the most abundant alkaloid in L
mutabilis, only induced insulin release by the islets that
were cultured in high glucose concentrations.7In the
present study, raw L mutabilis, with its entire alkaloid
content decreased blood glucose levels only in individ-
uals with high levels of glucose. This observation was
evident in a volunteer with fasting glucose of 143
mg/dL whose glucose dropped to 112 mg/dL after 90
min of lupinus consumption. This represents a decrease
of 22% in blood glucose.
In an in vivo model of diabetes induced by streptozo-
tocin the intra-peritoneal injection of quinolizidine
alkaloids provoked a decrease in blood glucose
concentrations.8In that study not all alkaloids showed
the same hypoglycemic effects. Thus, in diabetic
animals treated only with lupanine there was not a
decrease in blood glucose while in those animals
treated with 2-thionosparteine there was a significant
decrease in blood glucose at 90 and 120 min after alka-
loid administration.8This decrease in blood glucose
was similar to the observed after treatment with gliben-
clamide, a commonly drug used to decrease blood
glucose. However, administration of quinolizidine alka-
loids to non-diabetic rats did not change blood glucose
concentrations.8Regarding insulin, only administration 2-
thionosparteine significantly increased plasma insulin
levels in non-diabetic animals. In that study alkaloid
treatment increased blood insulin levels although the
increase was not statistically significant.8
Clinical studies in healthy volunteers or with indivi -
duals with type-2 diabetes have shown that intravenous
administration of lupinus spp alkaloids decrease blood
glucose and increase insulin. Thus, administration of
sparteine sulphate (240 mg i.v.) decreased blood glucose
after 20 minutes of infusion to normal subjects.11
Glucose decrease was accompanied with an increment
of serum insulin that also occurred 20 minutes after
infusion. These results do not agree with the animal
model of diabetes discussed previously where after
alkaloid administration there were no changes in either
glucose or insulin levels in animals that did not develop
diabetes.8Present results also indicate that oral admin-
istration of raw L mutabilis did not affect significantly
glucose or insulin levels in normal healthy volunteers.
The limited changes observed in blood glucose and
insulin could be due to the fact that participating volun-
teers were young healthy individuals. In normal
Hypoglycemic effect of Lupinus
mutabilis in human volunteers
431Nutr Hosp. 2012;27(2):425-433
Fig. 2.—Homeostatic model asessment (HOMA) in volunteers treated with lupinus or soy. Panel A normoglycemic subjects, lupinus
group. Panel B dysglycemic subjects, lupinus group. Panel C normoglycemic subjects, soy group. Panel D dysglycemic subjects, soy
subjects blood glucose concentrations are finely regu-
lated. Close regulation of blood glucose maintains a
physiologic constant range of glucose between 70 a
100 mg/dL.
On the other hand, Paolisso G. et al, have reported
that intravenous administration of sparteine sulphate
(240 mg i.v.) to subjects with type-2 diabetes
decreased blood glucose and increased insulin.9In
that study, changes in glucose and insulin were
evident after 40 minutes of intravenous alkaloid infu-
sion. In the present study, there was also a decrease in
blood glucose in volunteers with dysglycemia after 60
minutes of lupinus consumption. Regarding insulin,
in contrast to the observations of Paolisso G. et al, in
the present study there was not an increase in insulin
levels; on the contrary there was a statistical signifi-
cant decrease of the hormone after 90 minutes of
treatment. A potential explanation of these differ-
ences could be the fact that in the present study insulin
was measured only at two time points 60 and 90
minutes after L mutabilis intake while Paolisso et al
measured insulin every 10 minutes during one hour.9
This allowed them to measure the putative peak of
insulin after the release from the pancreatic β-cell.9In
addition, the type of treatments used in the present
and the indicated studies could explain the different
results on the levels of insulin. In the indicated studies
with normal individuals as well as with patients with
type-2 diabetes, purified lupinus spp alkaloids were
used intravenously while in the present study raw L
mutabilis beans were orally administered.11,9 Purified
alkaloids and raw lupinus could have a distinct phar-
macokinetics. Raw lupinus beans contain several
alkaloids and micro and macronutrients that could
modulate: a. the secretagoge activity of alkaloids; b.
the potential effect on insulin receptor; and c. insulin
half-life. Insulin is metabolized in the liver after its
release from the pancreas in a relative short time,
approximately 3.5 minutes. Insulin that reaches the
periphery, muscle and adipose tissue, after engaging
its receptor is internalized by the cells and subse-
quently degraded.18 During this process target cells
are stimulated to allow glucose uptake through
glucose transporter GLUT-4. Both events insulin
uptake and glucose transport inside the cells could
explain present observations of glucose and insulin
decrease after L mutabilis consumption. In addition,
the improvement in HOMA-IR observed in subjects
with dysglycemia that consumed L mutabilis could
also be the result of a decrease in blood glucose and
insulin levels. Future pharmacokinetics studies on L
mutabilis and its components such as proteins and
alkaloids, could clarify their effect on pancreatic β-
cells as well as insulin target cells.
There were no severe side effects after raw L muta-
bilis consumption both in normal or volunteers with
dysglycemia. However, some individuals with dysg-
lycemia that consumed lupinus showed transient dizzi-
ness, hypotension and blurred vision. These side
effects have been reported in individuals with poly-
morphism for the enzyme “debrisoquin hydroxylase”
that is responsible of the alkaloid sparteine metabo-
lism.19 Regardless the capacities to metabolize lupinus
alkaloids, 75% of these are excreted unchanged in the
urine within hours of consumption.20 Raw lupinus
consumption without medical supervision must be
discouraged to avoid potential toxicity and undesirable
side effects.
Further studies are needed to determine if lower
doses of raw L mutabilis decrease blood glucose and
insulin. At the moment, there is evidence that the effect
lasts at least 90 minutes which was the longest time
measured in the present study. In addition studies that
compare the effect of raw lupinus with the putative
effect of isolated proteins and alkaloids are also
We would like to thank all participating volunteers.
We also thank Maria Fernanda Loaiza, Cristina
Chavez, Sara Cifuentes, Jorge Reyes, Paulina Armas,
Patricio Rojas. Carlos Cobo (CC-Laboratories) for
their technical assistance. This work received partial
financial support from Chancellor Grants Universidad
San Francisco de Quito.
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Hypoglycemic effect of Lupinus
mutabilis in human volunteers
433Nutr Hosp. 2012;27(2):425-433
... Over the last two decades, lupins (Lupinus albus, L. angustifolius, and L. mutabilis) have attracted particular attention for their hypoglycaemic, hypocholesterolemic, and anti-inflammatory properties, especially regarding protein fractions [7][8][9][10]. Among them, γ-conglutin (γ-C) has been extensively studied for its postprandial glycaemic regulating activity in vitro [11,12], in vivo [13][14][15][16][17][18][19][20], ex vivo [21], and in humans [11,[22][23][24]. The consumption of foods containing bioactive proteins and/or peptides that can help in managing different chronic diseases (e.g., diabetes) is nowadays gaining attention. ...
... For example, in the case of pasta supplemented with a γ-C extract, the hypoglycaemic effect described could be related to the lower carbohydrate content rather than a direct contribution mediated by γ-C [16]. Several studies have been performed on dyslipidaemias in humans [23,55,56], in vitro [42], and in vivo [57][58][59]. Moreover, in this case, little evidence was collected on the direct effect of γ-C on lipid metabolism, leaving open the question if what was observed could be attributable to other molecules present in the preparations, such as the presence of Arginine and Lysine [56,58]. ...
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γ-Conglutin (γ-C) is the glycoprotein from the edible seed L. albus, studied for long time for its postprandial glycaemic regulating action. It still lacks clear information on what could happen at the meeting point between the protein and the organism: the intestinal barrier. We compared an in vitro system involving Caco-2 and IPEC-J2 cells with an ex vivo system using pig ileum and jejunum segments to study γ-C transport from the apical to the basolateral compartment, and its effects on the D-glucose uptake and glucose transporters protein expression. Finally, we studied its potential in modulating glucose metabolism by assessing the possible inhibition of α-amylase and α-glucosidase. RP-HPLC analyses showed that γ-C may be transported to the basolateral side in the in vitro system but not in the pig intestines. γ-C was also able to promote a decrease in glucose uptake in both cells and jejunum independently from the expression of the SGLT1 and GLUT2 transporter
... Lupinus mutabilis, commonly named Tarwi [57], is a legume usually consumed as cooked seeds , and is traditionally used to reduce glycemia after the meal [58]. Clinical trials showed that L. mutabilis reduces blood sugar in slightly hyperglycemic subjects, and cooked L. mutabilis seeds reduce glycemia in patients with type 2 diabetes, an effect related to its alkaloid content [58,59]. ...
... Lupinus mutabilis, commonly named Tarwi [57], is a legume usually consumed as cooked seeds , and is traditionally used to reduce glycemia after the meal [58]. Clinical trials showed that L. mutabilis reduces blood sugar in slightly hyperglycemic subjects, and cooked L. mutabilis seeds reduce glycemia in patients with type 2 diabetes, an effect related to its alkaloid content [58,59]. A recent study evaluated the anti-diabetic effect of L. mutabilis in the spontaneously diabetic Goto-Kakizaki (GK). ...
Diabetes mellitus (DM) is a chronic metabolic disorder affecting a vast number of people all around the world. Diabetes is mainly characterized by chronic hyperglycemia, resulting from defects in insulin secretion or insulin action, or both. To date, several glucose-lowering drugs have been used clinically. These drugs exert their anti-diabetic effect by stimulating insulin secretion, increasing peripheral absorption of glucose, delaying the absorption of carbohydrates from the intestine and reducing hepatic gluconeogenesis. The concern over effectiveness and side effects of currently available therapies in the treatment of Type 2 DM (T2DM) has promoted interest in discovery and development of natural antidiabetic drugs. Plants used in folk medicine to treat DM represent a viable alternative for the control of this disease. Several plants with antidiabetic properties exert their effects by inhibiting ATP-sensitive potassium (KATP) channels in the β-cell plasma membrane, resulting in membrane depolarization and stimulation of insulin release from insulin stores by exocytosis. In this article, we examined the results of earlier studies on the actions of natural compounds on pancreatic KATP channels. It is likely that these natural compounds can be employed as lead structures for the synthesis of therapeutic agents to treat T2DM in future clinical studies
... LM and SS have compounds with therapeutic potential, such as phenolic compounds and antioxidants (13,14) . While LM has been reported to lower the blood glucose levels by an unclear mechanism (15)(16)(17)(18) , potential anti-diabetic properties were already reported for CQ that inhibits the α-glucosidase enzyme (19) and for AC that inhibits the α-amylase (17,20) . On the other hand, SS is an alternative food for patients with conditions that require dietary changes (13,21) . ...
... To reduce glycemia in patients with diabetes the traditional use is to drink the water in which the seeds were washed (39) . It has been reported that LM decreases glycemia in patients with intolerance to glucose (16) , and in patients with type 2 diabetes due to the alkaloid content (15) . For this purpose we used unwashed seeds with high alkaloid content that has been claimed to be active component. ...
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Introduction: The prevalence of diabetes type 2 is increasing worldwide, thus the search of novel alternative therapies is needed. According to their traditional use, we selected five Bolivian plants Chenopodium quinoa (CQ) Amaranthus caudatus (AC), Chenopodium pallidicaule (CP), Lupinus mutabilis (LM) and Smallanthus sonchifolius (SS) that are traditionally used to control glycemia. Methods: The effect of a single oral administration of Ethanolic (EtOH), hydro-ethanolic (EtOH70) and aqueous (Aq) extracts from all plant species were tested for their effect on blood glucose in non-fasted mice and during the oral glucose tolerance test (OGTT). The effect on insulin secretion was evaluated in mice pancreatic islets. Results: EtOH70 extracts of all the plants showed glucose-reducing effect at the highest dose evaluated (2000 mg/kg b.w.). EtOH70 extracts improved the glucose tolerance evaluated by the OGTT in mice fasted for 12 hours. The extracts have different effects on glucose homeostasis since just extracts of AC, LM and CQ but not CP and SS increased insulin secretion as shown on mice pancreatic islets. The phytochemical qualitative characterization of EtOH70 extracts detected phenolic acids and flavonoids in AC, CP and CQ; alkaloids in LM and anthocyanidins in SS. None of EtOH70 extracts tested showed in vitro or in vivo acute toxicity at concentrations where they exhibit glucose lowering effects. Conclusions: We report here that extracts from AC, CQ, CP, LM and SS exhibit glucose lowering effect while just AC, CQ and LM stimulate directly the insulin secretion.
... In addition, the consumption of a lupin proteinbased beverage caused acute reductions in serum glucose levels in T2D patients (Dove et al., 2011). Fornasini et al. (2012) found that lupin protein did not reduce glycemia in normoglycemic individuals but induced a hypoglycemic effect in dysglycemic individuals. ...
... Several studies have confirmed the presence of a hypoglycemic effect on humans from plant proteins, including lupin proteins Bertoglio et al., 2011;Bouchoucha et al., 2016;Dove et al., 2011;Fornasini et al., 2012). This effect is attributed mainly to γ-conglutin (Cγ; Bertoglio et al., 2011;Lovati et al., 2012;Magni et al., 2004;Vargas-Guerrero et al., 2014); therefore, scientific interest has been focused on the biological effects of this protein. ...
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Although studies on lupin protein isolate (LPI) have indicated the presence of a preventive effect on insulin resistance (IR) and lipid disturbances, their influence on established pathological traits has received little attention. Here, we evaluated the in vivo effects of LPI on IR and steatohepatitis as well as its influence on genes involved in lipid and carbohydrate metabolism. We first induced IR and steatohepatitis in rats by maintaining them on a high‐fat diet for 5 weeks. Thereafter, we administered LPI to the rats daily for 3 weeks. LPI improved insulin sensitivity (AUC: 6,777 ± 232 vs. 4,971 ± 379, p < .05, pre‐ vs. post‐treatment values) and reduced glucose and triglyceride levels by one‐third. In addition, LPI‐treated rats exhibited attenuated steatohepatitis. At the molecular level, LPI treatment reduced liver Fasn gene expression substantially but increased Gys2 and Gsk3b levels. We concluded that the hypolipidemic and hypoglycemic activities of LPI may be caused by reduced liver lipogenesis and modulation of insulin sensitization mechanisms. Here, we evaluated the in vivo effects of LPI on IR and steatohepatitis, and its influence on lipid and carbohydrate metabolism genes. LPI improved insulin sentitivity and reduced glucose and triglyceride levels. Besides, LPI‐treated rats exhibited attenuated steatohepatitis. reduced liver Fasn gene expression substantially, but increased Gys2 and Gsk3b levels. LPI hypolipidemic and hypoglycemic activity may result from reduced liver lipogenesis and the modulation of insulin sensitization‐mechanisms.
... 23 Hypoglycemic effects were further reported in studies of diabetic patients, in which both serum glucose concentrations and insulin levels decreased following consumption of lupines. 24,25 Hypoglycemic effects were not found in normal subjects. 25 Additional work The plant is about 5 inches tall owing to its adaption to the high desert location. ...
... 24,25 Hypoglycemic effects were not found in normal subjects. 25 Additional work The plant is about 5 inches tall owing to its adaption to the high desert location. Seeds were most likely used by the ancestral Puebloans for food along with other plants. ...
Lupine (lupin) species have a broad geographical distribution and have long been used for ornamental, agricultural, nutritional, and medical purposes. As with other legumes, lupine seeds are rich in fiber and protein and could be a beneficial addition to the human diet, although some varieties also contain varying degrees of toxic quinolizidine alkaloids. Recent studies show that lupine consumption is associated with favorable effects on diabetes, hyperlipidemia, and hypertension and could be a valuable food for individuals with those conditions.
... Se ha demostrado que el consumo de chocho cocido en individuos disglicémicos (glucosa menor a 100mg/dL) y en individuos diabéticos disminuye significativamente los niveles de glucosa e insulina en sangre (Fornasini et al., 2012;Baldeon et al., 2012). Igualmente, estudios demuestran que la jícama reduce los niveles de glicemia en sangre, el peso corporal y el riesgo de cáncer de colon y se recomienda su uso como suplemento dietético para el control de enfermedades crónicas (Caetano et al., 2016). ...
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En el presente estudio se determinan, los conocimientos y usos de plantas medicinales como parte del tratamiento de los pacientes del club de diabéticos del Hospital San Vicente de Paul, Ibarra, Ecuador. El estudio fue cualitativo de cohorte transversal se realizó en 54 pacientes de 64 años, se realizaron entrevistas directas y toma de datos antropométricos. Los resultados indican que el 83% de los pacientes conoce e incluye las plantas medicinales en su tratamiento, ya sea por recomendación médica, amigos o conocidos, el 84% lo hace por mejorar la diabetes, el resto por optimizar otros problemas de salud y por usar algo nuevo, las cinco plantas mayormente usadas fueron: sábila (40%), estevia (36%), ajo (36%), cebolla-puerro (31%) y canela (31%). En cuanto a las partes de la planta utilizada, un 47% utiliza las hojas de las plantas, un 27% manifestó utilizar toda la planta, 20% utiliza el fruto y el 9% el tallo. El 71% consume las plantas mediante infusiones y el 2% consume la planta de forma natural y fresca. De las quince plantas medicinales que manifiestan consumir sólo tres son plantas de origen sudamericano, estas son la estevia, el chocho y la jícama. Se hace necesario difundir más los estudios científicos que avalan el conocimiento popular sobre nuestras plantas autóctonas, en esta comunidad y en los profesionales de salud relacionados con el tratamiento de la diabetes para que sean incorporadas al tratamiento combinado de esta enfermedad
... Lupinus synthesizes quinolizidine alkaloids (AQ) as part of a defense strategy against herbivores. Currently, Lupinus species find numerous applications, as a source of protein in food (Tapia and Fries 2007) and secondary metabolites with various biological activities (Fornasini et al. 2012), also improving the soil in crop rotation (Stepkowski et al. 2011). Another potential use of the species of the genus Lupinus is as green manure or in ecological restoration and reforestation programs (Ramírez-Contreras and Rodríguez-Trejo 2009). ...
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Plant biotechnology is an essential tool that allows agriculture improvement by increasing food production through tissue culture, molecular biology, and crop improvement. At present, agriculture is facing many problems that affect food production seriously; some of these problems are degradation of soils, salinity, contamination with heavy metals and hydrocarbons, drought, desertification, deforestation, and one of the solutions is biotechnology. This chapter will discuss aspects related to sustainable agriculture and food challenge, plant biotechnology, and plant biotechnology and sustainability. First, the incidence of agriculture is analyzed, on the one hand, in the reduction of hunger, and on the other, in the degradation of the environment, which can only be resolved through a sustainable model. Secondly, the most relevant applications of modern biotechnology in the accelerated propagation of plants, germplasm conservation, and genetic improvement are described. Next, both elements are linked, and it is analyzed how biotechnology can contribute to sustainability through modern technologies. The contribution of modern biotechnologies to sustainability in agriculture is illustrated through the presentation of examples of work done with the genus Lupinus. This genus comprises species useful for sustainable agriculture, which serve as a source of proteins and secondary metabolites, as well as in crop rotation. This chapter shows some of the results achieved in the multiplication and in vitro conservation of species from Lupinus, as examples of the application of biotechnology with an environment friendly approach.
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Experiments conducted in vitro and in vivo, as well as clinical trials for hypoglycemic therapeutics, support the hypoglycemic properties of the lectin γ-conglutin, a Lupinus seed storage protein, by a mechanism not yet been clarified. Structural studies established that binding of γ-conglutin, in native and denatured form, to insulin occurs by a strong binding that resists rupture when 0.4 M NaCl and 0.4 M galactose are present, suggesting that strong electrostatic interactions are involved. Studies on binding of γ-conglutin in native and denatured form to HepG2 membrane glycosylated receptors were conducted, which reveal that only the native form of γ-conglutin with lectin activity is capable of binding to these receptors. Glycosylated insulin receptors were detected on purified HepG2 cell membranes and characterized by 1D and 2D analyses. Preclinical assays with male mice (CD-1) indicated that native and denatured γ-conglutins display antihyperglycemic effect, decreasing glucose in blood comparable after 120 min to that exhibited by the animal group treated with metformin, used to treat T2D and used as a positive control. Measurement of organ injury/functional biomarkers (hepatic, pancreatic, renal, and lipid profile) was comparable to that of metformin treatment or even better in terms of safety endpoints (pancreatic and hepatic biomarkers).
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Metabolic syndrome (MetS) and type 2 diabetes (T2D) are metabolic alterations associated with high morbidity and mortality, particularly in low and middle-income countries. Diet has a significant impact on the risk to develop MetS and T2D; in this regard, consumption of fruits, vegetables, and protein rich foods (from plant and animals) are important to prevent and manage these pathologies. There are limited studies regarding the potential association between Andean foods rich in proteins and the presence of cardio-metabolic conditions in Ecuador. It is necessary to develop new low-cost, local-culturally acceptable strategies to reduce the burden of cardio-metabolic diseases. We describe the prevalence (baseline data) of MetS and T2D in the Ecuadorian cohort of the Prospective Urban and Rural Epidemiology (PURE) study and their potential association with the consumption of protein rich foods, including beef, white meat, dairy and legumes. In this cross-sectional study, we assessed 1,997 individuals aged 35–70 years (mean age 51 years, 72% women), included in the Ecuadorian cohort of the PURE study, from February to December 2018. The prevalence of MetS was 42% for male and 44% for female participants; the prevalence of T2D was 9% for male and 10% for female. Metabolic syndrome and T2D were more common in women older than 50 years of age with primary education or less, low economic income, and with obesity; MetS was more frequent in the rural area while T2D was more frequent in the urban area. Using logistic regression analysis, we observed a significant protective effect of higher consumption of dairy and legumes in the prevalence of MetS and T2D compared with low consumption. It will be important to develop policies for ample production and consumption of protein rich foods such as legumes and dairy, part of traditional diets, to reduce the burden of cardio-metabolic diseases.
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Biomedicina en Ecuador, contexto a futuro y memorias del segundo congreso en Loja
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We visualized insulin uptake in vivo across the apical membrane of the rat proximal tubule (PT) by confocal microscopy; we compared it with in vitro findings in a rat PT cell line (WKPT) using fluorescence microscopy and flow cytometry. Surface tubules were observed in vivo with a 633-nm single laser-illuminated real-time video-rate confocal scanning microscope in upright configuration for optical sectioning below the renal capsule. Fields were selected containing proximal and distal tubules; Cy5-labeled insulin was injected twice (the second time after approximately 140 min) into the right jugular vein, and the fluorescence signal (at 650-670 nm) was recorded. Fluorescence was detected almost immediately at the brush-border membrane (BBM) of PT cells only, moving inside cells within 30-40 min. As a measure of insulin uptake, the ratio of the fluorescence signal after the second injection to the first doubled (ratio: 2.11 +/- 0.26, mean +/- SE, n = 10), indicating a "priming," or stimulating, effect of insulin on its uptake mechanism at the BBM. This effect did not occur after pretreatment with intravenous lysine (ratio: 1.03 +/- 0.07, n = 6; P < 0.01). Cy2- or Cy3-labeled insulin uptake in a PT cell line in vitro was monitored by 488-nm excitation fluorescence microscopy using an inverted microscope. Insulin localized toward the apical membrane of these cells. Semiquantitative analysis of insulin uptake by flow cytometry also demonstrated a priming effect (upregulation) on insulin internalization in the presence of increasing amounts of insulin, as was observed in vivo; moreover, this effect was not seen with, or affected by, the similarly endocytosed ligand beta2-glycoprotein.
In this paper rapid procedures for the determination of total alkaloids (photometric, titrimetric) and for the semiquantitative determination of individual alkaloids (TLC) in the seeds ofLupinus mutabilis are presented. For all three methods an improved extraction procedure is employed. After transforming the alkaloids into their bases, the resulting material is dried with basic alumina and the alkaloids are extracted with chloroform. For the photometric determination of total alkaloids bromocresol purple is used as color reagent. The indicator for the titrimetric determination is tetrabromophenolphthalein ethyl ester. The individual alkaloids are evaluated semiquantitatively after Separation on TLC-plates and staining with Draggendorff reagent. All three screening tests are useful for the selection of low alkaloid Lupin strains and for the control of debittering processes.
The quinolizidine alkaloid composition of Lupinus mutabilis seeds was studied by high-resolution capillary gas-liquid chromatography (GLC) and capillary GLC-mass spectrometry. The occurrence of the known alkaloids sparteine, lupanine, a-isolupanine, 4-hydroxylupanine, and 13-hydroxylupanine was confirmed. In addition, more than 20 other alkaloids were present, including tetrahydrorhombifoline (6), angustifoline (7), multiflorine (12), 13-(angeloyloxy)lupanine (20), 13-(tigloyloxy)lupanine (21), 13-(benzoyloxy)lupanine (25), cis-13-(cinnamoyloxy)lupanine (26), trans-13-(cinnamoyloxy)lupanine (27), and ammodendrine (3). Other alkaloids were tentatively identified as 4,13-dihydroxylupanine (16), 4-(angeloyloxy)lupanine (23), and 13-(angeloyloxy)-4-hydroxylupanine (22). The quantitative composition of the alkaloid fraction is discussed with respect to the use of debittered seeds for human nutrition.
This review focuses on current evidence for pharmacogenetics for the 3 commonly used drug classes in treating diabetes: metformin, sulphonylureas and thiazolidinediones. Currently, metformin pharmacogenetics is focussing on drug transport with the recent finding that variation in OCT transporters might affect metformin response. An aetiological approach has identified monogenic patients with diabetes due to TCF1 mutations who are particularly sensitive to the hypoglycaemic effects of sulphonylureas, and KCNJ11 or ABCC8 mutations in which sulphonylureas can be used in place of insulin treatment. In Type 2 diabetes sulphonylurea response has been shown to be associated with variants TCF7L2 associated with type 2 diabetes risk. For thiazolidinediones, focus has been on PPARgamma variants although with no consistent result. Genome wide association studies offer great potential to unravel what genetic factors influence response and side effects of diabetes therapies. Large numbers of well phenotyped patients for response and side effect as well as similarly sized similarly phenotyped replication cohorts are required. Establishing such cohorts is a priority in diabetes pharmacogenetics research.
This is the first study to establish the prevalence of overweight and obesity among Ecuadorian adolescent students. The population studied was made up of 2.829 students, 1.461 females and 1.368 males between 12 and <19 years of age. One thousand four hundred and thirty five students were registered in 60 schools, public and private, in the six main cities of the Coastal Region; the remaining 1.394 students were registered in 60 schools, public and private, in the six main cities in the Andean Region. Height and weight were measured in all participants and the body mass index (BMI) of each individual was calculated. Overweight was diagnosed in those adolescents whose BMI was between percentiles 85 and < 95, and obesity was diagnosed in the subjects whose BMI was > 95. Results indicate that 21.2% of adolescents had excess weight: 13.7% were overweight and 7.5% had obesity. Excess weight was higher in the Coast (24.7%) than in the Andean Region (17.7%; P < 0.0001). In the same way, excess weight was higher among students attending private schools (25,3%) than in those attending public schools (18.9%; P < 0.0001). Data also indicate that excess weight was more common in women than in men, 21.5% versus 20.8%, respectively (P < 0.02). The study also indicated that 16.8% of adolescents were underweight. Taken together, these data indicate that 38% of the studied population was malnourished. It is necessary to take measures to prevent and treat these important public health problems in Ecuador.
The three best-described genetic polymorphisms of drug metabolism--the debrisoquin/sparteine type of oxidative polymorphism (hereafter referred to as the debrisoquin polymorphism), the polymorphism of N-acetylation, and the mephenytoin type of oxidative polymorphism--are reviewed. For all three polymorphisms, the poor-metabolizer phenotype is inherited as an autosomal recessive trait. The debrisoquin and mephenytoin oxidative polymorphisms involve defects in two separate cytochrome P450 enzymes. The prevalence of the poor-metabolizer phenotype for debrisoquin ranges between 2% and 10% for groups of various ethnic origins. The poor-metabolizer phenotype for mephenytoin comprises about 5% of the Caucasian population and about 20% of the Japanese population. N-acetyltransferase is a cytosolic enzyme whose clinical polymorphism was discovered using isoniazid as the substrate probe. The prevalence of the slow-acetylator phenotype among American and European Caucasian and American black groups is about 50%; among the Japanese it is about 10%. More than 20 agents are substrates for debrisoquin hydroxylase, about 15 for N-acetyltransferase, and 3-5 for mephenytoin. In poor metabolizers, debrisoquin can cause hypotension, and sparteine can cause blurred vision, headache, and dizziness. Clinical consequences of the slow-acetylator phenotype include increased susceptibility to systemic lupus erythematosus induced by procainamide and hydralazine, peripheral neuropathy induced by isoniazid, hydralazine, and dapsone, and sulfasalazine-induced dose-related leukopenia, nausea, vomiting, headache, and vertigo. After administration of mephenytoin, poor metabolizers have increased somnolence and intellectual impairment. Awareness of genetic polymorphisms of drug metabolism should improve understanding of interindividual variability in drug disposition and response.
Infusion of a therapeutic dose of sparteine sulphate, increased the basal plasma insulin level and lowered plasma glucose. When an intravenous glucose tolerance test was performed with the infusion, the total insulin AUC was significantly larger than in absence of sparteine (2025 vs 1464 microU/ml X min), plasma glucose levels were lower and improved glucose utilization was observed (kg:1.55 vs 1.39%). In the presence of arginine, sparteine sulphate stimulated both beta and alpha cells, increasing both the total insulin (1907 vs 1516 microU/ml X min p less than 0.02) and total glucagon AUCs (7616 +/- 654 vs 6789 +/- 707 pg/ml X min p less than 0.01). Thus, sparteine sulphate increased both basal and nutrient-induced insulin and glucagon secretion in normal man.
Sparteine sulphate, given i.v. as a bolus of 15 mg/ml plus 90 mg in 0.9% NaCl 100 ml over 60 min, increases plasma insulin and decreases plasma glucose and adrenaline in non-insulin dependent (Type II) diabetic subjects. The hypoglycaemic effect was also evident in the presence of a high plasma glucose level produced by Biostator changing glucose infusion from 20.2±2.8 to 26.4±4.2 mg · kg−1 · min−1 (p<0.01), and it was potentiated by simultaneous infusion of arginine. No additional effect of sparteine on the peripheral sensitivity to insulin were detected by the euglycaemic, hyperinsulinaemic glucose clamp technique, as the glucose infusion rate (3.1±0.8 vs 2.6±1.2 mg · kg−1 · min−1) was not statistically significant different in the last 60 min of the experiment. It is concluded that sparteine sulphate enhances β-cell secretion, causing a fall in the plasma glucose concentration.
The steady-state basal plasma glucose and insulin concentrations are determined by their interaction in a feedback loop. A computer-solved model has been used to predict the homeostatic concentrations which arise from varying degrees beta-cell deficiency and insulin resistance. Comparison of a patient's fasting values with the model's predictions allows a quantitative assessment of the contributions of insulin resistance and deficient beta-cell function to the fasting hyperglycaemia (homeostasis model assessment, HOMA). The accuracy and precision of the estimate have been determined by comparison with independent measures of insulin resistance and beta-cell function using hyperglycaemic and euglycaemic clamps and an intravenous glucose tolerance test. The estimate of insulin resistance obtained by homeostasis model assessment correlated with estimates obtained by use of the euglycaemic clamp (Rs = 0.88, p less than 0.0001), the fasting insulin concentration (Rs = 0.81, p less than 0.0001), and the hyperglycaemic clamp, (Rs = 0.69, p less than 0.01). There was no correlation with any aspect of insulin-receptor binding. The estimate of deficient beta-cell function obtained by homeostasis model assessment correlated with that derived using the hyperglycaemic clamp (Rs = 0.61, p less than 0.01) and with the estimate from the intravenous glucose tolerance test (Rs = 0.64, p less than 0.05). The low precision of the estimates from the model (coefficients of variation: 31% for insulin resistance and 32% for beta-cell deficit) limits its use, but the correlation of the model's estimates with patient data accords with the hypothesis that basal glucose and insulin interactions are largely determined by a simple feed back loop.